Ad Rijnberk · Hans S. Kooistra (eds.) Clinical Endocrinology of Dogs and Cats An Illustrated Text This page intentionally left blank Ad Rijnberk · Hans S. Kooistra (eds.) Clinical Endocrinology of Dogs and Cats An Illustrated Text Second, revised and extended edition © 2010, Schlütersche Verlagsgesellschaft mbH & Co. KG, Hans-Böckler-Allee 7, 30173 Hannover E-mail:
[email protected] Printed in Germany ISBN 978-3-89993-058-0 Bibliographic information published by Die Deutsche Nationalbibliothek Die Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.ddb.de. The authors assume no responsibility and make no guarantee for the use of drugs listed in this book. The authors / publisher shall not be held responsible for any damages that might be incurred by the recommended use of drugs or dosages contained within this textbook. In many cases controlled research concerning the use of a given drug in animals is lacking. This book makes no attempt to validate claims made by authors of reports for off-label use of drugs. Practitioners are urged to follow manufacturers’ recommendations for the use of any drug. All rights reserved. The contents of this book, both photographic and textual, may not be reproduced in any form, by print, photoprint, phototransparency, microfilm, video, video disc, microfiche, or any other means, nor may it be included in any computer retrieval system, without written permission from the publisher. Any person who does any unauthorised act in relation to this publication may be liable to criminal prosecution and civil claims for damages. Contents V Contents Contents . . . . . . . . . . . . . . . . . . . . . . V 2.3 Posterior lobe . . . . . . . . . . . . . 35 2.3.1 Oxytocin . . . . . . . . . . . . . . . . . 35 Authors . . . . . . . . . . . . . . . . . . . . . . IX 2.3.2 Vasopressin . . . . . . . . . . . . . . . . 35 2.3.3 Diabetes insipidus . . . . . . . . . . . . 37 Abbreviations . . . . . . . . . . . . . . . . . . . X 2.3.3.1 Central diabetes insipidus . . . . . . . . 37 2.3.3.2 Nephrogenic diabetes insipidus . . . . . 41 Preface to the first edition . . . . . . . . . . . . XII 2.3.3.3 Primary polydipsia . . . . . . . . . . . . 42 2.3.3.4 Algorithm for polyuria / polydipsia . . . 44 Preface to the second edition . . . . . . . . . . XIII 2.3.4 Vasopressin excess; Syndrome of inappropriate antidiuresis (SIAD) . . . 44 Clinical Endocrinology 3 Thyroids 3.1 Introduction . . . . . . . . . . . . . . 55 3.1.1 Hormone synthesis and secretion . . . . 55 3.1.2 Hormone transport, tissue delivery, 1 Introduction and metabolism . . . . . . . . . . . . . 58 1.1 Hormones . . . . . . . . . . . . . . . . 3 3.1.3 Regulation of thyroid function . . . . . 58 1.1.1 Chemical nature of hormones . . . . . . 3 3.1.4 Thyroid hormone action . . . . . . . . . 59 1.1.2 Storage, release, and transport . . . . . . . 4 3.2 Hypothyroidism in young animals . 60 1.1.3 Action, metabolism, and elimination . . . 5 3.2.1 Acquired juvenile hypothyroidism . . . . 60 1.2 Genes encoding hormones . . . . . . 6 3.2.2 Thyroid dysgenesis . . . . . . . . . . . . 61 1.2.1 DNA regions . . . . . . . . . . . . . . . 6 3.2.3 Defective thyroid hormone synthesis . . 62 1.2.2 Protein factors . . . . . . . . . . . . . . 6 3.2.4 Central hypothyroidism . . . . . . . . . 64 1.2.3 RNA processing . . . . . . . . . . . . . 7 3.3 Hypothyroidism in adult animals . . 64 1.2.4 Translation . . . . . . . . . . . . . . . . 7 3.3.1 Primary hypothyroidism . . . . . . . . . 64 1.2.5 Posttranslational processing . . . . . . . . 7 3.3.2 Central hypothyroidism . . . . . . . . . 71 1.3 Endocrine disorders . . . . . . . . . . 8 3.4 Hyperthyroidism and thyroid tumors 73 1.4 Clinical assessment . . . . . . . . . . . 10 3.4.1 Hyperthyroidism in cats . . . . . . . . . 73 1.4.1 History and physical examination . . . . . 10 3.4.2 Thyroid tumors and hyperthyroidism in 1.4.2 Laboratory testing . . . . . . . . . . . . . 10 dogs . . . . . . . . . . . . . . . . . . . 79 1.4.3 Diagnostic imaging . . . . . . . . . . . . 12 4 Adrenals 2 Hypothalamus-Pituitary System 4.1 Introduction . . . . . . . . . . . . . . 93 2.1 Introduction . . . . . . . . . . . . . . . 13 4.1.1 Synthesis and secretion of corticosteroids 94 2.2 Anterior lobe . . . . . . . . . . . . . . 14 4.1.2 Transport and metabolism . . . . . . . . 94 2.2.1 Somatotropin and lactotropin . . . . . . . 18 4.1.3 Regulation of glucocorticoid secretion . 96 2.2.1.1 Pituitary growth hormone . . . . . . . . 18 4.1.4 Regulation of mineralocorticoid 2.2.1.2 Mammary growth hormone . . . . . . . 19 secretion . . . . . . . . . . . . . . . . . 99 2.2.1.3 Prolactin . . . . . . . . . . . . . . . . . 20 4.1.5 Glucocorticoid action . . . . . . . . . . 101 2.2.2 Congenital growth hormone deficiency . 21 4.1.6 Mineralocorticoid action . . . . . . . . . 102 2.2.3 Acquired growth hormone deficiency . . 24 4.1.7 Adrenal androgens . . . . . . . . . . . . 103 2.2.4 Growth hormone excess . . . . . . . . . 25 4.2 Adrenocortical insufficiency . . . . . 103 2.2.4.1 Excessive pituitary growth hormone . . . 25 4.2.1 Primary adrenocortical insufficiency . . . 103 2.2.4.2 Excessive mammary growth hormone . . 27 4.2.2 Secondary adrenocortical insufficiency . 109 2.2.5 Prolactin and pseudopregnancy 4.2.3 Relative adrenocortical insufficiency . . . 110 in the dog . . . . . . . . . . . . . . . . . 30 4.3 Glucocorticoid excess . . . . . . . . . 111 2.2.6 Pituitary tumors . . . . . . . . . . . . . 31 4.3.1. Pituitary-dependent hypercortisolism . . 116 2.2.6.1 Hormone deficiency . . . . . . . . . . . 31 4.3.2. Hypercortisolism due to adrenocortical 2.2.6.2 Mass effects . . . . . . . . . . . . . . . . 32 tumor . . . . . . . . . . . . . . . . . . 125 VI Contents 4.3.3. Hypersecretion of sex hormones by 6.1.3.1 Genes essential for development of adrenocortical tumor . . . . . . . . . . . 130 Wolffian and Müllerian ducts. . . . . . . 188 4.3.4 Ectopic ACTH syndrome . . . . . . . . 130 6.1.4 Establishment of the phenotypic sex . . . 189 4.3.5 Food-dependent glucocorticoid excess . . 130 6.2 Abnormal sexual differentiation . . . 189 4.3.6 Iatrogenic hypercorticism and iatrogenic 6.2.1 Disorders of chromosomal sex . . . . . . 190 secondary hypoadrenocorticism . . . . . 131 6.2.1.1 Chimerism and mosaicism of 4.3.6.1 Glucocorticoids as pharmacological sex chromosomes . . . . . . . . . . . . . 190 agents . . . . . . . . . . . . . . . . . . . 132 6.2.1.2 XO syndrome (gonadal dysgenesis) . . . 191 4.3.6.2 Iatrogenic hypercorticism . . . . . . . . . 132 6.2.1.3 XXY syndrome . . . . . . . . . . . . . 191 4.3.6.3 Iatrogenic secondary hypoadreno- 6.2.1.4 XXX syndrome (X trisomy, corticism . . . . . . . . . . . . . . . . . 132 triple X syndrome) . . . . . . . . . . . . 192 4.3.6.4 Withdrawal from glucocorticoids . . . . . 134 6.2.2 Disorders of gonadal sex . . . . . . . . . 192 4.3.6.5 Alternate-day glucocorticoid therapy . . . 134 6.2.2.1 XY sex reversal syndrome (XY SRS) . . 193 4.4 Mineralocorticoid excess . . . . . . . 134 6.2.2.2 XX sex reversal syndrome (XX SRS) . . 193 4.4.1 Primary mineralocorticoid excess . . . . 134 6.2.3 Disorders of phenotypic sex . . . . . . . 195 4.5 Adrenal medulla . . . . . . . . . . . . 139 6.2.3.1 Female pseudohermaphroditism 4.5.1 Introduction . . . . . . . . . . . . . . . 139 (pseudohermaphroditismus femininus) . . 195 4.5.2 Pheochromocytoma . . . . . . . . . . . 140 6.2.3.2 Male pseudohermaphroditism (pseudohermaphroditismus masculinus) . 196 5 Endocrine Pancreas 7 Ovaries 5.1 Introduction . . . . . . . . . . . . . . 155 7.1 Introduction . . . . . . . . . . . . . . 203 5.1.1 The endocrine pancreas . . . . . . . . . 155 7.2 Estrous cycle, anestrus, pregnancy, 5.1.2 Insulin synthesis and structure . . . . . . 156 and parturition . . . . . . . . . . . . . 204 5.1.3 Regulation of insulin secretion . . . . . . 156 7.2.1 Estrous cycle, anestrus, pregnancy, 5.1.4 Actions of insulin . . . . . . . . . . . . . 158 and parturition in the dog . . . . . . . . 204 5.2 Diabetes mellitus . . . . . . . . . . . . 159 7.2.1.1 Estrous cycle . . . . . . . . . . . . . . . 204 5.2.1 Classification . . . . . . . . . . . . . . . 159 7.2.1.2 Follicular phase . . . . . . . . . . . . . . 204 5.2.2 Metabolic disturbances . . . . . . . . . . 160 7.2.1.3 Preovulatory luteinization and ovulation . 207 5.2.3 Diabetes mellitus in dogs . . . . . . . . . 161 7.2.1.4 Luteal phase . . . . . . . . . . . . . . . 208 5.2.4 Diabetes mellitus in cats . . . . . . . . . 167 7.2.1.5 Anestrus . . . . . . . . . . . . . . . . . 210 5.2.5 Problems associated with the regulation 7.2.1.6 Pregnancy and parturition . . . . . . . . 211 of diabetes in dogs and cats . . . . . . . . 172 7.2.2 Estrous cycle, anestrus, pregnancy, 5.2.6 Diabetic ketoacidosis (DKA) and and parturition in the cat . . . . . . . . . 213 hyperglycemic hyperosmolar state 7.2.2.1 Estrous cycle and anestrus . . . . . . . . 214 (HHS) . . . . . . . . . . . . . . . . . . . 172 7.2.2.2 Pregnancy and parturition . . . . . . . . 217 5.3 The hypoglycemic syndrome . . . . . 173 7.3 Medical pregnancy termination . . . 217 5.3.1 Insulinoma . . . . . . . . . . . . . . . . 174 7.4 Induction of parturition . . . . . . . 219 5.3.2 Nonpancreatic tumors associated with 7.5 Persistent estrus . . . . . . . . . . . . 219 hypoglycemia . . . . . . . . . . . . . . . 178 7.6 Split heat . . . . . . . . . . . . . . . . 220 5.3.3 Juvenile hypoglycemia . . . . . . . . . . 179 7.7 Hypoluteoidism . . . . . . . . . . . . 221 5.4 Other endocrine tumors associated 7.8 Prolonged anestrus . . . . . . . . . . 221 with the pancreas . . . . . . . . . . . . 179 7.9 Estrus induction . . . . . . . . . . . . 222 5.4.1 Gastrinoma . . . . . . . . . . . . . . . . 179 7.10 Estrus prevention . . . . . . . . . . . 222 5.4.2 Glucagonoma . . . . . . . . . . . . . . . 180 7.11 Cystic endometrial hyperplasia- endometritis . . . . . . . . . . . . . . 226 6 Gonadal Development and Disorders 7.12 Fertility disorders in the bitch due to breeding management problems . 228 of Sexual Differentiation 6.1 Introduction . . . . . . . . . . . . . . 187 8 Testes 6.1.1 Establishment of the chromosomal sex . . 187 6.1.2 Establishment of the gonadal sex . . . . . 187 8.1 Introduction . . . . . . . . . . . . . . 235 6.1.2.1 Genes essential for gonadal development . 187 8.1.1 Hormone synthesis and secretion . . . . 236 6.1.3 Development of the Wolffian and 8.1.2 Regulation of testis function . . . . . . . 237 Müllerian ducts . . . . . . . . . . . . . . 188 8.2 Hypogonadism . . . . . . . . . . . . . 237 .1 Vitamin D sources and synthesis .2 PTH synthesis and secretion . . . . . .1 Serial measurements of urine osmolality . . . . .4 Testicular neoplasia .2. .4 Vitamin D action .4 Weight loss in spite of good appetite 323 11. . . . . . . . 255 12. . . . . . . . . . .2. . . . . . .1 ACTH-stimulation test . . . . . . . . .3 Regulation of PTH secretion . high-dose suppression test thyroidism . . . . . 323 11. .1. . . .3. . 316 13.3 Vasopressin measurements during 9. . 261 12. . . . 305 9. 258 12. . . 278 9.5.3 Nutritional secondary hyperpara. . . . . 278 13 Treatment Protocols 9.2 Hypoparathyroidism . . . 279 13. . . 275 low-dose suppression test 9. . 310 9. . . 333 . . 255 12. . . . . . . . 306 9. . . . . . . . 308 9.1 Pituitary anterior lobe .1 Introduction .1 Parathyroid hormone . . . . . . . . . .1. 261 12. . . . . . . . 308 metabolism . . . . . . . . .3. . . . 323 11 Obesity 14. .1 Primary hyperparathyroidism . .4. . . 315 9. . . . . .3 Regulation of vitamin D metabolites . . . . . .1 CRH-stimulation test . . . . . . . . . .1 Hypophysectomy .1 Hypovitaminosis D . 271 (UCCR + o-HDDST) .3. . . . . . . . .6 Calcitonin-related disorders . . . . . . . . 246 9 Calciotropic Hormones 12 Protocols for Function Tests 12. . . 282 13. . . . . . . .2 Osteochondrosis . . . . . .1. 259 12. . . . .4. 256 12. . . . . . . . . . . . . . . . . .2. 239 8. . . . . . . . 280 13. . . . .2. 255 12. . . . . . . . 264 test (iv-LDDST) . 258 12. . . . . . . . . . . . . . .3 Breeding management of the bitch .1. 318 10. . . . . . . . . . . .2 TRH-stimulation test . . . . . . . . . .5 Male infertility . . . . . . . . . . . . .2 GHRH-stimulation test . . . . . . .6. . . . . .1. . . . . . . . . . .4 Urinary corticoid:creatinine ratios with 9. 320 10. . . . . . . .5 Vitamin D-related disorders . . . . . . . 309 9. . . . . . . . . Contents VII 8. . 307 9.8 Puerperal tetany . .3 Endocrine pancreas . .4 Calciotropic hormones and bone 12. . . . . . 297 11. . . . . . .2 Hypervitaminosis D and vitamin D 12. . 257 12. . 272 12. .1 TSH-stimulation test . . . . . . 291 13. .1.1 Treatment of diabetes mellitus in dogs and cats . .1.6. . . . . . . .2 Low-dose dexamethasone suppression 9. . . 297 11. . . . . . . . .1. .4 Hypercalcemia of malignancy . .1 Development of the parathyroid glands . . . . . .3. . . . .4. . . 266 12. . 294 14 Algorithms 14. . . . . . . . . . 307 9. . .1. . . . .5 Urinary corticoid:creatinine ratios with 9. .3 Erythropoietin . . .2 Modified water deprivation test . . . . . . . . . 309 9. . . . .2. .2 Natriuretic peptides . 323 14.2 Hormonal and metabolic changes . . . . . . . .1 Appetite regulation . . . 275 (UCCR + o-LDDST) . . . . . . . . . . . . . . .2. . .3 Hyperparathyroidism . 298 Index . 291 13. . . . . . . . . . . . . . . . . . . . . 269 12. 284 13. 262 12. 297 14. . . . . . . . . . . . .2 Management of diabetic ketoacidosis .3 Thyroid . .1. . .2 Adrenal cortex .1 Decreased osteoclasia . . . . . . . . . 293 10.3. . . .1. . 266 test (iv-HDDST) . .4. . . . . . . . .1 Pituitary . . . . . .1. . . . .2 Polyuria and polydipsia . . . . . . 306 9. . . . . . . . . 259 hypertonic saline infusion . . . . . 308 9. .1 GnRH-stimulation test . .1. . . . .4 Sample handling . . . . . . . . . 243 Protocols and Algorithms 8.1 Nutritional secondary hyper- calcitoninism . . . . . . . .3 Cryptorchidism .1. . .2 Vitamin D . . . . . .3 Calcitonin .2 Pituitary posterior lobe . 310 9. . . . . . . . .1. . . 317 10. . . . . 315 9.3.1 Introduction . . . .3. . . . . . 277 12. . . 253 12.1.2 Treatment of hypercortisolism with trilostane .4 Humoral manifestations of cancer . . . .2 Renal secondary hyperparathyroidism . . . . . .2 Pathophysiology .3. . . . . . . . 316 10 Tissue Hormones and Humoral 13.4 Adrenal cortex . . . . . .5. . . . . . . .5. . .2. 306 9. . . . 305 9. . . . . . . . .2. . 305 9. .1. 307 9.1 Introduction . . . . . . . .1. . 310 intoxication . .7 Miscellaneous . . . .3 Combined anterior pituitary function test 305 9. .1. . . . . .1.6.1 Endocrine alopecia . 306 9. . . .2. . .1. . . .3. .1. .1 Primary hypoadrenocorticism . . 317 Manifestations of Cancer 13. . . . .4. . 316 9. . . . . . . . . . . . .3 High-dose dexamethasone suppression 9. . . .4 PTH action . .1. . . . . . . . .1. 261 12.2. . . . . . . . . . . . .1 CT synthesis and action . . . . . . .2. . . . . . . . . .5 Ovary and Testis . . . .2 Vitamin D metabolism . . . .3 Treatment of hypoglycemia . 307 9. This page intentionally left blank . Dr. University of Georgia. DVM. Hazewinkel.A. George Voorhout Prof. Jan A. Institute for Animal Breeding and Genetics. Department of Pathobiology.M. Mol. Utrecht University. USA Photography Joop Fama Dr. van den Ingh Prof. Kooistra. Heidi J. NL Department of Clinical Sciences of Companion Animals. Dr. Dr. Germany Prof.A. University of Utrecht University. Contents IX Authors Sara Galac. Auke C. Frederik J. Robben. Herman A. Utrecht University. Faculty of Veterinary Dr. Dr. Vetsuisse Faculty. Faculty of Veterinary Medicine.E. Division of Diagnostic Imaging. Dr. Faculty of Veterinary Medicine. Prof. Utrecht University. Dr. Schaefers-Okkens. NL Dr. Medicine. Hans S. NL Veterinary Medicine. NL Dr. Contributors Jeffrey de Gier. DVM. Kuiper Multimedia department. College of Veterinary Medicine. Marianna A. Yvonne W. Meij. Ad Rijnberk. Dr. van Sluijs.W. Dr. Dr. Ted S. Ir. Reusch Small Animal Clinic. Prof. Dr. Tryfonidou Illustrations Department of Clinical Sciences of Companion Animals. NL Prof. Switzerland .G. Björn P. Margarethe Hoenig Department of Physiology and Pharmacology. Joris H. Claudia E. Pollak Utrecht University. Hanover. Zürich University. X Contents Abbreviations ACE Angiotensin-converting enzyme GH Growth hormone ACTH Adrenocorticotropic hormone GHRH Growth hormone-releasing hormone ADH Antidiuretic hormone GIP Gastric inhibitory polypeptide AL Anterior lobe (pituitary) GLP Glucagon-like peptide ALP Alkaline phosphatase GLUT Glucose transporter protein ALT Alanine aminotransferase GnRH Gonadotropin-releasing hormone AMH Anti-Müllerian hormone GR Glucocorticoid-preferring receptor ANP Atrial natriuretic peptide APUD Amine precursor uptake and HDDST High-dose dexamethasone suppression test decarboxylation HDL High density lipoproteins AQP Aquaporin HHS Hyperglycemic hyperosmolar state AR Androgen receptor HM Home monitoring (blood glucose) ARR Aldosterone:renin ratio (PAC:PRA) HSD Hydroxysteroid dehydrogenase ATR Angiotensin receptor AVP Arginine-vasopressin IAPP Islet amyloid polypeptide IGF Insulin-like growth factor BGC Blood glucose curve IGF-BP IGF-binding protein BNP Brain natriuretic peptide IL Interleukin Insl3 Insulin-like peptide 3 cAMP Cyclic adenosine monophosphate CBG Corticosteroid-binding globulin LDDST Low-dose dexamethasone suppression test CDI Central diabetes insipidus LDL Low density lipoproteins CEH Cystic endometrial hyperplasia LH Luteinizing hormone CIRCI Critical illness-related corticosteroid insufficiency MIT Monoiodotyrosine CGRP Calcitonin gene-related peptide MPA Medroxyprogesterone acetate CLIP Corticotropin-like intermediate lobe MR Mineralocorticoid-preferring receptor peptide a-MSH a-melanocyte-stimulating hormone C-PTH Carboxy-terminal fragments of PTH CRH Corticotropin-releasing hormone NDI Nephrogenic diabetes insipidus CT Calcitonin NFA Non-functional adenoma NEFA Nonesterified fatty acids DDAVP 1-deamino.9-D-arginine vasopressin NF-kB Nuclear factor kappa B DHEA Dehydroepiandrosterone NIS Sodium iodide symporter DHT Dihydrotestosterone NSH Nutritional secondary hyperparathyroidism DIT Diiodotyrosine DKA Diabetic ketoacidosis O.14-dihydro-15-keto prostaglandin F2a ER Endoplasmatic reticulum PL Posterior lobe or neurohypophysis PMDS Persistent Müllerian duct syndrome FNA Fine-needle aspiration PNMT Phenylethanolamine N-methyl transferase FSH Follicle-stimulating hormone POMC Pro-opiomelanocortin fT4 Free thyroxine Posm Plasma osmolality .p'-DDD 2.4'-Dichlorodiphenyldichloroethane DLA Dog lymphocyte antigen OPG Osteoprotegerin DNES Diffuse neuroendocrine system DOC Desoxycorticosterone PAC Plasma aldosterone concentration DOPA Dihydroxyphenylalanine PBGM Portable blood glucose meter PET Pancreatic endocrine tumor EHTT Ectopic hyperfunctioning thyroid PI Pars intermedia (pituitary) tissue PIF Prolactin-inhibiting factor b-END b-Endorphin PGF2a Prostaglandin F2a Epo Erythropoietin PGFM 13. TR Thyroid hormone receptor kappa b ligand TT4 Total thyroxine RAS Renin-angiotensin system rT3 Reverse triiodothyronine UACR Urinary aldosterone:creatinine ratio UCCR Urinary corticoid:creatinine ratio SIAD Syndrome of inappropriate antidiuresis Uosm Urine osmolality SPECT Single photon emission computed UTR Untranslated region (DNA) tomography SRIF Somatostatin-release inhibiting factor VLDL Very-low density lipoproteins SRS Somatostatin receptor scintigraphy VP Vasopressin SRY gene Sex-determining region of the Y chromosome XY SRS XY Sex reversal syndrome SS Somatostatin SSTR Somatostatin receptor ZFY Zinc finger protein. Abbreviations XI PP Pancreatic polypeptide T3 Triiodothyronine PPAR Perioxisome proliferator-activated T4 Thyroxine receptor TBG Thyroid hormone binding globulin PRA Plasma renin activity Tg Thyroglobulin PrRP Prolactin-releasing peptide TGF Transforming growth factor PRL Prolactin TLI Trypsin-like immunoreactivity PTH Parathyroid hormone TNFa Tumor necrosis factor a PTHrP Parathyroid hormone-related peptide TPO Thyroid peroxidase PU/ PD Polyuria /polydipsia TRH Thyrotropin-releasing hormone TSH Thyroid-stimulating hormone RANKL Receptor activator of nuclear factor. Y-linked . The in the regulation of the function of almost every organ sys- immune system is now also recognized as a regulatory system tem. Most of the chapters deal with separate endocrine glands. (2) the endocrine system. and (3) the im. in that they diagnostic and therapeutic protocols are included at the end share many common features. Because the clinician’s suspicion of the communications and controls within the organism by means presence of an endocrine disease is largely based upon pattern of chemical messengers. in which the physical changes play an important munication is covered in large part by three systems: (1) the role. en- docrinology itself occupies a common ground between bio- Within this wide spectrum of communication in the living chemistry. The features of nervous system. to veterinary clinicians in this fascinating field.. many illustrations have been included. istics. First. The whole of intercellular com. dogs and cats are the result of dysfunction of one or more of these glands and hence this book concentrates on the dis. Over the past few decades it has become appar. These will suffice in many cases. It in turn exerts a reciprocal enging combination of broad pathophysiological interest and controlling effect on neuroendocrine systems. clinical endocrinology is a classic characteristics of hormones. For each gland there is an introductory section on the relevant Utrecht. in part animal there are messenger substances which conform to the because of the first two features. Clinical endocrinology has at least four fascinating character- mate link between the nervous system and the endocrine sys. The authors hope that this book will serve as a helpful guide orders of these glands. thereby integrating the two into one control unit. Third. Fourth. products of endocrine discipline of contemplation. hormones and thus endocrine glands are involved tem.XII Contents Preface to the first edition Endocrinology is one of the disciplines concerned with disorders of the gland. mediators within the central nervous system. December 1994 morphology and physiology. physiology. but at some hormones. while several hormones can act as neurogenic time the help of a specialist may be required.e. some endocrine diseases differ in the dog and the cat to such mune system. Therefore the study of this discipline requires the chall- subject to endocrine control. an extent that separate descriptions are needed. and clinical medicine. recognition. at the level of the hypothalamus and pituitary there is an inti. Chapters on ent that the separation of these systems is artificial. Most of the endocrine diseases known to occur in orders are amenable to treatment. followed by descriptions of the Ad Rijnberk . and stimulating dis- glands which are transported by the blood to some distant site cussion. i. specific expertise in the field of endocrinology. The nervous system elaborates of the book to provide a quick reference for both students and compounds that can act as local mediators or true circulating practitioners. Moreover. Second. it is very fortunate that many endocrine dis- of action. reflection. and skill she biology to the clinical approach to the patient. Yvonne Pollak has contributed to our multifaceted field of endocrinology has a place and is worth work in clinical endocrinology in several ways. We are pleased that most of the authors and contributors for The editors hope that this new edition will serve as an up-to- the first edition also helped in preparing the second edition. involved in the wide range of diagnostic techniques that nu- ment. field of clinical endocrinology of companion animals. Belshaw. The information on calciotropic hor. In the 1960s continuing. The expertise and that the book may stimulate students to study this fascinating critical attitude of the coauthors and contributors was vital for discipline. His input is highly appreciated. clear medicine can offer. we pause to reflect upon the jour. we are grateful that new authors with spe. He has done so with helpful insight and sympathy. with whom the editors and several of Ad Rijnberk the authors have had the pleasure of working in endocrinol. and progress in diagnosis and treat. Hans S. further elucidation of olism and thyroid disease and thereafter became increasingly mechanisms of disease. and also digitalized and improved many of the older pictures. Together with the drawings these photographs are very essen- grated into a single chapter. the writing process and occurred in a very pleasant atmos- phere. and cific knowledge were willing to join in. ogy. Mr. mones is no longer distributed over three chapters but inte. Joop Fama chapters have been completely rewritten and new illustrations made several of the new photographs presented in this book have been included. The changes with this edition are in the addition she enthusiastically began assisting in studies of iodine metab- of newly recognized disease entities. she ap- In this second edition the information on basic and clinical plied her varied talents to preparing the drawings for the first endocrinology has been updated and ranges from molecular edition and with the same dedication. Utrecht. In addition. book. As for the first edi- tion. we hope that a brief general description of the For many years Mrs. tial for this illustrated text. date guide to veterinary clinicians in the rapidly developing At the same time. XIII Preface to the second edition As we complete the manuscripts and illustrations for the sec. has helped us in editing the English language of this ond edition of this book. Bruce E. accuracy. April 2009 Dr. ney from the first to the second edition. Kooistra . All of the has prepared the drawings for this edition. maintaining a special interest in the applications to clinical endocrinology. This page intentionally left blank . Clinical Endocrinology . 2 Introduction 1 Figure 1.4 Figure 1. (Modified from Webb and Baxter. or act inside the cell without being released (intracrine). acting on target cells via recep- tors (R).1: Chemical communication involves hormones (H) and neurotransmitters (N). (Modified from Webb and Baxter. with examples of each chemical type. or on receptors in the same cell (auto- crine).4 . The same neurotransmitters can be re- leased to act as hormones via the synaptic junctions or by direct release as hormones by the neuron.2: Sources of the major hormones. Neurons release neurotransmitters from nerve terminals. Hormones may reach the target cells through the circulation (endocrine). 2007). or act on neighboring cells (paracrine). 2007). The liver and kidney serve as major sites for metabolism and ex- cretion of hormones. Glandular biosynthesis and secretion.e. Professor of Physiology at endocrinologists include exocrine secretion (e. Many age. transmitter actions in the central nervous system. be both a hormone and a neurotransmitter. . the science concerned with hormones. Clinical endo. leukotrienes. amino acid ana- The traditional and still major part of clinical endocrinology logues. such as vitamin D and its metabolites. on the cell of origin (autocrine). triiodothyronine. The same molecule can of the body. 1. London.3 dinner with the distinguished biologist William Hardy. the active products of vitamins act through nuclear hormone receptors. Endocrinology also includes messengers that circulate pri- marily in restricted compartments such as the hypothalamic. endocri- nology. biological molecules. are derived from fatty acids (figs. They are produced by most cells and released with little stor- and within the secretory cell (intracrine) (fig. in milk and University College. are derived from a single amino acid. and (2) those in which the B mones (e. by proteolytic cleavage of protein prohor. Other forms of intercellular communication studied by coined by Ernest Henry Starling. organs whose primary function is not endocrine.1). progressing parallel to laboratory-based endocrine research. 1. or modified peptides.g. of which insulin and dihydrotestosterone are surface and nuclear receptors. and tion of hormones in specialized endocrine cells scattered in dopamine. As for steroid hormones. such as norepinephrine. jacent cells (paracrine).2 At catecholamines are hormones when released by the adrenal the same time. cific mRNAs. and estradiol. (GH) and follicle-stimulating hormone (FSH). such as the stomach. who pro. 1.1 During a conversation at a semen) and the release of pheromones (in air or water). epinephrine. they can be proteins (including gly- coproteins). For example. in the vascular bed). the way in which hor. Others. cholesterol derivatives. and act via both cell hormones. the heart. duced the Greek verb for »excite« or »arouse« (ormao). Thyrotropin-releasing hormone (TRH) is a hormone with those secreted externally (exocrine) into ducts such as when produced by the hypothalamus. to contrast the medulla and neurotransmitters when released by nerve ter- actions of substances secreted internally into the bloodstream minals. i.1 Hormones examples. and adipose tissue (see Steroid hormones are derived from cholesterol and are of two also chapter 10). and metabolic inactivation amino acids) or as large and complex as growth hormone all determine the effective hormone concentration.g. the gonadal and adrenal steroids. Catecholamines.2. have both paracrine actions in the tissues in which they are formed and classical endocrine actions at peripheral A little more than 100 years ago the term hormone was sites. such as dihydrotes. the small intestine. deals with the glands that produce hormones and in particular with the circulating concentrations of hormones to which Polypeptide hormones are direct translation products of spe- cells expressing specific receptors for hormones are exposed. They turned to a classical colleague. glands. thromboxanes. from circulating precursors. 3 1 Introduction 1 Ad Rijnberk Jan A. as well as messengers that act on ad. has enormously increased our understanding of physiological processes in health and disease. the word »endocrine« appeared.1 Chemical nature of hormones crinology. 1. but has several neuro- the lumen of the gastrointestinal tract.3). and pituitary portal system. such as endocrine organs.. Hormones may also be activated outside the types: (1) those in which the steroid nucleus is intact. has led to important discoveries having significant Chemically. tyrosine. peptides or peptide derivatives. hormones are derived from the major classes of impact on many disease states. are in part secreted by endocrine glands and in part formed in peripheral tissues Retinoids are derived from carotenoids (vitamin A) in food. cleared rapidly from the circulation. They can be as small as TRH (three mone is transported to target cells. In recent years the traditional view of the endocrine system’s glandular nature has broadened to include produc. 1.1. Eicosanoids. Mol 1. ring is open.. cleavage products of larger precursor proteins. including prostaglandins.2). the two decided that they needed a word for an agent released There are strong similarities in signaling mechanisms between into the bloodstream that stimulated activity in a different part the endocrine and nervous systems. or lipids (fig.. which have about 200 amino acid residues and molecular weights in the The capacity to form hormones is not limited to endocrine range of 22000–32000. tosterone. Since 1905. Each circle in the protein hormone represents an amino acid. The release process may involve freeing soluble derivatives from precursors by proteolysis (thyroid hormones from thy. In many instances the rate of hormone enters and interacts with its specific receptor in target cells release fluctuates.3: Examples of different types of hormones. just as shown for the polypeptide hormone. or passive diffusion of newly synthesized molecules and affinity of the proteins that bind it. This explains the half-life of only a few minutes in product. The distribution between bound and free hormone in plasma roglobulin). are released in a pulsatile fashion. 4 Introduction 1 Figure 1. the amount of The more insoluble a hormone is in water. the more impor- hormone stored is usually very small.6 considerable changes in hormone concentrations in plasma . exocytosis of storage granules (peptide hor. Even in cells with well-developed organelles for plasma of most of the nonglycosylated peptide hormones. the pituitary hormones being prominent Hence. Thyroid and steroid hor- are thyroglobulin. 1. release. and transport The majority of water-soluble hormones such as proteins and peptides are transported in blood without binding to specific Most endocrine cells have a limited capacity to store the final proteins. Protein- stored in the thyroid follicles. and the intermediate forms of bound hormones cannot per se enter cells but serve as a vitamin D stored in adipose tissue. such as the Golgi apparatus. is determined by the amount of hormone and the amount mones).1. changes in the amount of transport protein can cause examples. Many hormones. synthesis and release being tightly linked. and participates in the regulatory feedback mechanisms. reservoir from which free hormone is liberated for cellular uptake. The major exceptions tant is the role of transport proteins. The free hormone (steroid hormones). storing hormone. the precursor of thyroid hormones that is mones are largely transported bound to proteins.5.2 Storage. The hormone-receptor complex then binds to specific sequences – the positive and negative response elements – regions of DNA.g. thereby activating second messengers (fig. 1. and lipolysis) occur outside the nucleus. influence the steady state as long as the feedback control of fects on transcription. metabolism.4). they maintain the nomic effects mediated by the cytosolic glucocorticoid recep- amount of free hormone within a fixed (normal) range. (2) the DNA-binding domain. proteases. Peptide hormones are mostly inactivated in target tissues by Hormones exert their effects by binding to specific receptors. and (3) nonge- control hormone synthesis are intact. Steroid hormones bind to cytoplas- ceptor complex. In recent years it has become clear that apart from this classi- cal genomic mechanism of steroid action.4: Classical schematic model of hormone action. In this most common process. These hormones are trans- ported in plasma mainly bound to carrier proteins. genes. This complex can bind to specific regulatory mic or nuclear receptors. through which proteins are covalently modified. Activated cell surface recep- tors use a variety of strategies to transduce signal information. membrane-associated proteins. the cytosolic glucocorticoid recep- tor not only mediates the well-known genomic actions but is also involved in rapid direct effects in the cytosol. Many of the actions of second messengers (e. Many peptide hor- mones ultimately signal via regulation of protein phosphoryla- tion.3 Action. Steroid hormones and thyroid hormones act via structurally related intracellular receptors. cell membrane. steroids can also mediate rapid effects by nongenomic mechanisms. but they may also influence gene tran. which makes them soluble.7 1. hormones) is enhanced or suppressed (fig. Hormones 5 the carboxyl terminal domain that mediates ligand binding. and (3) synthesis and release is intact. 1. and Degradation and inactivation of hormone takes place in target elimination tissues as well as in nontarget tissues such as liver and kidney. with the recognition / binding site exposed on the cell surface. For gluco- corticoids three different mechanisms have been proposed: (1) nonspecific interactions with cellular membranes which change their physicochemical properties and the activities of without producing symptoms and signs of hormone defi.1. which amplify and pass on the molecular information. a phosphate group is donated to the protein by nucleotide triphosphates..4). membrane receptors are complex protein structures with in. This allows peptide hor- mones to rapidly change their conformation and thus the function of existing cellular enzymes [enzyme activation or inactivation]. The small amounts of free hormones are transported into the cytosol and bind to specific receptor proteins to form a hormone-re- Figure 1. dimerization. are proteins with similar overall structures and functions. A change in the rate of hormone degradation does not pendently: (1) the amino terminal domain that mediates ef. (2) specific interactions with a ciency or excess. tor. but if the control mechanism . and effects on transcription. As a result. Most lized and also largely conjugated. scription. It also allows somewhat slower changes invol- ving the transcription of genes coding for enzyme proteins and thus influencing the concentration of cellular enzymes [enzyme induction]. resulting in activation or repression of a restricted number of in promoter regions of genes in the chromosomal DNA. If the regulatory feedback mechanisms that membrane-bound glucocorticoid receptor. This ligand-receptor interaction causes the generation of a second the formation of messenger RNA is increased or decreased messenger. Peptide hormones and catecholamines bind to specific receptors in the Thereby it acts as a regulator of gene transcription. Intracellular receptors urine. Steroid and thyroid hormones are largely metabo- which can be on the cell membrane or intracellular. In the latter concept. in the liver and kidney and then excreted via the bile and tracellular and extracellular domains. Each is composed of three domains that can act somewhat inde. on gluconeogenesis and thus the synthesis and secretion of proteins (enzymes. 1 Peptide hormones and catecholamines operate via receptors located in the cell membrane. In 1.2. Conversely.)10 messenger RNA (mRNA). (Adapted Exons are the regions of the gene that are transcribed into from White. Histones proximately 30 bases upstream from the site at which tran. 2004.1 DNA regions Schematic illustration of the steps involved in the gene-encoded synthesis of a protein. i. each consisting of eight positively charged histone molecules.2 Protein factors many genes this region includes a short nucleotide sequence known as a TATA box (TATAAA or related sequence).11 chromatin domain (see chapter 1.10. These sequences are spliced Locus control regions out of the primary transcript before it leaves the nucleus These regions are required to establish a tissue-specific open (fig. which illustrate RNA processing. The different regions of a generic gene are shown in A. Figure 1.e. hanced by remodeling of nucleosomes to permit assembly of hancers.2) in the vicinity of a par- ticular locus and thus permit appropriate tissue-specific ex- Exons consist of coding sequences that are translated into pro. somes. One element of the promoter is the binding site for RNA polymerase II. sion of the genomic code.. Exons are usually interspersed with introns. Transcription of genes is mediated by the CpG islands interaction of many proteins with defined regulatory regions Cytosine methylation by a DNA methylase (DNA methyl- (or cis regulatory elements) present in the promoter region lo. This organization renders DNA relatively in- The cis regulatory elements that increase transcription inde. 1. changing the rate of hormone degradation may 1 have clinical consequences. This concerns not only the synthesis of protein hor- mones but also enzyme proteins for steroid synthesis and for processes such as post-translational modification of peptide hormones. Higher-order winding organizes nucleosomes Enhancers and silencers into chromatin. or in the 3'-UTR of the gene10: This minimizes expression of permanently inactivated genes when differentiated cells divide.9 and glucocorticoid insufficiency will ensue if the increased break- down is not compensated by increased adrenocorticotropin- stimulated production of cortisol. which is single stranded and has a sequence that corresponds to the coding (or sense) strand of DNA. . ap. or at some distance (up to thousands of genomic code.2 Genes encoding hormones Proteins play a pivotal role in the synthesis and action of hor- mones.2. and those that decrease transcription are called si. 1. tein and untranslated regions (UTRs) at both ends of the gene (5'– and 3'-UTR). or present islands and is associated with inactivation of gene expression.5: 1. Transcription is invariably controlled at least in part by se- quences located in the 5' flanking region of the gene before (5' or upstream from) the start of transcription.10 In this way the information poten- lencers. 6 Introduction is defective. the degradation of glucocorticoids is enhanced in hyperthyroidism8. hypomethylation Promoters is associated with active transcription. ation) gives rise to the formation of CpG (cytosine-guanine) cated upstream from the transcription start site. scheme is used in E but omitted in B–D. Within chromosomes the DNA is organized into nucleo- scription begins. Such elements can be located within a gene itself. tial of the genome is extended beyond the limitations of the usually in an intron. accessible to transcription factors. The same color Genes encoding proteins consist of several components. As an example. During transcription it is synthesized in the 5' to 3' direction by a transcriptional apparatus that »reads« the complementary (or antisense) strand of DNA.5). transcription complexes.2. Transcription can be en- pendently of their position and orientation are called en. cell specificity is achieved without expan- nucleotides) away from it. pression. within intron areas. the nucleotide sequences within introns are The promoter of a gene is bound by general transcription fac. found to be much less similar than the coding sequences. hances the initiation of translation.5).12 fits into the major groove between two turns of the DNA helix.1. This process is mediated by spliceo. The nascent protein is transported across the ER membrane somes. which is inserted in the may play a role in RNA stability. A tRNA is charged with the appropriate amino acid at its 3' end by a specific amino- Cap structure acyl tRNA synthase. where it is translated into protein (fig.2. The cap is formed by addition of a guanosine to the 5' end of the mRNA and methylation of this guanosine and subsequent 1. reads the mRNA nucleotide sequence in triplets or codons fig. This often requires interactions with chaperone teins.4 Translation atoms and are called zinc fingers. 1. The N terminus is bound by a ribonucleopro- repeated adenosines is added to the 3' end of the RNA. This 1 tors to form a transcription initiation complex that ultimately suggests that the exact sequence of an intron is relatively un- has a molecular weight of greater than 2 million Da. the formation of disulfide bonds. This class of regulators contains suppressors of tumor binding domains include an a-helical protein segment that progression and metastasis. and cell surface proteins play a pivotal role in endocrinology.6).4). ation. It stream from a consensus poly(A) addition site.10 MicroRNAs In the complex interplay of several factors influencing the Transcriptional regulatory factors generation and expression of mRNA. which are large complexes of small RNA molecules in an unfolded state and must then adopt the correct con- and proteins named snRNPs (small nuclear ribonucleopro. This structure is required for the export of mRNA from the nucleus. secretory also facilitates the binding of RNA to ribosomes and thus en. The reason for the presence proteins. These proteins are synthesized on ribosomes bound to the endoplasmic reticulum (ER) and undergo posttranslational Poly(A)tail processing. membrane of the ER and recruits specific proteins to form a transmembrane channel to begin transporting the protein Splicing of introns across the ER membrane after its synthesis. at which point the ribosome dissociates from the mRNA. which plays a role in into protein by the ribosomal protein synthesis apparatus that the morphogenesis of the pituitary gland (see chapter 2. This is poly(A)tails generally range between 50 and 250 bases and then bound by the SRP receptor. These microRNAs (miRNAs) of and at least one activation domain that interacts with el.2. tion. most of which are AUUAAA. or UAG). the signal recognition particle (SRP). script there is an open reading frame which is translated An example of such a factor is Pit 1. These tein complex.2. 4. 2.10 The first posttranscriptional event during the course of RNA maturation in the nucleus is the addition of a cap. UGA. This is followed by binding of other protein complexes and RNA polymerase II. 1. Almost all DNA. All of these proteins contain an N-terminal seg- In the nucleus most transcripts are clipped 12–16 bases down. The ribosome reads the sequence from the start codon AUG that encodes a methionine residue until it reaches a stop codon (UAA. Genes encoding hormones 7 General transcription factors different species. (fig. Then a nucleotide sequence consisting entirely of hydrophobic. AAUAA or consists of approximately 20 amino acids. ment called the signal peptide (see for example fig. Many of these domains (including those of the intra- cellular hormone receptors) are stabilized by chelated zinc 1. formation. 1. A part of important except for sequences involved in splicing and regu- this complex separates the DNA strands and allows binding lation of gene expression. adjacent to the TATA box.5 Posttranslational processing methylation of the adjacent nucleotide(s).5)10: complementary to a mRNA codon. The domains called home domains are 60 amino acid motifs that are most often found Within the nucleotide sequence of the mature mRNA tran- in transcription factors regulating embryonic development. glycosylation may also be required for .2.10 In addition to its contribution to proper folding or When genes encoding the same protein are compared among stability of the protein. and glycosyl- of interruptive introns in genes has not been established. small RNA sequences Each of these factors consists of a DNA-binding domain can also play a critical role. 20–22 nucleotides can silence gene expression after transcrip- ements of the transcriptional apparatus. and it As mentioned in the introduction of chapter 1.3 RNA processing Codons are actually read by small transfer RNA (tRNA) mol- The primary RNA transcript of a gene is modified in several ecules that are specific for each amino acid. and pronounced »snerps«). An important aspect of the maturation of RNA is the removal of introns by splicing. A tRNA mol- ways in the nucleus before being exported as mRNA to the ecule has a nucleotide triplet (called an anticodon) that is cytoplasm. i.5). 3.. contrary to the restrictive one-cell- . such mune disorders or by neoplasia and theoretically also by in- as parathyroid hormone (chapter 9. 4. and those for proteins that are secreted in a Endocrine glands may be injured or destroyed by autoim- regulated manner (hormones). mitochondria). many additional types of posttranslational processing.3 Endocrine disorders (see for example fig. are synthesized as fection or hemorrhage. These principles as well as the ones to follow are Certain proteins. pituitary cells can adapt via the classical feed-back concept. (Adapted from White.. which can be further subdivided: ditional processing. to agenesia of an endocrine gland or it may be iatrogenic hormones contain multiple peptide hormones within their (e. and the resulting hypofunction is preprohormones. inadequate stimulation of the gland and is then said to be secondary.e. such as proopiomelanocortin (fig. in recent years it has become clear that cells of one cell line may be transformed into another to satisfy the demand for a specific pituitary hormone. 8 Introduction 1 Figure 1. and only in transfer RNA (tRNA) in the region of the anticodon that interacts with mRNA through complementary base pairing.1). where they may undergo ad.. There are In hypofunction of a pituitary-dependent endocrine gland.6: Ribosomal protein synthesis. are synthesized as apo. Some prepro.10 mone and increased numbers of specific pituitary cells.1. includ. lamic-pituitary system in relation to a peripheral endocrine proteins that require the addition of functional groups such as gland (fig.g. Some peptide hormones. ing phosphorylation. binding of lipids. 2004. and U are nucleo- tides in RNA. heme before they are active.1). According to this concept each adenohypophyseal cell type produces a single hormone. They are sorted within the Golgi appar- atus into vesicles containing proteins destined for the cell sur. ac- cording to the one-cell-one-hormone concept. Deficient hormone production face (receptors). They are illustrated in mRNA only in the region in contact with the ribosome. Hypofunction can also be due to primary sequence. aa1–7 represent successive amino acids in the nascent polypeptide. due to castration). and chemical modifi. most of vesicles to the Golgi apparatus. particularly enzymes such as cytochrome illustrated by drawings depicting a generalized hypotha- P-450 (see for example chapter 4. Endocrine disorders occurring in the dog and the cat can be Secretory and cell surface proteins are transported in specific divided into the following six broad categories. 1. increased secretion of the corresponding pituitary hor- cation of amino acids. However.)10 proper targeting to subcellular organelles such as lysosomes 1.g. which is secreted upon stimulation by a par- ticular hypothalamic releasing hormone. A. Primary hypofunction may also be due that usually take place within secretory vesicles. Thus. This occurs at the site at which the enzyme is to function (e.3). They require additional proteolytic steps said to be primary.1.7). G. C. 1.8). The differences in hormone production are indicated by differences in thickness and continuity of lines and arrows.7. 1. Defective hormone synthesis perstimulation of the endocrine gland. of which there may be Genetic defects can cause abnormalities in hormone syn- several causes (secondary hyperfunction) (fig. Figure 1. mone action due to a receptor defect (right). Endocrine disorders 9 1 Figure 1.7: Left: Generalized hypothalamic-pituitary system and a related endocrine gland under normal conditions and as influenced by administration of a hormone produced by the peripheral gland.13 izing hormone receptors (chapter 4.5). For example. and (2) hormonally active lesion in the pituitary mone synthesis in a peripheral endocrine gland (left).9: Schematic illustration of two different forms of hormone excess: (1) tumor in a pe. the re- The most frequent causes of hormone excess syndromes are sulting syndrome of hormone excess is said to be iatrogenic. Rarely. the capacity of mature cell types without cell division is called adrenal cortex may express aberrant receptors such as lutein- transdifferentiation (chapter 3. Right: Illustration of primary and secondary (pituitary) hormone deficiency states. hypersecretion of hormone by a tumor of the endocrine gland (primary hyperfunction) and hypersecretion due to hy. see legend of fig.3. Excessive thesis. 1. 1. adenohypophyseal cells are not irre.7. For explanation. one-hormone concept. The hormone secreted by the peripheral gland is partitioned in the circulation between a small free fraction (open parts of arrows) and a large frac- tion bound to carrier proteins (dark parts of arrows). see legend of fig. . and (2) resistance to hor- gland (right). For explanation.3.8: Figure 1. Sometimes this leads not only to hormone deficiency hormone production may also be traced to cells that are not but also to manifestations of a compensatory adaptation. Schematic illustration of altered feedback control in situations of (1) defective hor- ripheral endocrine gland (left).1). (fig. such normally the primary source of circulating hormone (ectopic as goiter resulting from defective thyroid hormone synthesis hormone production. hormone hypersecretion is the result of expression or acti- versibly monohormonal but may become polyhormonal.4). vation of receptors in an endocrine gland that does not norm- This alteration of the morphologic features and the secretory ally harbor functional receptors of this type. see for example chapter 4. When hormones are used to treat nonendocrine diseases or when hormone Excessive hormone production replacement for an endocrine deficiency is excessive.9).3. 2. 1. as is insulin resistance in some forms of diabetes mellitus (chapter 5. patterns of physical characteristics of endocrine syndromes. chromato- Abnormalities in hormone transport graphy. as well as with the sexual cycle. Especially now that the definitive diagnosis can often be secured by labora.16 findings of the physical examination. The low percentage (쏝 1–10 % of the total) of unbound hormone exerts the biological effect. However. Many forms of hormone excess or deficiency lead to mani. Certain limitations must be kept in mind: . Thus it is possible for the level in an individual animal organ systems. and pregnancy.1). endocrine glands may be affected by abnormalities plasma: not impairing function. 10 Introduction Resistance to hormone action 1.1 History and physical examination The total hormone level reflects the amount of free hormone only if the amount and the affinity of binding protein remain The diagnostic process is hampered by the inaccessibility for constant or fluctuate within narrow limits.9). deranged hor. It The development of techniques for the measurement of hor- may be an inherited disorder involving one or more mole. and infiltrative diseases not leading to significant impairment of Several hormones are secreted in a pulsatile manner (fig. cortisol and adrenocorticotropin). parathyroids. in some cases the changes are very subtle and it Exocrine secretion of hormones and the release of phero- is necessary to rely completely on laboratory testing. such as the hypothalamic-pituitary portal system. mone production. Hormone resistance may also be proaches: acquired. cysts.6 Steroid and thyroid hormones are transported in plasma 1.. A common feature of hormone re. and weight loss or gain. physical examination of all of the endocrine glands except the thyroids. hormones is generally between 1 and 500 pM. Urinary excretion Measurements of urinary excretion of hormones have the advantage of reflecting average concentrations in plasma and hence average production rates over the time interval be- tween collections. Hormone concentrations in plasma sistance is an elevated concentration of the hormone in the The total concentration of steroid and thyroid hormones in circulation in the presence of diminished or absent hormone plasma ranges between 1 and 1000 nM. The range of reference values for most hormones is fairly mone secretion has consequences for the function of other broad. usually leading to multiple abnormalities to double or to decrease by half and yet still be in the refe- which often have a characteristic pattern. and do not festations that are readily apparent at the time of the initial reach the systemic circulation in appreciable quantities.g. The appli- cation of radioimmunoassay. Paracrine and autocrine effects of hormones are usually not tory data.2 Laboratory testing 1 Hormone resistance is defined as a defect in the capacity of normal target tissues to respond to the hormone (fig. the differential diagnosis of common problems such as weak- ness. These include tumors. while that of peptide action. Nevertheless. There are several reasons for caution in as- sessing isolated measurements of hormone concentration in Finally.15 For this reason it is sometimes useful to endocrine disease thus often begins with the recognition of a measure the concentrations of a related pair of hormones pattern of characteristics in the medical history and in the simultaneously (e. veterinary clinicians have learned to recognize the reflected by hormone concentrations in plasma. of a hormone in plasma provides a reliable assessment of hor- tion in plasma but not hormone action.4. The diagnosis of an rence range. Thus a cipline to a more quantitative one.5. and /or their concentrations may vary in a diurnal rhythmi- city. and testes.14 Some messengers circulate only in restricted compartments. Yet there are only a few change in the concentration of transport or carrier proteins in situations in which a single measurement of the concentration the plasma usually affects only the total hormone concentra. radioreceptorassay. including defects in receptors and in crine function in quantitative terms by the following ap- postreceptor mechanisms. mones in biological fluids has made it possible to assess endo- cular abnormalities. presentation of the patient for examination. and more recently molecular biological techniques Feedback control of hormone production and release is has transformed endocrinology from a largely descriptive dis- mediated by the concentration of free hormone. 1. 1. lethargy.10) hormone secretion. This is mones cannot be determined by measuring the hormone especially true when endocrine disease is being considered in concentration in plasma.4 Clinical assessment largely bound to proteins.4. is excreted in in- tact or conjugated form predominantly via the bile and only in very small amounts in the urine. and growth hor. Hormone receptors and antibodies The measurement of hormone receptors in biopsy material from target tissues may become increasingly useful in compan- ion animal endocrinology. A meal mune phenomena. thyrotropin [TSH] and thyroxine. Measurement of antibodies to hormones or antigens in endocrine tissues may also be essential in order to Figure 1. in which case the target gland is the pituitary and the measured response is the increment in the plasma concentration of ACTH. or it can be a pituitary hormone such as ACTH. 쎱 There is considerable individual variation in the meta- bolism. with the adrenal cortex as the target gland being assessed by the measurement of the increment in the plasma concentration of cortisol. The figure clearly illustrates the pulsatile character of hor.10: Results of measurements of cortisol. chapter 3. It involves either stimulation or suppression of endogenous hormone production. for which reason they are not generally available. 쎱 Changes in renal function may influence the rates of hor- mone excretion in the urine. Antibodies against hormones may also in- was given at time 0'. says. They are de- signed to determine whether negative feedback control is in- tact. adrenocorticotropin (ACTH). 1 vented by relating the hormone concentration to the uri- nary creatinine concentration. and hence urinary excretion. Suppression tests are utilized when endocrine hyperfunction is suspected. characterize certain endocrine abnormalities such as autoim- mone (GH) in frequently collected blood samples of a healthy adult dog. 쎱 The concentration of a hormone in urine is less mean- ingful if the hormone.. A hormone or other regulatory substance is administered and the inhibition of endogenous hormone secretion is as- sessed. Production and secretion rates These techniques can circumvent many of the problems as- sociated with isolated measurements of hormones in plasma or urine. Dynamic endocrine tests Dynamic testing provides additional information. especially in the diagnosis of hor- mone resistance. but they are difficult to perform and often require administration of radionuclides.17 . Stimulation tests are utilized most often when hypofunction of an endocrine organ is suspected. Dynamic tests continue to be of importance in the diagnosis of certain disorders but in circumstances in which hormone pairs can be measured accurately (e. of some of the pep- tide hormones. terfere with diagnostic procedures such as radioimmunoas- mone secretion. It can be circum. Clinical assessment 11 쎱 Collection of urine during a 24-hour period is a cum- bersome procedure in most animals. The tropic hormone can be a hypotha- lamic releasing hormone such as corticotropin-releasing hor- mone (CRH). such as thyroxine.1) they are required less often.3.g. In the most commonly employed stimulation tests a tropic hormone is administered to test the capacity of a target gland to increase hormone production. 60:65–71 miniature poodles in assocation with high urinary corticoid:creati- nine ratios and resistance to glucocorticoid feedback. VAN DER VLUGT-MEIJER RH.48:283–287. In: Rijnberk A. Molecular Endocrinology. ROBBEN JH.207–212. J Endocrinol 2005. 14. Oxford: Oxford Uni- versity Press. and magnetic resonance imaging (MRI). Clinical endocri. TESKE E. Medical History and Physical Examination in SNIJDERS C. and RIJNBERK A. Functional and morphological changes in the adeno- hypophysis of dogs with induced primary hypothyroidism. MOL JA. In: Gardner DG. van Sluijs FJ.4. RIJNBERK A. Shoback D. nology of dogs and cats. 5th ed. Hyperthyroidism due to an intrathoracic tumour in a dog with test results suggesting hyperadrenocorticism. 2. eds. 8th ed. Oxford: Elsevier Ltd. VAESSEN MMAR. JAVADI S. Pulsatile secretion pattern of growth hormone dur- pituitary enlargement with transdifferentiation. Ojeda SR. LÖWENBERG M. ALARCÓN C. of the functions of the body I. 12 Introduction 1. 2nd ed. Mol Cell Endocrinol 2002. DE LANGE MS. REFSAL KR. BEVERS MM. STAHN C. computed to- References 1. VAN HAAFTEN B.17–48. TSH hypersecretion. Companion Animals. PROVEN- CHER-BOLLIGER AL. 2007. J Vet Intern Med 2006. Lancet 1905. Alopecia in pomeranians and 1999. CERUNDOLO R.1–34. Aldosterone-to-renin and cortisol-to-adrenocor- ticotropic hormone ratios in healthy dogs and dogs with primary 8. Dordrecht / Norwell: Kluwer Academic WANG Q. RIJNBERK A. whereas the latter three may physical examination has been progressively overcome during be easier to perform but require expensive equipment as well the past two decades by the use of diagnostic imaging tech. Vet Rec 7. F. BOER P. MOL JA. OSKARSSON T. Mol Cell Endocrinol 2007. MASSADUÉ J. Fertil 2000. 3rd ed. RIJNBERK A. KOOISTRA HS. MAKER J. Imaging of the pituitary gland in dogs with pituitary-dependent hy- peradrenocorticism. High hypoadrenocorticism. ed.184:5–10. 2004. Genes and hormones. .160:393–397. HOMMES DW.2:339–341 Textbook of Endocrine Physiology. OKKENS AC. niques such as ultrasonography. Vet Clin North 9. eds. 13.3 Diagnostic imaging mography (CT). eds. Biol Reprod KOOISTRA HS. Greenspan’s basic and clinical Endo. Molecular mechanisms of glucocorticoid action and selective glu- cocorticoid receptor agonists. Amsterdam: Elsevier Academic Press. scintigraphy. A. 1996. urinary corticoid /creatinine ratios in cats with hyperthyroidism. Domest Anim En- ing the luteal phase and mid-anoestrus in beagle bitches. 2004.451:147–152. Endogenous Publishers. J Vet Intern Med 2004. 3. KOOI- STRA HS. Croonian Lecture: On the chemical correlation 10. VAN DER VLUGT-MEIJER RH. Nature 2008. BOLANDER FF. LLOYD DH. TRIP MR. 17. as immobilization which necessitates anesthesia. Amer: Small Anim Pract 2001. Introduction to Endocrinology.275:71–78. RIJNBERK A. PADUA D.1–5 human microRNAs that suppress breast cancer metastasis. 2007. BOS PD. loss of 5. hypersomatotropism.35:98–111. STASSEN QEM. DEN HERTOG.18:152–155. hypoprolactinemia. 2009. MEIJ BP. 4. 11. Lymphocytic thyroiditis. BUTTGEREIT 2007. GALAC S. GERALD WL. 12.31:915–933. SCHOE.197:81–87. Endocrine glands. WHITE PC. OKKENS AC. BAXTER JD. DIAZ ESPINEIRA MM. VAN DEN INGH TSGAM. HENDERSON J. J Reprod docrinol 2008. In: Griffin JE. KOOISTRA HS. KOOISTRA HS. KOOISTRA HS. RIJNBERK A. MOL JA.119:217–222. NACHREINER RF. crinology. of the oestrus cycle and anoestrus in beagle bitches.20:556–561. In: Rijnberk 6. J Small Anim Pract 18. POPP. VOORHOUT G. Ernest Starling and »hormones«: an historical commentary. GALAC S. WEBB P. KOOISTRA HS. DIELEMAN SJ. New York: McGrawHill Medical. Concurrent pulsatile secretion of luteneizing hor- mone and follicle-stimulating hormone during different phases 15. 16. TAVAZOIE SF. Hormones. TESKE E. VOORHOUT G. GRAHAM PA. STARLING EH.18 1 The former technique is relatively inexpensive but requires The inaccessibility of most of the endocrine glands for direct extensive operator experience. 1). for man)2 N. Lobus nervosus hypophysis Figure 2.A. Many key elements of this system are neither purely endocrine nor purely neural.V.1 Table 2.A. The hypothalamus For practical reasons the terminology in this book is confined to the exerts control over the anterior lobe (AL) through releasing and inhibiting factors that reach the AL three functional units: Anterior lobe (= Pars infundibularis and Pars cells via capillaries of the pituitary portal system.H. 2. There are three components: (1) A neuroendocrine system connected to an endocrine sys- tem by a portal circulation. and Nomina Anatomica (N. Infundibulum hypophysis (infundibulum) Pars distalis neuro.. and Posterior lobe ward projection of the hypothalamus.) and the variants in the Nomina Histologica Veterinaria (N.and monoamine-secreting cells in the anterior and middle portions of the ventral hypothalamus.V. Here they are released into capillaries of the hy- pothalamic-hypophyseal portal system for transport to the anterior lobe (AL) of the pituitary.V.A.2: Schematic representation of the relationship of the hypothalamus and pituitary. The neuroendocrine system consists of clusters of peptide.1 Introduction The hypothalamus and pituitary form a complex functional unit that transcends the traditional boundary between neuro- logy and endocrinology.1: Nerve fiber terminals containing corticotropin-releasing hormone (CRH) in the outer layer of the median eminence of a dog. Pars intermedia.).A. 2. Adenohypophysis (Lobus anterior) Pars infundibularis Pars proximalis Pars tuberalis adenohypophysis adenohypophysis Pars intermedia Pars intermedia adenohypophysis Pars distalis Pars distalis adenohypophysis Neurohypophysis (Lobus posterior) Pars proximalis neuro. trol.H. Introduction 13 2 Hypothalamus-Pituitary System Björn P.V. Meij Hans S. N.2 and table 2. Kooistra 2 Ad Rijnberk 2. The posterior lobe (PL) of the pituitary is a down- distalis of the adenohypophysis).11). 2. The pars intermedia (PI) is under direct neurotransmitter con- (see also fig. where they regulate hormone production and secretion (fig. Note the presence of CRH-immunoreactive fibers outside the terminal zone in close proximity to the capillary system. N.1: Terminology for the parts of the hypophysis (glandula pituitaria) according to the Nomina Anatomica Veterinaria (N. .2). visualized by indirect immunofluor- escence. Their products – releasing hormones and inhibiting factors – are transported by nerve fibers to terminals in the outer layer of the median eminence (fig. Figure 2. ported by nerve fibers that traverse the ventral hypothala. which is synthesized not only in the . b-endorphin (b-END). 2.2). (2) A neurosecretory pathway in which hormones are pro. 2. lactotroph. which was the lumen of Rathke’s pouch. in the fetal dog adenohypophysis ACTH- mus and pituitary stalk to terminate on fenestrated blood immunoreactive cells are the first to differentiate from the vessels in the neurohypophysis or posterior lobe (PL) pituitary progenitor cells.2). The Rathke’s pouch. tors play a relatively less significant role in control of PI func- sues. From the primary to the neural tissue of the PL to form the pars intermedia.4). and thyroid-stimulating hormone (b-LPH). 2. surrounding the AL cells (fig. permitting protein and peptide hormones mus. respectively (chapter 2. Following proliferation of the progenitor cells. leading to secretion of growth hormone a-MSH. of the median eminence (figs. leading 2. 14 Hypothalamus-Pituitary System 2 Figure 2. prolactin (PRL).3: Schematic representation of the ontogenesis of the pituitary gland. transcription factors involved in this process have been ident- ified (fig. The neurohypophyseal hormones are stored in secretory vesicles in the terminal ends of the nerve fibers The rostral hypophyseal arteries form the uniquely organized and secreted into the systemic circulation in response to capillary plexus of the median eminence that is in close pro- an appropriate stimulus. (2) the glycoprotein hormones (3) Pit1-dependent cell lines (somatotroph. ximity to nerve terminals of the hypophysiotropic neurons. Rathke’s pouch through the pituitary stalk and form a second capillary plexus subsequently separates by constriction from the oral cavity. the PI is poorly vascularized. endocrine cell phenotypes arise in a distinct temporal fashion. The intra- or cavity. blood supply. the precursor POMC. 2. and then back to the AL. from there to the infundibulum. median eminence. and TSH. (3) The pars intermedia (PI) is directly innervated by pre. from the AL to the PL. but while the PL has a rich Pituitary gland development is primarily the result of the in.5). This direct neural control is largely a tonic (dopami.3. The posterior wall of Rathke’s pouch is closely apposed Caudal hypophyseal arteries supply the PL. ACTH. In the dog pituitary vascularization involved in this has not been fully and the cat the adenohypophysis extends as a cuff or collar elucidated but there appears to be some degree of circulatory around the proximal neurohypophysis and even envelops part flow. Blood-borne fac- teraction between neuroectodermal and oroectodermal tis. The hormones of the third group are derived from (TSH). the different duced by neurons in the anterior hypothalamus and trans. The anterior wall thickens and forms the pars distalis of the AL. The vascularization of the PI is closely linked to that of the PL.5 (fig. the peptide hormones secreted by the AL can (2) Gonadotroph cells secreting follicle-stimulating hormone be divided into three categories: (1) the somatomammotropic (FSH) and luteinizing hormone (LH) hormones GH and PRL. FSH.2 Anterior lobe to secretion of adrenocorticotropic hormone (ACTH) and a-melanocyte-stimulating hormone (a-MSH) by In agreement with the main pathways of cell differentiation corticotrophs and melanotrophs. which arises from the roof of the primitive portal capillaries coalesce into a series of vessels that descend mouth in contact with the base of the brain. The blood-brain barrier is incomplete in the area of the dominantly aminergic nerve fibers from the hypothala. spaces and the nerve terminals contained therein. As in other species. and other charged particles to move to the intercapillary nergic) inhibitory influence.1).3. and (3) the corticomelanotropins thyrotroph cells). and b-lipotropin (GH). and LH.4 The adenohypophyseal cells follow three main pathways of differentiation: (1) Cells expressing pro-opiomelanocortin (POMC). plexus of the PL blood flows not only to the systemic circu- remaining separated from the AL by the hypophyseal cleft lation but also to the AL and the hypothalamus. In recent years several of the signaling molecules and tion. 2. These ter- minals respond to humoral and neuronal stimuli by secreting During embryogenesis the adenohypophysis develops from releasing and inhibiting factors into the portal system. Tpit = T-box pituitary transcription factor. . Neuro D1 = neurogenic differentiation factor D1. Lhx3/4 = LIM-domain transcription factors 3 and 4. J. Ptx1 = pituitary homeobox. (Courtesy of Dr. Belshaw. Th. (Courtesy of Prof. which is surrounded by a thin rim of PI.) (B) PAS-Alcian Blue-orange G stain of a sagittal section of a cat pituitary. Sections of a cat pituitary immunostained for a-MSH (C) and ACTH (D). Dr.) Figure 2. B. The AL is separated from the PI and PL by the hypophyseal cavity and surrounds it up to the pituitary stalk and median eminence. The third ventricle extends deeply into the PL (blue). Slob. SF1 = steroid- ogenic factor 1. The latter picture clearly illustrates that in the cat the AL also extends upward around the pituitary stalk. Pit1 = pituitary transcription factor 1. E. Goos and Mrs.5: Simplified model of the differentiation of AL cell lineages. Prop1 = prophet of Pit1. Each type of endocrine cell is labeled with the hormone it synthesizes. Anterior lobe 15 2 A B C D Figure 2. H. Steps in precursor cell differenti- ation and some of the involved transcription factors are indicated. LIF = leukemia inhibiting factor. The PI is a narrow zone around the periphery of the PL.4: (A) Sagittal section of a dog pituitary. also referred to as POU1F1. H&E stain. A. DAX1 = dosage sensitive sex-reversal-adrenal hypoplasia con- genital critical region on the X chromosome 1. 2. stress (pain. with 41 amino acids. They will be discussed in more detail in access to all types of cells in the AL. and PRL) is regu- lated via a feedback (closed loop) system. These may originate within the central nervous system adenoma resulted in cortisol excess. the structure of GHRH hypothalamic releasing hormone (HRH). 15 % lactotrophs. thesis and ultimate secretion represents a potential control and gonadotrophs (secreting LH and FSH). in been a matter of debate. hormone determine. GnRH. GH release stimulated by thyrotropin-releasing hormone (TRH) (see also 2 the section on diagnosis in chapter 3.e. 2. other signals are superim- cotropic cells in the anterior lobe (AL). with one exception.7. Under physiologic and most pathologic conditions the basal plasma concentration of each of the six major AL hormone systems (ACTH.3. the persistence of immunoreactivity in corticotropic cells exerted that represent the environment (temperature. Excessive ACTH production by this micro. horse. and low temperatures. mone available for release. adrenals..6 variation in amino acid sequences can occur with increasing length. dark).7). The existence of a separate PRL-releasing hormone has long hypothyroidism. Secretion of both AL hormones and hypophysiotropic hormones is suppressed by the products of target endocrine glands such as the thyroids. on the other side of the hypophysiotropic hormones (fig. mine. is no longer ten. and so-called paradoxical secretion. LH and FSH. light- indicates their insensitivity to negative cortisol feedback. At the left is a nest of immunopositive hyperplastic corti. 10 % thyrotrophs.8).6). lengths ranging from 3–44 amino acids (fig. separately or jointly. In the pars intermedia (PI). with primary blood-borne signals. The gonadotrophs are distributed diffusely throughout the gland. respectively) are stores a single hormone. The AL consists of a central »mucoid« wedge con. elucidated are.8 For example. as well as intrinsic rhythmicity. its secretion regulated by a specific identical in all mammals studied.4). and 14 amino acids. taining somatotrophs and lactotrophs. The releasing and inhibiting hormones are stored in nerve terminals in the median eminence in concentrations 10– 100 times greater than elsewhere in the hypothalamus. Yet CRH. and thus the hypophysiotropic hormones secreted into it gain media (fig. by anatomic segregation but by the presence of specific recep- tors on individual types of AL cells. In addition to its major role as a neurotransmitter. the efficiency topological and numeric organization. Whereas the structures of TRH.1). posed. These regulatory factors influence peptide synthesis and /or ing GH).6: their own secretion directly by acting on the hypothalamus Pituitary of a dog with pituitary-dependent hypercortisolism. Apart from this long-loop feedback. Modulation of the amount of mRNA. and soma- It is now clear that the classic concept that each cell type tostatin (three. These multifunctional AL The only nonpeptide hypophysiotropic hormone is dopa- cells are involved in cell plasticity processes directed at in. TSH. immunostained with (short-loop feedback).3). which is best known of transcription and translation. ten. Specificity is achieved not chapter 4. it is creasing hormone production during demanding physiologic the most important inhibitor of prolactin (PRL) secretion.9 hibit mixed phenotypes with multiple HRH-receptor ex- pression and /or hormone storage. It has been concluded that regulation . where each of the steps in hormone syn- TSH). and 10 % gonado. 2. 16 Hypothalamus-Pituitary System dogs with primary hypothyroidism longstanding thyroid hor- mone deficiency may lead to AL cells staining for both GH and TSH. Species trophs. The distribution The hypophysiotropic hormones whose structures have been of cell types is roughly 15 % corticotrophs. fear). and intracellular degradation of stored and cat. able. The distribution point in the regulation of circulating hormone levels (see of the various secretory cells of the AL is not random but has a fig. the amount of hor- taining thyrotrophs and corticotrophs and lateral wings con. some hormones such as PRL regulate Figure 2. the processing from prepro- for the human pituitary gland but may also be true for the dog hormone to hormone. i. which reduced immunoreactivity in the rest of (open loop) and can be mediated by neurotransmitters and the AL via negative feedback. GH. The hormone-producing cells of the AL are classified accord- ing to their specific secretory products: somatotrophs (secret. dog. ovulation. Thus influences are hypophyseal cavity (HC). The portal blood flow to the pituitary is not compartmentalized corticotropic cells of the AL but also in cells of the pars inter. is identical in man. corticotrophs (secreting ACTH and related peptides). and pathophysiologic situations such as lactation. peptides with sequence 50 % somatotrophs. Upon this powerful feedback control an antibody to ACTH. varies. lactotrophs (secreting PRL). and rat. thyrotrophs (secreting release in AL cells. and gonads (see also chapter 1. Some anterior pituitary cells are multifunctional and ex. 1. LH = lutein- izing hormone. GHRH = growth hormone-releasing hormone. TSH = thyroid-stimulating hormone. PrRP = prolactin-releasing peptide. Figure 2. PRL = prolactin. a-MSH = a-melanocyte-stimulating hormone. AVP = arginine-vasopressin. TRH = thyrotropin-releasing hormone. Anterior lobe 17 2 Figure 2.8: Structure and main function of hypothalamic hypophysiotropic hormones. FSH = follicle-stimulating hormone.7: Schematic illustration of the hypophysiotropic regulation of the secretion of hormones by the adenohypophysis. GnRH = gonadotropin-releasing hormone. IGF-I = insulin-like growth factor-I. PIF(DA) = prolactin-inhibiting factor (dopamine). . GH = growth hormone. ACTH = adrenocorticotropic hormone. CRH = corticotropin-releasing hormone. 12 GH release is characterized by rhythmic pulses and intervening troughs (fig. 1.16.2. They are both peptidergic and nonpeptidergic in structure. The direct catabolic (diabetogenic) actions of GH are shown on the left side of the figure and the indirect anabolic ac- tions on the right.10). ghrelin. a peptide primarily formed in the liver under the influence of GH. and differ by only one amino acid from that of the cat. single-chain polypeptides containing 190 (GH) GH release via the GHS receptor.11 It is possible that 2. but also via receptors different some biological activities. GH itself exerts a short-loop negative feedback by activating somatostatin neurons. 1.2.23 This (PRL) intrachain disulfide bridges (fig.20 others being discussed in detail in other chapters. has also been identified.13–15 all acting as stimulators but none of which has yet emerged as The amino acid sequences of canine PRL and feline PRL the primary PRL-releasing hormone.17 In nonprimates a single gene have been proposed. whereas GH levels between pulses are primarily under the control of 2.18.9).9: Figure 2.21. IGF-I. Basal plasma GH concentration (mean ± SEM. Five SS receptors (sst1–5) are expressed in the Only two of the six AL hormones are discussed here. and for these reasons they are often from GHRH-R. The action of dopamine as an inhibitor and several hypothalamic amino acid sequences of canine and porcine GH are identical factors (mainly serotonin) as well as systemic and local factors. PrRP can in- crease PRL responses to TRH several-fold.3). However.7). PrRP. 2.10: The secretion of GH is under inhibitory (somatostatin) and stimulatory (GHRH) hy.22 The endogenous ligand and 199 (PRL) amino acids and having two (GH) or three for the GHS receptor. n = 6) in beagles (red line) and pothalamic control and is also modulated by a long-loop feedback control by Great Danes (green line) from six to 24 weeks of age. classified together as somatolactotropic hormones. 2. sst2 being the predominant subtype in the dog.10 Several candidates differ in eight amino acids. a family of paralogous genes related to PRL. including TRH and a PRL-releasing encodes for GH. 18 Hypothalamus-Pituitary System 2 Figure 2.1.1 Pituitary growth hormone PrRP primarily regulates food intake. Their molecular 28-amino-acid-peptide is primarily expressed in enteroendo- . of PRL release should be viewed as a fine balance between the weights are approximately 22 and 23 kDa. The gastric peptide ghrelin is the natural ligand for the GH secretagogue receptor that stimulates GH secretion at the pituitary level. Several synthetic GH secretagogues (GHSs). the pituitary. stimulate rather large.19 31-amino-acid-peptide. whereas in several species there is a large peptide (PrRP) from the hypothalamus (fig.1 Somatotropin and lactotropin somatostatin (SS) or somatotropin-release inhibiting factor (SRIF) (fig. The GH pulses predominantly reflect the pulsatile delivery of GHRH from the hypothalamus. Somatotro- pin or growth hormone (GH) and lactotropin or prolactin Pituitary somatotrophs are not only stimulated via GHRH (PRL) have similarities in amino acid composition and share and its receptor (GHRH-R). respectively. increases plasma PRL concentration but by many times less than TRH. comparative study in both Great Dane and Beagle pups the lin (as does IGF-II). Figure 2. of IGF-I.10). whereas in the BPs).2 Mammary growth hormone sight is gained into possible differences in IGF-receptor expo. Progestin-induced GH is not re- crease to adult levels by about half a year of age. is not as strict as suggested In adult dogs there is a strong linear correlation between above.37. There is little structural heterogeneity among species. thereby increasing body weight. Contrary to insulin.35 Yet it may be ques. ghrelin accelerates gastric and intes- tinal emptying. the IGFs are bound centrations were not significantly different.25. The six IGF-BPs are but can also be of mammary origin. consistent with their long. human and dog ghrelin differ in only two amino acids. while basal IGF-I produced in the liver but also directly and by stimu- plasma GH concentrations are quite similar among various lation of local IGF-I secretion in several tissues. no in.1. In the 1970s and 1980s known as important modulators of IGF actions. the administration of progestins to dogs was found to be the serial measurements of plasma GH concentration have re.27–29 In young dogs ghre- lin is a more potent GH secretagogue than GHRH. growth hormone excess. the IGF-binding proteins (IGF.2. 2. The slow anabolic effects are mediated via a growth factor primarily synthesized in the liver and known as insu- lin-like growth factor-I (IGF-I). insulin being the acute and IGF the rather than IGF-I is the main determinant of body size. a single IGF-I nucleotide polymor. distraction-induced bone regeneration in dogs.31 The coding sequence of canine GHR has extensive homology with that of several other species.34 In addition. in nonprimate mammals such as the dog it can only bind to its specific receptor.11: bolic actions and slow or hypertrophic actions. 2 pose stores. while reducing mobilization of adi. breeds. plasma IGF-I concentrations have been in the growth plate GH stimulates cell differentiation directly found to be six times higher in standard poodles than in toy and clonal expansion indirectly through the local production poodles. secretion was high until the age of seven weeks. as illustrated in fig. This prolongs their half-life.41 These term growth-promoting action. The immunopositive staining is lo- catabolic responses are due to direct interaction of GH with cated in cells of hyperplastic ductular epithelium. In addition. while ghrelin administration in- creases food intake (chapter 11. For example.30 Although in primates GH can bind to both the GH receptor (GHR) and the prolactin receptor. indicating that it evolved from a common nutritional conditions were such that the plasma IGF-I con- ancestral molecule. In its chemical structure IGF-I has approximately 50 % sequence similarity with insu. 2. Thus far only total IGF-I concentration has been measured. the target cell and result in enhanced lipolysis and restricted glucose transport across the cell membrane due to insulin an- tagonism. In miniature leased in a pulsatile manner.38 Long-term infusion of IGF-I does not sti. For example.1. GH exerts its growth-promoting effect not only via plasma total IGF-I concentration and body size.36 In addition.40 In a (fig. The acute Histologic section of the mammary gland of a progestin-treated dog. foci of hyperplastic ductular epithelium in mammary tissue mulate their growth.43 This progestin-induced GH originates from adult dogs.39.33 tioned that the separation of the two opposing biological ac- tions.9. and is not inhibited by the administration of and values in young animals are within the reference range for somatostatin.24 Ghrelin not only stimulates GH release but also stimulates food intake. In line with these growth-promoting effects of GH.44 The gene encoding mammary GH is identical to . In the Beagles GH to carrier proteins in plasma.26 In dogs and cats plasma ghrelin concen- tration has been reported to increase during fasting and to decrease after food intake. long-term regulator of anabolic processes. For example. Anterior lobe 19 crine cells of the gastric fundus. cause of elevated plasma GH levels and physical changes of vealed that the initially very high levels in Great Dane pups de.32 The effects of GH can be divided into two main categories: rapid or meta. In dogs circulating GH not only originates from the pituitary sure among dogs of different body size. Insulin and IGF seem to observations indicate that GH hypersecretion at a young age complement each other. phism haplotype is common to all dogs of small breed and the expression of the GH receptor increases locally during nearly absent in those of giant breeds. GHR. Great Danes it remained high much longer (fig.11). does not respond to stimulation poodles the GH level does not change significantly with time with GHRH.1). but GH administration does. 2. Without measurement of free IGF-I and /or IGF-BPs. 2. The insulin recep- tor and the IGF-I receptor belong to the same subfamily of As a closing remark on the actions of GH it should be men- receptor tyrosine kinases. indirectly im- munostained with monkey-anti-canine GH.42 tioned whether IGF-I is the main determinant of body size. 48 the second part of the luteal phase (fig. In bitches plasma PRL concentration increases during (fig.49.1.47.2. The plasma GH profile during the inhibitory and stimulatory factors. mandatory for maintaining progesterone secretion during . Blood samples were collected at 10-min intervals for 12 h in the first.53. In contrast to the adenohypophysis. tomy. In male dogs castration does not affect plasma also enhance the risk of malignant transformation and promo.46 cystic endometrial hyperplasia in the bitch. that encoding GH in the pituitary gland.51. which has consequences for the pulsatile secretion pat.12). in four stages of the luteal phase and during second. * Indicates midanestrus. the does not originate from uterine epithelium and that mammary mammary gland lacks expression of the transcription factor GH is not required for the development of progestin-induced Pit-1. In addition.3 Prolactin cycle. PRL is also secreted in first half of the luteal phase is characterized by higher basal pulses. and fourth quarter of the luteal phase (luteal phases) 1–4 and during midanestrus. Among the many functions ascribed to PRL.58 PRL is an essential luteo- enhances malignant transformation in an autocrine tropic factor in canines (in contrast to humans) and thus manner. with an associated inhibition of pro- grammed cell death.12. has been substantiated in pregnant bitches by the adminis- tor. its involvement mary cancer there is evidence that locally produced GH in reproduction is best known. it is now clear that progestin-induced GH in plasma rather than directly. 2. third.12: Figure 2.50 In both humans and dogs with mam.54 Progesterone-induced release of mammary GH is a normal physiological process during the luteal phase of the estrous 2.13: Mean (± SEM) basal plasma GH concentration and mean (± SEM) area under the curve (AUC) for GH above Plasma PRL concentrations in six beagle bitches the baseline in six Beagle bitches.48 The associ- ation of increasing PRL and declining plasma progesterone The local production of GH. PRL concentration. 2. See also legend to fig. the expression of the GH recep.52 Although there are similarities between proges.57 tion of tumor growth. tin-induced epithelial changes in the mammary gland and the late GH promoter activity in the mammary gland indirectly uterus. 20 Hypothalamus-Pituitary System 2 Figure 2. Under the influence of the above-mentioned hypothalamic tern of pituitary GH. gonadal hormones modulate PRL secre- plasma GH levels and lower GH pulses than during anestrus tion.45 Progestins stimu.55. and the associated production of IGF and IGF-BPs appear tration of a progesterone-receptor antagonist and by ovariec- to participate in the cyclic changes in the mammary gland.56 Both interventions caused plasma PRL concen- The presence of this highly proliferative environment may tration to rise. 2.13). significant difference. 71 .14).63.73.62 As will be discussed in chapter 2. German shepherd dogs with pituitary dwarfism have a com- pend on PRL. Hypophysectomy 2.5 and chapter 7.59–61 Consistent with the secretion patterns of GH and deficiency PRL (figs. Inadequate GH secretion early in life causes retardation of mary epithelium is followed by lobular-alveolar differenti. and GnRH) in eight Ger- man shepherd dogs (-앪-) with pituitary dwarfism (means ± SEM if exceeding the size of the symbols). 2.2. Pit-1. and the LIF-receptor gene (fig.5) as litter.64 milk) and galactopoiesis (maintenance of milk secretion) de.13). 2. the GH-induced proliferation of mam.66 The search for glands. Dwarfism due to GH deficiency is best known as a ation under the influence of PRL. 2.2.2 Congenital growth hormone and treatment with dopamine agonists shorten the luteal phase.2.14: Responses of plasma GH. allowing them to care for and nurse a Prop-1. the normal lifespan of the corpora lutea. served (fig. and ACTH to the combined injection of four hypothalamic releasing hormones (CRH.67–70 bitches not caring for pups may also undergo behavioral The gene encoding for Lhx3 appears to be the most likely site changes in this stage of the cycle. PRL. LH. as well as impaired release of gonadotropins. whereas ACTH secretion is pre- As discussed in more detail in chapter 2. The curves with shaded areas represent the responses (mean ± SEM) in healthy beagles (-앬-)72.58 bined deficiency of GH. nonpregnant candidates for pituitary dwarfism in German shepherds. Anterior lobe 21 2 Figure 2.12. growth.5. TSH. and PRL. TRH. of the mutation. Lhx4.65 Diagnostic imaging and histological pregnant and nonpregnant bitches (but not queens) have examination often reveal cystic changes in the pituitary gland similar luteal phases and similar changes in their mammary and hypoplasia of adenohypophyseal tissue. Not only mammogenesis genetically transmitted condition (autosomal recessive inheri- but also lactogenesis (acquisition of the ability to produce tance) in German shepherd dogs and Carelian bear dogs. 2. Lactogenesis appears at the end of the luteal phase in the causative gene defect has excluded transcription factors nonpregnant bitches. GHRH. TSH. width 4. almost woolly hair coat (fig.5 mm.4 mm) and the greater part of it lacks contrast enhancement due to the cyst. Unilateral or bilat- eral cryptorchidism is common in males and the females often Routine biochemical variables are usually not abnormal. the animals have a ponent. maldevelopment of glomeruli due to lack of GH pointed muzzle. lose appetite. except that plasma creatinine is elevated in most of the pitu- itary dwarfs. As can be expected in secondary hypothyroid- . There is and low filtration pressure due to lack of thyroid hormone. usually no remarkable delay in dentition. At the age of three years (B) the pituitary is enlarged (height 6. As function.6 mm.3 mm) but having a radiolucent area due to a cyst (arrow). (B) Dwarf German shepherd dog at one year of age.. have frequent anovulatory estrous cycles.15: (A) Four-month-old German shepherd dog with pituitary dwarfism.e. This stage usually ap- lanugo or secondary hairs and lack of primary or guard hairs. pears by the age of two to three years and is commonly associ- This stagnant development of the skin and coat finally results ated with severe secondary hypothyroidism and impaired renal in alopecia and a thin and grayish-brown-pigmented skin. and turn into thin. width 5. 2.16: Contrast-enhanced CT images of a six-month-old dwarf German shepherd dog (A) with a pituitary of normal size (height 3.15). 2. The woolly appearance of the coat is due to complete lack of development of primary guard hairs. i. resembling that of a fox (fig. The latter may have both a renal and a prerenal com- well as proportional growth retardation. with the characteristic fox-like face and alopecia developing on the neck. 22 Hypothalamus-Pituitary System 2 A B Figure 2. Clinical manifestations Initially the dwarfed dogs are lively and alert – they can be Affected animals are usually presented at the age of two to five amusing and even quite appealing – but eventually they be- months because of poor growth and an abnormally soft and come lethargic.15). dull. A B Figure 2. The latter is due to retention of hairless animals with a sad appearance. ing the reference range. In parallel with this a-adrenergic drugs such as clonidine and xylazine can be used physical improvements. sire. the combined AL. sidered that the apparently dwarfed animal is the result of an healthy dogs. plasma IGF-I concentration rises and (chapter 12. However.16). eventually becoming so large as to cause pearance (chapter 3. particularly those that are brachycephalic. The lack of homologous GH for therapeutic use in dogs led mal recessive inheritance.17). plasma IGF-I con- German shepherd dogs (345 ± 50 µg/l).1. tissue and the release of the resulting GH into the systemic circulation (fig. body weight. may unexpected and perhaps unrecognized mating with a small also harbor small pituitary cysts. a stimulation test should be muzzle becomes less pointed and a complete adult hair coat performed. grows (fig.79 Proligestone has been reported stimulation test (fig. plasma concentrations of T4 and TSH are The amino acid sequence of IGF-I is less species specific than low. GHRH. in part because it resulted in vital organs such as the heart. The possibility should also be con. antibodies to the heterologous GH.2).6). liver. If the growth plates have not homologous radioimmunoassay. They may become larger as the animal ferential diagnosis. 2. Mean plasma IGF-I concentration (± SEM) is lower that of growth hormone and therefore it can be measured in a (62 ± 10 µg/l) in pituitary dwarfs than in immature healthy heterologous assay. 2.5 to 5.76.77 Differential diagnosis Diagnostic imaging (CT or MRI) at a young age often reveals Congenital hypothyroidism may be the most important dif. IGF-I concentration.1.0 mg/kg usually highly suggestive of GH deficiency.14). employing a quently at six-week intervals. 2.37. or with primary hair appears (fig.65 GH deficiency has centration is usually low in German shepherd dwarfs. Hypochondroplastic dwarfism in Irish Treatment setters has been reported to occur as result of a single autoso.14 and chapter 12.75 Retardation of growth can also be to initial attempts at therapy with bovine and human GH. small pituitary cysts. However. a definitive diag.80 . Subcutaneous injections of medroxy- Although the medical history and the physical changes are progesterone acetate are given in doses of 2. neurological symptoms (see also chapter 2.17: A female German shepherd dog with pituitary dwarfism before (A) and after two years of treatment with medroxyprogesterone acetate and l-thyroxine (B). Since basal GH values may yet closed some increase in body size can be expected. or is simply a small individual within the normal bio- logical variation. to be similarly effective in a dose of 10 mg/kg every three ferred over repeated single stimulation tests.3) is to be pre.11) offered an alternative approach to cir- Diagnosis cumvent this problem. initially at three-week intervals and subse- nosis requires measurement of GH in plasma.74 which may also lower plasma IGF-I concentration. As mentioned above. interpre- an undersized kitten with bilateral corneal opacity in which tation of results must also take account of the possibility of a GH deficiency was diagnosed on the basis of a low plasma low caloric intake and particularly a low protein intake. The also be low in healthy animals. although it results in a quite different ap. and kidneys. even rarely been mentioned in cats but there has been a report of when age and size are taken into account. 2. the result of undernutrition or congenital abnormalities of This was not very successful.2).6). ghrelin.78 The ability of progestins roid administration at an early age also quite rapidly retards to induce expression of the GH gene in canine mammary growth (chapter 4. weeks.2. Corticoste. ism (fig.3. 2. Anterior lobe 23 2 A B Figure 2. To test GH secretion alone. When insight in the secretory capacity of plasma GH concentration usually increases without exceed- other pituitary hormones is required. from metabolic and cardiovascular complications to a reduced quality of life as a result of diminished physical and mental energy. percortisolism has been excluded and hypopituitarism with megalic changes (chapter 2. the condition has been given names such as »adult- Without treatment the prognosis for German shepherd dwarfs onset growth hormone deficiency« and »growth-hormone is usually poor.3. cystic endometrial hyperplasia (chapter 7. Substitution alopecia«. according to the sult in skin atrophy and hair loss (hypothyroidism. When recurrence of hy- tinuing treatment becomes overtreatment. as in the treatment of pituitary-dependent hypercortisolism (chapter 4. leads to a very low plasma GH level that does not respond to stimulation.81 As was in- itially the case in humans. and hyperestrogenism due to testis tumor).3. for in about ting to the animal’s misery. mainly involving the trunk. 2. and »alopecia X«. has become available for therapeutic use.1). tation with cortisol and thyroxine. and growth of the guard hairs is variable.18).1). At this stage owners usually re. Apart from growth hormone deficiency due to damage to the pituitary gland. By the age of three to five years the animal has responsive dermatosis«. is keeshond. the perineum. however. Although treatment with heterologous GH has had poor to moderate Prognosis results.2) can be expected to ing administration of a progestin will lead with certainty to bring improvement.1). 2. Because this treatment can plain some forms of alopecia occurring in breeds such as the result in GH excess leading to diabetes mellitus.3 Acquired growth hormone deficiency Hypophysectomy. leading to acro. treatment with IGF-I concentration approaches 200 µg/l. but is now known to be the result of mild hypercortisolism deficiency in humans produces a wide array of manifestations. tisolism. hypercor- principles in chapter 3. this intervention in dogs and cats is Figure 2. provided that complications such as pyoderma can be managed and acromegaly due to overtreatment is avoided. The alopecia has been described in both sexes. chow chow. which can be avoided by ovariohysterectomy before the start of the treatment. development of percortisolism and they are receiving appropriate supplemen- mammary tumors. and the neck.10). It rence of isolated growth hormone deficiency in mature dogs. certainly when the the absence of GH response to stimulation.3 IU per kg body weight. »congenital adrenal therapy for the secondary hypothyroidism can partly correct hyperplasia-like syndrome«.2.3.2. thereby contribu. if they have not done so long before this. Adult-onset growth hormone 1 year was the only problem. and of plasma IGF-I and glucose.83 this.2. thin. severe growth hormone deficiency has been demonstrated by continuing treatment for a few month.4). (chapter 4. either pGH or progestins (chapter 2. is administered in thrice weekly subcutaneous doses of It has been proposed that such a deficiency of GH may ex- 0. Treatment with thyroxine and either progestins or growth 2 hormone usually leads to a relatively healthy life for many years.18: usually followed by long-term substitution with orally admin- An eight-year-old male Pomeranian in which progressively increasing alopecia for istered cortisol and thyroxine. monitoring Pomeranian (fig. continu. be attributable to any of the endocrine diseases known to re- panied by thyroid hormone replacement. one-third of the cases the GH response to stimulation has .1. This type of alopecia has been presumed to be due to GH deficiency. The lanugo hairs regrow but the any age but usually beginning at one to three years of age. for almost three decades there have been re- In recent years porcine GH. in part due to impaired illustrated by alternative names such as »castration-responsive renal function and secondary hypothyroidism.2. at of the utmost importance. Occasionally recovery is very rapid and con. which is identical to canine GH ports in the veterinary literature on the spontaneous occur- (chapter 2. the caudal surfaces of the thighs. 24 Hypothalamus-Pituitary System quest that the animal be euthanized.82 Some dogs do not regain their liveliness or their muscle mass and hair coat following hypophysectomy. The entity does not seem to be well defined. infrequently. even There are. and dull. This may be prevented by dis. some adverse effects. »biopsy-responsive alopecia«. miniature poodle. Uncertainty about the role of GH is usually become bald. In females. but continuing expansion of the pituitary cyst may im- pair the function of adjacent brain tissues. at least once every six weeks. including recurrent though the hypophysectomy has brought an end to the hy- periods of pruritic pyoderma and. The alopecia does not appear to Treatment with either progestins or pGH should be accom.1–0. GH release in pulses is impaired. GH excess (fig.2). seemingly unrelated measures such as cas. in Pomeran- ians both with and without alopecia.19: A male Dalmatian dog at five years of age (A) and at ten years of age after developing acromegaly (B). Hypersecretion of growth hormone in the adult results in a cretion is not on very solid ground. breeds as well remains to be determined.85 Thus the proposed relation between some forms of this adult-onset alopecia and decreased GH se.98.2. been normal. Serial measurements of urinary corticoids with low-dose dexamethasone suppression tests Clinical manifestations satisfied two criteria of hypercortisolism in both groups.2. and viscera. Whether sponse to stimulation. tisolism is discussed in more detail in chapter 4. some of the physical and biochemi- preliminary study in miniature poodles with alopecia has led cal changes in dogs with primary hypothyroidism may be to the proposal that mild cortisol excess may be responsible caused by GH excess resulting from the adenohypophyseal for the altered GH responses. increased cortisol production and decreased sensi. The recently described dog with acromegaly of pituitary namely. and the enlarged tongue.92. In dogs and cats. Note the overall increase in body size.4. origin had very pronounced characteristics of longstanding tivity to glucocorticoid feedback. duced hypersecretion of GH in the mammary gland This lack of response is most likely a functional disturbance. The latter form of GH excess is discussed in chapter 3. In stimulation with either GHRH or a-adrenergic agonists such addition.87–90 In dogs with pituitary-dependent hyper- cortisolism. A (chapter 2. The pituitary origin of the disease in hu- IGF-I has been measured. who derived reference range.3.19). 2. but only recently has The hypothesis that both the alopecia and the lack of growth GH hypersecretion been confirmed in a dog with acromegaly hormone response to stimulation might be the result of mild and a somatotroph adenoma. probably as a re- sult of alterations in pituitary somatotroph function and 2. mans and dogs. dogs can develop the syndrome from progestin-in- as clonidine or its structural analog xylazine (chapter 12. Yet in some in which there was a normal re. tration or administration of testosterone were followed by the appearance of a new hair coat. and is used here as the prototype for . treatment with GH was reported to be this type of alopecia is the result of hypercortisolism in other effective. it has invariably been within the mans was recognized in 1886 by Pierre Marie. for when plasma bone. as in humans.84 its name from the Greek words akron (extremity) and megas (large) for the characteristic enlargement of the hands and The fact remains that in some mature dogs with alopecia feet. the GH excess can be there is no response or only a weak response of plasma GH to caused by a somatotroph adenoma of the pituitary gland.93 This form of hypercor. 2.1. Anterior lobe 25 2 A B Figure 2.1.84 Furthermore.97 In cats the disease is less rare hypercortisolism has recently been tested in alopecic Pomer.2).1. there is a true growth hormone deficiency. the thick folds of skin on the head and neck.4 Growth hormone excess lation in either group.91 Pituitary tumors that might have secreted excessive amounts of GH have been reported in dogs94–96.99 anians and miniature poodles. In others.86 Glucocorticoids are well changes brought about by deficiency of thyroid hormone.1 Excessive pituitary growth hormone changes in suprapituitary regulation. known to suppress the GH response to various stimuli in hu.1.3. and probably underdiagnosed. Finally. the mean circulating GH concentration did not increase significantly after stimu.2. It is even unlikely that syndrome characterized by overgrowth of connective tissue. 103 Feline GH can be size of the paws. due to GH-induced insulin resistance. with a heavy head. It is considered to be a species-specific ef. increasing stiffness. with increased col- periosteal reaction. In cats the main differential diagnosis is hypercortisolism. megaly. 26 Hypothalamus-Pituitary System 2 A B Figure 2. In some there is a sys- The osseous changes caused widening of the interdental tolic cardiac murmur and late in the course of the disease spaces. (B) Contrast-enhanced CT image through the pituitary fossa revealed an enlarged pituitary gland. weight gain.102. physical changes. the finding of plasma GH 쏜 7. progna- cluded thickening of the skin. periarticular leads to hypertrophy of the myocardium. Three weeks after transsphenoidal hypophysectomy. Chronic GH excess rigidity – due to articular cartilage proliferation. namely.5 IU/kg body the owner may have noticed polyphagia.100 which can also give rise to insulin resistance (chapter 4. the cats. cause impaired vision. increasing 쏜 590 µg/l is usually diagnostic. Basal plasma GH was 51 µg/l and IGF-I was 3871 µg/l. It is pri.103 cats are presented because of poorly controllable diabetes mellitus. The only other remarkable finding in routine elevated levels of hepatic enzymes secondary to the hepatic blood examinations was mild anemia. lipidosis. 4. Initially. and weight per injection and /or having physical signs of acro- polyuria and polydipsia. In cats requiring lente insulin in doses 욷 1.20). Almost all of the affected should also be considered. and is associated with de- pletion of the erythroid cell series as well as cellular atrophy in Differential diagnosis the bone marrow. as well as mild hyperproteinemia and hyperphos- mocytic anemia has been found in dogs treated with pharma. and broader facial features. physical examination reveals a heavy head. six to 15 years of age. the difference is not always obvious and thus scribed in cats. some owners have noted lameness.20: (A) An eleven-year-old castrated male cat with acromegaly and diabetes mellitus requiring 25 IU of insulin four times daily. particularly of the head and thia inferior.3). it is a well-recognized syndrome. and severe spondylosis deformans. weight gain. the cat no longer required insulin.2 µg/l and IGF-I betes mellitus. and neck congestive heart failure may develop.97 The soft tissue overgrowth in. nine teeth. The simultaneous occurrence of both a somatotroph principle the physical changes are the same as in the dog but adenoma and a corticotroph adenoma (double adenoma) usually less pronounced (fig. description of the condition. cological doses of porcine GH. lagen content. and Diagnosis probably prior to the development of the diabetes mellitus.5 mm in height and 4. the . and circling movements excessive panting. and there may be tolerance. The cat has a sturdy physique and somewhat coarse facial features.6). In the stage of insulin-resistant dia. Normochromic nor. and enlargement of the tongue with respiratory stridor.101 If the pituitary tumor is very large. Also visible are thick mucosal folds of the palatum molle which almost completely obliterated the nasopharynx (arrowhead). Laboratory (chapter 2. Laboratory findings usually include hyper- examinations revealed normoglycemia with impaired glucose glycemia and glucosuria without ketonuria.2. cats with insulin resistance are usually tested for both dis- marily a disease of castrated males. Al- though GH excess and hypercortisolism lead to different Now that more than 100 cases of acromegaly have been de. difficulty in standing up. Meta.2 mm in width (arrow). mydriasis. The owner had noticed that it was becoming larger. phatemia. In about half of measured in heterologous radioimmunoassays. and polyuria and polydipsia. fect. 2. In orders. it may bolic changes were manifested in polyphagia. increased distance between upper and lower ca- neck. and stiffness and lameness. In five cases cobalt 60 (gamma) progestins may also give rise to GH excess and signs and radiation lowered the insulin requirement transiently and re.128 Depending on the receptor profile of the tumor.10). as long as the insulin-resistant diabetes mellitus can be diabetes mellitus. the dogs and cats.6.113 nancy are similar (chapter 7. elevated GH with normal IGF-I in 11 % of pituitary gland should be visualized by computed tomography noncured patients.1).2.110 Some of these incon. and well-toler- in an assay for human IGF-I and because this is more readily ated in humans with acromegaly. In acromegalic cats the short-term prognosis may be relatively trations. which may lead to underdiagnosis. for studies in rats two years.124 duced the size of the pituitary tumor. radiation. several. this approach is not an option for to diagnose acromegaly in diabetic cats.118 In one cat treated with the somatostatin ana- logue octreotide.122 Administration of has been radiation therapy. acromegaly.99. reducing both GH and IGF-I levels and the size of the tumor.117 Possible adverse effects of radiation therapy are dis.103 2 IGF-I is bound to a transport protein and is much less subject to fluctuation than is GH. Transsphenoidal hypophysectomy in one the luteal phase of the estrous cycle. injection of octreotide was introduced recently to evaluate acromegalic subject. the release of GH from mam- treatment. the reported.. insulin resistance was reduced but plasma IGF-I con. This fibroepithelial hyperplasia can half. Feline IGF-I can be measured mant has been reported to be effective. megalic cats. 2.114 A pre-entry test with a single intravenous value can be the fortuitous result of a secretory pulse in a non. Those responding favorably might be candidates for long-acting release (LAR) octreotide treatment.108 On the other hand. how- as an active disease process. itary tumor usually result in death or euthanasia within one to sistencies may be related to nutritional status. In hu- GH concentration increased.2 Excessive mammary growth hormone ing frequency.4. or all of ator radiation reduced the insulin dose in another cat by the mammary glands. somatostatin It is discussed in more detail under the heading of estrus pre- analogues are effective in a high percentage of humans with vention (chapter 7. safe. managed satisfactorily.112. It can cussed in chapter 2. symptoms of acromegaly.105 Since a high serum GH levels.109.106. acromegaly can also be expected to occur during pregnancy. plasma IGF-I concentration may be lowered and plasma can be monitored by measurements of plasma IGF-I. It does. i.116 Beta radiation reduced the in. although this usually requires large pected. Anterior lobe 27 species-specific assays for dogs and sheep. also be caused by the administration of synthetic progestins such as megestrol acetate and medroxyprogesterone acetate. 2. have a local proliferative effect that also involves IGF-I127 sulin requirement only slightly in one cat but linear acceler.107 Compli- observed in nonacromegalic insulin-resistant diabetic cats. and recently the occur- The most frequently reported treatment for feline acromegaly rence of this in two bitches was reported. plasma GH concentration was normal- ized119 but in four others octreotide had little or no effect on . Its amino acid sequence is less The recently introduced GH-receptor antagonist pegviso- species specific than that of GH. 24 %. it is commonly used species-specific antagonists. increased IGF-I levels have been daily doses of insulin at considerable expense. false-negative IGF-I results can be ex.2. In humans transsphenoidal adenomectomy is the mary tissue is a normal physiological process in dogs during treatment of choice.1. Nonelevated IGF-I concentrations Prognosis have been reported in cats with elevated plasma GH concen. and may result in marked enlargement of one. recommended cut-off value is high (1000 µg/l)99. it is advisable to collect three to five the potential effectiveness of octreotide treatment in acro- samples for GH assay at 10-min-intervals.2. there have been few reports of experience with As mentioned in chapter 2.2.123.104.111 mans IGF-I is considered to be the best biochemical marker for this purpose. In some middle-aged and cat led to reversal of insulin resistance and complete cessation older bitches sufficient amounts of GH may be released to re- of diabetes mellitus102 and cryohypophysectomy in two others sult in acromegaly (and diabetes mellitus).120 As long as there are no available than suitable assays for GH. ever.20).106 However. and elevated IGF-I with normal GH in or magnetic resonance imaging (fig.114.e.115 In one cat in which linear accelerator (high-energy x-ray) radiation was Progestins also induce GH expression in mammary tissue in used. and /or a somatostatin analogue poor. cats125. occur in young queens at the time of their first estrus.2. Because progeste- resulted in diminished insulin resistance and lowering of rone levels in bitches during nonpregnant metestrus and preg- plasma IGF-I concentrations. cations such as congestive heart failure or an expanding pitu- constituting false-positive results.121 Treatment Although acromegaly is being recognized in cats with increas. but the GH does not reach the systemic circulation126 centration remained elevated and the acromegaly continued and consequently does not lead to acromegaly. although inconsistent results have been When the diagnosis of acromegaly has been confirmed. The response to treatment of the somatotroph ade- and humans have shown that when nutritional condition is noma by surgery.107 Particularly in acromegalic cats with untreated good. especially when given frequently and in relatively to five weeks after estrus and produces the same signs and symp. 2. 2. high doses (fig. 28 Hypothalamus-Pituitary System 2 A B C D Figure 2. three months after ovariohysterectomy. B) An eight-year-old female beagle with severe acromegaly and diabetes mellitus that developed during the current metestrus. and abdominal enlargement due to viscero- megaly (fig. respiratory stridor. (C. most of these changes regress fol. During the two previous metestrus periods the owner had noticed polyuria. 129 Clinical manifestations Progestins used for estrus prevention can produce similar Canine acromegaly due to mammary GH typically begins three changes.1: thick folds of skin on the head and neck.130 . and fatigue and snor- ing. A comparative study of the effects of toms characteristic of excess pituitary GH described in two progestins revealed that they resulted in similar plasma chapter 2. and similar degrees of insu- tigue. and excessive panting and snoring. the glucocorticoid activity which is intrinsic to proges- Early mild forms are usually primarily characterized by poly. The latter may be due in part to progressively more severe.133 uria. sometimes polyphagia. polyphagia.21). concentrations of GH and IGF-I.2. tins. fa.21: (A. until the full clinical picture develops.132.4.129. Laboratory studies often reveal hyperglycemia and increased lowing metestrus but with successive estrous cycles they become plasma alkaline phosphatase. polydipsia. Initially.22). The polyuria is without glucosuria unless diabetes mellitus also develops from the repeated exposure to GH excess. prognathism with widening of the lin resistance. D) The same dog.131 interdental spaces. Note the heavy body and the large tongue. The soft tissue overgrowth has regressed but the bony changes causing prognathism and widened inter- dental spaces remain. and thick folds of skin on the neck. induced by thrice yearly injections of medroxyprogesterone acet- ate for prevention of estrus. It had high plasma levels of GH (욷 45 µg/l). 2.3. intolerance to warmth (frequent panting. complete exhaustion of the pancreatic b cells. including the spe. (D) Physical examination revealed prognathism.22: (A) A female mongrel Belgian shepherd dog at the age of three years. exaggerated growth of the coat. the greater In pronounced cases the clinical features. due to the reversal of the soft tissue changes. increase in abdominal size. as does the thickening of oropharyngeal Diagnosis soft tissues and thus the associated snoring.21).134 Differential diagnosis tory results. Treatment gether with the increase in abdominal size. and a relatively large tongue. may mimic the Progestin-induced acromegaly can be treated effectively by signs of hypercortisolism. other diseases. (C) After the coat was clipped the physical changes were more prominent: heavy head. for the sooner treatment is started. The animal may then change dramatically (fig. (B) Two years later the dog was presented because of decreased endurance. However. and hyperglycemia which. It to the animal. In cases in which the GH excess did not lead to is usually advisable not to delay treatment pending the labora. The bony changes As in pituitary GH excess. to. the elimination . and inspiratory stridor. Redundant folds of skin on the withdrawal of exogenous progestins and /or by ovari(ohyster)- head and neck may also occur in primary hypothyroidism ectomy. preference for cool places). trunk and limbs. Anterior lobe 29 2 A B C D Figure 2.1). the chance of preventing permanent diabetes mellitus (see cific medical history. leading to GH excess (chapter 3. are not easily confused with those of below). polyphagia. in some dogs the metabolic changes lead to polyuria. The size of the abdomen decreases. measurement of plasma GH (at appear to be irreversible but do not appear to cause problems 10-min intervals) and of IGF-I will confirm the diagnosis. wide spacing of the teeth. 56.21.5 µg/l to a mean around 5.0 µg/l138. but there is as yet no long-term experience with pseudopregnancy it rises to around 35 µg/l or higher. This is primarily a consequence of a rapid decrease in proges- tially block glucocorticoid receptors. Diabetes dopregnancy. as they are known to lower rises only slightly during the luteal phase. The dog was in the lu. In most nonpregnant bitches it ceptor blockers may be helpful. The horizontal bar indicates refer- lowing reversal of the insulin resistance caused by progesterone-induced GH ex. 30 Hypothalamus-Pituitary System 2 Figure 2.5 Prolactin and pseudopregnancy in to leave the home. of the progesterone source by the ovari(ohyster)ectomy may Pathogenesis prevent persistent diabetes mellitus (fig. Fol.23).136 Some caution seems warranted. Clinical manifestations About four to eight weeks after estrus. for they also par. 2.2. aggression. In bitches (but not queens) the secretion of progesterone dur- ing the luteal phase is quite similar to that during pregnancy Serious problems can arise in dogs in which the progestin (chapter 7.24: Plasma GH and insulin concentrations (log scales!) in the dog shown in fig. bitches in pseudopreg- nancy may exhibit behavior which can be interpreted as nest building and caring for offspring. cess. Only in bitches predisposed to Prognosis pseudopregnancy does it induce the substantial increase in Dogs with progestin-induced GH excess have a good progno.2. In contrast. It is therefore not surprising that the resulting causing the acromegaly has been administered only recently. and fre- quent licking of the abdomen. the second half of pregnancy. mammary development and /or behavioral changes are barely distinguishable from Treatment and prognosis those of late pregnancy or lactation. If its effects are mild it is generally referred secretion varies from only a few drops of a clear or brownish to as a physiological or covert pseudopregnancy.1). but in those with overt megaly135. but sometimes the changes predisposed to development of overt pseudopregnancy.140 mellitus resulting from the progesterone-induced GH excess is thereby also sometimes reversible. The mammary cycles in the bitch. in overt or clinical pseudopregnancy. The arrow marks the start of treatment. from a mean around plasma GH and IGF-I concentrations in canine acro. loss of appetite. and the mothering of the dog objects. Some breeds such as the In most dogs the symptoms of pseudopregnancy cease spon- Afghan hound and the basset hound appear to be especially taneously after a couple of weeks.137 are so severe and long lasting that the owners cannot cope .137. both the hyperinsulinemia and the hyperglycemia disappeared. but an abrupt decrease does not always lead to pseudopregnancy. Other signs are restlessness. terone secretion48. Progesterone-re.139 their use. 2. effects can closely mimic pregnancy. PRL which in turn triggers the symptoms and signs of pseu- sis following elimination of the progestin source. Mean (± SEM) plasma concentration of PRL in six pseudopregnant Afghan immediately before and after ovariohysterectomy (arrow). The mammary glands can de- Pseudopregnancy is the syndrome that more or less accom. ence ranges in anestrous bitches137. daily). Hounds before and during ten days of metergoline administration (2 mg twice teal phase of the estrous cycle and had developed persistent hyperglycemia. digging. Plasma PRL rises during for its action may persist for several months. 2. This can include reluctance 2. fluid to considerable amounts of true milk. velop to such an extent that the body contour closely re- panies the extended luteal phase of all nonpregnant ovarian sembles that of late pregnancy or lactation.23: Figure 2. 2. LH.145. This drug lowers PRL release (fig. half for the first four days and by administering the drug after meals. daily for six days). and alopecia (chapter 2. There was marked atrophy of the testes (B). The interpretation of results of suprapi- tuitary stimulation tests (chapter 12. It has been reported that long-term adminis. the cavernous 2. There were as yet no neurological symptoms. GH deficiency is not easily recognized as a revealed dural invasion in as high as 45 % of cases.147 Their bromocriptine.148 The enlarging pituitary may also 2.2) results in testis atrophy (fig. either systemic or cussed in chapter 3. skin tumors have a high rate of recurrence after surgical resection.137 and PRL) can occur. Gonadotropin deficiency in female dogs manifestations.1 and chapter 2. only manifested by somnolence. In male dogs continuing gonadotropin defi- chapter 4. slight alopecia in the groins and flanks. respectively.2).. can be avoided by reducing the dose by occurrence in dogs and cats has not been explicitly reported.3. some in. Secondary adrenocortical failure as a within the central nervous system.1) may pose problems when there is also hormone excess that affects the secretion of other pituitary hormones. FSH. The serotonin antagonist metergoline (0.144 The diagnosis »inva. TSH.6 Pituitary tumors affect the function of the neurohypophysis (chapter 2.1 mg/kg twice may also be anterior pituitary failure.146 (chapter 4.2. muscle atrophy.1 Hormone deficiency sinus.2.2. Vomiting. thyrotroph twice daily for ten days) and cabergoline (5 µg/kg once (staining for TSH) and null cell (immunonegative) adenomas. ACTH.4. prolactin occur in humans but have not been described in dogs and can be suppressed and pseudopregnancy terminated by ad. 2. Pituitary adenomas are considered to be benign.143. Clinically nonfunctional adenomas (NFAs) constitute ministration of: 50 % of all pituitary adenomas in humans and include gon- 1.25: A nine-year-old male boxer dog with a large pituitary tumor and secondary hypothyroidism. Anterior lobe 31 2 A B Figure 2.e. There 2. 2. atrophy. which frequently occurs with The main consequences of NFAs are mass effects.6. but hyperexcitation.24) anterior pituitary hormone deficiency. Microscopic examination has In adult animals. and a thin coat (A). Prolactinomas ciency (chapter 8. Dopamine agonists such as bromocriptine (10 µg/kg adotroph (staining for FSH. Partial or total TSH The diagnosis pituitary carcinoma is reserved for tumors with deficiency is often a component of hypopituitarism and is dis- demonstrated metastatic dissemination. The resulting cortisol deficiency purposes it can also be used in dogs and cats. may remain unnoticed because of the naturally long interes- cotroph adenomas or somatotroph adenomas are discussed in trous interval.142 Because distinct clinical syndrome.3. cy of all six major hormones (LH. and frequent whimpering may occur. The . partial or complete daily for ten days).3).25). although longstanding GH defi- of their extension and infiltration of regional structures these ciency leads to reduced physical activity.2. but in hu- mans they can invade the adjacent dura mater.141 from pressure by the tumor on adjacent brain structures.2. cats. GH.1. with them and ask for treatment. i. For this purpose. and a-subunit).2) contributes to gradual deterioration of the animal and a relatively trivial illness or anesthesia can precipi- Pituitary tumors have both endocrine and nonendocrine tate vascular collapse.3. In principle. and the sphenoid sinus. result of ACTH deficiency may occur late in the development sive adenoma« is a contradiction in terms but for comparative of large pituitary tumors. The nonendocrine manifestations of pituitary adenomas result tration (쏜 14 days) may lead to coat color changes. deficien- without the risk of vomiting. Endocrine excess syndromes caused by corti. crease in aggression. 152 hypopituitarism should rest on direct evidence of deficiencies of the pituitary hormones themselves. circling. and a history of epileptiform seizures. The mass effects may also appear rather suddenly. In the fifth on the diaphragma sellae. dog the pituitary hemorrhage without tumor was probably pansion is sufficiently rostral – the optic chiasm. may raise suspicion of on the optic chiasm to such an extent that visual disturbances anterior pituitary failure. and cycling movements in lateral recumbency. the hypothalamus and – if the ex. e. cranial pressure. Measurements of loss due to increasing anorexia. description of the animal’s tendency to lower its head to avoid being patted. and TRH. originating from the B pars intermedia. The rarely reveals edema of the papilla. but consciousness.4 cm. Ophthalmoscopic examination PRL – permit assessment of pituitary reserve capacity. (B) Necropsy revealed a necrotic and hemorrhagic pituitary corticotroph adenoma. including plished by stimulation tests with hypophysiotropic hormones dullness.154 nerve function. itary gland. In four dogs there was a Continued suprasellar expansion of the tumor exerts pressure large corticotroph adenoma with hemorrhage. weight such as GHRH. but because of the lack of an autoanamnesis. as Differential diagnosis in man. to metabolic disorders such as hypothyroid- fect from a pituitary tumor may be supported by the owner’s ism and hepatic encephalopathy.26) or a nontumorous pitu- compresses the hypothalamus (chapter 2.3).3.150. In humans mis. testes become very small and soft and as a result the epididy. peracute headache. such as parasellar lesions and increased intra- sion. CRH.151 Suspicion of a mass ef. and continuous howling. Seizures usually eral endocrine glands. 32 Hypothalamus-Pituitary System 2 Figure 2. LH. 1.. This can be accom- Physical examination can reveal a variety of signs. and occasionally mydriasis the respective pituitary hormones – GH. tests can in principle be performed in an outpatient setting.153. often the Due in part to the nonspecific character of the signs and veterinarian must at first rely on rather vague and nonspecific symptoms. compressing the surrounding brain.7 × 1. The three most severe cases were presented as emergen- cies with sudden collapse and severe depression.g. but the diagnosis of partial or total are noticed by the owner. a tendency to seek seclu. and loss of itary disease that remains restricted to the pituitary fossa. This syndrome has now been described in five dogs. These include lethargy. The mass contained cavities filled with fluid resembling A blood. The MRI scan revealed an irregular pituitary mass. one or more of the above neurological signs.26: (A) Gadolinium-enhanced axial MRI scan of an eleven- year-old female castrated Jack Russell terrier admitted as an emergency after the sudden onset of continuous panting. . and with or without anisocoria. It is caused by either hemorrhage or infarction more common when the suprasellar extension of large tumors within a pituitary tumor (fig. 2. circling. in two there 2. this is known as pituitary apoplexy and it is characterized by Neurohypophyseal dysfunction is unusual in anterior pitu.2 Mass effects was blindness and bilateral mydriasis.6.149 The expanding tumor can be expected to cause headache and visual field defects in the dog and cat. vomiting. Very large pituitary tumors may cause pressure and low urinary corticoid excretion. ACTH. Progressive enlargement of the mass may give Diagnosis rise to severe neurological abnormalities such as pacing. logic diseases. which does not change. and a decrease in appetite. visual impairment. is more easily delineated. Lateral supra. the differential diagnoses range from other neuro- symptoms. head Laboratory findings indicating low basal function of periph- pressing. GnRH. a low plasma thyroxine level do not occur. part of the hemorrhagic diathesis due to idiopathic throm- sellar extension of a pituitary tumor may impair oculomotor bocytopenia.2. 2 mm). 2. When provide imaging of the pituitary with high spatial and contrast pituitary apoplexy is suspected.6 mm. (C) A ten-year-old female Australian terrier with dexamethasone-resistant pituitary-dependent hypercortisolism without noticeable neurological symptoms.28) pituitary hormones in each sample (chapter 12. revealing pituitary enlargement and its relation- .9 mm). blood should be collected im. 2. Contrast enhancement enables the visualization of a normal-sized pituitary. resolution.6 mm. the margins of which are indicated by A–B (3.7 mm).0 mm).27: Transverse CT images of skulls of three dogs and one cat. but it is cumbersome to perform them separately. Anterior lobe 33 2 A B C D Figure 2.1. Hence a mediately to determine whether interference with vasopressin combined anterior pituitary test has been developed.6 mm and C–D = 9.6 mm) and C–D (5. C–D = 17. C–D = 17. (A) A healthy beagle. in which release has led to hypernatremia.153 all four hypophysiotropic hormones are injected within 20 s and blood samples are collected for measurements of all four Contrast-enhanced helical CT (fig. Contrast en- hancement reveals a very large pituitary (A–B = 16.27) and MRI (fig. (D) A 14-year-old castrated male domestic shorthair cat presented with mild symptoms and signs of pituitary-dependent hypercortisolism and central blindness. A very large pituitary is revealed by contrast enhancement (A–B = 13.3). (B) A twelve-year-old female mongrel greyhound with pituitary-dependent hypercortisolism. Contrast enhancement reveals a definitely enlarged pituitary (A–B = 8. 34 Hypothalamus-Pituitary System 2 A B Figure 2.6 months in dogs162 and 17. hair loss.1).161 Median survival time has been reported to be 22.6). of radiation administered. hypophysectomy. transsphenoidal debulking can be con- administration of thyroxine (10–15 µg/kg twice daily) and sidered. In the healthy dog the hypophyseal cleft between the an- terior lobe and the neurointermediate lobe can be distinguished (arrow).2. Immediate corticosteroid administration is logical manifestations. Most experience with medical with a macrotumor and diabetes mellitus may not require in- treatment has been gained in dogs with pituitary-dependent sulin treatment after the completion of a series of fractionated hypercortisolism.3. In the dog with pituitary-dependent hypercortisolism there is suprasellar extension of the pituitary mass.4.28: Sagittal MR images of the skulls of a healthy dog (A) and a dog with pituitary-dependent hypercortisolism (B). The ani- hormones inadequately produced by the target glands. gonadal hormones are not essential.3.1) and with increasing with vasopressin insufficiency (chapter 2. Hypophysectomy is used successfully to treat pituitary-de- terior lobe in large pituitary tumors might be compatible pendent hypercortisolism (chapter 4.160 Radiation therapy increases survival time over that in stitution dose (chapter 4.158 may reveal the location of an adenoma or microadenoma in the anterior lobe. cositis.5 mg/kg twice daily). cortisone (0. pharyngeal mu- D2 receptor and has a longer half-life than bromocriptine. Cats GH excess in chapter 2.159 It reduces the size of the tumor and thereby the neuro- will be temporary. and mild otitis externa. among the nonresponders were relatively also allow visualization of the posterior lobe. Its displacement many dogs with large pituitary tumors. Dopaminergic drugs such as bromocriptine radiation therapy treatments (chapter 2.25–0. this can be limited to oral If the tumor recurs.159 . por.1).4 months in cats.1). any improvement ities.156 experience it has been used to remove pituitary tumors up to 2 cm in diameter.4. and radi. Cabergoline has a higher affinity for the changes (erythema. The outcome is better in dogs with indicated in cases suspected of pituitary apoplexy.2. This results in some improvement in alertness and also in appetite if the animal Radiation therapy is indicated in both dogs and cats when a had been anorectic. ship to surrounding structures and bony anatomic landmarks goline decreased cortisol production and decreased tumor for surgical intervention. Especially when by virtue of its size the pituitary tumor is already causing neurological abnormal- tumor has already had neurological effects.164 do not effectively decrease cortisol production157.3. in such a mild neurological signs than in those with severe signs or stu- crisis the dose should be four to five times the long-term sub. whereas the inability to visualize the pos. brain necrosis /fibrosis) depends on the pressed in tumorous and nontumorous dog pituitaries20. in 17 volume of brain tissue treated and the daily and the total dose out of 40 dogs with pituitary tumors. However. Since mal can resume a normal life for months to years after surgery. The risk of late side effects Despite the fact that D2 receptors are only moderately ex. persecretion and thus dogs with pituitary-dependent hyper- ation therapy (see also discussion on the treatment of pituitary cortisolism may require continued medical treatment. treatment with caber. Total or subtotal removal of large pituitary Treatment tumors with mass effects gives immediate relief in the form of Anterior pituitary failure can be treated by substitution of the decreased neurological signs and return of appetite. untreated dogs. (hearing impairment. but better results have been obtained with the dopamine D2 receptor Acute side effects of radiation treatment include local skin agonist cabergoline.163 Radi- In principle there are three options to reduce the size of the ation therapy does not cause a prompt change pituitary hy- pituitary tumor: medical therapy.3.155 Dynamic helical CT and MRI size. leukotrichia). 1. Note the differences in scale of the y-axis. the posterior lobe or neurohypophy- sis is an extension of the ventral hypothalamus. lease. The release of oxytocin is brought about through a neuroendocrine reflex. from which axons extend through the pituitary stalk to the poster- ior pituitary.1 Oxytocin Oxytocin stimulates milk ejection by contraction of the myoepithelial cells surrounding the alveoli and ducts in the mammary gland.29). Specialized neurons called osmoreceptors are con. the hormone.167 Therapeutically.3. trations. Plasma vasopressin (VP) concentration in blood samples collected every 2 min for pulsion of the fetus. the stress of fear vasopressin) plays a vital role in water conservation.166 Primary uterine iner. They are synthesized as part of a large precursor molecule composed of a signal peptide.3. Positive interactions between humans and dogs are associated with several neurohumoral changes in both species.173 The opioid me- (fig.169 separate from the supraoptic nuclei. Oxytocin differs from vasopressin only at positions three and eight. VP like and the administration of preanesthetic or anesthetic agents other pituitary hormones is secreted in a pulsatile fashion may increase plasma VP concentration. Osmotic stimulation increases both basal and pulsa- tile VP secretion (fig. The two neurohypophyseal hormones are synthesized in the supraop.165. 2.171 In addition. including an increase in plasma oxytocin.e. 2. centrated in the anterior hypothalamus.170 The major determinant of its release is plasma thadone in particular has a strong stimulatory effect on VP re- osmolality. 2.174 .168 Results of recent behavioral studies indicate that oxytocin also increases trust among hu. aiding in ex. Suckling of the nipple sends neural impulses to the brain that reach the hypothalamus and direct the release from the neurohypophysis. in dogs and cats arginine vasopressin elevated plasma VP concentrations have been found in dogs ((A)VP) or antidiuretic hormone (ADH) (in pigs: lysine with dilated cardiomyopathy. Oxytocin has an essential role in activat- ing maternal behavior. In dogs plasma oxytocin concentration 2 h in a five-year-old beagle under basal conditions (upper panel). instead of phenylalanine and arginine (fig. They are stored in secretory granules within the nerve terminals in the neurohypophysis and are released by exocytosis into the bloodstream in res- ponse to appropriate stimuli. oxytocin also plays a role in social attachments and affiliations. oxytocin is widely used to sustain uterine contractions. which is near but mans.03 ml/kg/min for 1 h).29: rhythmic myometrial contractions in the uterus. lactated Ringer’s solution. respectively. i. considered to be a direct effect.3 Posterior lobe As illustrated in fig. and a carrier protein termed neurophysin and (for vasopressin only) a glycopeptide. This area is supplied with blood by small perforating branches of the anterior cerebral arteries.2. Volume and the expulsive stage of parturition.170 Significant changes in circu- 2. electrolyte losses due to blood sampling were corrected by intravenous infusion of tia in bitches is associated with low plasma oxytocin concen.172. 2 tic and the paraventricular nuclei in the hypothalamus.2 Vasopressin lating blood volume and blood pressure may also influence VP release and the setting of osmoregulation. It also stimulates Figure 2. it contains the amino acids isoleucine and leucine.3). Apart from its role in parental care.. The nonapeptides oxytocin and vasopressin contain internal disulfide bonds linking cystine residues at positions one and six.28). Posterior lobe 35 2. The hormones vasopressin and oxytocin are formed by separate neurons and migrate down the axons in- corporated in precursor proteins. and during os- motic stimulation (lower panel) with hypertonic saline (infusion of 20 % NaCl at increases during late pregnancy and further increases during 0. Significantly As in most mammals. 2. in that drinking not only leads to satiation drinking decreases vasopressin secretion within minutes. solute-free water is reabsorbed osmotically through the cells of the collecting ducts. V2 receptors on renal collecting by VP than by water intake regulated by thirst. of thirst but also to cessation of vasopressin secretion. The remainder is diluted to an osmolality of about 80 mOsm/kg by selective reabsorption of sodium and chloride in the ascending limb of Henle’s loop and the distal convoluted tubule. and glucose. amino acids. The effects of VP are mediated by three receptor subtypes: V1 ance is accomplished more by free water excretion regulated receptors on blood vessels. resulting in the excretion of small volumes of concentrated urine. The anterior hypothalamus not only contains osmoreceptors In dogs drinking induces volume-dependent oropharyngeal regulating VP secretion but also thirst osmoreceptors. an additional 5 % of the water is withdrawn from the descending limb of Henle’s loop (without solute) by the hypertonic interstitium. In dehydrated dogs tially interwoven. Under physiologic conditions water bal. while Posm is still elevated. The signals that inhibit thirst and vasopressin secretion. Tight junctions on the lateral surface of the cells pre- vent unregulated water flow. fluid balance is regulated by presystemic signals. In the absence of VP urine passes largely unmodified through the distal tubules and collecting ducts. and depend on the hor- . About 75 % of this is passively reabsorbed in the proximal convoluted tubule together with the active transport of solutes such as sodium. Following this isotonic reabsorption. in the collecting ducts (fig. The adjust- In addition to systemic signals – primarily plasma osmolality ments of water reabsorption needed to maintain water and (Posm) and blood volume – influencing VP secretion and electrolyte balance occur in the distal convoluted tubules and water intake.177 motic threshold for VP secretion is slightly lower than that for thirst perception. In presence of VP. 36 Hypothalamus-Pituitary System 2 Figure 2. and V3 receptors mediating ACTH secre- tion from the adenohypophysis (chapter 4. well before control of vasopressin secretion and thirst sensation are par. 2. This antidiuretic effect is mediated via a G-protein-coupled V2 receptor that induces (via cyclic AMP) translocation of aquaporin (AQP2) water channels into the apical membrane. resulting in maximal water diuresis. the ingested water has left the stomach. potassium.30).176. The os.175 duct epithelial cells.30: In a medium.1).to large-size dog the kidneys filter about 90 liters of plasma daily. bicarbonate. 32). AQP-2 is the major VP-regulated water channel.33).3.183–185 There are two pathogenetic categories can be distinguished: possible mechanisms for the impaired release.30). uria (fig. Figure 2.182 lowing the administration of vasopressin. with suprasellar extension can compress the hypothalamic nu- . After VP withdrawal.186. In complete CDI there is very little increase in urine osmolality with increasing The term diabetes insipidus is derived from the Greek diabai. with increasing plasma osmolality but in subnormal amounts ity lower than that of blood plasma and so dilute that it is al. ing pituitary adenoma in the anterior lobe increasingly com- ing insufficient VP release (central diabetes insipidus). During stimulation by VP a small percentage of AQP-2 is ex. plasma osmolality. 2.31: creted into the urine. The green area represents the range in healthy dogs. Among the possible causes of impaired VP release.3. is less pronounced or absent. hancement of the neurohypophysis (neurohypophyseal flush) sulting in a tendency to plasma hypotonicity and conse. the term diabetes insipidus (DI) only denotes polyuria. (1) The enlarg- 쎱 A disturbance of the hypothalamic-pituitary system caus. (3) a rise in urine osmolality fol- hibit basal vasopressin release in dogs.3 Diabetes insipidus have been recognized in dogs and cats.181 Even physiological increases in cortisol in.180 Glucocorticoids also interfere with the action of VP. and water permeability decreases.3.1). The cellular mechanism of VP activity in the renal tubule involves binding to specific 2 contraluminal V2-receptor sites on the serosal surface of the cell. (2) absence of renal disease. AQP-3 and AQP-4 are local- ized in the basolateral membrane of the collecting duct and permit water to pass from the cell to the interstitium. During dynamic computed to- sipidus). This urinary AQP-2 excretion closely Relation of plasma vasopressin (VP) concentration to plasma osmolality in nine reflects changes in VP exposure and has been proposed as a dogs with pituitary-dependent hypercortisolism (red dots) and six dogs with marker for collecting duct responsiveness in polyuric dogs. 2. an intra- DI and polyuria can be regarded as synonymous. Pathogenesis Both complete and partial central diabetes insipidus (CDI) 2.179 hypercortisolism due to an adrenocortical tumor (blue asterisks) during hypertonic saline infusion. VP facilitates the diffusion of water from the collecting ducts into the hypertonic renal medulla. leading to itary fossa. Aldosterone stimulates sodium and water reabsorption and potassium excretion (chapter 4.31). 2.1 Central diabetes insipidus although in dogs loss of reactivity of the osmoreceptor system The disease is characterized by three primary findings: (1) di- also seems to contribute to the corticosteroid-induced poly. thereby causing polyuria. most tasteless. 2. From a pa. re. In hypercalcemia AQP-2 down- regulation and reduced apical plasma membrane delivery of AQP-2 play important roles in the development of poly- uria. and hormones can influence the action of VP. mography the normally characteristic and distinct contrast en- 쎱 Sustained and excessive drinking (primary polydipsia). Several different aquaporins (AQPs) in the kidney have been characterized. presses the posterior lobe in the restricted space of the pitu- 쎱 A disease or functional change of the kidney.178 Within a few minutes VP can increase water permeability of the cells of the collecting ducts by stimulating translocation of AQP-2 from an intracellular reservoir to the apical plasma membrane (fig. 2. Posterior lobe 37 mones aldosterone and VP. In fact. lute urine in spite of strong osmotic stimuli for VP secretion. When diabetes mellitus has been excluded.187 (2) Large pituitary tumors quently little or no stimulation of VP release. drugs. AQP-2 is redistributed into the cell by endocytosis. The animal is essentially devoid of re- nein (passing through) and the Latin insipidus (without taste). cranial tumor is likely in middle-aged and elderly animals. resulting in pressure atrophy of the posterior lobe insufficient response to VP (nephrogenic diabetes in. leasable VP (fig. and phosphorylation of proteins that lead to transient insertion of water channels (aquaporins) in the luminal membrane of the cell. and diminished VP release. each correlating with well-defined segmental permeabilities in the nephron. In partial CDI there is release of VP It is characterized by large volumes of urine with an osmolal. (fig. Cations. an adenylate cyclase response. thophysiological point of view three fundamentally different most often a primary pituitary neoplasm. impairing VP synthesis probably via degeneration of the head trauma remained unclear. water deprivation led to a slow. and VP deficiency and inability to react adequately to osmotic sti. praoptic nuclei in healthy dogs revealed that VP-positive cells though in one of these cases the pathogenetic role of an early tend to decrease after hypophysectomy. Both mechanisms can contribute to known to be a cause of CDI.33: The effect of water deprivation on body weight. provides the diagnosis of complete central diabetes inspidus.192.188 CDI may be overlooked because of the polyuria caused by the glucocorticoid excess (fig. (chapter 4.31).193–196 There may be muli. CDI CDI can also occur as a complication of pituitary surgery. Diabetes insipidus appears immedi- ately following surgery197 and often disappears spontaneously Neoplastic nonpituitary lesions reported to cause CDI in.183 tisolism (chapter 4. probably by regeneration of disrupted pituitary corticotroph adenoma has caused hypercortisolism axons in the pituitary stalk.32: Figure 2. urine osmolality (Uosm) in a four-year-old castrated male cat with polyuria and subnormal rise in urine osmolality (Uosm). This. plasma osmolality (Posm). An immunohisto- mation of larva migrans. The arrow indicates the time of injection of va. polydipsia following head trauma. 2.1). clei. after days to months.185. al. It may be difficult to diagnose CDI in patients in which a spontaneous remission. may become apparent when the hypercortisolism has been most often performed to treat pituitary-dependent hypercor- eliminated by treatment.190 CDI has also been described in chemical study of the hypothalamic paraventricular and su- association with congenital pituitary anomalies191.1).189 A non. 38 Hypothalamus-Pituitary System 2 Figure 2. there are now several reports of this cats.198 The incidence of . The dehydration-induced rise in Posm did not result in a sustained findings are compatible with partial central diabetes insipidus. neurons.3. These sopressin (VP). If the pituitary stalk is sectioned so high clude meningioma and malignant lymphoma. in combination with the sharp rise following vasopressin ad- ministration.192 Severe head injury is hypothalamic neurons. and In a five-month-old mongrel dog with polyuria. particularly in condition. as to induce retrograde degeneration of the hypothalamic neoplastic cause of CDI is the trauma and subsequent inflam. the CDI can be permanent.3. After this reached a definite plateau. rise in Uosm. the administration of vasopressin (VP) caused a further 60 % increase. 194 Both urine specific gravity (Usg) and urine osmolality (Uosm) will be below that of plasma: Usg 쏝 1. This term is used in cases in which there is no demonstrable lesion in the hypothalamus or pituitary. This can also occur when the causative trated male Old English sheepdog (-앪-) with polycythemia due to renal neoplasia. life-threatening hy. pyometra206. both of which are in. requiring micturition almost every hour throughout day and night. and at all dosteronism204. Posm 쏜 375 mOsm/kg).e.6). lesion extends to the thirst center and adipsia develops. CDI caused by head trauma may not only be associated with soft tissue and skeletal lesions.193. hepatoencephalo- ages acquired kidney disease may cause polyuria.202 Clinical manifestations The major manifestations are polyuria.5-year-old cas- by ataxia and sopor. Lower 쏜 170 mmol/l. Especially in pathy207. These include hypercortisolism (fig. although the subsequent course of the disease.208 middle-aged and elderly animals. diagnostic imaging. polydipsia. endocrine conditions such as diabetes mellitus. i.34). Blood examination usually reveals no abnormalities except for slight hypernatremia due to inad- equate replenishment of the excreted water. 2. Differential diagnosis Apart from central diabetes insipidus there are in principal only two basic disorders which can account for the polyuria: nephrogenic diabetes insipidus and primary polydipsia with polyuria. Other conditions such as hepa. and 9. and hypercalcemia of ma. pyometra. in severe cases of complete CDI water intake may be so enormous as to interfere with food intake and thus re- sult in weight loss..34: held from an animal with complete CDI. the risk is higher in dogs with large pituitary tumors.3). hyperparathyroidism. and a near- continuous demand for water. tention) may cause hypervolemia and thereby lead to an al- lignancy must be considered.199–201 Apparently the magnocellular neurons do not resume function after being compressed for a long 2 time. such as secondary hypothyroidism.3. hypercortisolism.31). This may be the case especially in young animals. Posterior lobe 39 prolonged and permanent CDI after hypophysectomy in dogs with pituitary-dependent hypercortisolism is correlated with pituitary tumor size. It can be assumed that in some of these conditions the hor- hyperthyroidism. 2. tered setting of the osmoreceptor system and consequently to toencephalopathy and polycythemia may also be associated delayed and decreased VP responsiveness to osmotic stimu- . Upper panel: ten- pertonic encephalopathy occurs within a few hours (PNa+ year-old castrated male German pointer with primary hyperaldosteronism. In several of these conditions impaired VP (chapter 2.3.203 The green areas represent the range in healthy dogs. GH excess205. There remains the possibility of the so-called idiopathic form of CDI. In animals in which a large neoplasm is the underlying cause. but a wide variety of conditions cause polyuria. Figure 2. initially manifested panel: nine-year-old castrated male Labrador retriever (-앬-). If water is with.2. release and /or interference with its action has been docu- frequent. but damage to the hypothalamus-pitui- tary region may cause additional hormone deficiencies. hyperaldosteronism. progestin-induced (luteal phase) monally induced changes (corticosteroid-induced sodium re- GH excess.3. mented.010 and Uosm 쏝 290 mOsm/kg.2 and chapter 2. although in mild cases Uosm may be up to 600 mOsm/kg. hyperal- Young animals may have congenital kidney disease.3. and polycythemia (fig. or autopsy may eventually reveal a lesion that could not be identified initially. Although in partial CDI water intake and urine volume may be only moderately increased. there may be additional neurological symp- toms and endocrine deficiencies (chapter 2. In severe cases water intake and urine volume may be immense. Relation of plasma vasopressin (VP) concentration to plasma osmolality (Posm) during hypertonic saline infusion in three dogs with polyuria. conjunctival administration is difficult.5–4 µg DDAVP) admin- for the differential diagnosis of polyuria. the result of disturbed VP secretion. The polyuria in these conditions will at least in part be ciently to cause CDI.32 and per ml). has been used drop of the intranasal solution (= 1. In able concentration of urine during dehydration. adenohypophyseal function should be studied Relation of plasma vasopressin (VP) concentration with plasma osmolality during (chapter 12. hyporesponsiveness of VP to a hypertonic stimulus the first 24 h after surgery. despite prophylactic administration has been observed in polyuric dogs which otherwise meet of desmopressin. 9-D-arginine vasopressin [Minrin®. When there is a history of head trauma or suspicion of a pi- tuitary lesion /tumor that might cause additional pituitary Figure 2.210 In severe CDI the water deprivation test gives the correct diagnosis. 2 An overall diagnostic approach to the polyuric dog is pres- ented in chapter 2.33 and described in detail in chapter 12.197 In reliable.35: deficiencies. but some owners (in part for finan- are used as an index of VP release.211 Also in humans it has been fact that the hypercortisolism-induced vasopressin resistance .1. tration of desmopressin is started immediately after surgery.3. cases does a pituitary tumor interfere with VP release suffi- lease.2. and 0. The owner then administers desmopressin (DDAVP) for four to five days and collects another series of urine samples during the last day of desmopressin treatment. 2.2. especially near the end of the period of dehydration. In dogs and cats undergoing hypophysectomy the adminis- but in all other categories of polyuria. is unpleasant for the animal.213 In the presence of a pituitary adenoma the neurohypophysis can be displaced or no longer be visible (chapter 4. CT and /or MRI. Malmö. polyurias due to other both dogs and cats undergoing hypophysectomy for pituitary- diseases may also be associated with disturbed VP release. In cats in which to VP release is a combination of hypertonicity and hypovol. The neurohypophysis can be visualized with dynamic CT.215. intranasal solution (100 µg sopressin administration. As indicated at the end of chapter 2.2. In dependent hypercortisolism. relies heavily on the emptying of the bladder at each collec. the test is istered in the conjunctival sac twice daily sufficiently controls difficult to perform correctly. and oral (tablets with 0.1) and the pituitary gland should be visualized by hypertonic saline infusion in two dogs with central diabetes insipidus caused by a pituitary tumor. 0.3. central diabetes insipidus is very unlikely and instead there is primary polydipsia or functional nephrogenic diabetes in- sipidus. mild hypernatremia can occur in addition. the stimulus cial reasons) administer it only twice daily. One 2. Treatment mones such as corticosteroids with the action of VP can also The vasopressin analogue desmopressin or DDAVP contribute to the polyuria. as mentioned above.3) or water restriction. With the administration of three drops /day urine production tion.3. However. Furthermore.1). increasingly the diagnostic procedure starts with serial Uosm measurements in urine samples collected by the owner at home. in only a small proportion of lation. and is indirect because changes in urine concentration usually returns to normal.3.35 and chapter 12. Ferring AB. in which there is vari.195 (fig 2.209 See also legend to fig.212 Thus in some dogs it may remain a thorny problem to distinguish between polyuric entities. It is available for use in humans in ampoules for paren- For some time the water deprivation test combined with va. the polyuria in most dogs with central diabetes insipidus.216 This is probably in part related to the criteria of primary polydipsia.4 mg). As discussed there.187 However. it may be less healthy dogs this prevents postoperative hypernatremia. the injectable form emia.1 mg two to three times daily has been reported to be an ef- VP during osmotic provocation by hypertonic saline infusion fective alternative.214 In a series of five cats with CDI the oral administration of ¼ to ½ tablet of A more direct way to diagnose CDI is by measuring plasma 0. If Uosm remains 쏝 1000 mOsm/kg.34. (1-deamino. polyuria and polydipsia cease after ad- ministration of desmopressin and Uosm rises from low values to 쏜 1000 mOsm/kg. as shown in the figures 2. 40 Hypothalamus-Pituitary System demonstrated that the chronic overhydration of primary polydipsia can downregulate VP release in response to hy- pertonicity. In a similar manner polycythemia may impair VP re. (1 ampoule) can be given once or twice daily. interference of cations such as Ca2+ and hor.4. However. Sweden]) is the drug most commonly used for treat- Diagnosis ment. teral injection (4 µg per ampoule).2. In both complete and partial cen- tral diabetes insipidus.2. 4. Treatment with desmopressin is continued for three weeks. in some of these conditions the polyuria VP also has some effect. it was hypothesized that the polyuria was due to chapter 2. paraneoplastic) interference with the production or function of AQP-2. Juvenile-onset renal diseases have been reported to occur as tomy in dogs with pituitary-dependent hypercortisolism dep. but the polyuria may not be the iatro- mals with the complete form are always at risk of life-threaten.008–1. Untreated ani. case reports218. Desmopressin has little or no effect.g.. or hypophysectomy. there are reports of nephropathies in which than a few hours.226 Particularly with tubular changes and fibrosis in congenital form appears to be extremely rare.. Posterior lobe 41 is insufficiently compensated in the postoperative period by infusions and water intake.e. If additional pituitary deficiencies have been revealed as a re- sult of head trauma. in a dog with may lead acceptable lives for many months. If polyuria recurs when desmo.225 These animals usually 2. glomerular basement dis- orders.3. In contrast. ous underlying abnormalities have been reported in familial renal disease. although in- able to concentrate urine despite adequate plasma levels of itially the presenting problem may have been poor physical VP. NDI. These approaches are discussed in more detail in myosarcoma. Those with CDI caused by a pituitary tumor polyuria was the main presenting problem. such as amyloidosis.34).223 Prognosis In the absence of a tumor the long-term prospects are good. the persistence of CDI after hypophysec.220.2.3.36: for the posterior pituitary. tial diagnoses of CDI (chapter 2. in which the defect was renal. acquired or secondary NDI is the most common In the rare patient with severe congenital NDI. Among the few the renal medulla. e. As mentioned under pathogenesis. for poor response to desmopressin may also occur in ascribed to a low affinity of the V2 receptors for VP. Vari- ends on the size of the pituitary tumor. presented with polyuria due to the isosthenuria.2).2).219 is one in which necropsy revealed a por- toazygos shunt and renal medullary lesions. of VP.218 In humans mu. In several of the partial and acquired forms of NDI. pituitary tumor. Usg may be below that of isosthenuria. As discussed at the water deprivation produces some urine concentration and end of chapter 2. until the tumor extensive cryptococcal lesions in the renal medulla. polydipsia. Results of serial measurements of urine osmolality (Uosm) before (blue line) and pressin is discontinued. (Usg 1.221 In dogs familial occurrence of NDI has this does not necessarily mean that the primary abnormality is been documented in huskies.3.3.2 Nephrogenic diabetes insipidus develop chronic renal insufficiency and consequently may be In nephrogenic diabetes insipidus (NDI) the kidneys are un. it is resumed for as long as needed. 2.1).1. Plasma VP measurements during the may be the result of downregulation and reduced apical water deprivation test and /or during hypertonic saline infu- plasma membrane delivery of AQP-2.1). In a dog that had par. Total hypophysectomy deprives the animal of the neurohypophyseal storage of VP and the ability to release it after stimulation. Usually the pituitary stalk is sectioned low enough to preclude retrograde degeneration of the supraoptic and paraventricular neurons and there is suf- ficient leakage of VP from the stalk to prevent CDI.3. . Diagnosis tations of the genes encoding for the VP receptor and the Serial measurements of Uosm reveal it to be low with only AQP-2 water channels have been identified in families of minor fluctuations.2 and chapter 13.217 In time the axons of the magnocellular neurons may regenerate to establish new neurohemal connections to form a substitute Figure 2. urine osmo- cause of polyuria in dogs and cats and may be caused by a lality is not increased by water deprivation in the modified wide range of endocrine and metabolic disorders. and polycystic kidney disease. but NDI patients. and primary tial NDI that disappeared upon removal of an intestinal leio. during desmopressin administration (red line) in a dog with primary hyperaldos- teronism (see also upper panel of fig.6. tumor-associated (i. for it is uncertain whether suffi- cient hypothalamic VP will reach the systemic circulation. and if so. tropic problem that causes the owner to consult the veterin- ing dehydration if they do not have access to water for more arian. The condition may be congenital or acquired but the condition. 2.012).224 begins to cause mass effects (chapter 2. familial diseases but also as isolated cases of renal failure.2.3. how long the recovery from the surgical damage to 2 the pituitary stalk will take.222 conditions causing severe vasopressin resistance (fig. Chronic renal failure in adult animals leads to isosthenuria Appropriate treatment relieves the symptoms. Several of water deprivation test (chapter 12.3.3. nor by administration these have already been mentioned in the section on differen.36). they should be treated as required with thyroxine and /or cor- tisol (chapter 3. However. sion may help to differentiate among CDI. 2.3.5-year- old male Border collie (red line).3. Hydrochlorothiazide can also directly increase Figure 2.228 tion behavior: a 9. Hydrodiuril®. As a result. Oropharyngeal signals inhibiting thirst or sign and urine specific gravity (Usg) was 1. or blood pressure as a result of ab- for nine months. The dog had developed the habit of beginning to drink ex- normally prevent the dog from drinking an amount of water cessively at around 17. There is no urinary concentrating defect and at various times during the day the dog may produce either highly diluted urine or concentrated urine. unremarkable drinking and micturi- ably by inducing AQP-2 expression independent of VP. Dogs with more pronounced primary polydipsia exceed the iatrotropic threshold and are presented to the veterinarian be- cause of polyuria and polydipsia.227 However.37: water permeability in the medullary collecting ducts.010).3.009 to 쏜 1. but not normalized.025 in the morning urine sample brought by the owner. Placing the dog in a completely different en- vironment. prob- Fluctuations of urine osmolality (Uosm) in samples collected at home in two healthy dogs with.229 In none of these dogs was the sometimes marked variation in water intake and urine volume considered by the owners to be associated with abnormal drinking. The history and physical examination revealed no other symptom sorption of the water. The problem may also develop later in life. but Uosm also decreased sumption was shown to fluctuate with food intake and exer- sharply earlier in the day when his wife prepared to take the dog for a walk.00 h. before any detectable change in plasma from a six-year-old West Highland white terrier that had polydipsia and polyuria osmolality. In a series of 89 healthy pet dogs. This in excess of its physiological need.37).38). there is increasing evidence that sodium depletion and increased proximal tubu- lar water reabsorption do not solely account for the antidiu- retic effect.208 2. according to the owners. when the owner was expected home from work. as during hospitalization. 42 Hypothalamus-Pituitary System Treatment Oral administration of hydrochlorothiazide (Esidrex®. in which case water intake was in excess of the fluid losses via diarrhea and vomiting. This is said to be the case in hyperactive young dogs that are left alone for many hours during the day or have undergone important changes in their environment. less sodium and water are de- livered to the collecting tubules and urinary volume is re- duced. plasma volume. has sometimes stopped the problem. the glomerular filtration rate de- creases and proximal tubular reabsorption of sodium and water increases.230 Figure 2. 2. water con- resulted in a marked decrease in Uosm by 18.3 Primary polydipsia Primary polydipsia occurs primarily in dogs and is character- ized by a marked increase in water intake that cannot be ex- plained as a compensatory mechanism for excessive fluid loss. Marked fluctuations in Uosm may also occur even though the owner observes nothing re- markable in the dog’s drinking behavior (fig. Oretic®) (2–4 mg/kg twice daily) and a low-sodium diet can decrease 2 urine volume219.035 ± 0. Transient primary polydipsia has also been reported to occur in association with gastrointestinal disease. It has been proposed that the thiazide diuretic and a low sodium diet cause extracellular volume contraction.050) with a mean (± SD) of 1541 ± 527 mOsm/kg (Usg 1. other brand names: Microzide®.5-year-old castrated male schnauzer (blue line) and a 2.38: As mentioned in chapter 2. Novar- tis. Consequently. such as in the excitement of anticipated pleasure of going for a walk (fig. albeit probably without a significant change in urine osmolality.30 h. Nevertheless.2 satiation of thirst occurs in Urine osmolality (Uosm) in two series samples collected at 2 h-intervals at home dogs during drinking. Uosm in morning urines ranged from 273 to 2620 mOsm/kg (Usg 1. cise: dogs consumed 40 % of their total daily water intake . It is not clear whether the latter indicates a primary disturbance in osmoreceptor function and regulation of VP secretion. the fluctuations are not so pronounced in all dogs with primary polydipsia and in some Uosm fluc- tuates between about 200 and 600 mOsm/kg. although values at the upper limits of the reference ranges have also been reported.2) can be very helpful. However. The results of routine blood examinations are usually unre- markable. The water bowl can be re. 223–1658 mOsm/kg in the former and 88–1387 mOsm/kg in hypertonicity (figs. . or that it is the result of chronic overhydration downregulating VP release in re. day are the least difficult to treat. Figure 2. although effective. In the Jack Russell terrier the Dogs with strong fluctuations in Uosm at set times during the effect of hypertonic stimulation on plasma VP was interpreted as a hyperresponse. but in which water deprivation leads to Uosm 쏜 1000 mOsm/kg in 쏝 8 h.234 During hypertonic saline infusion abnormalities in VP release may include episodes of hypersecretion as well as delayed and low responses to plasma hypertonicity.212.29 and 2. 2.233 Diagnosis Marked fluctuations in Uosm in serial urine samples collected at frequent intervals and some values 쏜 1000 mOsm/kg (fig.39: sponse to hypertonicity. there may be an as yet ill-de- fined disturbance in osmoreceptor function and regulation of VP secretion (see above). In dogs with less pronounced spontaneous fluctuations in Uosm at low values.232 The occasionally observed early Plasma vasopressin (VP) concentration during hypertonic saline infusion in a six- month-old Jack Russell terrier (upper panel) and a two-year-old Maltese dog »hyperresponses« might represent erratic secretory bursts.34. 2 ride the oropharyngeal and osmotic signals that normally re- sult in appropriate water intake. may increase Posm and lead to severe sensations of thirst. Posterior lobe 43 during 2 h after eating dry food. In some of these dogs Posm may not be low and water restric- tion. except for Posm and plasma sodium concentration. 2. In such cases a water deprivation test (chapter 12. Although the current criteria for primary polydipsia appear to be fulfilled. which are often at or just below the lower limit of their re- spective reference ranges.2) provide the diagnosis of primary polydipsia. some caution is warranted.38 and chapter 12. but (lower panel). 2.211 the latter. Basal plasma osmolality (299 and 306 mOsm/kg) and basal plasma so- dium (143 and 146 mmol/l) were near or below the lower limit of the reference Treatment ranges for Posm (303–320) and for PNa+ (141–150).2. and after treadmill running for 30 min water intake was higher than the water losses dur- ing the exercise. The results of serial measurements of Uosm were characteristic of might also reflect the pulsatile release pattern induced by the primary polydipsia. In the Maltese dog the VP response also appeared unrelated to the gradual rise in Posm. Within 8 h of water deprivation Uosm should exceed 1000 mOsm/kg with weight loss 울 3 % and only slight in- creases in Posm and plasma sodium concentration.39). moved during periods when excessive water intake can be ex- pected and the conditioned behavior can be discouraged.232 Plasma VP measured during the water deprivation test in dogs with primary polydipsia remains low232. in agreement with the earlier observation that production of highly concentrated urine can occur with relatively low VP concentrations. 211 See also legend to fig.232 Both hy- ponatremia and normonatremia have also been reported in humans with primary polydipsia.231 These factors together with other environ- mental factors and /or moments of intense interactions in some dogs seem to bring about a complex of signals that over. 239 Of the (chapter 14. some of the re- ence of low plasma osmolality. drome may arise as a consequence of uncontrolled VP release calcemia (lymphoma. In such a schematic symptom. and coma. situation can be achieved. resulting in dilute urine at low plasma sodium 1804 mOsm/kg). resetting of the osmostat in which VP secretion can be fully 2 veal the continuation of marked fluctuations (e. rectly treated with DDAVP seem to be at risk of developing clude diagnostic imaging of the abdomen. In hyponatremia. the approach proceeds to the last part of the In principle both defective water excretion and increased algorithm. aggravated by a low-sodium diet. three reported cases of SIAD with polyuria as the presenting lem is much more frequent than in cats. Brain cells may adapt to chronic hypotonicity by extruding electrolytes. Dis- 2. water intake may lead to plasma hypotonicity. 44 Hypothalamus-Pituitary System Prognosis extent of causing clinical manifestations of cellular overhy- While the owner may report that the dog’s drinking be. sists. These tests are described in detail in chapter 12. anal sac tumor). which seems paradoxical in causes water retention and may lower plasma osmolality to the presumed VP excess. lular edema the hallmark of acute hypotonia. 2. In addition to endogenous VP excess. Particularly dogs with primary polydipsia incor- examination outside the neurohypophyseal system may in. Reduced suppressibility of VP ported cases included polyuria. which is essen- tially hyponatremia. two were considered to be idiopathic240 and the approach the nuances of the previous sections are omitted. Unlike extra- tial diagnoses discussed in the previous sections: central dia. The subject of polyuria and abnormal- . and the third was attributed to Dirofilaria im- previous sections are integrated with the help of an algorithm mitis infestation.. from surgically damaged hypothalamic centers in combi- nation with underestimated perioperative blood loss.215 to dry food.242 The syn- and physical examination235. and primary compressed against the unyielding cranium. Pathogenesis Of the three reported cases of SIAD in dogs without polyuria. syndrome of cerebral edema. reveals a lesion in the kidneys or adrenals. In principle this condition is associated with highly havior has improved and that polyuria and urinating in the concentrated urine but in humans there is also a variant with house have ceased. generalized seizures. Syndrome turbed brain function usually prevents the animal from con- of inappropriate antidiuresis tinued drinking. two-thirds of the The last part of the algorithm includes three test procedures relative water surplus is intracellular. transsphenoidal resection of pituitary adenomas. Clinical manifestations mality is found.236 Only a few cases of the syndrome have the abnormality. for example. If no abnor. but if hypotonicity is severe the adaptive losses may be insufficient to prevent clinical manifestations.3. the owners may have learned to live with concentrations. making generalized cel- that may provide a definite choice among the three differen. Hypo- Laboratory examination begins with checking urine glucose natremia due to SIAD has also been reported after hypophys- and specific gravity. lethargy.3.2. follow-up measurements of Uosm may re. such as possible causes of hyper. tremor. it is possible that similar abnormalities are produced by excessive administration of va- If laboratory examinations do not provide a diagnosis. Then it SIAD is also known to occur in humans as a complication of gives attention to relevant points in the signalment. which allows Posm to rise and leads to re- (SIAD) covery.2). If ultrasonography the hypotonicity syndrome.4 Vasopressin excess. This syndrome includes weak- where attention is also given to the relation between Uosm ness. 345 to suppressed. It may happen that an animal presented ectomy in dogs with pituitary-dependent hypercortisolism with a seemingly convincing history of pu /pd has only in.3.3.1. and was attributed to hypothalamic damage and severe in- creased water intake because the owner has changed the food traoperative arterial hemorrhage. and nausea. but with the measures described above an acceptable with and without polyuria. further sopressin. and may culminate in resting and Usg. the distending brain is betes insipidus. dration. nephrogenic diabetes insipidus. been described in dogs but there also appear to be two forms. provoking the polydipsia. The algorithm begins with the problem presented in the medical history: polyuria /polydipsia (pu /pd). the imaging may be expanded to CT and /or MRI.232 In most cases the excessive drinking per.3.4 Algorithm for polyuria / polydipsia one was considered to be idiopathic237. The blood tests relate to the differential diagnoses listed in chapter 2.g. in which the prob. history. cranial tissues that can expand freely. This is primarily for dogs.241 guide. third was associated with a tumor in the thalamus and dorsal but by virtue of its simplification it may be helpful as an initial hypothalamus. In addition to neurological manifestations. Elevated or normal VP secretion is inappropriate in the pres. the second was due to In this section the diagnostic approaches discussed in the three encephalitis238. 243 As discussed in chapter 2. RHODES SJ.319:1–19. A higher tial causes of hypotonicity such as hypoadrenocorticism. RJM. ROSENFELD MG. Treatment ports on dogs with primary polydipsia. HNASKO R. plasma hypotonicity may develop at relatively low in. HULLINGER RL.149:2159–2167. BEN-JONATHAN N.3 and in re. male and female mice after acute cold stress.74:337–342.3. If primary polydipsia is associ. NÚÑEZ L. tors in individual rat anterior pituitary cells during maturation. The endocrine system. SAVAGE JJ. treatment consists of restriction of fluid intake. YADEN BC. Fetal development of the pituitary gland 11. SENOVILLA L. Receptor-specific VP(V2) antagonists. sia the animal’s behavior will indicate continuing thirst but 쎱 Improvement after fluid restriction. VAN WOLFEREN M. the anterior pituitary. RIJNBERK A. more recent nonpeptide V2-re- have been reflections of the strong pulsatile nature of VP re.3.237 hypotonicity in schizophrenic patients with primary polydip- sia.251:143–151.3. Continuing urinary ated with an abnormality in renal free water clearance such as and insensible fluid losses then induce a negative water bal- SIAD. NISHIOKA S. 5. CRESPO M.31:119–124. and hospital-acquired fluid hyponatremia.232 Healthy medi. CROUGHS 7. 3rd ed. Gene 2003. pu- Neurosci Lett 1987. with polyuria. In the event of hyponatremia due to SIAD after hypophysec- um-sized to large dogs have sufficient diluting capacity to tomy in dogs. Prognosis 쎱 Inappropriately high urine concentration in the presence In what has been described as the idiopathic form of SIAD of plasma hypotonicity. Endocr Rev 2001. berty and senescence. This may not be very effec- takes. dose rate may be required to achieve long-term resolution of pothyroidism. Int J Biochem Cell Biol 2006. Dopamine as a prolactin networks. When intake ex. hy. MOL JA. Although in- be present. MALLO F.179 References 1. 3. 2. 4.237 imbalance. Neuropeptides 1994. logical symptoms.559–585. CHENG CHK. If the disease is caused by a tumor As mentioned above. dilutional hypotonicity occurs and neuro. Transcriptional control during mammalian anterior pituitary 9. and im- ceeds this amount. ance and fluid volume is restored. fluid restriction should also be effective. the neurological signs will only reappear when too much water is given accidentally. In humans SIAD has been implicated as contributing to tive in cases in which there is high urine concentration. Organization of ovine corticotrophin-releasing factor immu. Posterior lobe 45 ities in VP release was discussed in chapter 2. Measurements of urinary AQP-2 may help to unravel the role of VP in these conditions. GLEIBERMAN AS. Rapid changes in anterior pituitary cell phenotypes in 1993. GARCÍA-SANCHO J. recent diuretic use. polyuria can be questioned. KIRATIPRANON P.3. these high responses might in large part itially not very effective244. However. In: Evans HE.146:4627–4634. water restriction may allow the animals to live 쎱 Plasma VP concentration inappropriately high relative to an almost normal life for several years. Mil. excrete up to 5–8 l of free water per day. Physiol Rev 2007. Changes in expression of hypothalamic releasing hormone recep- noreactive neurons in the canine hypothalamo-pituitary system.3. Cells of 2007. Philadelphia: WB Saunders Co CHO J. . 2 logical symptoms may develop. Endocrinology 2008. Pre- development. Anat Rec 1998. GARCÍA-SAN- ler’s anatomy of the dog.27:7–13. may block the action of VP in the collecting duct cells with primary polydipsia and thus a similar combination could and thus promote water excretion specifically. KWANT M.245. (PRL) inhibitor.215. SPUCH C. it will determine the prognosis. VP hyperresponsive. ed. so-called aquaretic ness to osmotic stimulation has also been reported in dogs agents. VILLALOBOS C. the diagnosis of SIAD in dogs with or comparable lesion. Endocrinology 2005. dicted primary and antigenic structure of canine corticotropin-re- leasing hormone. Endocrine 6. The dog recovered from the neuro- The diagnosis of SIAD begins with exclusion of other poten. CHAN C-B. STOLP R. mediate cessation of desmopressin.87:933–963. ZHY X. although hyponatremia persisted. close monitoring of plasma sodium concentration. 8. Then the following criteria should be fulfilled: 쎱 Plasma hypotonicity (Posm 쏝 280 mOsm/kg).246 One has been used in one dog with SIAD with good results. YEUNG C-M. ceptor antagonists are effective and can be administered or- lease in stimulated conditions (fig.29). ALVAREZ- in the beagle.170 ally. MELOEN R. SASAKI F.38:1441–1449. Molecular physiology of pituitary development: Signaling and transcriptional 10. VILLALOBOS C. LEUNG P-S. DIZ-CHAVES Y.22:724–763. Prolactin-releasing peptide (PrRP) in- creases prolactin responses to TRH in vitro and in vivo. 2. PÉREZ-TILVE D.211. SENOVILLA L. As in primary polydip- Posm. STEINBUSCH HWM.216 In chronic SIAD.237 Administration of 3 mg/kg every 12 h re- Diagnosis sulted in marked aquaresis. SUTTER NB. NODA S. . 35. VAN KOETSVELD PM. BHATTI SF. subcutaneous. Prolactin binding cat and opossum. 30. physiological. Stimulation of DAVIS S. LIN XZ. PAR- the growth hormone (GH)-insulin-like growth factor I axis by daily KER HG. BOUIN M. Mammalian genome projects reveal new growth hor- mone (GH) sequences. KANGAWA K. Endocrinology 1999. TAKAYANAGI Y. BENTLE KA. KAIYA H. MOL JA.152:155–160. Ghrelin is a growth-hormone – releasing 36. Pituitary function. ing and endocrine responses of plasma ghrelin in healthy dogs. HOSODA H.316:112–115. and sequencing of cDNA encoding the cat growth hormone. 34. and pharmacological 37. in benign and malignant mammary tissue of female dogs. NAGANOBU K. bat. GIANOTTI L. Biological. WARREN WC.78:693–698. CASTRO-PERALTA F. LAWLER DF. hyrax. KELLE M. Amsterdam: Elsevier. BACH LA. WOLFSWINKEL J. Am J Vet Res 2006. RIJNBERK A. NAKAHARA K. A single IGF1 allele is a major determinant of small size in dogs. YOKOYAMA M. 2008:561–604. MOL JA. Insulin and insulin-like growth-factor I disease. SAT in mammary gland tumors of dogs and cats. LARK KG. DUPONT J.81:4249–4257. HOSODA H. SOARES MJ. Influencing the between-feed- 16. DEGHENGHI R. TRANDER EA. NAP RC. BOGOSIAN G. HAZEWINKEL HAW. MOL JA. Eur J Bruss ML. NAKAHARA K. intranasal. J Clin Invest 2008:118:4014–4024. FRETWELL N. HELLMÉN E. Effects of food intake and food withholding on growth hormone. VAN DER LELY AJ. KARLINS E. PADHUKASAHASRAM B. Expression and molecular characterization of the 20. Domest Anim Endocrinol 1993. JOHNSON GS. OS- jects. Endogenous prolactin-releasing peptide regulates food emptying in rats. EBERLING P. MAT- SUO H. HO-CHEN JK. VAN GARDEREN E. QUIGNON P.146:26–32. KONNO T. and oral administration in man J Clin Endocrinol Metab 1994.32:93–105. intake in rodents. VAN DER GUGTEN AA. BARRERA-SALDANA HA. TAŞDE- FUKUSUMI S. AIN R. Harvey JW. Gene 1994. KOOISTRA HS. NORTON RS. Ef- cDNAs coding for cat growth hormone and prolactin. LENG G.402:656–660. KOOISTRA HS. CAMANNI F. IDA T. 23. HOFLAND LJ. KANGAWA K. MEIJ BP. Two new peptides to improve post-operative gastric ileus in dog. Gene fects of growth hormone secretagogues on the release of adenohy- 1996. BHATTI SFM. DUCHATEAU L. HEADEY SJ. elephant. MOSHER DS. Trends Endocr Metab 2005. ZHAO K. RUTTEMAN GR. VAN DER POEL HJA. SATYARAJ E.Suppl 1:31S-32S. pophyseal hormones in young and old healthy dogs. In: Kaneko JJ. a new synthetic hexapeptide. 21. J Clin Endocrinol Metab 1996. PIERRE S. Nature 1999. Horm Res 2001.6:829–835. POITRAS P. ST. concentrations of growth hormone (GH) and insulin-like growth factor I (IGF-I) in Great Dane pups fed different dietary levels of 25. BEVERS of armadillo. Cloning 2007. Purification and characterization of feline ghrelin and its possible role.25:426–457. 46 Hypothalamus-Pituitary System 12. YADA T. Insulin-like growth factor I in the dog.17:858–877. MISDORP W. WAYNE RK.67:1557–1563.55 (Suppl 2):22–26. NAP RC. 26. 19. SELMAN PJ. Front mone-releasing activity of hexarelin. DE 17. Gen Comp Endocrinol 2008. 6th ed. ground squirrel. MURAKAMI N. GHIGO E. teins – the pieces are falling into place.149:4357–4366.168:247–249. BANNON P. BUSTAMANTE CD. MEIJ BP. receptors: similarities and differences in signal transduction. NAKAZATO M. The rat prolactin gene family locus: species-specific gene family ex. hedgehog. L’HEUREUX MC. OBAY DB. 14. Clinical Biochemistry of Domestic Animals.17:161–172. SCHALKEN JA. VAN HAM LML. KAMI N. 18. BACH MA. UETA Y. WISSINK EHJ. MM. Growth hor.140:5907–5914. RUTTEMAN GR. 38. Effect of ghrelin on gastric myoelectric activity and gastric ONAKA T. HOF. RIJNBERK A. MIR E. Characterization of the GH-encoding genes 31. JONES PG. Vet J 2006. HANSON JM. Horm Res 1987. ASCACIO-MARTINEZ JA. NORDBORG M. MURA- 2028–2034. JF. growth hormone cDNA codes for a mature protein identical to pig KOOISTRA HS. growth hormone receptor in canine mammary tissue and mammary WAAIJERS AM. Regul Pept 2008. KOJIMA M. EIGENMANN JE. WILLEKES-KOOLSCHIJN N. TSCHOP M. MATSUMOTO H. pathophysiological. HEIMAN ML. shrew. DE BRUIN C. eds. DUCHATEAU L. Anti- cancer Res 1986. CHAPMAN IM.95: M. DOI K.24:531–534. MIYAZATO M. CHASE K. NAKATA M. ALAM SM. 29. 22. HINUMA S. plasma ghrelin concentrations in healthy dogs. Expression and functional analysis of dopamine receptor subtype 2 and somatostatin receptor subtypes in canine Cushing’s 33. Domest Anim Endocrinol 15. MOL JA. 24. OFLAZOĞLU HD. Mamm Genome 2006. Cloning of the VLIEGHER SP.10:237–247. LAND LJ. Endocrinology 2008. hormone in the dog. Pep. LeROITH D. protein. VAN CAUTER E.172:515–525. MOL JA. KUBO A. Age-related plasma aspects of ghrelin. after intravenous. Growth hormone mRNA 28. RUTTEMAN GR. TÜMER C. Endocr Rev 2004. J Clin Invest 1995. TRUDEL L. ZHU L. KOJIMA M. Gene 1995. VAN GARDEREN E. Growth and growth tides 2003. VAN HAM LM.16:228–234. A dog 27. GRAY MM. KANGAWA K. MERA T.143:277–280. ARVAT E. MOL JA. oral administration of a GH secretagogue (MK-677) in healthy sub. LAMBERTS SWJ. MOL JA HAZEWINKEL HAW. WALLIS M. IMBIMBO BP. Vet Quart 1994. TOMASETTO C. GHIGO E. tumors. Endocrinol 2005. SWENNENHUIS pansion. Science 2007.28:160:311–312. VAN DER LELY AJ. 32. LENAERTS V.155:271–279. 2 13. IGF-binding pro- acylated peptide from stomach. DATE Y. UITTERLINDEN P. BARRERA-SALDAÑA HA. RIJNBERK A. Effects of gon- 1994. 54. RIJNBERK A. MOL JA. OKKENS AC. AC. 63. AAME. MERTANI HC.25:155–174. Morphogenic and tu. DUCHA- TEAU L. VAN HAM LML. ONCLIN K. TERLOU M. GULER HP BINZ K. Evidence for prolactin as the main luteotropic factor in the cyclic ing the luteal phase and mid-anoestrus in beagle bitches. SCHALKEN JA. JÖCHLE W.32:183–192. MOL JA. BEN-JONATHAN N. Domest Anim 1997. OKKENS AC. BEVERS MM. TIMMERMANS-SPRANG EPM. LOBIE PE. What in mammary gland tumors of dogs and cats. GLUCK- MAN PD. Lack of association of proges- STERHUIS MA. LEE WM. MOL JA. OKKENS AC. Domest Anim Endocrinol 2007. RIJNBERK A.33:294–312. Acta Endocrinol tumours.19:177–190. KOOISTRA HS. Acta Endocrinol prolactin. 2008. SEEFELDT A. 42. OKKENS 43. growth hormone receptor in a canine distraction osteogenesis model. Pituitary dwarfism in German shepherd dogs: Additional evidence of simple autosomal recessive 50. LEE K-O. tin-induced cystic endometrial hyperplasia with GH gene ex- HAZEWINKEL HAW. Domest Anim Endocrinol lifespan of the corpus luteum in the cyclic dog. RUTTEMAN GR.14:25–38.77:187–192.29:1–41. MOL JA. Crosstalk between GH / IGF-I axis and growth factors: prolonged treatment of mini-poodles with recom. steroid hormones (progesterone. MOL JA. THEYSE LFH.28:481–486. inheritance. RAO NAS. BHATTI SFM. J Reprod dog. KOOISTRA HS. Proc Natl Combined pituitary hormone deficiency in German shepherd dogs Acad Sci USA 2004. EIGENMANN E. GÜNZEL-APEL A-R. 1989. OOS- TERLAKEN-DIJKSTERHUIS MA. ESCHRICHT FM. WILLEBERG P. RIJNBERK A. and prolac- and prolactin during progression of the luteal phase in healthy dogs: tin on progesterone secretion during mid-pregnancy and -diestrus. in the dog originates in the mammary gland. Theriogenology 2000. mal and neoplastic mammary gland of the bitch: a review. adectomy on prolactin and LH secretion and the pituitary-thyroid axis in male dogs. Fertil 2000. 49. 355–361. carcinoma cells by autocrine human growth hormone. Termination of DOORN J. LAPENSEE CR.53:941–950. 47.197: 64. KOOISTRA HS. pression in the canine uterus. 1986. RAO NAS. BEVERS MM. VAN DEN BROM WE. Theriogenology 2009. SELMAN PJ. Influence of hypophysectomy on the struct in canine mammary cells. Prolactin in canine and feline reproduction. Nord Vet Med 1976. In vivo investigation of luteal func- 48. SELMAN PJ. SPRANG EPM. 46. Theriogenology 2006.34:403–310. 56. SELMAN PJ. MOL JA. Mol Cell Endocrinol 2002. 52. 2 40. RUTTEMAN GR. MUKHINA S. Domest Anim Endocrinol 2003. VAN DIELEMAN SJ. Secretion of growth hormone tion in dogs: effects of cabergoline. LUBBERINK activation of a growth hormone (GH) promoter-luciferase con. a review. insu.119:217–222. VOORHOUT G. J Reprod Fertil 2008.12:193–201. 62. VAN NECK JW. morigenic potentials of the mammary growth hormone /growth hormone receptor system. Domest Anim Endocrinol 2000. 17b-estradiol) in canine mammary binant human insulin-like growth factor 1. References 47 39. KOOISTRA HS.170:479–484. MISCHKE R. VOORHOUT G. KOIVISTO M. RIJNBERK A. RUTTEMAN GR. HAZE- mid-gestation pregnancy in bitches with aglepristone. JÄGGI S.101:15166–15171. WOLFSWINKEL J. 51. TRYFONIDOU MA. Pituitary dwarfism in Carelian 153–165. QUEIROGA FL. J Steroid Biochem Mol Biol 2008. a progeste- WINKEL HAW. Large MALA M.Suppl 51: rol metabolism with moderate effects on intestinal mineral absorp. Hereditas 1977. 59. Growth hormone mRNA 58. Progestin-induced growth hormone excess URHAUSEN C. KOOISTRA HS. MOL JA.71:746–753 45. DEN HERTOG E. ZIMMER. OOSTERLAKEN-DIJKSTERHUIS MA.197:167–172. Ovariectomy during the luteal phase influences secretion of gestins and growth hormone excess in the dog. Trans. KRAMER S. Reprod lin-like growth factor (IGF) and IGF-binding proteins in the nor. OKKENS AC. MOL JA. young age. KOOISTRA HS. ANDRESEN E. MOL JA. VOORHOUT G. KOOISTRA HS. tion and specific effects on bone formation in growing dogs raised on balanced food. VAN GARDEREN E.110:76–82. J Reprod Fertil 1997. VASTENBURG M. Growth hormone modulates cholecalcife. J Reprod Fertil 1997. ANDRESEN E. GALAC S. autosomal recessive inheritance. Endocrinology BEYERBACH M. PÉREZ-ALENZA MA. RIJNBERK A. VERSTEGEN JP. The role of progestins. KIRPENSTEIJN J. Domest Anim Endocrinol 1997. J Endocr 2001. bear-dogs: evidence of simple. J Clin Invest can we learn from rodents about prolactin in humans? Endocr Rev 1995. MOL JA. 53. WILLEMSE AH.125 (Suppl 1):42–47 bitch.Suppl 51:339–344. DUCATELLE R. with dwarfism. VAN GARDEREN E. HOLL MS. ILLERA JC. OKKENS AC. OKKENS AC. DIELEMAN SJ.121:456–464. OKKENS AC. MOL JA. SILVAN G. LAPENSEE EW. TSHA- 41. RIJNBERK A. Pro. Pulsatile secretion pattern of growth hormone dur.66:484–490. 61. ZAPF J. WILLEMSE AH.84:232–234. SELMAN PJ. growth hormone. 55. FROESCH ER.95:2028–2034. and insulin-like growth factor-I in the 1991.24:266–273. a dopamine agonist. DIELEMAN SJ. DIELEMAN SJ. Phenotypic conversion of human mammary 65. VAN GARDEREN E. PEÑA L. DIELEMAN SJ. 44. . Expression of osteotropic growth factors and rone receptor antagonist. MOL JA. BUTINAR J. GUO K. HOPPEN H-O. VAN DEN INGH TSGAM. E. body size in the dog is associated with transient GH excess at a KOOISTRA HS. RIJNBERK A. 60. OOSTERLAKEN-DIJK. J Bone Miner Metab 2006. FAVIER RP. MAN D. Small stature and insulin-like LOPES CS. Vet Quart 1990. WILLEBERG P. BEVERS MM. Mol Cell Endocrinol 2002. CORYN M. VAN GARDEREN 57.134:287–292. 13:161–170. Clon- ing of the canine gene encoding transcription factor Pit-1 and its 82. ADAMS V.154:505–512. VAN STEENBEEK FG.13: 88. 206–210. 48 Hypothalamus-Pituitary System 66. REGNIER A. Res Vet Sci 2006. Domest 77. HERRTAGE ME. 84. Vet Rec 1993. BODINI C. LEEGWATER PAJ. WALLASCHOFSKI H. LANTINGA-VAN LEEUWEN IS. HOL. HANSSEN I. 85. BEVERS MM. characteriz. Exclusion of the lim homeodomain gene LHX4 as a candidate gene 83. Congenital hyposomatotropism in a 89. SPARKES AH. 69. MEIJ BP. MOL JA. BHATTI SFM.197: LEEGWATER PAJ. Alterations in anter- J Small Anim Pract 1998. The leukemia inhibitory factor receptor gene is not in. Cytogenet Cell Genet 2000. 2008. MOULD JRB. itary function after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism. KOOISTRA HS. growth hormone-releasing hormone and clonidine in dogs with J Small Anim Pract 2008. VILLAREAL DT. volved in the etiology of pituitary dwarfism in German shepherd dogs. PETERSON ME. J Endocrinol 1997. shepherd dogs. Acta Endocrinol 19990. 80. ISAKSEN CV. KOOISTRA HS. 79.9:305–311. Growth hormone deficiency in the adult. MAZZIOTTI G. Use of proligestone in RENIER C. Pituitary Mamm Genome 2000. and physical mapping of the canine prop-1 gene (Prop1): ex. McCONNELL F. MOL JA. WEISS EP. LOTHROP CD. Acute effects of cortisone acetate on growth hormone response to growth hormone-releasing hor- 73. BREEN M. BOSSONI S. KOOISTRA HS.226:1494–1497. 74.155:518–521. BRABANT G. HAUG E. MOL JA. Pituitary function and morphology Progestin-induced growth hormone (GH) production in the treat- in two German shepherd dogs with congenital dwarfism. BONADONNA S. RIJNBERK A. MOL JA. Assessment of a combined anterior pituitary function test 542–545. itary 2007. RIJNBERK A. SCHMEITZEL LP. . MEIJ BP. KOOISTRA HS. 531–539. BEVERS MM. GIUSTINA A. Pathophysiology of canine growth hormone- 70.7:681–687. VAN HERPEN H. 1346–1349. VOORHOUT G. VAN OOST BA.58:169–173. with congenital growth hormone deficiency.24:59–68. RIJNBERK A. RIJNBERK A.134:171. crinol 1998. MOL JA.10:129–133. RIJNBERK A. J Am for pituitary dwarfism in German shepherd dogs. dwarfism. VAESSEN MMAR. RUTTEMAN GR. LEE. KLEIN S. SCASE TJ. Vet Med Assoc 2005.43:164–170. GARNIER F.197:57–62. ALTSZULER N. MOL JA. DOGA M. bodies to biosynthetic human growth hormone in the dog. ior pituitary function of dogs with pituitary-dependent hyperadre- nocorticism. 86. LOSZY JO. Hypochondroplastic dwarfism in the Irish setter.11:31–36. SELMAN PJ. Rec 2004. J Small Anim Pract 2002. Cloning. MOL JA.88: 81. 1996.49:306–309. Aging Cell 92. Residual pitu- 140–144. Vet Rec 1994. DOGA M. HAMANN F.42:1881–1883. WM. 2 67. DONALDSON D.81:316–320. Anim Endocrinol 2003. KOOISTRA HS. exclusion as candidate gene in a canine model of pituitary dwarfism. Pulsatile secretion pattern of growth hormone in dogs with pituitary-dependent hyperadrenocorticism. MEIJ BP. mone secretion in spontaneous canine hyperadrenocorticism and its reversal after treatment. ROMANELLI G. MOL JA. Vet Rec ment of dogs with congenital GH deficiency.122: responses after single administration of thyrotropin-releasing hor. HANSON JM. Long-term effects of calorie or protein restriction on serum IGF-I and IGFBP-3 concentrations in humans. RIJNBERK A. MEIJ BP.10: MEIJ BP.144:644–646. MOL JA. VAN OOST BA. 76. FONTANA L.15:93–102. VAN HERPEN H. KOOISTRA HS. 90. IMHOLZ S. Domest Anim Endo- 1999. GRAMMELTVELDT AT.155: 68. VAN OOST BA. Production of anti. FRANK LA. Proc 16th ECVIM-CA Congress. Oral low-dose dexamethasone suppression test using urinary corti- coid /creatinine ratios: a dose-finding study in healthy pet dogs. RIJNBERK A.133: BERK A. GIRELLI A. Normal levels of serum IGF-I: determinants and validity of current reference ranges. Growth hormone responses to domestic shorthair cat presenting with congenital corneal oedema. BARTELS T. Domest Anim Endocrinol 1996. MOL JA. BREEN M. RENIER C. Cushing’s syndrome. Res Vet Sci 1995. in beagle dogs: Rapid sequential intravenous administration of four hypothalamic releasing hormones. Genetic cause of pituitary dwarfism in German 1333–1341. RIJNBERK A. Am J Vet Res 1981. J Am Vet Med Assoc 1990. crinol 2002. responsive alopecia. LEGATI F. MOL JA. Domest Anim Endocrinol 87. Hormonal abnormalities in Pomeranians with normal coat and in Pomeranians with growth 71. 91. 75. Amsterdam 2006:176. Pitu. HAZEWINKEL HAW. Comp Contin Educ Pract Vet 1988. KOOISTRA HS. Vet 78. VERSTEEG SA.39:10–14. GIUSTINA A. GOLA M. BEVERS. FALCK G. MEIJ BP. hormone-responsive dermatosis. VOORBIJ AMWY. 2006. mone and combined administration of four hypothalamic releasing hormones in beagle dogs. LANTINGA-VAN LEEUWEN IS. MOL JA. Suppression of growth hor- 465–468. Growth hormone-responsive alopecia in dogs. RIJN. KOOISTRA HS. GOTTSCHALK S. Mol Cell Endo. KNOTTENBELT CM. the management of three German shepherd dogs with pituitary ation. Disturbed release of growth hormone in mature dogs: a comparison 72. RIJNBERK A. RIJNBERK A. LOTHROP CD. clusion as a candidate for combined pituitary hormone deficiency in German shepherd dogs. Thyroid-stimulating hormone mone in normal adult subjects. KOOISTRA HS. J Endocrinol 1997. GANDINI G. RE. Dordrecht/Boston 1996. hormone-secreting tumor shrinkage after 3 months of octreotide- long-acting release therapy predicts the response at 12 months. THEON AP. GOOSSENS MM. CHURCH DB.35:352–361. J Small Anim Pract 100. NIESSEN SJM. VAN DEN INGH TSGAM. Long-term effects of calorie and protein restriction Anim Endocrinol 2007. treatment for acromegaly. J Vet Intern Med 1990.160:393–397. Measurement of growth hormone and insulin-like 2 94. PREZIOSI R. RIJNBERK A. NELSON RW. Vet Rec 119. PETERSON ME. LOTHROP CD. HOL- HS. megaly: an underdiagnosed endocrinopathy? J Vet Intern Med 2007. J Am Anim Hosp Assoc 1984. LAWRANCE J. . WERGIN treotide in cats with diabetes mellitus. Cobalt 60 ir- mone in juvenile miniature poodles. VAN DEN INGH TSGAM. BREARLY MJ. GRASSO LFS.21:889–891. J Small Anim Pract 2002. DE BURLET G. NELSON RW. M. Domest LOSZY JO. Hypothalamus-pituitary system. KOOISTRA 111. VAN OOSTERHOUT MFM. Clin Endocrinol 2009. NIESSEN SJM. TAYLOR RS. SAVASTANO S. HOLMBERG DL. HIGHAM C. MEIJ BP. CLAFFEY FP. 2006. 97. VERHOEVEN BJP. RIJNBERK A. Feline acro. dation and application of a radioimmunoassay for ovine growth hormone in the diagnosis of acromegaly in cats. HOLDER D. NELSON RW. RUTTEMAN GR. LOMBARDI G. 96. Cardiac changes induced by excess exogenous growth hor.160:902–907. FRACASSI F. KLEY S. PO- mellitus with pituitary neoplasms in a horse and in a dog. PATRICK DH. 1993. 104. 112. Vet J 2008. KASER-HOTZ B. KLEIN S. CHURCH DB. KOOISTRA HS. LITTLER RM. Elevated 118. KOBLIK PD ELLIOTT DA. PIVONELLO R. CHEN HY. EIGENMANN JE. SON SA. CHUNG TT. KING JM. MAHONEY P. MOROFF SD. J Vet In. J Am Vet Med Assoc 1998. 105. VAN DER VLUGT-MEIJER RH. COLAO A. PRAHALADA S. Vet Pathol 1996. DIANA A. Vali. CERUNDOLO R. LEWITT MS. 98.11–34. GALDIERO growth hormone levels and diabetes mellitus in a cat with acro. ed.26:185–200. ZAPF J. AURIEMMA RS. BLOIS SL. In Rijnberk A. STABINSKI LG. Diabetes mellitus in a dog with a growth hormone-producing acidophilic 110. HOLMBERG DL. WORTMAN JA. WEISS EP. AA. MOONEY CT. STOKHOF 115. Tierärtzl growth factor 1 in cats with diabetes mellitus.32:43–54. WATSON ADJ. Alopecia in pomeranians and diabetes mellitus in five cats with somototrophic abnormalities. noma treated with hypofractionated radiation. BOROFFKA SAEB. ance imaging and treatment by cryohypophysectomy. References 49 93. MORRISSEY 2008. Cryohyophysectomy used in the treatment of a case of feline acromegaly. Vet Rec 2007.71:68–91. J Feline Med Surg 2004. five cats.3:1–16. HASKINS ME. Pharmacological and toxicological effects of 114. Aging Cell 2008. TRYFONIDOU MA.213:374–376. SLINGERLAND LI. Feline Med Surg 2000. VAESSEN MMAR. PETERSON ME. NORMAN EJ. Serum insulin-like growth factor-1 con. FONTANA L. KHALID M. TAN K. KAVANAUGH JF. Investigation of serum adenoma of the adenohypophysis. ABRAMS-OGG ACG. FELDMAN EC.7:681–687. Cornell WELL SE. 103. MORRI- Pathol 1998. MOL JA.49:596–600. LUKSCH F. POLTON GA. Acromegaly in cats: Are we only diagnosing the tip of the iceberg? J Vet Intern Med 2007. J Small Anim Pract 2006. GRECO DS. FAMIGLI-BERGAMINI P. REUSCH CE. Acromegaly due to a somatotroph adenoma in a dog. PETRIE G. Domest Anim Endocrinol M. NELSON RW. MOL J. Kluwer Academic Publishers. DRAKE WM. 117. Acromegaly in a cat: diagnosis by magnetic reson- 99.47:392–395. Regulation of insulin-like growth factor- Vet 1962. BENTINCK-SMITH J. CHURCH DB.130:209–215. Über Hypophysentumoren beim Hunde. STARKEY SR. Radiotherapy of pituitary tumours in 2008. KASS PH. 102. ROHRER CR. FELDMAN EC.4:192–201. centration in cats with diabetes mellitus and acromegaly.21:892–898.21:899–905. 107. J Endocrinol 2000. CASELLA M.158:195–200.20:747–752. FIDEL J. 2007. J Clin Endocrinol Metab 2008. RIJNBERK A. VAN KEULEN LJM. accepted radiation of pituitary gland tumors in three cats with acromegaly. J miniature poodles in association with high urinary corticoid:creati. J Comp Path 2004. nine ratios and resistance to glucocorticoid feedback. LLOYD DH. Somatotroph and corticotroph pituitary 116. REUSCH C. Growth megalic features. Growth hormone excess and the effect of oc.34:682–685.43:303–307. Resolution of adenoma (double adenoma) in a cat with diabetes mellitus and hy. 120.93:3436–3442. RIJNBERK A. CHURCH DB. POL- LARD R. KHALID M. Acromegaly in 14 cats. IGF-I levels amongst diabetic and non-diabetic cats. PETRIE G. Can Vet J SMYTH JBA.52:133–145 binding protein-3 ternary complex in feline diabetes mellitus. STANKEOVA S. 101. Toxicol RANDOLPH JF. WESDORP JL.166:21–27. TRAINER PJ. 108. TAN K. Diabetes 109. Vet Rec Arch 1923. VEGTER AR.33:451–453. 95. KOOISTRA HS. VAN ZWIETEN MJ. FOODMAN MS. Diagnosis and management of KOOISTRA HS. VOORHOUT G. PETER CP. REFSAL KR. on serum IGF-I and IGFBP-3 concentration in humans. Long term experience of pegvisomant therapy as a tern Med 2007. STEWART WA. HAZEL SJ. 113.6:149–155. Clinical endocrinology of dogs and cats.1:183–190. chronic porcine growth hormone administration in dogs. BERG RIM. diabetes mellitus but not acromegaly in a cat with a pituitary ade- peradrenocorticism. VILLAREAL DT. GAUDIANO F. 106. Suppl 57:55–60. RUTTEMAN GR. Pro- gestin treatment in the dog: I. WOLFSWIN- KEL J. 50 Hypothalamus-Pituitary System 121. Dioestrous ovariectomy: a model to study the role of progesterone in the onset of canine pseudopregnancy. BEVERS MM. phobe carcinoma with a low level of serum gonadotropin and aspermatogenesis in a dog. SATO J. KOOISTRA HS. growth hormone overproduction and naturally occurring canine LAWS ER. EIGENMANN JE. Acta Endocrinol 1981. surgery. MOL JA. MARTÍN DE LAS MULAS J. WATSON ADJ. 147. LOPES M-BS. The long-term significance of microscopic dural invasion in single injection of depot medroxyprogesterone acetate. growth hormone 141. Effects on the hypothalamic-pitu- 146. Steroids 1996. ELLEGALA DB. growth hormone in relation to ovarian activity in the dog. MOL JA. 126. J Reprod Fertil ate. Divergence between growth hormone Effect of somatostatin analogue SMS 201–995 and antiprogestin and insulin-like growth factor-I concentrations in the follow-up agent RU486 in canine acromegaly. Acromegaly associated with transient 148. mRNA in mammary gland tumors of dogs and cats. REYMUNDO C. Secretion of prolactin and carbohydrate metabolism. RIJNBERK A. EIGENMANN JE. LAWS study of feline mammary fibroeptithelial hyperplasia following a ER. GOBELLO C. HORI T. and glucose homeostasis. KONTOGEORGOS G. ABS B. TAVERNE MAM.44:240–242. BELSHAW BE. NOMIKOS P. OKKENS AC. STEFAN- DER GAAG I. SELMAN PJ. ORDÁS J. AGRAWAL A. MEIJ BP. HORVATH E. ALEXOPOULOU O. Theriogenology 2008. 136. KOOISTRA HS. DIELEMAN SJ. GOYA RG. RIJNBERK A. insu. 131. and 137. BASCHAR H. PUENTE S. RUTTEMAN GR. 132. BUTLER WR. 133. pathological and immunohistochemical 142. SCHEITHAUER BW.76:227–233. 125. MACKAY GA. PERNICONE PJ. Front Horm Res 1987. DIELEMAN SJ. BROGLIA G. RIJNBERK A. changes in spontaneous and aglepristone-induced parturition in dogs.98:599–602. 1987. KOVACS K. OKKENS AC. SELMAN PJ. GOBELLO C. MEIJ BP. BEX M.38:99–107. Clinical. RIJNBERK A. MOL JA. NIERS B. NA- lin-like growth factor.7:43–52. VAN 143. NORMAN EJ. 129. THAPAR K. RIJNBERK A. troversies in the management of non-functioning giant pituitary macroadenomas. CINCU R. MURRAY D. GORYO M.42:354–357. 124. J Small Anim Pract 2003. J Clin Endocrinol Metab 2005.131:413–421. SELMAN PJ. . CASTEX G.90: 3089–3099. 193–198. J Endocrinol 1997.154:505–512. Reprod Dom Anim 2001. colour changes associated with cabergoline administration in Res Vet Sci 2004.95:2028–2034. KOOISTRA HS. J Am Anim Hosp Assoc 1981. 134. BEVERS cortisol in dogs developing mammary nodules and a acromegaly- MM. 135. FROESCH ER.106:1173–1177. ORDÁS J. II. Pro- gestin treatment in the dog. MILLÁN Y. RIJNBERK A.17:813–822. VAN GARDEREN E. Res Vet Sci 140.69:399–407.96:195–208. Eur J Endocrinol 1994. Progestagen- induced and spontaneous canine acromegaly due to reversible 144. Neurosurgery 1996. ALTSZULER N. KIRIHARA N. prolactin. TSUTSUI T. Current concepts and con- rone and glucocorticoid receptor.61:133–137. HAMP- SHIRE J. NAITO Y. Proliferative activity and invasiness among pituitary diabetes and acromegaly. Pituitary carcinoma in an Airdale terrier. adenomas and carcinomas: An analysis using the MIB-1 antibody. MAITER D. Coat and insulin growth factor-I in feline fibroadenomatous change.36:115–119. Effects on growth hormone. Acta Endocrinol 1983. New Zeal Vet J 2006. ZAPF J. 145. WOLFSWINKEL J. KALTSAS GA. J Reprod 127. CASTEX G. 130. DA SILVA ILHA MR.63:183–185. Hormonal 360–364. ALDEN TD. 128. 2003. RUTTEMAN GR. YANO A. Can Vet J itary-adrenocortical axis. DE LA SOTA RL. 123. VENKER-VAN HAAGEN AJ. OSAWA T.131:422–430. of pituitary carcinomas. GROSSMAN AB. MARTÍN DE LAS MULAS J. SATO R.44:352–354.104:167–176. ALTSZULER N. Influence of medroxyproges- terone acetate (Provera) on plasma growth hormone levels and on 138. SELMAN PJ. PETERSON ME. CONCANNON PW. MOL JA. J Neurosurg 2002.93:1324–1330. Fertil 2001. LORETTI AP. OKKENS AC. HAMPSHIRE J. RIJNBERK A. BAAN M. Theriogenology 2007. Progesterone-controlled EANU L. TOMIZAWA N. J Am Vet Med Assoc anterior pituitary function of dogs with pituitary-dependent hy- 1980. Alterations in overproduction of growth hormone in a dog. GOEL A. EIGENMANN JE. 2 122. Effects of megestrol acetate on glucose to- lerance and growth hormone secretion in the cat. Growth hormone. HANSEL W. MOL JA. BUCH- growth hormone oveproduction: clinical picture and patho. RIJNBERK A. Eur J Endocrinol KADA K. J Clin Endocrinol Metab 2008. peradrenocorticism.17: of acromegaly. J Feline 354 patients with pituitary adenomas treated with transsphenoidal Med Surg 2005. Diagnosis and management genesis. FELDER M. dopregnant bitches: a clinical study. EIGENMANN RY. WOLSKY KG. Immunohisto- chemical expression of progesterone receptors. 1997. Plasma concentrations of prolactin in overtly pseudopreg- like appearance during treatment with medroxyprogesterone acet- nant Afghan hounds and the effect of metergoline. Endocrinology 1980. bitches. J Vet Med Sci 2001. MOL JA. DE GIER J.67: 1032–1038. Clin Neurol Neursurg 2007. lated diabetes mellitus in two dogs. VELKE. EIGENMANN JE. CORRADA Y. RUTTEMAN GR. Growth hormone 139. KINAI M. ESPINOSA DE LOS MONTEROS A. T’SJOEN G. Pregnancy-re. Pituitary chromo- 1994.54: KINDAHL H.177:534–537.109:645–650. CONCANNON PW. Binding specificity of medroxyprogesterone acetate and proligestone for the progeste. Suppl 51:295–301. J Clin Invest Plasma progesterone and prolactin concentrations in overtly pseu- 1995. 68:1169–1176. betes mellitus. en. 166. BEVERS MM. CASTILLO VA. BERGSTRÖM A. MEIJ BP. In: Kro- vival. and pathologic findings associated with large pitu. Radiation therapy for pituitary tu. A. MAYER MN. PETERSON ME. J Small Anim Pract 2006. ment. 329–333.4: noma with associated oculomotor nerve lesion in a cat). RICHTER MA. 174. vier. Can Vet J ing in dehydrated dogs.240:E394–E401. Can Vet J 2007. J Vet Intern Med 2003. surgery. Larsen PR. and vasopressin secretion. J Am Vet Med 2007. 172. MEINTJES RA. MICHIELETTO A. J Endocrinol 2004. Dynamic computed tomography of the pituitary gland in dogs with pituitary-depend. SCHMIDT P. cuitry of trust and trust adaptation in humans. Tierärtztl 209–217.180:439–448. Philadelphia: Saunders Else- Vet Intern Med 2007. Somatotropes Hypophysenadenom mit Läsion Coarse fractionated radiation therapy for pituitary tumours in cats: des N. SON K. HILBE M. BAUMGARTNER T. and during osmotic stimulation in dogs. OKKENS AC. BREARLY MJ. GÓMEZ NV. Polonsky KS. 171. REINER RF. Prax 1998. Suspected pituitary apoplexy in a Ger- man shorthaired pointer. Pituitary apoplexy. MOL JA. Physiol tumor irradiation in cats. 175. VAN DER VLUGT-MEIJER RH. Neurologic. Satiety and inhibition of vasopressin secretion after drink- rotumors in dogs: a retrospective study of 12 cases. KWANT MM. 177. Posterior pituitary. CARILLO JM. SWENSON L.54:359–363. Vet J 2003. OLSSON K. Plasma oxytocin concentrations docrinologic. 170. 639–650. KNOTTENBELT CM. Effects of anesthesia. SARFATY D. oculomotorius bei einer Katze (Somatotrope pituitary ade. FRACASSI F. Melmed S. salt appetite. HÄGGSTRÖM J. Mol Cell Endocrinol 2002. 158. LONG SN. BERTOLINI G. J Pharmacol Exp Ther 1989. Cushing’s disease in dogs: Caber. DIANA A. OLS- 152. LITTLER RM. KOOISTRA HS. J Am Vet Med oxone in conscious dogs. HEINRICHS M. LAGERSTEDT AS. VOORHOUT G. J Vet Med A 2007.193:854–856. BERGSTRÖM A. CALDIN M. dog. VAN DEN INGH mest Anim Endocrinol 2004. SAY DJ. HYDBRING-SANDBERG E. Oxytocin shapes the neural cir- 154. VAN DEN BROM WE. after water deprivation. WOLFSWINKEL J. Res Vet Sci 2008. STRICKER EM. 162. RAM- BERG D. HAUPTMAN JG. ent hyperadrenocorticism. 173. Physiological reactions to fear provocation in dogs. tile secretion pattern of vasopressin under basal conditions. TAVERNE MA. 161. ROBINSON AG. CABRERA BLATTER MF. FELDMAN E. ALLGOEWER I. nocorticism. References 51 149. 169. LAGERSTEDT 2 150. THEON AP.165: 153. VAN VONDEREN IK. VAN DER VLUGT-MEIJER RH. Increased plasma concentrations of vasopressin. CROUGHS RJM.27:1–12. MOL JA. J Textbook of Endocrinology. BRUNNBERG L.118:271–277. Plasma 160. HANSSON K.21:1027–1033. THEON AP. cor- mas and macroadenocarcinomas in dogs treated with mitotane for tisol and prostaglandin F2alpha metabolite during labour in the pituitary-dependent hyperadrenocorticism: 13 cases (1981–1986). 155. MAYER MN. TSGAM. Vasopressin. trations in healthy dogs. and prognostic factor in dogs with pi. Pulsa- hyperadrenocorticism. DEVAUCHELLE P. and catecholamine concentrations in dogs with dilated cardiomyopathy. Effects of radiotherapy on pituitary corticotroph mac.179:281–287. KLARENBEEK M. GARCÍA JD. DE FORNEL P. VOORHOUT G. Neuron 2008. . ODENDAAL JSJ. MANDRIOLI L. a retrospective study of 12 cases. VONLANTHEN A.26(K):267–272. Eight cases (1976–1984).48:481–486. nenberg HM. FISCHBACHER U. NISTAL-HERRERA JF. VON WALTER LW. J Vet Intern Med 2006. PHILIPP K. FELDMAN EC. cortisol.61:1273. Neurophysiological correlates of affiliative behavior between humans and dogs. 157. mors in the dog and cat. HELLEBREKERS LJ. KENT MS. GRINS. during late pregnancy and parturition in the dog.20:1151–1154. BOMMARITO D. Theriogenology itary tumors in dogs. KEIL LC. RIJNBERK A.85:26–34. WILLIAMS 296–301. TIDHOLM A. Pituitary macrodenoma in a cat with dia. Vet Compar Oncol 2006. POLTON GA. NELSON RW. ROSSETTI E. TREUIL PL. GREVEL V. NACH- goline treatment. LUND K. HÖG- ticosteroid secretion in dogs with pituitary-dependent hyperadre. hypercortisolism and neurological signs. MOL JA. J Am Vet Med Assoc 1989. J Small Anim Pract 2003. GANDINI G. melanotrophin and cor. 2008. Am J Physiol 1981. Am J Vet Res 2005.48:316–318. THRASHER TN. Behav 2007. WOOD SL. ROSEN. KOOISTRA HS. RIJNBERK A. IHLE SL. 11th ed. Megavoltage irradiation of pitu. Outcomes of pituitary control of thirst.248: Assoc 1998.17:773–780. FRANSSON B.47:456–460.91:404–412. NIESSEN SJM. J Vet Intern Med 2007. arginine vasopressin response to intravenous methadone and nal- itary macrotumors in dogs with neurologic signs. FEHR E. Do- 156.66:1709–1717.58: like disease in 4 dogs. J Endocrinol 1988. oxytocin. Presystemic signals in the 163.194:1612–1617. FORKMAN B.263–295. 165. 167. SVARTBERG K. ANDERSON TJ. MEIJ BP. DELISLE F. OOSTERLAKEN- Imaging of the pituitary gland in dogs with pituitary-dependent DIJKSTERHUIS MA. Acta Physiol Scand 2003. 176. Williams tuitary masses treated with radiation therapy and untreated dogs. Ef- fects of bromocriptine on corticotrophin. LALIA JC. AS. HOFFMANN ML. and intravenous ad- ministration of fluids on plasma antidiurectic hormone concen- 159. Primary uterine inertia in 27 bitches: aetiology and treat- WIS G. KINDAHL H. Am J Vet Res 2000. 168. RIJNBERK A. FELDMAN EC. 151. eds.197:81–87. VERBALIS JG. Sur. Assoc 1988.21:1251–1257. neurologic response. Pituitary macroadeno.213:225–231. 2007. GRECO DS. 164.44:497–502. LARUE SM. CLARK EG. Dynamic computed 202. Concurrent cen. J Vet Intern Med 2003. SHEMESH O. HARA Y.17:773–780. transsphenoidal hypophysectomy in dogs with pituitary-depend- ent hyperadrenocorticism.45:504–409. VAN DEN INGH TSGAM. FRØKIAER J. RIJNBERK A. VAN ’T HOOFD MM. GOOSSENS MMC. MOL JA. 201. RIJNBERK A. VOORHOUT G. with polyuria as the leading symptom. SEGEV G. SMITH JR. J Small Anim Pract 1999. KOOISTRA HS. 204. STERCHI HP. Osmoregulation of 197. BIERY DN.9:2181–2193. Aldosteronoma in a dog 190. SCHWEDES CS. 186. MOL RAMSEY IK. J Vet Intern Med 1995. MEIJ BP. GRIFFEY SM. VAN SLUIJS FJ. ROBERT- renocorticism associated with high plasma adrenocorticopin con. Progress in transsphe- noidal hypophysectomy for treatment of pituitary-dependent 184. J Small Anim Pract 2004. Persistent polyuria in Med Sci 2006.40:392–396. DIGNEAN MA. WOLFSWINKEL hyperadrenocorticism in dogs and cats. JOHNSON GC. MOL JA. GOPAL MS. sipidus in a cat. RAFF H. 189.65:17–22. MAZAKI-TOVI M. 194. VOORHOUT G. Vet Quart 1089. RIJNBERK A. BOER P.86:102–105. Vet Med Sci 2003. NEZU Y. Vet Rec 2008.107:830–40. 203. MEIJ BP. Central diabetes insipidus in a dog with a 2002. sponse to osmotic stimulation and effects of desmopressin on uri- tral diabetes insipidus and panhypopituitarism in a German shep. KOOISTRA HS. VOORHOUT G. MOE L.24:569–573. SARFATY H. J Small Anim Pract 1999. hibit basal vasopressin release in conscious dogs. SON GL. CAMPBELL FE.11:193–197. RIJNBERK A. GALAC S. TAODA T. MCNEILL JR. MOL JA. WOLFSWINKEL J. Hypodipsic hypernatremia in a dog with defective os- centration and a hypothalamic /pituitary mass. SANNO N. J Am Vet Med Assoc 1989. J Neurosurg 2007. Domest Anim Endocrinol 2004.9:361–365.19:687–94. pro-opiomelanocortin-producing pituitary tumor not causing hy- peradrenocorticism. KOOISTRA HS. 188. Am J Physiol TERAMOTO A. JOHNSON SE. MARPLES 2005. VAN DEN INGH TSGAM.7:135–139. Neurohypophyse beim Hund. MØLMEN GS. Transient diabetes insipidus in a dog with acro- megaly. FERGUSON DC. POST K. nary concentrating capacity in dogs with pyometra. LARSEN NH. TAODA T. HERRTAGE ME. 191. THOMPSON H. NIELSEN L. 185. aquaporin-2 excretion in dogs: a marker for collecting duct re- sponsiveness to vasopressin.7:333–339. Central diabetes insipidus in dogs: hypophysectomy in treatment of dogs with pituitary-dependent 20 cases (1986–1995). RIJNBERK A. J Small Anim Pract 1983. TESKE E. RAMSEY IK. two dogs following adrenocorticolysis for pituitary-dependent hy- peradrenocorticism. Imaging of the pituitary gland in dogs with pituitary-dependent KOOISTRA HS. VAN DEN focal B cell lymphoma in a dog. hyperadrenocorticism. HAN JS. OLY- tomography of the pituitary gland in dogs with pituitary-depend.128: 483–486. 187. RIJNBERK A. MOL JA. Decreased aquapo- rin-2 expression and apical plasma membrane delivery in kidney collecting ducts of polyuric hypercalcemic rats. Mol Cell Endocrinol 2002. systemic vasopressin release during long-term glucocorticoid ex. NYK GP. diagnosis and oral desmopressin therapy. VAN VONDEREN IK. BIEWENGA WJ. MEIJ BP.68:1–7. VOORHOUT G.65:404–408. VAN DER VLUGT-MEIJER RH. 181. Efficacy of transsphenoidal CRIEFF JC. AROCH I. MEIJ BP. HARB MF. MELLANBY RJ. Aust Vet J 2008. TAGAWA M. MASUDA H. KOOISTRA HS. Vasopressin secretion in re- 192.27: 195. ELWOOD CM. CHANG Y-P. VAN DER VLUGT-MEIJER RH.17: a cat. ZANESCO SA. J Vet Intern Med 2005. BOER WH. Central diabetes insipidus associated with primary JA. Diabetes insipidus and hyperad. ghan hound pups. J Feline Med Surg 2005. Am J Vet Res herd dog. Traumatic partial hypopituitarism in urinary dilution and concentration. D. Congenital diabetes in- sipidus in a kitten. Prognostic factors for outcome after hyperadrenocorticism. PAPANEK PE. Physiological increases in cortisol in. SCOTT-MON. 52 Hypothalamus-Pituitary System 178. HANSON JM. HANSON JM.266:R1744–1751. HARA Y. 2004.194:1086–1088. FUJITA Y. PERRIN IV.197:81–87. NELSON RW. Schweiz Arch Tierheilk 1986. DENNIS R. J Vet 183. JEFFERY ND. 206. HASEGAWA D. 1994. TAKEKOSHI S. 199. 1994. J Am Soc Nephrol 2006. MEIJ B. FELDMAN EC. J Am Vet Med Assoc 1996. HERRTAGE ME. .193:835–839. TESKE E. IJZER J.40:271–274. Acta Endocrinol acetate for diabetes insipidus after hypophysectomy in the dog. 205. 141–153. BREDHAUER B. VOORHOUT G.20:227–240. VAN VONDEREN IK.209:1884–1888. OSAMURA RY. VOORHOUT G. Urinary Secondary hypothyroidism following head trauma in a cat.124:583–588. 200. Domest Anim Endocrinol Diabetes insipidus centralis durch Larva migrans visceralis in der 2001. J 1991. WINTERBOTHAM J. VOORHOUT G. Body water homeostasis: Clinical disorders of 193. SCHRIER RW.204:922–925. NEZU Y. INGH TSGAM.197:89–96. Trauma-induced diabetes in- 1998. Mol Cell Endocrinol J. HAMMOND GJ. NIELSEN S. Functional and morphological changes in the hypothalamus-pitui- tary posterior lobe system after hypophysectomy in dogs. TAGAWA M. Congenital central diabetes insipidus in two sibling Af- ent hyperadrenocorticism. EARM J-H. BESTETTI GE. HEIENE R. CHRISTENSEN BM. MASON KV.162:124–126. RIJNBERK A. BIEWENGA WJ. J Am Vet Med moregulation of antidiuretic hormone. 1820–1832. J Am Soc Nephrol 196. J Feline Med Surg 180. Central diabetes insipidus in five cats: clinical presen- tation. 2 179. VAN VONDEREN IK. 182. MASUDA H. DiBARTOLA SP. KNEPPER MA. 198. Prophylactic efficacy of desmopressin cess: A study in dogs with hyperadrenocorticism. J Am Vet Med Assoc Assoc 1988. MAGALDI AJ. MOL JA.65:1518–1524. MOSES AM. KYEARM J-H. PITTARI JM. Assessment of pituitary SPRANG EPM. hydrochlorothiazide in lithium-induced nephrogenic diabetes in- sipidus is associated with upregulation of aquaporin-2. JOO KW. VOORHOUT G. Res 1992. TAKEMURA N. J Small Anim Pract 2003.265:R1247–1252. VAN 1998.28:245–251.14:81–97. eds. 220. Central diabetes insipidus in a cat. VOORHOUT G.12:13–24. KNEPPER MA. Medical history and physical examination in porin 2 mutations in nephrogenic diabetes insipidus. Wien Tierärtzl 2001. KRAUS JS. Nephrogenic diabetes insipidus in a dog 233. MEIJ BP. POST GS. COHEN M. J Recept 1995. J Small Anim Pract 234. HELLEBREKERS LJ. 217. RIJNBERK A. Am J Vet Res 2004. Vet Surg on water intake and urine excretion in dogs). 218. Vet Surg 1998. J Am Vet Med Assoc 2003. 6th ed. two dogs following adrenocorticolysis for pituitary-dependent hy- peradrenocorticism. 232. J Am Vet Med Assoc 1999. Aqua. DEEN PM. Semin companion animals. with renal medullary lesions. BIEWENGA WJ. HENDERSON SM. VAN VONDEREN IK. 1999. 2nd edn. Successful long-term treatment of congenital nephrogenic diabetes insipidus in a dog. ELWOOD CM. PETERSON ME. nephropathy in two related Pembroke Welsh corgi puppies. KIM G-H. van Sluijs FJ. VAN VONDEREN IK. CLAYTON B. Evaluation Medicine. ticoid excess and impaired osmoregulation of vasopressin release in RASCHER W. VAN DEN INGH TSGAM. TIMMERMANS- SPRANG EPM. BIEWENGA WJ.44:280–284. Chronic glucocor.215: two dogs with secondary polycythemia. NA lated AVP release in patients with primary polydipsia. 235. New insights into the paradoxical effect of thia- to osmotic stimulation in 18 young dogs with polyuria and poly. Am J Phy. Vet Quart 1989. VAN DER VLUGT-MEIJER RH. Feline Pract and interindividual variation in urine osmolalilty and urine spe- 1996.13:419–425. Antidiuretic effect of siol 1993. VAN OS CH. schizophrenic patients. KOOISTRA HS. cific gravity in healthy pet dogs of various ages. Cryptococcal pye- 209. RIJNBERK A. LANGSTON CE. VAN VONDEREN IK. 216. NaCl co- 213. Familial renal disease in dogs and cats. MEIJ BP. VAN DEN INGH TSGAM. BEHNSEN K. LEE JW. VAN DEN INGH TSGAM. transporter. CHANG HR. Effect of methadone on plasma arginine vasopressin level and urine production in consicous dogs. KOOISTRA 223. GRÜNBAUM EG. J Am Vet Med Assoc 1979. 228. McKAY LW. MOL JA. HAN JS. BROWN BA.18:800–806.30:72–86. 231. in healthy dogs.11:30–35. GRUYS E. RIJNBERK A.207–212. In: Rijnberk 221.39:592–594.11:193–197. RIJNBERK A. MOL JA. Results of transsphe. eds. . J Vet Intern Med 1997. 224. Nephrol Dial Transplant dipsia. 229. Disturbed vasopressin release in function after transsphenoidal hypophysectomy in beagle dogs. zur Wasseraufnahme und Harnabgabe beim Hund (Investigation itary-dependent hyperadrenocorticism in 7 cats. BEVERS MM.136:279–286. 222. LUZIUS H. Eur J Pharmacol 1987.12:351–368. 211. RITCHEY JW. Nephrogenic diabetes insipidus in a dog 2 HS. J Vet Intern Med 1993. MEIJ BP. J Clin Endocri- nol 1996.24:18–21. RIJNBERK A. SEGUIN MA. HESS M. ROBERTSON GL. 208. WIMERSMA GREIDANUS TB. St Louis: Elsevier Saunders 2005:1819–1824. four dogs with so-called primary polydipsia. Domest Anim Endocrinol V2-receptor in inherited nephrogenic diabetes insipidus.45:568–571. polydipsic.81:163–169.222:180–183. FAHRENHOLZ F. RIJNBERK A.15:1903–1905.15:2836–2843. Transsphenoidal hypophysectomy for treatment of pitu. DiBARTOLA SP.174: HEDEKER D. MORITZ A. and epithelial sodium channel. 215. TESKE E. Juvenile insipidus. LUCHINS DJ. Edinburgh: Saunders Elsevier Nephrol 2008. In: Et- tinger SJ. Endocrine glands. zides in diabetes insipidus therapy. betes insipidus. JANS DA. References 53 207. Intra- 214. ation between gastrointestinal disease and primary polydipsia in peradrenocorticism. Polyuria and polydipsia and disturbed vasopressin release in with intestinal leiomyosarcoma.27:246–261. NEWMAN SJ. GOLDMAN MB. plasma sodium. VAN VONDEREN IK. Vasopressin receptor mutations in nephrogenic dia. KOOISTRA HS. Textbook of Veterinary Internal 210. KOOISTRA HS. ZENTEK J.7:113. The influence of polydipsia on water excretion in 830–834. JOLES JA. J Vet Intern Med 2004. RIJN. KOOISTRA HS. 212. hyponatremic. J Vet Intern Med 1818–1820. of the plasma vasopressin. 2000. HAZE- WINKEL HAW. J Vet Intern Med Domest Anim Endocrinol 1997. J Small Anim Pract 2004. RIJNBERK A. Ein Beitrag BERK A. and urine osmolality response to water restriction in normal cats and a cat with diabetes 226.28:252–265. VAN DEN BROM WE. three dogs. Semin Nephrol 2008. SCASE TJ.11:300–303. 219. Impairment of osmotically stimu. Feldman EC. LOONEN AJ. TIMMERMANS- HAZEWINKEL HAW. 2009. A potential causal associ- noidal hypophysectomy in 52 dogs with pituitary-dependent hy. Mschr 1994. ROBERTSON GL. OH YK. VOORHOUT G. MOL JA. KNOERS NV. A. MEIJ BP. LEVY JK. MEYER HP. 230. MEIJ BP. J Am Soc Nephrol Dynamic computed tomographic evalution of the pituitary gland 2004. ROTHUIZEN J. 1997.81:1465–1470. A low affinity vasopressin dogs with hepatic encephalopathy. 225. Persistent polyuria in lonephritis in a dog. MEYER H. Vasopressin response 227. BICHET DG. 24:244–245. An overview of SR121463. BIEWENGA WJ. 242.117:230–234.356:2064–2072. hanced vasopressin secretion in schizophrenic patients with hypo- natremia and polydipsia. KELLY DF. Cardiovasc Drug Rev 2001. New Engl J Med 2007. an orally active vasopressin V(2)-receptor 241.175:181–186. KRUTH SA. after transsphenoidal surgery for pituitary adenoma. Granu- lomatous amebic meningoencephalitis causing the syndrome of 244. 238. BROFMAN PJ. of the aquaretic vasopressin antagonists d(CH2)5[D-Tyr(ET) tern Med 2003. RIJNBERK A. LUCHINS DJ. Horm Metab Res 1992. Delayed hyponatremia diuresis. 54 Hypothalamus-Pituitary System 236. 246. HOUSTON DM.78:825–830. FLEEMAN LM. BERL T. . FOSSETT D. YAMAMURA Y. Psychotic excerbations and en- Aust Vet J 2000. KEOUGH L. MOL JA. antagonist – pharmacology and clinical trials.83:363–367. Tolvaptan. hormone secretion in a dog. J Neurosurg 1995. 239.19:201–214. Report of nine cases. GOLDMAN MB. J Vet In. non-peptide vasopressin V(2) receptor antagonist. IRWIN PJ. Syndrome of inappropriate antidiuretic Rev 2007. a selective 1979. PANDY GN. ALLEN DG. NAKAMURA S.30:423–425. ROOT CR. Arch Gen Psychiatry 1997. ELLISON DH. MOL JA. KNOSTMAN KAB. FUJIKI H. Cardiovasc Drug NATO MT. SPI. The syndrome of inappropriate anti. J Am Vet Med Assoc 245. POOK H. VAN OOSTERHOUT ICAM. 240. Effect inappropriate secretion of antidiuretic hormone in a dog. WEST J. MIYAZAKI T. LAWS ER JR. 243. 2–Val4]AVP and d(CH2)5[D-Phe2–Phe4]AVP on urine produc- tion in healthy dogs. PHILLIPS PA.17:230–234. MORI T. HEDEKER D. 237. BREITSCHWERDT EB. Acta Endocrinol 1988. Effects of an 2 oral vasopressin receptor antagonist (OPC-31260) in a dog with syndrome of inappropriate secretion of antidiuretic hormone. Inappropriate secretion of antidiuretic hormone in a dog. ROBERTSON GL. Can Vet J 1989. SERRADEIL-LEGAL C. RIJNBERK A. Inappropriate vaso- pressin secretion in two dogs. DIBARTOLA SP.54:443–449.25:1–13. Its wall is a single layer of cranial thyroid artery. illustrating the variable size of the thyroid follicles. roglobulin-producing follicular cells originate from a midline evagination of the pharyngeal epithelium. a branch of the common carotid. . Normal thyroid glands led with a colloid containing a large (~ 660 kDa) glycoprotein are not palpable. 55 3 Thyroids Ad Rijnberk Hans S. The lumen is fil- which enters the internal jugular vein.5.5'-L-tetraiodothyronine or L-thyroxine (T4). 3.3'-L-triiodothyronine (T3). Several of the genes involved in the early and later stages of thyroid In the dog and the cat the thyroid glands are separate lobes morphogenesis have been identified. escent (fig. (B) Immunoperoxidase stain for the calcitonin-secreting C cells or parafollicular cells in a healthy adult dog. The main hormonal secretory product of the thyroid gland tion. The thy. such accessory tissue is the sole functioning Most of the circulating T3 is produced in peripheral tissues by thyroid tissue and its secretion may be insufficient to maintain deiodination of the outer ring of T4. 3. The calcitonin- producing cells – parafollicular or C cells – are derived from the neural crest. Inner ring deiodination A B Figure 3. Rarely. 3. terfollicular spaces (fig.2.1. They are covered ventrally by the sternohyoid The basic functional unit of the thyroid is the follicle. and thyroid epithelial cells which are cuboidal or flat when qui- the principal venous drainage is via the caudal thyroid vein. called thyroglobulin (Tg)2 that is unique to the thyroid and within the sequence of which the thyroid hormones are syn- The thyroids are assembled from two different embryologic thesized and stored.1 lying beside the trachea from about the third to the eighth tracheal ring.5. The thyroid primordium begins descending toward its 3.1) and columnar when active.3'.1 Hormone synthesis and final position while still connected to the floor of the pharynx secretion by a narrow channel. a hol- and sternothyroid muscles.1: (A) Photomicrograph of the thyroid gland of a healthy adult dog. The C cells are largely located in the in- structures. mal. creted in much smaller quantities (about 20 % of that of T4). which leads to the frequent occurrence of other thyroid hormone. reflecting their dual endocrine function. originating from the fourth pharyngeal pouch. The major blood supply is via the low sphere 30–300 µm in diameter. Kooistra 3 3. the thyroglossal duct and during the descent remnants of tissue may be left along the tract. In addi.1). in their development the thyroids are intimately related is 3.2).1 Introduction a normal metabolic (euthyroid) state (chapter 3. The to the aortic sac. is se- accessory thyroid tissue in the mediastinum of the adult ani. 2: Chemical structures of the amino acid tyrosine. . namely. intrathyroidally formed iodotyrosines (MIT and DIT) and iodothyronines (T4 and T3). and two products of the peripheral deiodination of T4. T3 and reverse T3 (3'.5'.3-triiodothyronine). 56 Thyroids 3 Figure 3. 3). rT3) (fig. This prop. Iodination of the tyrosine residues of Tg results in the located at the basal membrane of the thyrocyte (fig. then moved into the colloid by exocytosis (fig. Pseudopods isotope of pertechnetate (99mTcO4–) a valuable radionuclide from the apical plasma membrane surround a portion of the for imaging the thyroid by scintillation scanning. these ions are also not organically bound in the thyroid and hence their duration within the thyroid is short. including propylthiouracil. The thiocarba- The gastric mucosa.2). (3) coupling of two DIT molecules to form T4 or MIT + DIT to form T3 (see also fig. (2) oxidation of the iodide by thyroid peroxidase (TPO) and transfer of the oxidized iodide to tyrosine residues of thyroglobulin (Tg). The iodination is catalyzed by thyroid peroxidase (TPO). 3. a mem- Iodide. called pendrin. 3.5 Their result- thyroid. saturable. methimazole. useful in the treatment of hyperthyroidism (chapter 3. This phagolysosome moves to- dized in the presence of hydrogen peroxide (H2O2) to a reac. and also able to concentrate iodide via NIS but in contrast to the carbimazole. are competitive inhibitors of TPO. Secretion of thyroid hormones requires that Tg be taken back erty together with a short physical half-life makes the radio. inorganic iodide is rapidly oxi. (5) fusion of colloid droplets with lysosomes (Ly) and subsequent hydrolysis of Tg with release of T3 and T4. is thought to facilitate the form the iodothyronines. This coupling reaction occurs separately from iodination but is also catalyzed by TPO.3). (4) endocytosis or pinocytosis of colloid droplets. The formation of monoiodotyrosine (MIT) and diiodotyrosine resulting thyroid:plasma iodide ratio is ~ 25. 3. and choroid plexus are mide drugs. Tg valent anions such as thiocyanate (SCN–). Introduction 57 3 Figure 3. salivary glands. into the thyroid cell via pinocytosis (fig. MIT and DIT then undergo oxidative coupling to thyroid cell protein.1).2). Studies in dog thyroid is actively transported (»trapped«) from the extracellular cells have shown that the regulatory cascade controlling H2O2 fluid into the thyroid follicular cells by an active. they do not bind it organically.3: Two follicular cells.2). unlike iodide. and pertechnetate (TcO4–).3'. which derives its energy from generating system of macrophages and leukocytes. colloid to form an intracellular colloid droplet. brane-bound heme-protein enzyme. which remain bound to Tg until se- apical transfer of iodide into the follicular lumen. the main building block of the thyroid hormones. These tissues as well ing ability to block thyroid hormone synthesis makes them as the thyroid also concentrate structurally-related mono. However. representing thyroid hormone bio- synthesis (left) and secretion (right): (1) Active trans- port of iodide from the blood into the thyroid cell via sodium iodide symporter (NIS). An additional (DIT). (6) deiodination of free iodotyrosines and intrathyroidal reutilization of iodide. 3. perchlorate is iodinated at the apical (follicular) border of the cell and is (ClO4–). This iodide carrier is a large (쏜 600 amino acids) transport protein called sodium iodide symporter (NIS). mainly thyroglobulin (Tg). 3.3). ward the basal aspect of the cell and becomes smaller and . 3.5'-triiodothyronine tive intermediate that is then incorporated into tyrosine resi- (reverse T3.6 Each droplet is enclosed in a membrane derived from the apical border and Once within the thyroid cell.4. is combined with a lysosome.4 Na+-K+-ATPase. generation in thyrocytes is different from that of the O2- energy-dependent process. dues of acceptor proteins.3 creted (fig. results in the metabolically inactive 3. 16 The concentration and /or capacity of circulating binding compounds may be changed by a variety of diseases and phar. Dogs have a high-affinity thyroid tration. and it also catalyzes the degradation of T3 to tion to these binding proteins.14 and T3. amin A)-binding protein.3'-T2). 3. stimulating hormone. The a-subunit is identical to a number of different transporter protein families. Glucocorticoids and acetyl. Mu. adequate thyroid hormone effect at the tissue level. the dog and the cat the genes encoding the b-subunit of TSH tations in one of these carriers in humans have been found to have been cloned and sequenced. for then the T3:T4 ratio in the thyroid secretion in- that is maintained constant by the feedback regulatory system creases. Factors that impair T3 formation. sion of T4 to rT3. As mentioned above. which in part exists as a complex with retinol (vit. 3. Overall.1. T3 has a higher binding affinity for nuclear T3 re- (fig.17. the lower binding of both T4 and T3 in canine plasma. which primarily deiodinates the min and prealbumin bind thyroid hormones with low affinity.1. and physiologic and delivery. a 28 kD glycoprotein secreted bolism have been identified.3). thereby affecting primarily the plasma total teins in plasma than does T3.2 Hormone transport. The TSH molecule con- tissue-specific as well as generalized transporters belonging to sists of an a.05 % of T4 and less than 0. Each of that of gonadotropins. and D3) that catalyze these reactions differ in tissue localization. tissue enzymes (D1.15 There is no convincing evidence that low circu- hormones can be bound to lipoproteins and also to trans.7 of T4. which results in T4 having a thyroxine (TT4) concentration. In both structure that alter the specificity of the target substance. ceptors than does T4 and therefore outer ring monodeiodi- lation in significant quantities and in healthy dogs only very nation generates a more biologically active iodothyronine. ity of type 3 deiodinase (D3). Tg itself is normally not released into the circu.6 days in dogs. as well as the inactive iodotyrosines. T4 binds more tightly to binding pro- macologic agents.18 erence ranges for TT4 for the total dog population. Low TT4 concentrations have been reported in whippets. Thus the biological activity of thyroid hormone is additionally regulated locally by tissue- Plasma T4 and T3 are largely bound to protein. salicylic acid are known to lower plasma TT4 concentration the kinetics of thyroid hormone distribution and turnover are without affecting the concentration of free T4. roidal disease. in part because of ferences may also account for deviations from established ref.15 The notion that the thyroid itself con- 0. Thus it is the free hormone concentration that de.3'-di- iodothyronine (3. much more rapid in dogs than in humans. compared dogs of small breeds tend to have somewhat higher plasma to about seven days in humans. respectively. lower metabolic clearance rate and longer half-life. be associated with severe psychomotor retardation and greatly sosomal proteases (fig.10 Breed dif. The three deiodinase 3. of the thyroid hormones. such as fasting and nonthy- termines thyroid status irrespective of the total hormone con.5 % of T3 circulate as »free« or tributes little to the T3 pool does not apply to states of hyper- unbound hormone.3 the impaired conversion of T4 to T3 is probably beneficial in sparing protein catabolism. peptides. almost invariably increase plasma rT3 concen- centration in the plasma. a minor part of the thyroid 3. vents conversion of T4 to T3 by instead catalyzing the conver- bumin acts as a thyroid hormone binding protein. Indeed.19. 58 Thyroids more dense with progression of the hydrolysis of Tg by the ly.3'-T2. inner ring. It decreases the T3:rT3 ratio in two ways: it pre- Cats do not appear to have a high-affinity TBG. substrate specificity. TSH). with small variations in confers on the TSH molecule its biological activity. This digestion of Tg releases T4 elevated plasma T3 levels. In general. whereas the b-subunit is distinct and these families has many members. but it is the free hormone concentration function. T3 small quantities can be measured in the peripheral blood by a has approximately three to four times the metabolic potency sensitive homologous immunoassay. in addition to which albu.8 In addi. The biologically active thyroid hor. T4 and T3 are inactivated by inner ring deiodination to rT3 and 3.and ab-subunit. lating T3 concentrations in illness are associated with in- thyretin. The plasma half-life of T4 is about 0.9. There is increasing evidence for by the anterior lobe of the pituitary. TT4 concentrations than do those of large breeds. and in- dividual amino acids. predominantly in the liver 3 the circulation by the action of intracellular deiodinase and kidney. About 80 % of the secreted T4 is whereas MIT and DIT are largely prevented from release into deiodinated to form T3 and rT3. which means that almost all thyroid hormone meta- bolic action can be ascribed to the action of T3.20 Like all pituitary hor- . Less than specific deiodinases. and that appears to parallel the rate of cellular uptake of these hormones. There is evidence that illness leads to increased activ- hormone binding globulin (TBG). and in sled dogs and greyhounds both TT4 and free T4 concentrations have been reported to be relatively low.3 Regulation of thyroid function In recent years several plasma membrane carriers for transport Thyroid function is mainly regulated by thyrotropin (thyroid- of both T4 and T3 to intracellular sites of action and meta.11–13 3.3). Deiodination is the most significant metabolic transformation mones T4 and T3 diffuse from the cell into the circulation. D2. only preal. and metabolism pathophysiologic modulation. For example. Re- ficient or excessive iodine supply. It thus stimulates the 3 generation of cyclic adenosine monophosphate (cAMP) as a second messenger inside the cell (fig. TRH interacts with specific receptors The hypothalamic-pituitary-thyroid axis. Hypothalamic TRH reaches the thyro- tropic cells in the anterior lobe of the pituitary via the local portal vessels and on pituitary thyrotropic cells to release TSH and on lacto- enhances TSH secretion.24 those that are euthyroid.4). involving novel extranuclear (nongenomic) mechanisms. primarily by lowering the ex. thereby accelerating resorption of Tg and subsequent hor- mone release. This autoregulation enables cently a cell surface receptor for iodothyronines was dis- immediate adaptation to acute iodide excess (e. In Ca2+-ATPase accounts for a large fraction of the effects on ca- several species each of the two TR genes yields at least two lorigenesis. covered to occur on a structural protein (integrin) of the fection of a large area of skin with iodine) that might other. TSH rapidly pro- motes pinocytosis at the apical border of the follicular cell.7. 3. The ability of thyroid hormones to affect There are multiple TRs.4). Na+-K+-ATPase concentration in muscles is differentially spliced products.1.27 .g. formed by D2. and thyroid enlargement may ensue to the extent that the glands become palpable (goiter).2). At initiation these nongenomic mechanisms do not depend There is also an intrathyroidal regulation of thyroid function upon intranuclear complexing of TR and thyroid hormone which is especially important in the presence of either insuf.7). The mitogenic action of TSH in dog thyroid is entirely me- diated by cAMP.4). from disin. There is characteristically a lag time of hours or days before thyroid hormones reach their full physiological effects. albeit that the fluctuations in its plasma concentration are very small. also occurs at the paraventricular nucleus of the hypothalamus.4 Thyroid hormone action respects thyroid hormones can be viewed as tissue growth fac- tors. but some of them require T4 and are insensitive to T3. plasma membrane of virtually all cells. Introduction 59 mones. taining body temperature and may be unable to survive in a longs to the family of steroid-thyroid-retinoid receptors. quite similar to that of steroid hormones (fig.21 TSH stimulates the thyroids by interacting with specific cell surface (G-protein-linked) receptors on thyroid follicular cells to enhance the activity of adenylcyclase. TSH is released in a pulsatile fashion (fig. particularly systemically and locally tropic cells to release prolactin (fig. particularly in the euthyroid state. Negative feedback by T3. stimulation of the basal metabolic rate or calorigenesis. which is produced locally by 5'-deiodination (D2). Long-term TSH stimulation leads to thyroid hypertrophy and hyperplasia. In many 3. inhibited primarily by T3. The TR be. 1. but they have effects in almost all tissues of the body. 1. Ani- This nuclear thyroid hormone receptor (TR) has a high affin. mals deficient in thyroid hormones have difficulty in main- ity for T3.23 On the other suggestion that these nongenomic actions contribute to a hand. earliest recognized physiological effect of thyroid hormones is ceptor. been complemented by reports on thyroid hormone action 3. Thyroid hormones. Somatostatin and possibly other neuropep.8).4). cold environment. this receptor before the thyroidal organic iodine stores (Tg) are exhausted. in iodine deficiency thyroid function is increased long basal setting of cellular functions.22 The regulation of TSH secretion is primarily under the dual control of the hypothalamic TSH-releasing hormone (TRH) Figure 3. exert negative feedback at the pituitary and hypothalamic levels.. The mediated by an interaction of T3 with a specific nuclear re.25 The normally stable wise lead to hyperthyroidism. ambient concentrations of thyroid hormone have led to the pression of the genes encoding TPO and NIS. and also by T3 derived from the sys- temic pool of free T3 (fig.4: and thyroid hormones. mediates actions of thyroid hormone on intracellular protein The thyroid also adapts to low intake of iodine by preferential trafficking and on plasma membrane ion pumps. 1. In the past decade this classical or genomic mechanism has tides exert an inhibitory influence on TSH release (figs. this being best exemplified by the consequences of thy- Most of the effects of thyroid hormones are thought to be roid hormone deficiency at a young age (chapter 3. 2.26 synthesis of T3 rather than T4. divided into a. TSH secretion is produced T3. 2. 15-fold greater than its affinity for T4.and b-forms on the the genes encoding for proteins such as Na+-K+-ATPase and basis of sequence similarities and chromosomal location. and this seems to hold true for much lower in dogs with spontaneous hypothyroidism than in the dog as well. 29. in the midline. cause of acquired juvenile-onset hypo- tainly in iodine.2 Hypothyroidism in young insufficient production of thyroid hormone despite the compensatory thyroid hyperplasia. The scan reveals only one small area of 131I radioactivity is compatible with the heterogeneous character accumulation. increased TSH Iodine deficiency is the classic cause of acquired juvenile hy. The patchy distribution of the physical activity. and duration-dependent man- ner. are rather rich in iodine. The lack of this essential ingredient of the thyroidism is lymphocytic thyroiditis. cranial to the normal site of the of the tumor: Areas lacking the capacity to trap radioioidide thyroid glands.5: dog’s growth had been retarded and it had disproportionately Scintiscan of a dog with a bilateral thyroid tumor (palpated short legs. It occurred in times when owners took too lit. 3. 60 Thyroids 3 Figure 3. Rarely the process . which prominent sign of congenital or juvenile-onset hypo. Cranial to the reference mark (square dot) hair.31.34 erally the notion that dogs and cats are carnivores. a breeding line in a closed colony of cats. However. In mild deficiencies the increased capacity for hor. dose-dependent. Sub- mingled with areas that do accumulate it (predominantly fol- stitution therapy with l-thyroxine was followed by regrowth of licular tumor tissue). pable thyroid lobes. The dog was presented because of longstanding symmetrical areas of alopecia on the flanks.2. but also to clinical manifestations of hypothyroidism.32 There have been reports of dogs in which treatment with sulfonamides for several weeks led not only to low 3. A diet consisting of meat alone is deficient in many respects and cer. fig. Animals with severe iod- animals ine deficiency are presented with the combination of large Early in life the presence of thyroid hormones is crucial for goiters and signs of hypothyroidism such as sluggishness and growth and development of all body tissues and particularly retarded growth. on the midline over the cricoid cartilage there is an accumu- lation of radioactivity in a thyroglossal duct remnant (at the level of the lingual bone).28 Hence disproportionate dwarfism may be a in which it is customary to feed manufactured diets. with symptoms such plasia. in severe iodine deficiency there is of primary hypothyroidism in adult dogs. Particularly in young dogs. necrosis. There were no symptoms of reduced mental or outlines indicated by solid lines). Antimicrobial sulfonamides are known to inhibit TPO in a reversible.9) can result in pal- pothyroidism. Another. thyroidism. in addition to the signs also seen in adult-onset hypothyroidism (chapter 3.3). secretion (via negative feedback.30 This entity is no longer seen in countries the skeleton. 1. and /or hemorrhage) are inter- roglossal duct was insufficient to maintain euthyroidism. as lethargy and a dull hair coat already present at the age of mone production compensates sufficiently and euthyroidism seven weeks. The Figure 3. It has been reported in thyroid hormones results in TSH-induced thyroid hyper. Apparently this small remnant from the thy- (anaplastic tumor.33. very rare.6: Rectilinear 131I-scintiscan of a four-year-old female German Pointer weighing 18 kg.35 Lymphocytic thyroiditis is the common cause is maintained.1 Acquired juvenile hypothyroidism plasma TT4 concentrations. migration.38–40 . 3. pericardial aorta. although during embryonic life. B) A female Bouvier des Flandres presented at the age of one year for retarded growth and sluggishness. 3. It may also be associated with the absence of normal thyroid glands and yet its function may be insufficient to prevent hypothyroidism (fig. a dull facial expression. Com- 3. Note the more alert expression and the growth in height.7).5). and growth of the thyroid known to occur in cats. The age in months is indicated on each radiograph.2 Thyroid dysgenesis plete athyreosis has also been found (fig. Probably related to the rapidly en- suing sexual maturation (the dog came into estrus after two months of treatment).2. The dog was in good nutritional condition. retarded. 3. In humans mutations have been found in the genes en- descent of primitive thyroid tissue together with the aortic sac coding transcription factors and the TSH receptor. (C. of autoimmune destruction of the thyroid glands occurs dur. D) The same dog after four months of oral substitution with l-thyroxine. The search for the etiology requires molecular studies of the genes involved Ectopia of thyroid tissue is common in the dog and is also in the differentiation. In about 50 % of adult dogs. accessory their involvement in the general population of patients with thyroid tissue can be found embedded in the fat on the intra. and a large tongue. (chapter 3.7: (A. Radioiodine scintigraphy revealed complete athyreosis. Accessory thyroid tissue may also lie cranial ing adolescence and as a consequence the dog’s growth can be to the thyroid glands as a remnant of the thyroglossal duct.2) or it may be an incidental finding during scan- ning for other reasons (fig. the growth plates closed and there was no further growth in height.6). in addition to its developing the signs of hypothy. It may be detected because it gives rise to a neoplasm roidism of the adult.37 In most cases it is the result of the gland.36. thyroid dysgenesis has been questioned. It had disproportionately short legs. Hypothyroidism in young animals 61 3 A B C D Figure 3.4. but weighed only 13 kg. 2. the additional growth may be marginal because ad- ministration of thyroxine will also lead to closure of the Figure 3. hypothermia. Such congenital defects are rare and although in prin- The manifestations of hypothyroidism due to thyroid dysgen. Treatment As soon as the condition is diagnosed. There was a defect in the organification mental retardation. The mental sluggishness disappears. The animal will become much more lively and will develop a normal hair coat. Enlarged thyroid glands of an eleven-month-old male Pomer. In complete athyreosis. symptoms ity have been found thus far in the dog and the cat. dogs of both breeds the same mutation was found in the gene but are shed when treatment with thyroid hormone is given. TPO activity can be demonstrated. twice daily). It is suggested that this mutation was crossed into rat terriers from toy fox terriers. i. Growth in height is slow and the affected animal engages in Recently the familial occurrence of congenital hypothyroid- little physical activity in comparison with littermates.43.51 A DNA-based test Radiography of the spine and long bones reveals delayed skel. 62 Thyroids bones the appearance of ossification centers is delayed and physeal growth is retarded. hypoactivity. and usually there is little evidence of persisting anian. treatment should be started with l-thyroxine (10 µg l-thyroxine per kg body weight. for in some animals the defect is complete and no dominal distension. ciple any step in thyroid hormone synthesis may be affected.7).. The goitrous glands were first noticed when the dog was five months old.50 may even give rise to spinal cord compression. while in others it is par- tial.45–47 Of are noticed during the second or third month of life.8: growth plates (fig. The animal was of about normal size of congenital hypothyroidism in children. suckling difficulties. has been developed for detection of carriers of this autosomal etal maturation and abnormally short vertebral bodies that recessively inherited defect. The coat may be thin and described in toy fox terriers and rat terriers. the facial features become ficiently migrated to the plasma membrane.44 3 Diagnosis Measurements of plasma T4 concentration before and after stimulation with TSH (chapter 12. insuf- comes relatively large and broad.42 encoding TPO.3 Defective thyroid hormone synthesis Congenital hypothyroidism may also occur because of an enzyme deficiency that prevents synthesis of thyroid hor- Clinical manifestations mones. 3. a dreaded complication of late detection of iodide in the thyroid.49 puffy. geneous. 3. Animals with some animals may not reach this age. In the affected lacking guard hairs. its head be. but had a thin hair coat and retention of deciduous teeth after eruption of the permanent teeth. The disorder appears to be hetero- cats). The epiphyseal dysgenesis may also be associated with scattered foci of ossification.28 When the disease remains unrecognized. and the tongue becomes broad and thick (fig. localization of the enzyme within the thyroid cell. the physes of the vertebral bodies and the long bones are still open at the age of three or four years.1) will confirm the diag- nosis of primary hypothyroidism. esis vary according to the duration and severity of the disease only unresponsiveness to TSH and defective peroxidase activ- before therapy is instituted. Abnormalities in the this so-called organification defect concentrate iodide in the newborn that may suggest hypothyroidism include a large thyroid but have limited ability to utilize the iodide in thyroid fontanel (which should be closed at birth in dogs but not in hormone synthesis. In the long .7). giving the epiphyses a granular appearance.41 Deciduous teeth persist into adulthood. and ab.3.48. When hypothy- roidism is not detected early enough during skeletal matu- ration. although these the latter seems to be the least rare form. however. Mental ism with goiter due to an organification defect has been development appears to be retarded.e.50. In the latter case the defect may be due to an abnormal As the hypothyroid puppy or kitten grows older. Thyroid scintiscanning may reveal the cause to be ventral midline ectopia or complete athyreosis. 3. .10: secretion. is given (fig. This requires in vivo studies with radioiodine. When a goiter is de- tected. The thyroid glands could not be palpated. In comparison with the healthy kitten (A). The hypothyroidism was caused by the lack of organification of iodide by the thyroids (fig.10). Treatment As in all forms of hypothyroidism except that caused by iodine deficiency. 3. Clinical manifestations The clinical hallmark of these defects is the combination of goiter and hypothyroidism (fig.1). treatment consists of oral administration of l-thyroxine (chapter 3. stimulation with TSH is redundant. The diagnostic challenge is the elucidation of the defect in thyroid hormone synthesis that is causing the increased TSH Figure 3. as is readily demonstrated by the precipitous discharge of the due to release and rapid reuptake. such as perchlorate or thiocyanate. 3. The severity of both the goiter and the hypothyroidism may vary considerably and it may also be difficult to palpate a goiter in a very young animal (fig. competes for uptake. If Measurements of thyroidal radioiodide uptake (RIU) at 15-min intervals (red line) there is an organification defect. Hypothyroidism in young animals 63 3 A B Figure 3.8).9: Two eight-week-old littermate kittens. 3. as the goiter is al- ready evidence of increased endogenous TSH secretion. Diagnosis The diagnosis of hypothyroidism can be confirmed by measuring the plasma T4 concentration.2. 3. The iodide accumulated very rapidly in the the thyroid is elevated but the iodide is not organically bound.9). The clinical features of the hypothyroidism do not differ from those in thyroid dysgenesis (chapter 3. the uptake of radioiodide by in a cat with defective organification.2. thyroid and remained at a constant level of about 17 % of the administered dose. while those of the healthy kitten have changed to the yellow of adulthood. The latter was demonstrated in a repeat test accumulated radioactivity from the thyroids when an ion that (blue line) by intravenous administration of the competing ion perchlorate (arrow). the hypothyroid kitten (B) has a more infantile appearance with its round head and small ears and also its blue irises. which caused an abrupt discharge of radioactivity.2).10). This will lower TSH secretion and as a result the goiter will shrink. It has been reported that the polyuria) have been observed. This can seem to play little or no role in thyroiditis in dogs. of the immunoassays to the extent that the reference range is mary hypothyroidism (chapter 3.58.52. mune thyroiditis. Antibodies against Tg form a heterogeneous group directed at hypothyroidism due to central causes is less severe than pri.56 In a hormone may cause either falsely elevated or lowered values. . companied by decreased secretion of other pituitary hor- mones. The best known example of secondary hypothyroid.1 Primary hypothyroidism species (chapter 3. young boxer with congenital hypothyroidism supposedly of Although antibodies against thyroid hormones are not un- central origin. in part because a small but significant fraction of thyroid gland function (~ 10–15 %) is independent of TSH. antibodies recognizing epitopes of a thyroid the presumed TSH deficiency was secondary or tertiary. These Tg antibodies occasionally interfere Isolated TSH deficiency (monotropic deficiency) has been with immunoassays used to measure the plasma concen- suggested as the most likely abnormality in a family of giant trations of thyroid hormones. So-called idiopathic forms.59 but it phase of destructive thyroiditis.64. known as the polyglandular failure syndrome. This is probably due to release development of canine hypothyroidism is associated with loss of thyroid hormone into the circulation during an acute of self-tolerance in lymphocytes (CD4+ T cells) to Tg. Hypothyroidism has also been reported in a dog fol- In the spontaneous form a progressive autoimmune process lowing external radiation therapy for a functional thyroid leads to lymphocytic infiltration and disappearance of thyroid carcinoma.63 Circulating antibodies against Tg are de- ciency of adenohypophyseal hormones.3 Hypothyroidism in adult ciencies. The immunologic damage may also involve one or more other endocrine glands and lead to multiple endocrine defi- 3. study of dogs with primary hypoadrenocorticism.58 The immu. Hyposecretion of TSH is usually ac. atrophy. ism at an early age is that of pituitary dwarfism in German autoantibodies against Tg may serve as markers of autoim- Shepherd puppies that is characterized by combined defi. especially in cats treated for hyperthyroidism. ciency. are also thought to Clinical manifestations be the end result of an autoimmune disorder. Thyroiditis usually remains unnoticed. In these animals the tected in over 50 % of hypothyroid dogs. an antibody can be directed against a fragment that con- tains T4 or T3.53 In these dogs manifestations of hy. exceeded.66 Hypothyroidism can also be iatrogenic.57 but this is now known to be associated with pri.58 deficiency. plasma growth hormone concentration was common.67 follicles.3. The hypothyroidism may be an ad- verse effect of radioiodine therapy or bilateral surgical thyroid- Pathogenesis ectomy. in which there is thyroid atrophy without inflammatory infiltrate. In about 95 % of cases had concurrent endocrine gland failure.55 It has been questioned whether the type of assay.2). The animals combination of hypothyroidism and hypoadrenocorticism is known as Schmidt’s syndrome. especially T3. an as. When an epitope includes a hormonogenic mary hypothyroidism. As the autoimmune TSH deficiency is associated with absolute deficiencies of destruction progresses. but the distinction is not destruction is a slow process and clinical manifestations of necessary in the initial differentiation between primary and thyroid hormone deficiency only become evident after 3 central hypothyroidism.3.62 in be classified as pituitary (secondary hypothyroidism) or hypo. it should be noted that they rarely affect the results elevated.61 Antibodies against TPO Central hypothyroidism is due to TSH deficiency. 64 Thyroids 3. The immune-mediated thalamic (tertiary hypothyroidism).60. Eventually most dogs with is not clear whether this is cause or effect.1). thyroidism occurring less frequently. The absence of inflammation is likely to result in the pothyroidism are overshadowed by those of growth hormone disappearance of antibodies from the circulation over time. transient signs of hyperthyroidism (mainly characterized by tis has not yet been elucidated. although very rarely nologic and molecular pathogenesis of autoimmune thyroidi.1). while secretion of luteinizing and adipose tissue and the inflammatory cells disappear. destruction of 쏜 75 % of the thyroid follicles.2. thyroid follicles are replaced by fibrous growth hormone and prolactin. Although they may not be of great pathogenetic importance. In studies of the thyroiditis probably develop signs of thyroid hormone defi- possible involvement of dog leukocyte antigen (DLA). contrast to thyroiditis in humans.4.4 Central hypothyroidism sociation was found in several breeds between canine hypo- thyroidism and a DLA-allele. hypothyroidism of adult onset it is a primary thyroid disorder and in 5 % or being the most frequent and diabetes mellitus and hypopara- less it is due to TSH deficiency (pituitary or hypothalamic).65 In a large retrospective Hypothyroidism is the clinical syndrome resulting from defi.58 This is especially true for T4. about 5 % cient production of thyroid hormone. sulting in the histological appearance of noninflammatory paired (chapter 2. re- hormone and follicle-stimulating hormone is less severely im. Depending on schnauzers with dwarfism.2. several epitopes. which occurs frequently in this 3.54 site. There may be concurrent effects of growth hormone and growth hormone excess (figs. there is no pronounced breed predisposition. Most hypothyroid breeds may be affected more frequently than those of small dogs have some degree of mental dullness. A few follicles of different sizes can still be recognized. Diffuse. Acquired primary hypothyroidism is mainly a condition of Central to the clinical manifestations is usually a history of young-adult and middle-aged dogs. The thickening and puffiness are evidence of Thyroid hormones influence the function of almost all tissues cutaneous mucinosis or myxedema. 3.70 ally.72 It may be due to both hypothyroidism systems. Although dogs of large slowing of mental and physical activities. (D) Adipose tissue with small clusters of thyroid follicular cells and small aggregates of C cells.73 Occasion- excess (see chapter 2 and the section on diagnosis below).71 . often containing lymphocytes. Hypothyroidism in adult animals 65 3 A B C D Figure 3. Small groups of pale C cells lie between the follicles. often subtle. lethargy.69 with pigmentation). (B) Thyroid follicles with high cuboidal epithelium and almost no colloid. owner until after treatment has been started. slight to moderate lymphocytic infiltration. the dermis of glycosaminoglycans and hyaluronic acid with pothyroidism involves manifestations from nearly all organ associated edema.74.12–3.75 considerably: lethargy may be noticed within a few months but skin changes can take almost a year.68 ual in onset. Among the neous primary hypothyroidism in an adult cat. and dis- breeds. and sometimes unrecognized by the There has been only one convincing description of sponta.70. thick folding of the skin. including Malassezia infections. These symptoms are grad- incidence is equally distributed between males and females. and of thyroid biopsies (B–D) from dogs with primary hypothyroidism in different stages of loss of thyroid epithelium: (A) Thyroid follicles lined by low cuboidal epithelial cells and filled with colloid. and a puffy fa- cial appearance.16).12). 3.11: HE-stained sections of the thyroid gland of a healthy dog (A). hypothyroidism is associated with secondary skin infec- The time required for clinically appreciable effects differs tions. (C) Severe lymphocytic infiltration and loss of follicles. The inclination to exercise (fig. a five-year-old observable changes in the hair and skin are alopecia (often spayed female domestic shorthair cat. which is accumulation in of the body and thus the classical clinical picture of overt hy. 14: and Endocrine Loss of libido Galactorrhea Skin of a six-year-old female poodle with primary hypothyroidism. 66 Thyroids 3 Figure 3. 3.18) Facial nerve paralysis Lameness Gastrointestinal Diarrhea Hematological Nonregenerative anemia Biochemical Hypercholesterolemia Elevated creatinine kinase Hypertriglyceridemia Hyponatremia Mild hyperglycemia Hyperkalemia . groin. and above the eyes.1: dogs System Common Less common or rare Metabolism Weight gain Low body temperature Appetite unchanged or reduced Cold intolerance Skin and Hair Coat coarse and scanty Hyperpigmentation Nonpruritic truncal alopecia Secondary pyoderma starting over points of wear Mucopolysaccharide thickening Seborrhea of skin (myxedema) Cardiovascular Bradycardia. most noticeably in the thick folds on the shoulders and lower parts of the is alopecia and pigmentation of the skin of the flanks. showing dark Testicular atrophy Polyglandular deficiency pigmentation and a somewhat roughened surface resembling emery paper. (Schmidt’s syndrome) Neuromuscular Lethargy and somnolence Vestibular ataxia Stiff gait Head tilt (fig. 3. forelegs.1: Clinical manifestations of primary hypothyroidism in adult Table 3. The A four-year-old male boxer with primary hypothyroidism. The latter together with drooping of the upper eye- lids gave the dog a somewhat tragic facial expression. its coat is thin and there inelastic. The skin was thick and dog’s lethargic appearance is quite apparent. In addition.12: Figure 3.17) Cool skin Reproductive Persistent anestrus Gynecomastia Figure 3. weak peripheral Poor peripheral circulation pulse and apex beat Low voltage ECG (fig.13: A four-year-old male mongrel shepherd dog with primary hypothyroidism. The stiff gait had caused abnormal wearing of the nails of the front feet. and nose. Table 3. and short coat. The puffy appearance due to myxedema produces a lethargic or tragic facial expression. A B Figure 3. (B) There was an impressive regrowth of hair after seven months of substitution therapy with l-thyroxine.16: (A) A two-year-old female Leonberger in which primary hypothyroidism caused marked loss of hair. The blepharoptosis contributes to this appearance. (B) These changes were especially appreciated in retrospect. . coarse.15: (A) A four-year-old female German shepherd with primary hypothyroidism. leaving a sparse. when the dog was reexamined after four months of substitution therapy with l-thyroxine. Hypothyroidism in adult animals 67 3 A B Figure 3. However.85 paper speed 25 mm/s). monology (lethargy misinterpreted as exercise intolerance) tems are illustrated in figs. Middle: Leads aVR.79 and locomotor disturbances.78. and III.1). The atrophy of the skin and its With regard to the latter. tually all nonthyroidal diseases. Right precordial leads CV6LU.83 (chapter 3. and aVF. surgical and nonsurgical trauma. 3. Lethargy. In less pronounced (= less long- standing) cases the ECG changes may be less remarkable or even absent. metabolic (hepatoencephalopathy) or cerebrocortical disease torrhea.1. a VL. The terms nonthyroidal illness and sick eu- signs due to atherosclerosis and thromboembolic events.18: A five-year-old female boxer with primary hypothy- roidism and signs of vestibular disease manifested by a head tilt. Consequently.87 For this reason stimulation tests widely. plasma concentrations of TT4 and free T4 (fT4) are below the Routine laboratory examinations can reveal several hemato. hydrocephalus). stimulation test using measurement of plasma TT4 concen- thyroidism. Illness in this context comprises vir- the hyperglycemia are usually mild.27 while hypothyroidism has also been reported to be associated with generalized myopathy. a hypothyroid dog is presented as an emergency in a As a measure of thyroid function.86. as a serious predisposing factor. There was also facial nerve palsy. 68 Thyroids 3 Figure 3. T4 has to be preferred over comatose state. it is not uncommon for dogs with tration does not distinguish with sufficient accuracy between . In most dogs with primary hypothyroidism.76 This can occur with persisting galac.82. CV6LL. These features are regarded as manifestations of a more Figure 3. acity in the skeletal muscles.3) and of thyroid homeostasis.1 lists the clinical manifestations by organ system. Low ambient temperatures can cause decom. The TRH- possibility that the presented problems could be due to hypo.79 with hyperlipidemia ECG recording from a four-year-old male boxer with pronounced hypothyroidism (calibration: 1 cm = 1 mV.1).85 thyroid syndrome have been introduced for this derangement Both the nonregenerative anemia (see also chapter 10. Table 3. trogen excess (chapter 8. reference range. CV6RL. Possible without a thyroid disorder because of drugs or illness consequences of severe hyperlipidemia include neurological (chapter 3.17 and 3.2). the Differential diagnosis finding of a low basal plasma thyroid hormone concentration Because the presenting symptoms of hypothyroidism can vary is of little diagnostic value.17: generalized polyneuropathy.77 vestibular disease. II.3).18. There is low voltage of the deflections in all leads. T3 because it is produced exclusively by the thyroid gland position of hypothyroidism into myxedema coma with severe while T3 in plasma is largely derived by peripheral conversion hypothermia.80. Changes in a single or orthopedics (locomotor disturbance). Left: Leads I. they can also be decreased in dogs logical and biochemical abnormalities (table 3. (encephalitis.81 Diagnosis Rarely.4) and hypercortisolism (chapter 4. a common pitfall in diagnosis is simply to overlook the using either TSH or TRH have been advocated. For example. generalized locomotor problems can adnexa must take into consideration such conditions as es- be explained by a severe reduction in Na+-K+-ATPase cap.78. may be mistaken for the causative disease. of hypothyroidism to be presented for attention to cardiopul- which some changes in the cardiovascular and nervous sys.84. and inadequate caloric intake. the most organ system sometimes dominate to the extent of obscuring common sign of hypothyroidism. and V10. ments.5 years while receiving l-thyroxine substitution (beginning of substitution marked by arrow).97 dogs with hypothyroidism and those with nonthyroidal ill. PRL. there is now experimental evidence that it plify assessment of the canine pituitary-thyroid axis by the may not be so much the assay but rather the changes in pitu- paired measurement of T4 and TSH. primary hypothyroid. GH. . It was hoped that a single itary function with time that can explain the low TSH values blood sample would suffice to confirm the diagnosis of pri.93–95 Meanwhile. it was found this is followed by a gradual loss of the feedback response of that in as many as one-third of dogs with primary hypothy. found in some dogs with primary hypothyroidism.19.19: Mean (± SEM) basal plasma concentrations of TSH. Hypothyroidism in adult animals 69 3 Figure 3. This is accompanied roidism. Asterisks indicate statistically significant difference from value at time zero. binant human (rh)TSH instead of bTSH. large vacuolated thyroid deficiency cells. questioned.86.92 However. Three of these dogs were followed up for 1. gested to improve the diagnostic value of TSH measure- noassays for plasma TSH in dogs would greatly aid and sim.89. and LH measured at two-month intervals in seven spayed beagles with induced hypothyroidism at time point 0.96 lation with bovine TSH (bTSH).91 by hypersecretion of GH and hyposecretion of PRL. As illus- mary hypothyroidism by revealing a low T4 concentration in trated in fig.90 Strategies for modification of the TSH assay have been sug- It was expected that introduction of a homologous immu. TSH to low plasma T4 concentrations. The Frustration with the limitations of the available endogenous associated pituitary enlargement is characterized by thyro- canine TSH assay caused most clinicians to resume using the trope hyperplasia. plasma TSH concentration was not elevated.88 Until the end of the last century.92 albeit now usually employing recom- ness. using causes an initial increase in plasma TSH concentration but the TSH-stimulation test as the gold standard. the induction of primary hypothyroidism the presence of a high TSH concentration. 3. TSH-stimulation test. However.87. the ism in dogs was diagnosed by the finding of a low plasma TT4 gold-standard status of the TSH-stimulation test has been (and /or fT4) concentration insufficiently responsive to stimu. 22). or even a thyroid 4 the omission of hypoprolactinemia in intact males and fe. and The results of these studies on the adenohypophyseal changes fusiform shape are particularly characteristic of primary hy- in primary hypothyroidism provide an explanation for the pothyroidism.96 In high-resolution ultrasonography of the thyroid glands. On the contrary. chemical assessment of the pituitary-thyroid axis – such as versible by substitution with l-thyroxine. The latter is associated with the devel. and three years after thyroidectomy (B).21: Sections of the pituitary gland of a hypothyroid dog: (A) stained with an antibody against GH (brown) and (B) with antibodies for both GH (blue) and TSH (orange).96. homogeneity.21). plasma prolactin concentration may hypothyroidism in dogs. loss of echogenicity. indicative of transdifferentiation for primary hypothyroidism. 3. 70 Thyroids 3 Figure 3. although the result may not be responsiveness to stimulation with TRH. When TT4 is low but TSH is (figs.99 injection (fig. trous cycle and the hypothyroidism may even be associated there was no overlap in thyroid uptake at 45–120 min after with galactorrhea. Contrast enhancement reveals the normal size of the pituitary gland before thyroidec- B tomy and its enlargement after the induction of hypo- A thyroidism. Several cells are positive for both GH and TSH. In dogs with clinical formation about thyroid function. Both large and normal-sized cells stain positively for GH.96 If they are not. A B Figure 3. with 99mTcO –.3.1).20 and 3.100 In a study of 99mTcO4– uptake in be elevated in intact females that have recently entered an es. a TSH-stimulation test can be opment of thyrosomatotropic cells and paradoxical GH. performed (chapter 12.98 The pituitary conclusive. 3. within the reference range. In addition. and double-staining cells.102 Demonstration of circulating antibodies low plasma TSH concentrations that have been observed but to Tg indicates the presence of thyroiditis but provides no in- do not resolve the diagnostic dilemma. methods not involving bio- enlargement and the functional changes are found to be re. the combination of a low plasma on pathogenesis.97.101. dogs with primary hypothyroidism and nonthyroidal illness. the absence of antibodies against Tg does TT4 and an elevated plasma TSH concentration is diagnostic not exclude hypothyroidism. biopsy – seem to be the most reliable for diagnosing primary males. high-resolution ultrasonography.97 Similar changes a radionuclide scan or thyroid uptake measurement with are observed in dogs with spontaneous hypothyroidism.20: Transverse CT images of the skull of a beagle prior to induction of hypothyroidism (A). As indicated in the section signs of hypothyroidism. dogs with anti- . trauma. the dose should be adjusted. 3. plasma T4 concentration should be above the lower limit of the reference range for the type of dog (chapter 3. inactive epithelium (compare with fig. peaks around 4–6 h later. Plasma T4 con- centration increases following oral administration. the pharmacokinetic properties of liquid l-T4 support the use of a dose of 20 µg/kg once daily.22: variation in intestinal absorption of T4.2. Prognosis Hypothyroidism is one of the most gratifying diseases to treat. Most commonly oral supplementation with tablets of synthetic l-thyroxine is started at a dose rate of 10 µg/kg twice daily.105 Accord- ing to the authors. uptake of the injected dose. Spontaneous causes in. The condition is rare com. When blood is collected at 10–12 h after the last dose.1).2). The long-term prognosis is excellent.23: pared with primary thyroid failure. further follow-up Median values and ranges for thyroidal uptake of 99mTcO4–. Because of the individual Figure 3. Hypothyroidism in adult animals 71 bodies against Tg may have thyroiditis that has not yet re- sulted in hypothyroidism. A recently introduced solution of l-T4 for oral administration has a higher bioavailability than the tablet formulation.2 Central hypothyroidism (see also chapter 3.107 Central hypothyroidism can also result from surgical removal of a pituitary tumor. when T4 is administered orally its bioavailability is low and variable. due to incomplete and variable gastrointestinal absorption. 3 portunity to regulate the amount of T3 generated by normal physiologic mechanisms. H&E-stained section of the thyroid of a nine-year-old long-haired German pointer clude tumor of the pituitary or adjacent regions and head with secondary hypothyroidism.106 Tertiary hypothyroidism has been documented in a dog with a large pituitary tumor and effacement of the over- lying hypothalamus.3. and then declines until the following dose is given. because of the ease and completeness with which it responds to treatment. Treatment Although T3 is the metabolically active thyroid hormone.108 .103 However.104 A follow-up examination is made after two months. Note the large follicles and the flat. it is not the supplement of choice. Both T4 production rates and parenteral l-T4 replacement doses required to maintain euthyroidism are around 5 µg per kg body weight per day.4) In central hypothyroidism the thyroids are not affected pri- marily but are deprived of stimulation by TSH. With appropriate treatment and follow-up examinations every half year. usually all of the alterations as- sociated with hypothyroidism are reversible.1. Appropriate T4 therapy results in normal levels of both T4 and T3. es- pecially when the solution is given without food. 3. Histological examination reveals no loss of follicles but rather the charac- teristics of inactivity (fig. in 14 dogs with primary hypothyroidism (green) and 13 with nonthyroidal illness (orange). Figure 3.23). expressed as percent examinations and adjustments may be needed. A primary advantage of pro- viding the »prohormone« T4 is that the body is given the op. 3. If it is not. 25).3. Hypofunction of any other endocrine glands resulting from pituitary hormone deficien. the thickening that occurs in primary hypothyroidism is partly a 3 consequence of the associated growth hormone excess.2) before T4 therapy is begun. and (2) the morphology of the pituitary and adjac- ent areas by diagnostic imaging (chapter 2. Prognosis In the spontaneous forms the prognosis is completely depen- dent upon the course of the causative lesion in the hypo- thalamus-pituitary area.1). Progression of a functional thyroid tumor to a state of hyperthyroidism (upper fined to treatment for a coexisting ACTH deficiency. A prerequisite for correct interpretation of these tests is the certainty that the low T4 (and TSH) con- centrations are not caused by illness or drugs.1). During development to treat an eventual deficiency by cortisol supplementation of a nonfunctional destructive thyroid tumor (lower figure). .2.3. TSH release successively even advisable to assess pituitary-adrenocortical function and declines and the unaffected thyroid tissue becomes inactive.25). and even obscure the manifestations of pituitary failure. contralateral unaffected lobe. although repeated stimulation may be necessary (chapter 12. In the iatrogenic form following hypophysectomy. but thickening of the skin is less pro- nounced (fig. In the presence of an ACTH-secreting tumor.6). In practice this is usually con. As described in the previous section.1). It is figure). Figure 3.2. thyroid hormone (chapter 4. accompany. such as a corticotrope ade- noma that is hypersecreting ACTH.24: cies should also be corrected. 2. In addition.3.6 and 12. Treatment Treatment with l-thyroxine is the same as in primary hypothyroidism (chapter 3. 2.2. diagnostic assessment should include (1) the se- cretion of other pituitary hormones (see also chapters 2.3. Not uncommonly. As hypersecretion of thyroid hormone progresses. supplementation with l-thyroxine (and glu- cocorticoids!) enables the animal to live a healthy life for many years (chapter 4. On the contrary. Diagnosis The diagnosis of central hypothyroidism should be based on the demonstration of low concentrations of T4 and TSH in plasma. In central hypothyroidism the persisting negative feedback on TSH secretion that is responsible for this is lacking. The symptoms and signs arising from such a pituitary tumor may precede. 72 Thyroids Clinical manifestations The clinical picture is similar to that of primary hypothy- roidism. there is often impaired secretion of other pitu- itary hormones such as growth hormone and gonadotropins (fig. although generally less pronounced.1).1). plasma T4 concen- tration increases in a TSH-stimulation test. central hypothyroid- ism may only become manifest after reversal of the associated hypercortisolism (chapter 4. There may be lethargy and alopecia. This will avoid the secretion is sustained via the feedback-controlled increased secretion from the risk of precipitating a crisis due to glucocorticoid deficiency. the lesion causing reduced TSH secretion is a hormone-secreting tumor. A TRH- stimulation test can be used if there is reason to suspect terti- ary hypothyroidism. In secondary hypothyroidism. There is no breed or sex predilection. intrinsic cell abnormalities must be responsible for its However. accounts for only 3 % of cases in cats. elderly cat with an in- creased appetite and polyuria (fig. In an elderly cat. but there is lethargy and anorexia rather than hyperactivity The pathogenesis of adenomatous thyroid hyperplasia in cats and increased appetite.111 The most likely candi- with increasing size produce such an excess (fig. The condition resembles toxic nodular goiter roidism«. more often. it may unregulated growth and function. This form.4.112. with a mean age of twelve to stage. plasia or adenoma. such as restraint. Thyroid carcinoma. In about 10 % of cases the clinical picture may be quite dif- thyroidism in dogs. involving one or. if the tumor produces thyroid hormone. The thyroid creased appetite – may be sufficient reason to suspect hyper- hormone excess is produced by thyroid adenomatous hyper. roid cat is that of a skinny. thyroidism. 3. which the owner also observed when the cat was at rest. The classic presentation of a hyperthy- they are discussed separately in the following sections. It is likely to give the impression of a tense and anxious animal with an impaired tolerance for any stress. which is the main cause of hyper. The hypermetabolic state caused panting (B).24) that the dates are thought to be mutation of the TSH receptor or mu- animal develops symptoms of hyperthyroidism.4 Hyperthyroidism and thyroid (Plummer’s disease) in humans.113 invariably the case in cats and is only occasionally seen in dogs. Because the clinical aspects of thyroid hormone excess on organ systems that lead to vet- thyroid neoplasia differ considerably between dogs and cats. in rarely is veterinary help sought because of a mass detected by which TSH-receptor antibodies stimulate the thyroid.1 Hyperthyroidism in cats tems can be affected and the associated signs and symptoms are listed in table 3. adenomatous tissue into nude mice has shown that its growth tion in two ways. erinary examination. most commonly it is the physical does not depend upon extrathyroidal humoral stimulation. This full spectrum is less likely to be Feline hyperthyroidism is a relatively common disease of present now that the disease is usually recognized in an early middle-aged and elderly cats. In dogs.25: This twelve-year-old castrated male cat was presented for weight loss and extreme restlessness. Thus it is the signs and symptoms due to effects of been observed in dogs or cats.25). In these cats weight loss remains an important feature.109 ferent. This is almost tation of its associated G proteins.114 Many organ sys- 3. has not the owner. may represent an end-stage of the disease and may . 3. 3.2. Clinical manifestations The adenomatous glands tend not to become very large. Instead. Hyperthyroidism and thyroid tumors 73 3 A B Figure 3. Its nutritional condition was poor and its behavior was frantic (A). Experimental transplantation of the Neoplastic transformation of the thyroid may come to atten. restless. weight loss – often together with in- 13 years. so A disease entity comparable to Graves’ disease in humans. both thyroid lobes.110 presence of the tumor that is first detected by the owner. called »apathetic hyperthy- is not clear. The thyroids of hyperthyroid cats contain multiple hyperplastic nodules surrounded by in- tumors active follicular tissue. Gastrointestinal Increased fecal volume Diarrhea and vomiting Differential diagnosis Skin and Hair Unkempt hair coat There are at least two nonthyroidal disorders that may simu- late certain aspects of the syndrome. the T4 con- lead to a variety of physical changes but may also give rise to centration in plasma exceeds the upper limit of the reference several biochemical abnormalities (table 3. * May be found.121 Con- sistent with the effect of thyroid hormone on Na+-K+-AT- Renal Polyuria (low urine s. However. the first step should be a careful palpation of the neck area by gently sliding the thumb and index finger along the sides of the trachea. In about 90 % of cats The multisystemic effects of thyroid hormone excess not only presented with the syndrome of hyperthyroidism. Rarely the thyroid enlargement arises from ectopic A wide range of clinical features has been associated with (sometimes intrathoracic) thyroid tissue.) Mild elevation of plasma Pase (chapter 3. First.2).1. vigor.2). also be associated with cardiac disorders (see also table 3. The thyroids are This severe form of feline hyperthyroidism has also been usually easily moved along the trachea. although it Metabolism Weight loss in spite of Mild hyperthermia is often still within the reference range. the weight loss in Hematological Neutrophilic leukocytosis with Hematocrit elevated eosinopenia and lymphopenia combination with increased appetite and large volumes of (= stress leukogram?) somewhat fatty feces may be mistaken for pancreatic insuffi- ciency and less likely for gastrointestinal lymphoma. whereby urea and creatinine the possibility of coexisting hyperaldosteronism (chapter 4. For reasons explained above (chapters 3. the animal is still suspected of hyperthyroidism. The thyroids are only loosely attached to the surrounding tissues and there- fore enlargement usually causes descent along the trachea. including arterial hypertension and hypokalemic myopathy. it Respiratory Panting Dyspnea seems to have little clinical significance. measurement of the plasma concentration of T4 is of greater diagnostic value than that of T3. and stress may cause acute elevation of be noted that occasionally thyroid enlargement is found with- plasma thyroid hormone concentration and have been impli. Enlargement of one or called »thyroid storm«. normal range. concomitant nonthyroidal disease coid:creatinine ratios.g. Weight loss in spite of Urinary corticoid:creatinine increased appetite together with polyuria also raises the possi- ratio elevated bility of diabetes mellitus.117 The hemodynamic alterations of may lower the value below the reference range. T4 values may be in the high- centrations of liver enzymes and increased urinary corti. In such cases the disease may develop cated as possible precipitating factors for »thyroid storm«. but routine urinalysis will immedi- Hypokalemia ately resolve this. as in the Biochemical Elevated plasma ALT. 3. LDH Mild hyperphosphatemia* latter case there will be inappetence. It is not clear whether in these cases The final diagnosis ought to rest on a direct measurement of possible coexisting conditions such as hyperaldosteronism thyroid function. In addition. 74 Thyroids Table 3. including elevated plasma con. Radioactive iodine therapy.115 with time. out hyperthyroidism.4). The survival of 3 Cardiovascular Tachycardia (gallop rhythm) Cardiac murmur treated hyperthyroid cats does not seem to be affected by post-treatment azotemia. (chapter 4. cats with mild hyperthyroidism.118 Of more concern has been the increase in the plasma creatinine System Common Less common or rare concentration after treatment of hyperthyroidism. this form of the disease.4) may play a role.2: Clinical manifestations of hyperthyroidism in cats hyperfiltration. thyroid surgery.116. Although considered polyphagia Anorexia to be the unmasking of preexisting chronic kidney disease. AP.1. Plasma T4 concentration fluctuates over time and in are reversed with treatment. but probably not a direct manifestation of hyperthyroidism. sometimes even as far as the thoracic inlet. the measure- ria is regarded as a reflection of glomerular hypertension and ment of T4 can be repeated two to four weeks later. The often observed mild proteinu.120 Al- Left ventricular hypertrophy Congestive heart failure though these abnormalities have not been associated with (echocardiography) any symptom or sign. .119 Studies of calcium homeostasis in Pounding heart beat Cardiac arrhythmias feline hyperthyroidism have revealed several alterations. it should ous thyroid palpation. a term used for a rare clinical entity in both lobes can be found by an experienced examiner in up humans.122 When hyperthyroidism are responsible for marked increases in the plasma T4 concentration falls within the reference range and glomerular filtration rate. hypokalemia may be found. and is also resolved with treatment.3.4) concentrations* should be considered. to 90 % of cats with hyperthyroidism. there has been one report of a hyper- Neuromuscular Restlessness (irritability) Weakness thyroid cat with hyperphosphatemia and calcification of its Muscle wasting paws that resolved with return to the euthyroid state. Diagnosis When hyperthyroidism is suspected. Most of these range.1). Nonthyroidal disease may be associated with false chapter 3. values than in normal cats (fig. the T4 concentration cent antithyroid medication. T4 concentration 2–4 h after the last jection.e. in the small molar glands may be superimposed over the zy- ism. Following seven tor complicating the interpretation of the T:S ratio may be re- eight-hourly oral doses of 15–25 µg T3. CA. DPC. Undetectable and low TSH concentrations have roid scintigraphy is largely due to pertechnetate accumu- also been reported in cats with histological evidence of nod. lation in the zygomatic and molar salivary glands.26). This offers an additional tool in the diagnostic approach to feline hyper. Nevertheless.127 the limit of quantification (see also fig.27: Thyroidal radioiodine uptake (RIU) (median and range) in 20 hyperthyroid cats Thyroidal 99mTcO4– uptake (median and range) in 18 hyperthyroid cats (beige) and (green) and ten healthy house cats (hatched). Los Angeles. USA]) below image of the two thyroid lobes.124 13 healthy house cats (blue).24). Diagnostic thyroid:salivary gland ratio (T:S ratio) using the more intense Products Corporation.126 The best correlation of 99mTcO4– uptake with roidism have plasma TSH concentrations (measured with an plasma T4 concentration has been found to be the 20-min assay for canine TSH [Immulite canine TSH®.26: Figure 3.129. The uptake visualized in the head of the cat by routine thy- thyroidism.131 dose of T3 remains practically unchanged. 3.130 Another fac- concentration in a T3-suppression test. Enhanced thyroidal 99mTcO4– in healthy cats is suppressed to low values.. scintiscanning with 99mTcO4– reveals in- Although not available in all clinics. The uptake ular thyroid disease. Due to the auto. valuable because it is usually higher than in healthy cats tration.1 99mTcO4– is also taken up by the thyroid gland but positive results and therefore feline hyperthyroidism should not organically bound. uptake has been found following withdrawal.128 Different sedative-anesthetic protocols influence thyroid and salivary One can also consider testing the suppressibility of plasma T4 gland uptake of 99mTcO4– in different ways. 3.125 As explained in formation. Hyperthyroidism and thyroid tumors 75 3 Figure 3. the unaffected tissue.125 In most cases measurement of fT4 concentration by direct perthyroid cats there is rapid uptake of the tracer to higher equilibrium dialysis adds little or no useful diagnostic in. mild or subclinical hyperthyroid.122 Recently it was reported that cats with hyperthy.124 In hyperthyroid cats. In hy. 3.27). the measurement can be not be diagnosed solely on the finding of a high fT4 concen.123 gomatic uptake on routine ventral planar images. radioiodine uptake creased uptake in hyperplastic thyroid tissue and no uptake in studies with 131I or 123I may contribute to the diagnosis. because TSH secretion is suppressed by . (fig. although the nomous (TSH-independent) character of T4 hypersecretion T:S ratio was significantly elevated only at 4 h after tracer in- in hyperthyroid cats. i. 29). Thyroid scintigraphy terion for treatment with cardiac-related drugs.133 In case of doubt. diovascular effects of hyperthyroidism before general anes- functioning thyroid tissue (EHTT) is present. diluted with at least an equal volume of Ringer’s solution. 3. in a dose of 1–2 ml/kg. Following removal of the thyroid tissue the capsule is excised. beta blockers are a short-term alternative. cal incision. After incision on the ventral side of the gland. although the prevalence of congestive heart failure is low.132 tions (see also chapter 4. By careful exploration through the thoracic inlet. although the latter is extremely rare.127 Visual inspection may have of 0. mia.5 mmol Ca2+/kg body weight as calcium gluconate.28: bilateral thyroidectomy can be performed without a high Scintigraphic images 30 min after intravenous injection of 0. preserving only a small cuff of the thyroid capsule and the blood supply to the parathyroid gland.24. EHTT oc. It may be dif- ficult to locate the parathyroid gland because of the anatomi- A B cal changes caused by the thyroid nodule. They range from lethargy. and muscle tremors (face.5– incidence of hypoparathyroidism. It is lower specificity than the T:S ratio. reluctance sensitivity for the diagnosis of hyperthyroidism than calcu.115 Systematic echo- ing surgery (fig. ears) to tetany and con- lation of the T:S ratio. Boxtel. foci of vulsions. Aescu- 4 administration is safe and provides equivalent diagnostic laap. quantitative uptake If plasma calcium is 쏝 2.6 MBq) 99mTcO4– in healthy cats (in dorsal recumbency).109 Although mia can be corrected preoperatively by administration of 99mTcO – is usually administered intravenously. anorexia. Oral supplementation with calcium car- bonate. With this approach either unilateral or Figure 3. 3. and when there is suspicion of distant cardiography revealed clinically relevant pretreatment abnor- metastases.8 mCi (18. Pertechnetate scintigrams have advantages over quantitative The most serious postoperative complication is hypocalce- uptake measurements.127 Using a pinhole collimator. 3 Thyroidectomy is performed by the modified intracapsular dissection technique. In both images the focal uptake in anterior mediastinal region are approached by a caudal cervi- the head is in salivary tissue. calcium borogluconate is given subcutaneously appropriately obtained reference values. Preoperative treatment con- the T4 excess (figs. 3. and magnifying glasses should be used.4).115 enlargement can be palpated. depending on the skill and 27.5–0. EHTT in the ventral cervical or (B) Asymmetrical uptake in two normal lobes. 3. experience of the surgeon. The technique thesia and surgery. and (3) inhibition of secretion by antithyroid drugs.109. When the facilities are not a limiting factor. is also very useful in cases of recurrence of the disease follow. malities in less than 10 % of hyperthyroid cats and tachycardia curs in about 9 % of cases and has a significant effect on (쏜 220 bpm in a clinical setting) was cited as the main cri- the rate of recurrence after surgery. 76 Thyroids Treatment There are three options for eliminating the excess production of T4: (1) radioiodine ablation of the thyroid. Tetany may be provoked by handling the cat. (A) Symmetrical uptake in two normal thyroid lobes. the anterior mediastinum can be reached sufficiently to find and remove the lesion. (2) surgical thy- roidectomy.0 mmol/l or 10 % below the pre- measurements may be helpful if values can be compared with operative value. to move. Thyroid scintiscanning siderations are primarily centered on control of the hyperthy- is especially useful in hyperthyroid cats in which no thyroid roidism rather than on its cardiovascular consequences. 15–20 mg/kg per meal. visual inspection of a scan has equal or greater roidectomy. since the observer may be better to avoid this dramatic event by routinely measuring misled by the asymmetry of the thyroid glands that occurs in plasma calcium concentration at about 20 h after surgery. to determine whether one or Antithyroid drugs (see below) can be used to control the car- both thyroid lobes are affected and whether ectopic hyper. signs of which appear within 24–72 h after bilateral thy- roid lesions.135 Hypokale- should be performed preoperatively in all cases. thyroid tissue is gently teased away from the capsule by blunt dissection with scissors and a moistened cotton-tipped swab. Apart from its value in localizing thy. some euthyroid cats. but if these drugs cause serious side effects.134 The increase in cardiac output in hyperthyroidism may de- compensate subclinical heart disease. the first option is to be preferred. Treat- higher uptake can be identified in the scan that may represent ment should be given promptly by intravenous administration an early stage of hyperplasia. NL]) or by intravenous or subcutaneous injec- images. subcutaneous potassium orally (2 mmol KCl twice daily [Tumil-K®.29). is started as soon as the cat .28. polyuria. and irritable behavior after bilateral thyroid surgery.29: Thyroid scintiscans. if there is para- thyroid damage. (C) An eight-year-old castrated male cat with persistence of hyper- thyroidism after thyroid surgery. (D) A 13-year-old castrated male cat with weight loss and polyphagia. (A) An eleven-year-old castrated male cat with signs and symptoms of hyperthyroidism (weight loss. There is high uptake in the nodule and no visualization of the nonaffected lobe. There is high uptake near the thoracic inlet. Weesp. (B) A twelve-year-old neutered female cat with persistent weight loss. The normal fol- glands. NL] is given in a dose of ation of postoperative hypocalcemia. thereby decreasing the severity and dur- Solvay Pharmaceuticals. function may result. There is high uptake at the location of the right thyroid and at the tho. Plasma T4 concentration is measured after four weeks and then every six months. Careful postoperative 0.05 mg once daily for three days and then lowered to monitoring of plasma calcium must be continued until this is 0. However. There is high uptake at the location of the right thyroid and at the thoracic inlet.025 mg once daily. increased appetite. The parathyroid gland is cut into small pieces and in. temporarily in about 5 % of cases.136 measured at least twice daily. Radioiodine (131I) by its b-radiation selectively destroys hy- thyroid autotransplantation has been proposed as a treatment perfunctioning thyroid cells while sparing the suppressed nor- for accidental removal or devascularization of all parathyroid mal thyroid tissue and the parathyroid glands. In addition. Hyperthyroidism and thyroid tumors 77 3 A B Figure 3. ence range. Resumption of parathyroid of the radioiodide is preferred. The doses of dihydrotachysterol and calcium carbon. C D racic inlet and lower uptake at the location of the left thyroid. licles gradually resume function and there is usually no need serted into a small pocket made by blunt dissection in one of for administration of thyroxine.109 Para. and anxious behavior) and uni- lateral thyroid enlargement. twice daily on the fourth day after bilateral thyroidectomy. The dose is adjusted as needed to With an experienced surgeon. Plasma calcium concentration is ascertained. recovery can take weeks to months. Oral substitution with l-thyroxine is started in a dose of 50 µg ate are adjusted to maintain plasma calcium within the refer. gradually decreasing to once weekly. vomiting of fluid and food. dihydrotachysterol [Dihydral®. resumes eating. Subcutaneous administration the sternohyoideus muscles. but it can also be administered . hypocalcemia occurs only maintain plasma T4 concentration within the reference range. four.5 mg per cat twice daily. methimazole can ops within a few months. Since both hypothyroidism and Using the same dose. and the plasma T4 concentration. Apart from specific equipment. leukocyte and thrombocyte counts. and gastrointestinal upsets (anorexia. radioiodine therapy is certainly that tolerate methimazole without side effects. For carbima- zole the starting dose is 2. matting of hair. Complete cure is achieved by a greater than 90 %. Using mazole is converted to methimazole but yields only half the this scoring system 131I dose is 3.146 for it is curative in virtually all cases.137 In less than 5 % cats treated with radioiodide. facial excoriation.150 The ointment is applied to the inner surface of ticularly those in which pretreatment scintigraphy revealed the pinna. the size of the thyroid gland(s) (by palpation hibiting TPO (chapter 3. the survival time has been reported to be signifi.137 With long-term follow-up the percen. for which lowering of If the hyperthyroid state persists for longer than three months the dose may be adequate. and When the cat has returned home the owners must also follow plasma concentrations of liver enzymes.147 radiation safety precautions are required and the animals must There have been anecdotal reports that side effects are less be hospitalized in a nuclear medicine isolation ward for at common with carbimazole than with methimazole. characterized by symptoms such as be administered in transdermal formulations in which plu- lethargy. Par. or by a TSH-stimulation test (chapter 12.1). twice daily). and blood dyscrasias or hepato- after the initial treatment. it has lower efficacy than oral methima- relapse can occur after treatment with radioiodide. Continued methimazole Facilities for radioiodine treatment are only available in administration in the presence of thrombocytopenia has led licensed hospitals or clinics. It has been questioned whether this is as.140 With exclusion of preexisting methimazole and include blood dyscrasias (neutropenia renal disease. Cats with with the antithyroid drug methimazole. and T4. the treatment protocol should include control the hospital when the radiation dose has decreased to a safe examinations at two.5 mg twice daily) is effective concentration. but this least one week.146 close proximity to the cat and. The related compound carbi- and /or imaging).139 response after two to four weeks is inadequate. and /or thrombocytopenia). The starting dose of methimazole is methimazole does not affect the response to radioiodide ther. Chronic trans- ing of a low plasma T4 concentration with a high plasma TSH dermal methimazole dosing (2. 78 Thyroids intravenously or orally.5–5 mg per cat twice daily.138 It has also plasma methimazole concentration as the same dose of methi- been shown that a fixed dose of 4 mCi is effective and that the mazole. zole. during the first week following 131I treatment. permanent hypothyroidism devel. including epistaxis and oral bleeding. certain safety precautions. retreatment should be considered. 1. When oral administration poses problems. It exerts its effect by in- and symptoms.148.145 The doses needed to control hyperthyroidism in 3 timing of discontinuation of antithyroid medication with cats differ accordingly.1). equally effective (5 mg once daily for one week and then tage of cats developing hypothyroidism may rise to 30 %. of hematocrit.149 able to test thyroid function at least once a year.0–6.25–2. »simple« gastrointestinal disturbance. it is not convincingly less The time between treatment with radioiodide and relapse is often associated with serious side effects than oral treatment.3. Relapse as a result of newly developed nodular hyperplasia in Although fewer gastrointestinal side effects have been re- the remaining unaffected thyroid tissue is very uncommon. generally three years or more.138 The dose can be determined by a Of the available antithyroid drugs the imidazole derivative scoring system that takes account of the severity of the signs methimazole is most commonly used.141 methimazole-induced blood dyscrasias usually recover within a week of discontinuing the drug. cilitate drug absorption across the epidermis. nonpruritic seborrhea sicca.1.144 ing the ointment. The owner is in- bilateral hyperactivity are at risk of developing a low plasma structed to wear gloves or finger cots for the procedure and to T4 concentration. probably because of lower bioavailability. pathy. Higher doses are often needed for destruction of all malignant tissue in cats Side effects have been reported in 18 % of cats treated with with thyroid carcinoma. This work-up should also be performed if a cat becomes ill during methimazole treatment.146 In cats From a medical point of view.137. it is advis.143.149 Administration of carbimazole in ointment form is is generally needed. vomiting). to hemorrhages. its efficacy is the most attractive option. Caretakers are exposed to radiation while in has not been substantiated. alternating ears with each dose. in lowering plasma T4 concentration in hyperthyroid Life-long supplementation with thyroxine (50 µg twice daily) cats. creatinine. The diagnosis is confirmed by the find.0 mCi. in which case methimazole should be discontinued. to differentiate between a Approximately 5 % of treated cats fail to respond completely. also to the radioactivity in urine and in saliva In keeping with the possibility of these adverse reactions to accumulated on the cat’s coat. and six weeks with measurement level as determined by the local radiation control authority. hepatotoxic- cantly longer in cats treated with 131I than in those treated ity.145 noninvasive procedure without complications. remove crusted material with moistened cotton before apply- sociated with clinical manifestations of hypothyroidism.137 . ported with transdermal treatment.142 The cat is discharged from methimazole. This can be increased if the apy. and ronic lecithin organogel acts as a permeation enhancer to fa- marked weight gain. usually due to adenomatous hyperplasia in less in metastases). The disease did not Careful palpation of the neck may reveal a slightly enlarged recur in the twelve-month follow-up period.155 ment to adjacent structures and metastasis to regional lymph nodes. Their malignant nature may already be evident dur- euthyroidism lasted less than six months and there was a high ing physical examination.30: A nine-year-old male boxer in a very poor nutritional condition as a result of hyperthyroidism (A).158. There were no thyroid. By the time of a follow-up examination five months later (B). Percutaneous ethanol injection (PEI) under ultrasono. including the severe polyuria.159 An intriguing difference is observed the contralateral lobe or ectopic tissue. the influence of iodine in the canine diet is fective. hyperthyroidism in dogs jection of 96 % ethanol into the thyroid lesion causes hemor- rhagic necrosis and fibrosis.156 one type or the other. with a mean duration of eu. 3. Most of the benign tumors (adenomas) are small and follow-up alone for small autonomously functioning nodules commonly not detected during life. In the great majority Of the possible risk factors contributing to the development of hyperthyroid cats either methimazole or carbimazole is ef.162 although in one study a high prevalence of thyroid are adverse reactions to the drug.30). the dog had gained 5 kg in body weight. Removal of a small thyroid adenoma resulted in resolution of the symp- toms and signs. 3. both solid and follicular tissue. but the prognosis depends in part on whether there unclear. solid.161 there is no risk of hypoparathyroidism and seldom need for supplementation with thyroid hormone. Over 85 % of the canine thyroid tumors discovered adverse effects other than mild dysphonia. features of hyperthyroidism resolved. Percutaneous ultrasound-guided radiofrequency heat ablation. there being a high incidence of hypodiploidy treatment the prognosis is as good or better. Hyperthyroidism and thyroid tumors 79 3 A B Figure 3.2 Thyroid tumors and graphic guidance is an alternative treatment in humans. tumors in necropsy material was ascribed to insufficient . the owner. of thyroid cancer. for even with bi. They only very occasion- in humans who refuse 131I therapy.4.152 PEI is regarded as the first-line Thyroid neoplasia accounts for about 2 % of all canine tu- treatment for recurrent thyroid cysts and as an alternative to mors. because of changes such as attach- incidence of laryngeal paralysis and Horner’s syndrome. After radioiodine in DNA ploidy.154 The results in clinically are rather large (diameter 쏜 3 cm). ally become cystic and thereby large enough to be detected by port on the use of PEI for solitary nodules in four hyperthy. and ma- seven cats with bilateral thyroid lesions were less satisfactory: lignant. also the pattern of circulating thyroglobulin levels and the cessful surgery. that of the dog – particularly the follicular type – Prognosis most closely resembles human follicular carcinoma. larities include not only the clinical behavior of the tumor but the prognosis for restoration of health is excellent after suc. The simi- In cats without severe complicating cardiac or kidney disease. performed in nine cats. Among thyroid cancers of domestic animals. in canine tumors. There may be recurrence months or years after conservation of TSH receptors in the primary tumors (much thyroidectomy. also lowered plasma T4 Microscopic examination reveals most tumors to consist of concentration only transiently. seem to occur infrequently in dogs with thyroid carcinoma.151 In. It had also become so lively and strong again. that it was difficult to keep on the table for the photograph.157 A benign thyroid tumor may also be detected roid cats.153 There has been one re. while some largely consist of thyroidism of four months. Plasma T4 concentration decreased and the clinical because of symptoms suggesting hyperthyroidism (fig.160 Mutations in tumor suppressor gene p53 lateral involvement or the presence of ectopic thyroid tissue. not concentrating pertechnetate. table 3. to the deep cervical lymph nodes.167 Thyroid carcinosarcomas. iodine intake.166. as it is in humans.165 Recently the familial ness. 80 Thyroids 3 A B Figure 3. and invasive tumor may even damage the cervical sympathetic mute-cross dogs was reported.163 Lymph drains from the canine thyroid primarily Metabolism Weight loss via the upper pole lymphatics in the cranial direction. causes no discomfort. including the pituitary gland.164 due to: (1) thyroid enlargement and (2) hypersecretion of thy- roid hormones. The pertechnetate scan (B) shows it to be functionally inactive.157 The signs and symptoms are growth of residual follicular epithelium.170 While metasta. Anorexia mans.168 System or organ Common Less common or rare Thyroid Unilateral tumor Bilateral tumor Metastasis of canine epithelial thyroid carcinomas is relatively Usually large Irregular shape common.166 Medullary thy. hoarse- nomas arising from follicular cells. Gastrointestinal system Dysphagia sis of thyroid carcinoma to bone is not uncommon in hu. most often to the lungs and regional lymph Enlarged regional lymph nodes nodes. Thyroid tumors arise not only from follicular epithelium but also from the parafollicular C cells (fig.31: A nine-year-old female boxer (A) with an enormous thyroid tumor causing tracheal obstruction and dysphagia (note the salivation).31.157 Neuromuscular system Painful neck Horner’s syndrome . 3. and tracheal obstruction (fig. cause an emergency situation of rapidly increasing swelling in roid carcinoma in dogs does not seem to be associated with activating mutations in the RET proto-oncogene.3: dogs teogenic or cartilaginous or both) elements. they may cause pressure symptoms such as dysphagia. These so-called Most thyroid tumors are discovered by the owners as a pain- medullary thyroid tumors are relatively rare in dogs. Table 3. The uptake by the parotid salivary glands (at the top of the scan) is normal. consisting of both malignant epithelial (follicular) and mesenchymal (usually os. However. possible role of chronic TSH exposure in promoting neoplastic There is no sex predilection. are extremely rare.169 Metastasis occurs to many Respiratory system Respiratory distress other organs. The large size of the tumor causes lateral displacement of the nonaffected thyroid in which pertechnetate uptake is normal. it is rare in dogs. A large occurrence of medullary thyroid carcinoma in Alaskan mala. as the tumors increase in size viously thought and are of lower malignancy than the carci.1). This also points to a years (range 5–15 years) and boxers are overrepresented.3: Manifestations of nonhyperfunctioning thyroid tumors in Table 3. causing Horner’s syndrome.3). Clinical features roiditis was found to be associated with a high incidence of The mean age of dogs presented with thyroid tumors is nine thyroid tumors in a colony of beagles. Such thyroid tumors are referred to as being »cold«.157. 3.171 Arterial invasion may has not yet been identified in this pedigree.157 It has less mass in the midcervical or ventrocervical region that been suggested that they may be more prevalent than pre. but a predisposing gene defect trunk.163 Hypothyroidism due to lymphocytic thy. A low plasma T4 and high plasma TSH. very similar to that cats but hypofunction. and anterior cervical move along the trachea. or only at low levels. but palpation may also reveal attach- edema. Thyroid Neuromuscular system Weakness Restlessness tumors also very rarely infiltrate the skin. lipoma. can be found in dogs in which the normal thy- often less severe (table 3. The protein products of these genes include System or organ Common Less common or rare somatostatin.157 Respiratory system Panting Cardiovascular system Tachycardia Differential diagnosis Forceful heart beat The differential diagnosis for a large cervical mass includes Renal system Polydipsia and polyuria inflammation (pharyngeal penetration by a foreign body). pericardial effusion. lymphoma.32).33) in ectopic thyroid tissue should be considered. and other tumors.172 Tumors Diagnosis and staging arising from thyroglossal duct remnants develop in the ventral The location and extent of the mass is determined by careful midline cranial to the larynx and may involve the base of palpation of the underside of the neck while the animal is sit- the tongue and the hyoid bones (fig. tide.7 MBq (100 µCi) 131I–.32: (A) Scintiscan of a nine-year-old female miniature poodle with a midline cervical mass at the level of the hyoid bone. In this dog. the administration of 740 GBq (20 mCi) 131I– intravenously produced complete and per- manent ablation of the tumor. Tumors originat. Small to medium-sized tumors are usually easy to cause arrhythmias. (B) radioiodide uptake in the thyroids and the mass. the ventral cervical region due to hemorrhage. in nor- mal C cells. 3. proopiomelanocortin. Occasionally there are symptoms roid tissue is replaced by bilateral thyroid carcinoma or pre- of hyperthyroidism without palpable thyroid enlargement. There is normal uptake in both thyroids and even higher uptake in the mass.174 It may result in the and TSH.157. vasoactive intestinal pep- Thyroid Unilateral tumor. 3.177 Such systemic effects also Metabolism Weight loss in spite of Intolerance to hot occur in dogs: an otherwise unstoppable diarrhea in a seven- good appetite environment year-old collie ceased immediately after removal of a medul- lary thyroid carcinoma.33). indicating syndrome of hyperthyroidism. Hyperfunctioning thyroid tumors result in which case an intrathoracic hyperfunctioning tumor in a high plasma T4 and low plasma TSH (fig. Gastrointestinal system Diarrhea hematoma. and gastrin-releasing peptide. The mass did not produce excessive thyroid hormone. 3. Biochemical studies in similar cases have revealed that such tu- mors produce an iodoprotein similar to albumin and almost no Tg. . (fig. 48 h after intravenous administration of 3. ting in a relaxed position with its head lifted and tilted slightly ing from ectopic thyroid tissue at the base of the heart may backward.176.4). for plasma TT4 was 46 nmol/l and uptake by the thyroids was not suppressed.4: Manifestations of hyperfunctioning thyroid tumors in dogs that are not normally expressed. mimicking inflam- Fatigue and lethargy Muscle atrophy mation with abundant granulation tissue.174. in some patients causing small or medium-sized profuse. Functional Hypersecretion of thyroid hormone occurs in about 10 % status can be tested by measuring plasma concentrations of T4 of cases of thyroid tumor in dogs.173 ment of the tumor to adjacent structures and enlargement of the deeply located cranial cervical lymph nodes. Hyperthyroidism and thyroid tumors 81 3 A B Figure 3. watery diarrhea. existing thyroiditis.175 Medullary thyroid carcinomas in humans may express genes Table 3. Pulmonary metastases can (tumor fixed to surrounding structures). and stases.30. The surgical excision of well-en- rection.175 Plasma T4 was 62 nmol/l and TSH was 쏝 0.179 Blood contamination may be avoided by using a small lignant. 3. N(regional lymph node).02 µg/l. 2–5 cm. These techniques are more sensitive for this pur. regional lymph node meta. range of lymph node involvement from none to bilateral mography.180 the identity of the mass. The high uptake in the cranial portion of the thorax is due an autonomous hyperfunctioning thyroid tumor in the A B cranial mediastinum. 3. necrosis.33: Scintiscans 45 min after intravenous injection of 74 MBq 99mTcO4– in an eleven-year-old. Diagnostic imaging techniques such as ultrasonography. Staging of the tumor can be performed according to the puted tomography. There is normal distribution of radioactivity in the salivary glands and gastric mucosa (B). 쏝 2 cm. showing a small hyperfunctioning (»toxic«) tumor of the left thyroid A B and no visualization of the right thyroid due to feed- back suppression of pituitary TSH secretion.34: (A) Scintiscan of a dog with a nonhyperfunctioning (also called »nontoxic«) thyroid tumor.5). four main staging groups can be distin- Cytological examination of fine needle biopsies may reveal guished (table 3.5). hemorrhage.178 whether or not distant metastases have been detected. Using these indicators. although it may be difficult to obtain aspirates without excessive blood and cystic tumors often Treatment contain a mixture of bloody fluid and degenerated tumor As the great majority of the clinically detected tumors are ma- cells. with the substages »a« (lymph node freely mov- pose than scintigraphy because the metastases. inserting it into the tumor in only one di. and aspirating with a syringe no larger than 5 ml. and 쏜 5 cm dia- roidal origin can usually be resolved by a pertechnetate or meter). M0 and M1 indicate when solid or anaplastic. the mass should be surgically removed without delay. com. 3.36). by computed to. N0–N2 represents the be detected by radiography and. Uptake in the contralateral lobe is not sup- pressed. provided it is resectable. Figure 3. The distribution of radioactivity in the tumor is irregular (see also fig. may not trap pertechnetate. if necessary. but almost none in the thyroid glands (A). calcification. (WHO).162 capsulated and freely-movable thyroid carcinomas is often . vascular displace. and magnetic resonance imaging can be of standardized scheme of the World Health Organization great help in identifying cysts.178 Doubt as to whether a mass is of thy. involvement. subdivided into »a« (tumor freely movable) and »b« iodide scintiscan (figs.33–3. particularly able) and »b« (lymph node fixed). M(distant metastasis) classification.180 In this T(tumor). 82 Thyroids 3 Figure 3. (B) Scintiscan of the boxer of fig. range of tumor size (0. needle (쏝 22 G). T0–T3 represents the ment. and invasion. neutered male Jack Russell terrier presented for gradually increasing polyuria and polydipsia. (B. (A) A pertechnetate scintiscan reveals no uptake by the tumor.8 × 3. (B) Computed tomography (CT) reveals the mass to the right of the trachea (7.35: A 13-year-old female Husky that had undergone surgery for thyroid carcinoma two years before.0 × 2.36: A ten-year-old female West Highland white terrier with hyperthyroidism (plasma TT4: 150 nmol/l) and a palpable mass in the neck suggesting bilateral thyroid tumor. Hyperthyroidism and thyroid tumors 83 3 B A Figure 3. It appears to accumulate contrast medium. C B A Figure 3.9 cm) at the level of the 2nd cervical vertebra (arrows). (A) A pertechnetate scintiscan also gives the impression of bilateral hyperfunctioning thyroid tumor. Recurrence of the tumor was visible in the neck for a few months. C) The CT scan reveals instead a single tumor on the left and atrophy of the thyroid on the right (arrows). . The administration of four once-weekly frac- III T3 Any N M0 tions of 9 Gy was reported to halt tumor growth in all 13 dogs Any T N1 b or N2 b M0 studied and to result in tumor regression in most. dogs with medium-sized or small well-encapsulated carcino- larly in dogs with hypersecreting tumors the high uptake and mas. and the frequency of mitoses. taking into account ble. Tumor IV Any T Any N M1 growth rate rather than the presence of lung metastases was an important determinant of survival time.173 cellular and nuclear polymorphism.32).186 The stringent regulatory require. Symptoms and signs of hyperthyroidism disappear ness. M0) and III (T3a. invasive tumors. Prognosis mors arising from intrathoracic thyroid tissue may be resecta. Permanent alopecia and change in thyroid carcinomas tend to be well circumscribed and resect. hair color and skin pigmentation are common after radiation able. opioids. surgical resection carries a good prognosis.162 their close attachments to the hyoid apparatus and the tongue. and prolonged hospitalization limit the might stimulate growth of persistent or recurrent neoplastic availability of this treatment option.2) will be necessary in addition to thyroxine re.1). In low-risk patients l-thyroxine is given to return TSH levels to within the reference range. Surgical excision of ectopic carci. including . flammatory drugs. placement (correction of induced hypothyroidism) and (2) ments regarding radionuclide use.187 In other words.193 This treatment has two objectives: (1) hormone re- high-dose 131I therapy. TSH suppression. appears to be the most Dogs with large. soft and ing groups II (T2a. N0. M0) resulted in highly palatable food).b N0 M0 size. and cough). complete organification of 131I should result in a high radio- nuclide concentration within the tumor. Patients with high- External beam radiation therapy with a linear accelerator risk thyroid cancer receive higher doses to achieve complete or a cobalt therapy machine is indicated when complete ex. Thyroid-cell proliferation is TSH dependent (chapter 3. namely those with large and bilateral thyroid carcinoma. trachea.. the size of the tumor and bi- options should be considered. yielding a high ef.195 twelve treatments (4 Gy three times weekly).b T2 a. may lead to considerable reduction in tumor vol- Staging group Primary tumor Regional Distant lymph nodes metastases ume.157. important prognostic factor for canine thyroid tumors treated eral or ectopic. such as 3 T1 a. In most cases the acute side effects long-term survival in the majority of the dogs.192 In addition.185. and supportive care (e.187 only be possible if the tumor is well circumscribed and an external parathyroid can still be identified.187. It may take 8–22 months to achieve the maximum reduction in tumor I T1 a. N0. Particu. In principle. hoarse- curative.165 When there are bilateral tumors. treatment of hypoparathyroidism considered in dogs with a high risk of developing metastases. The histological grade of malignancy.5: Clinical staging of canine thyroid tumors180 the primary tumor and regional lymph nodes in the treat- ment field. and because of abundant neovascularization.185 Median survival deed.190 Hypothyroidism can be a late effect of irradi- made to spare one of the parathyroid glands. 84 Thyroids Table 3.b N1 N0 or N1 a M0 M0 those with distant metastases and discomfort caused by the primary tumor. in radioiodide is an attractive alternative (fig. 3. although this is ation of thyroid tumors. administration of lateral occurrence are critical factors. which implies a state of subclinical hyper- cision of the tumor is not possible and radioiodide therapy is thyroidism that will need careful monitoring for cardiovascu- unlikely to be effective. in humans it has been reported that tumor recurrence time was significantly greater for dogs with local or regional rates can be lowered if l-thyroxine is given after surgery to tumors (stage II or III) than for those with stage IV tumors. Pain is managed by application of anti-in- (fig. even though in some cases there was favorably by TSH-suppressive treatment with l-thyroxine. There have been studies in which and since carcinomatous thyrocytes do have TSH recep- 131I therapy – irrespective of thyroid hormone status – ex. particularly if they are bilat.185 patients with nonmetastasized differentiated thyroid carci- Myelosuppression has been recognized as a complication of noma.3) fective dose of radiation. tors. 3.67. If no parathyroid Chemotherapy with either doxorubicin or cisplatin may be tissue can be preserved.184. the need for relatively large hormone suppression (reduction of plasma TSH levels that and repeated doses.181 Excision of movable thyroid carcinomas in stag.g.182 Medullary are resolved in 3–4 weeks. are often poor surgical candidates and other by thyroidectomy.191 placement (chapter 3.194. an attempt should be treatment.1. and esophagus (mucositis causing dysphagia. (chapter 9. Partial remissions have been reported but there are no reports nomas at the base of the tongue poses a challenge because of on improved (progression-free) survival time. tissue). capsular and vascular in- vasion.159 it can be assumed that the prognosis can be influenced tended survival time.183 Ectopic tu.189 Full-course radi- ation therapy leads to acute side effects in the skin (moist skin desquamation and hair loss) and in the mucosa of the larynx. even to a clinically undetectable level.29). In- little or no reduction in tumor mass. Radiation protocols employing lar disease.188 Palliative treatment can be considered in dogs that II T0 N1 M0 are not candidates for full-course radiation therapy.3. COOPER DS. SHIEL RE. 15. nomic actions of thyroid hormone. PELGRIMS N. New York: McGrawHill. Thyroid 27. 226–231. UZUKA Y. Cloning and characterization of canine thyroglobu- 16. HAY ID. LEE J-Y.463–472. TIDHOLM A. ovary cells. Werner & Ingbars’s The Thyroid.29:211–218. DE MOUSA S. 5th ed. KAPTEIN E. Thy- 722–746. 209–280. and transient expression in the Chinese hamster clinical endocrinology. In: Braverman Cloning and sequencing of feline thyrotropin (fTSH): heterodi- LE. RIJNBERK A. messenger RNA in the myocardium of dogs with dilated cardiomyo- mone concentrations in sled dogs. RIJNBERK A. DREMIER S.18:363–378. siol Endocrinol Metab 1993. . 8. DAVIS PJ. FORTEMAISON N.18:19–29. Physio- teins in the cat as compared to dog and man). RAYALAM S. GREENSPAN FS. BROM WE. EIZENSTAT LD.25: Biochemical mechanims of thyroid hormone deiodination. BRENNAN SF. DE FELICE M. MIOT F. J Am Vet Med Assoc 2004. BIGLER B. ROGER P. DAVIS FB. A 3. CARRASCO N. MOL 21. 2864–2871. eds. model of iodine kinetics in the dog. VISSER TJ. healthy. The thyroid cloning and expression in Escherichia coli. Domest Anim Endocrinol 2000. Thyroid development and its dis. Domest Anim Endocrinol 2006. KESTER MHA. roid disorders. MAPK and induction of angiogenesis. VAN GEFFEN C. MOORE GE. 8th ed. 13. DE RICK A.299–332. DAMINET S. DRVOTA V. In: Gardner DG. JANSEN J. Front Neuroendocrinol ing greyhounds. Vet J 2006. 1078–1093. Endocr Rev 2004. 2004.95: Thyroid physiology and diagnostic evaluation of patients with thy. NEL. LI OW. LADENSON PW.8:509–519. HINCHCLIFF KW. Mechanisms of nonge- CT.32: Press. VERK- hormone transporters in healthy and disease.72:667–697. eds. MAENHAUT C. meric and yoked constructs. OMODO-ELUK AJ. Domest Anim Endocrinol 2007. peroxidase and Na+/I– symporter mRNAs in dog thyroid.27:E90–100. BARANDES M. differentiation by thyrotropin and other factors. Canine thyrotropin beta-subunit gene: 5. 12. 2008. MCGRAW RA. 178–189.172:135–140. eds. The Thyroid. 6. Serum thyroid hormone concen. LARSEN PR. References 85 References 1. Physiol Rev 1992. 7. 22. KUIPER GGJM.22:113–125. 2007. PEETERS ME. Vet J 2003. EVERTS ME.30: delphia: Lippincott Williams & Wilkins. 25. GERVY C. Mol Influence of acetylsalicylic acid and ketoprofen on canine thyroid Cell Endocrinol 1997. LAMY F. MOONEY 26. VISSER TJ. HOENIG M.60:848–852. 2. CAPEN CC.131:195–203. ing hormone in dogs during euthyroidism and hypothyroidism. MIOT F. VAN BREE H. Thyroid 2005. Domest Anim Endocrinol 1991. SHAHRARA S. Integrin aVb3 contains a cell surface re- ROOVER K. BELSHAW BE. DUMONT JE. SCHAAFSMA IA. DUCHATEAU L. ceptor site for thyroid hormone that is linked to activation of trations and thyroglobulin autoantibodies in trained and non. Vet Rec 2007.146: trained healthy whippets. DE VIJLDER JJM. YANG X. Schweiz Arch Tier. GROSSE WM. Shoback D. Polonsky KS. Ojeda SR. 8th ed. MAENHOUT C. DAVIES TF. Secretion pattern of thyroid-stimulat- bulin. MILICI C. 2000. function tests. VAN DEN JA. 203–217. PEETERS RP. Influence of drugs on thyroid function in dogs. 11th ed. UYTTERSPROT N. DEBUNNE A. SARASHINA T. logical and pathological regulation of thyroid cell proliferation and heilkd 1976. SYLVÉN C. KOOISTRA HS. MOHAMED SN. 2008. roid 2005. Thyroid hormone concentrations in young. DAMINET S. Upregulation of thyroid hormone receptor b1 and b2 SON S JR. DUCHATEAU L. Domest Anim Endocrinol 2002. MOL JA. GRIFFIN JE. FERGUSON DC. 17. Oxford: Oxford University 3 lin complementary DNA. 11. Thyroxinbindende Serumproteine bei der Katze im Vergleich zu Hund und Mensch (Thyroxine-binding serum pro. In: Kronenberg HM. DAVIS FB. DAVIS PJ. 23. eds. FERGUSON DC. Endocrinology 2005. KOOISTRA HS. DAMINET S. BECKER DV. Regulation of H2O2 generation in thyroid cells does not involve Rac1 activation. FERGUSON DC. Domest Anim Endocrinol 2000. TANABE S. J Vet Intern Med 2003. LANSING L. DUMONT JE. 20.118:559–562. Effects of racing and nontraining on plasma thyroid hor. Greenspan’s basic and clonal antibodies. PIERCY RJ. Eur J Endocrinol 2005. In: Griffin JE. Am J Phy- 4. VAN EMST MG. FERGUSON DC. DUMONT JE. 757–768. generation of mono- gland. SU X. HÄGGSTÖM J.161:616–619. SCHLUMBERGER M-J. Utiger RD. BAVEGEMS V. Larsen PR.15:787–798. VERSCHUEREN CP.21–51.152:127–133. KATAKAM P. CROUBELS S. Melmed S. BERGH JJ. Characterization of and radioimmunoassay for canine thyroglo. Am J Vet Res 1999.294–318. Moderate doses of 10. pretrain. 14. SUZUKI H. LEONARD JL. Phila.15: pathy or chronic valvular disease. Exercise-induced hyperkalemia in hypothyroid dogs. DIAZ-ESPINEIRA M.166:224–232. 9. Comparative anatomy and physiology.15: LEIJ CB. 18. SATO M. Text- book of endocrine physiology. Endocrinology 1974. BERMAN M. 24. delphia: Saunders/Elsevier. SELMAN PJ. LEE JA. HOENIG M. SCHMIDT KE. Williams textbook of endocrinology. DI LAURO R. 19. iodide in vivo inhibit cell proliferation and the expression of thyro- VAN GEFFEN C. HOYBERGS Y. FRIESEMA EC. BOER P. LIN H-Y. Phila. orders: Genetics and molecular mechanisms. Thyroxine and triiodothyronine distribution and metabolism in thyroxine-replaced athyreotic dogs and normal humans. Domest Anim Endocrinol 2000.44:1257–1265.2:143–146. CROWE A. Letter to the Editor. JONES BR GRUFFYDD – JONES TJ.10:15–28. due to defective organification: data suggesting loosely anchored ent hypothyroidism in mice induced by commercial trimethoprim. result in a localization defect and cause congenital hypo- thyroidism. G77IR.131:145–148. Congenital hypothyroidism in a cat. FURUJO M. PETTIGREW R. RIJNBERK A. 55. Congenital hypothyroid dwarfism in a lesc Med 2007. LAPPIN MR. KAMPSCHMIDT K. KAWANO J. roidism with goiter in Toy Fox Terriers. Vet Path 2007. 35. SHELTON GD. Acta Endocrinol 1991. thyroid tissue in a cat. QUIMBY FW. Comp Med 2006. 47.35–59. family of giant schnauzers. Congenital hypothy- Med Assoc 2008. 2008. J Vet Med Sci 2005. LÄNGER F.45:168–170. J Vet Intern Med 2003. Clinical Endocrinol- ogy of Dogs and Cats. FELDMAN EC. J Vet Intern Med 1991. J Am Vet LOWRIE C. Vet Rec 1992. TURNER JL. R665W and in a dog. HAMANN F. J Vet Intern Med 1991.19:177–190. SCHUMM-DRAEGER PM. 41. nine congenital hypothyroidism: skeletal changes with delayed OKAZAKI T. KIESS W. In: Kronenberg HM. 40. KOOISTRA HS. LIPSITZ D. POLAK M. Clin Biochem 54. Hodges CM. REFSAL KR. PARTINGTON BP. SJOLLEMA BE.232:1181–1185. UMEKI K. LÉGER J. ICHIBA Y. OGATA E. ZABORSKY F.230:29–30. 37.214:1028–1031. FYFE JC.5:306. SAUNDERS MH. 48. 11th ed. NACHREINER RF. Clinical hypothy. thorakalem Schilddrüsengewebe des Hundes mit 131I (Demonstra. 1999. LA PERLE KM. 44. Combined pituitary hormone deficiency in German shepherd dogs with dwarfism. Dose-depend. KARGES B. MOTO I. RIJNBERK A. VOORHOUT G. SASAI K.7:164–169. MARKOVITS JE.125:435–440. DEVLIN EE. VAN VLIET G. TYLER JW. Congenital hypothyroidism in a dog due to iodide organifi- cation defect. GRECO DS. nation in rat terrier dogs with congenital goiter and a mutation in Verh Dtsch Ges Path 1996. Thyroids. Endocr Dev 2007. HERMANN G. WHITTEMORE JC. ed. Pituitary function and morphology tion of intrathoracic thyroid tissue in dogs by means of 131I). 86 Thyroids 28. venile-onset hypothyroidism in a dog. GOOKIN JL. 57. PATNAIK AK. Melmed S. GRECO DS. Phila- 39. HORIKOSHI H. LIEB AS. Vet Radiol 1991. 3 30. New Zeal Vet 46. NUTTALL WO. 34.129:245–251.37:617–631. USADEL 51. SC. CASTANET M. dysgenesis. NABETANI T. GROOTERS AM. Preliminary studies on congenital hypothyroidism in a family 31.32:171–177. 2007. Vet Clin Small Anim 43. Williams Textbook of Endocrinology.5:57–65. 42.377–409. SPARKES AH. PEZZANITE J 1986. Etiopath- ologic findings of canine hypothyroidism. KOOISTRA HS. PECHMAN RD. responses to canine thyroglobulin of peripheral blood mononuclear cells from hypothyroid dogs. TANASE H. the thyroid peroxidase gene. eds. RIJNBERK A. ARATAKE Y.34:31–35. The radiographic appearance of ca. Pediatr Ado. 58. 56. J Small Anim Pract 1993. FYFE JC. SEELIG DM. DECKER CJ. PETERSON ME. Congenital hypothyroidism in two cats 32. J Endocr 1990. ALTHOLTZ LY. Congenital hypothy- roidism: from Paracelsus to molecular diagnosis. Vet Rec Zeitschr Path 1966. Inhibition of peroxidase-catalyzed of Abyssinian cats. DEN HARTOG MT. Can Vet J 2004. CHASTAIN CB. PETERSON ME. HÜBNER K.44:50–56 36. MYERS AM AVERY PR. POTEET BA. GRAHAM CL.39:511–518. BRENT GA. thyroperoxidase. Shipman LW. J Feline Med Surg 2000. MCNEEL SV.187:948–950. J Small Anim Pract 59. DJEMLI A. BLESSING MH. reactions by arylamines: Mechanism for the anti-thyroid action of sulfamethazine. HE Q. 49. Inherited primary hypothyroidism with treatment. DE VIJLDER JJM. J Am Vet Med Assoc 1999. DOERGE DR. RIP- PEGATHER K. Congenital hypothyroidism in a boxer dog. Goitrous hypothyroidism associated with treatment 50. Congenital hypothyroidism. 38. Two novel mis- roidism associated with trimethoprim-sulfadiazine administration sense mutations in the thyroid peroxidase gene. KUDO K. LARSEN PR. 52. GOTTSCHALK S. DANG V. CHO DY.80:297–301. WATSON ADJ. CASPAR G.11:118–127. 45. VAN DIJK JE. Dordrecht/Boston: Kluwer 1996. MOONEY CT. Ectopic lingual 53. Larsen PR. MOL JA. SUGANUMA T. . Hypothyroidism and 2006.144:644–646. Tetraparesis due to vertebral physeal fracture in an adult dog with congenital hypothyroidism. TANI H. sulfamethoxazole rodent feed. Spontane Hashimoto-artige Thyreoiditis im HUNTA A. DAVIES TF. JEZYK PK. LUCKE VM. RIJNBERK A.56:395–401. BABA E. ANDERSON TJ. MIZUSHIMA H.38:364–367.34:72. GREGORY BL. Über den Nachweis von intra. Familial forms of thyroid delphia: Saunders/Elsevier. BARTELS T.75:14–24. SUMMERS BA. Proliferative 1997. FETRO VM. In: Rijnberk A. CNS hypomyeli- Modell der Katze (Spontaneous Hashimoto-like thyroiditis in cats). Am J Vet Res 1983. BUNCH SE. J Am Vet Med Assoc 1985. Eur J Endocrinol 2002. thyroiditis. TREPANIER LA. Iodine deficiency in working dogs. FORTMEYER HP. DELA- KH. YAMA- 33. with trimethoprim-sulfamethoxazole in a young dog. GRAHAM PA. What is your diagnosis? J Am Vet Med Assoc 2007. Chem Res Toxicol 1994. PETERSON ME. thyrotropin resistance in Japanese cats. KOTANI T. Polonsky KS. SZABO SD.146:491–498. WELLS KL. 29. Frankf in two German shepherd dogs with congenital dwarfism. MOL JA. HIDGON A. GRAHAM PA.17 :50–57.67:363–368. Ju. PARKER W. thyroidism with a common major histocompatibility complex DLA PERSECHINO A. and athe- rosclerosis in dogs. HESS RS. 80. OLIVA G. MORIELLO KA. 85. MELIAN C. MATSUOKA LY. 77. and thyro- 74.145:481–487. 89. AUBERT I. roidism. and thyrotrophin concentrations in dogs with nonthyroidal disease. SKYDSGAARD M. Domest Anim Endo- tern Med 2006. J Am Vet Med Assoc 1996. SPODNICK GJ. betes mellitus. eds. haematological and biochemical characteristics of canine hypothy. dog after surgery and radiation therapy for a functional thyroid ade- nocarcinoma. Measurement of serum total thyroxine. Nemaline Rods in canine myo- pathies: 4 case reports and literature review. PIKULOVA J. Myxedema coma leading to respir- atory depression in a dog. CATCHPOLE B. JAGGY A. Neurological manifestations of hypothyroidism: a retro- spective study of 29 dogs. VAN WINKLE TJ. SHELTON GD. Hypothyroid- enzyme-linked immunosorbent assay for the detection of thyroglo- associated central vestibular disease in 10 dogs: 1999–2005. Antigens 2006. MAYR A. YUNCKER C. MELIAN C. References 87 60. FRANK LA.17:59–63. ENG A. J Am Vet Med Assoc 1993. MOORE GE.216:713–717. GLAUS T. PIKULA J. SCOTT-MONCRIEFF JC. RIJNBERK A. KRAMER RW. Epidemilogical. ANGLES JM. Can Vet J 2004. OLIVER JE. apy XI. BUDSBERG SC. 69. sche Schäferhund mit Hypothyreose – ein Fallbericht (Generalized ation of hypothyroid disease in Doberman Pinscher dogs with a rare Malassezia dermatitis in a German shepherd dog with hypothyroid- major histocompatibility complex DLA class II haplotype. Vet Quart 1995. LEVINE J. Unusual manifestations of hypothyroidism in 61.38: 572–575.20:1363–1369. In: Kirk RW. 65. J Vet Intern Med 66. J Vet Intern Med 1993. Thyroxine- Polyglandular deficiency syndrome in a Boxer dog: thyroid hor. VAN DEN INGH TSGAM. BANDOUCHOVA H.37: Vet Med Assoc 1997. KINTZER PP. DODDS WJ. Assocation of canine hypo. GRAHAM PA. Schmidt’s syndrome in a dog: a case report. DIXON RM. J Am of hypothyroidism in dogs and cats.21: 70. Generalisierte Malassezien-Dermatitis bei einem Deut- LE. Wien Tierärtzl Mschr 2007. 72. BEST SJ. NICHOLS R. HILLBERTZ NS. 1316–1322. Association between dia- roidism. BARNES A. MAHAFFEY EA.45:318–320. neous involvement of acromegaly. Hypothyroidism in a by severe hypothermia. DUNSTAN RW. DELAUCHE AJ. KASS PH. J Am Vet Med Assoc 2000.202:1859–1860. KASS PH. Pretreatment clinical 1998. hyperlipidemic Labrador retrievers. arni Med 2007. NACH. free thyroxine.94:169–174.21:1396–1402. LEONARD J. Hyperprolactinaemia and galactorrhoea associ- class II allele.7:272–276.32:628–634. Neurologic dysfunction in hypothyroid.15:525–536. 78. 3 CARMICHAEL NG. RUSBRIDGE C. roid hormones on the skin of beagle dogs. HØIER R. J Vet Intern Med 2001. dogs. Am J Vet Res 2006. 84. Philadelphia: Saunders 1992.12:424–430. WOJCIECHOWSKI JW. MOONEY CT. and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979–1993). CREDILLE KM.32:481–487.419–422. triiodothyronine. RAM.35:132–136. JENSEN AL. PRICE GS. 63. 87. roid dogs. J Am Anim Hosp Assoc 1996. KOOISTRA HS. Associ. . OLLIER WE. 86. CUDDON PA. Bonagura JD. Tissue Antigens 2006.142: 1820–1823. The effects of thy. mucins in hypothyroid dogs. Serum total thyroxine. Development and validation of an improved 79. DELVERDIER M.PATZL M. (TRH) to thyrotropin (TSH) stimulation for evaluating thyroid DIETRICH JE. RÉGNIER A. 76. responsive unilateral forelimb lameness and generalized neuromus- mone and glucocorticoid deficiency. Vet Clin Small Anim 2007. Histochemical study of cutaenous J Am Vet Med Assoc 2001. ated with primary hypothyroidism. LEE WM. SKOPEK E. RAND JS. and thyrotropin concentrations in the diagnosis of canine hypothy- REINER RF. DIXON RM. KENNEDY LJ. Primary hypothyroidism in dogs is associated with elevated GH release.330–334.40:72–78. Arch Intern Med 1982. CIARAMELLA P.15:539–546. MOL JA. PETERSON ME. HENIK RA. KANTROWITZ LB. CORTESE L. PODELL M. J Endocrinol 2001. DEVOE K. REID WJ. DOLIGER S.208:85–91 82. J Small Anim Pract 1997. SLATER MR. total triiodothyronine. PETERSON ME.68:82–86. J Vet Intern Med 2003. DIXON RM. MOONEY CT. DIXON RM. J Small Anim Pract 1999. Detection of auto- antibodies against thyroid peroxidase in serum samples of hypothy. ROSSMEISL JH PANCIERA DL. function in dogs. TUCKER KA. Comparison of thyrotropin-releasing hormone 73. FERGUSON DC. LONGEART L. free thyroxine. PETERSON ME. MORÉ J. J Vet Intern Med 2007. Clinical signs and concurrent diseases tropin concentrations for diagnosis of hypothyroidism in dogs. 83. J Vet Intern Med 1994.67:53–56. KENNEDY LJ.168:59–66. 81. Current Veterinary Ther- SEY IK. HAPP GM. Intravenous administration of levo- thyroxine for treatment of suspected myxedema coma complicated 67. HUSON HJ. clinical. hypothyroidism or hyperadrenocorticism.219:765–769. HIGGINS MA. Vet Path 1995. FOX 75. FALDYNA M. Vet Rec 1999. KOOISTRA HS. KRISTENSEN F. Veterin. Vet Radiol Ultrasound 1994. OLBY NJ. KLAPPENBACH K. Spontaneous adult- onset hypothyroidism in a cat.67:809–814. Histochemical characterization of the cuta. 709–722. NICHOLS R. HAPP GM. 64.17:489–494. crinol 1998. Evaluation of serum free thyroxine 71. CHASTAIN CB. ATKINSON K. POWEL HC. HAJKOVA P. VITALE CL. WORTSMAN J. J Vet In- bulin autoantibodies in canine serum samples. DIAZ ESPINEIRA M. NACHREINER RF. IVERSEN L. 62. 68. Tissue ism – a case report). RIJNBERK A.8:328–336. QUARMBY S. VERSTEGEN J. MAGNOL JP. ROETHEL C. 88. KUPCHELLA CE. cular disease in four hypothyroid dogs. 95. J SON AP. clinical and laboratory Thyroid sonography as an effective tool to discriminate between features of 126 hyperthyroid cats. HOENIG M. J Endocrinol dogs.37:745–754. REUSCH CE. J Vet Intern Med 2007. Residual pi- ombinant human thyroid-stimulating hormone (rhTSH) on thy. WARD CR. NELSON RW. 105. netics of total thyroxine in dogs after administration of an oral sol- stimulating hormone for thyrotropin stimulation test in euthyroid ution of levothyroxine sodium.34:176–181. SAUVÉ F. Pharmacokinetics of L-thyr- 3 oxine after its oral administration in dogs. PETERSON ME. Am J Physiol 1993. PETER- VAN DER VLUGT-MEIJER RH. Diagnosis of canine hypo. thyroxine-replaced athyreotic dogs and normal humans. and large-breed dogs.33:228–235. J Vet Intern Med 2005. BREYER U. KOOISTRA HS. hypersomatotropism. KASPERS B. ers with nonthyroidaal illness. euthyroid sick and hypothyroid dogs. 109. POLLARD RE. DE ROOVER K. Thyroid 2002. Results of thyroidectomy in 101 cats with hyperthyroidism. J Vet Intern Med 2006. PARADIS M. NAAN EC. 115. Am J Vet Res 2006. MOL JA. Feline thyroid adenoma are in part associated with mutations in the Gsa gene and not with polymorphisms found in the thyrotro- 99. 108. MOL JA. RIJNBERK A. SAMII VF. ACKE E. RAVIS WR. MOONEY C. KIRPENSTEIJN J. plasma thyroxine concentration. DIAZ ESPIÑEIRA MM. WARD CR. of feline hyperthyroidism. KRAFT W. SIEBER-RUCKSTUHL NA. GALAC S. Functional and morphological changes in the adenohypophy. and euthyroid Golden Retriev. KOOI. DIAZ ESPIÑEIRA MM. LE TRAON G. THODAY KL. MEINKOTH JL. HOLT D. 91.31:951–962. KASS PH. 106. RIJNBERK A. IVERSEN L. 110. Domest Anim 111. Use of recombinant human thyroid. THODAY KL. DAVID. Feline thyroid storm. J Vet Intern Med 2009. FERGUSON DC. 92. loss of TSH vest 1987. PUGGIONI A. 88 Thyroids 90.37:647–669. Vet Clin Small Anim 2007. NACHREINER RJ. Endocrinol 2008. . Adenohypophyseal function in dogs with primary hypothy- roidism and non-thyroidal illness. Pharmacoki- 93. KASS PH. MELLANBY RJ. BECKER DV.67:70–77. MEIJ BP. MOONEY CT. Testing for hypothyroidism in dogs. KEMPPAINEN RJ. Evaluation of proteinuria in hyperthy- roid cats. BRÖMEL C. tuitary function after transsphenoidal hypophysectomy in dogs roid-stimulating hormone (TSH) response testing in euthyroid with pituitary-dependent hyperadrenocorticism. 94. TRIP MR. DEEG C. PEETERS ME. WARD CR. DAMINET S. MOL JA. and pituitary enlargement with transdifferentiation. 107.37:633–645. POLLAK YWEA.264:E90–100. VAN DIJK JE. hypersecretion. Autonomy of growth and of iodine metabolism in hy- HS. KOOISTRA SON ME. Irish Vet J 2007. DOXEY DL.19: 491–498. BURGAUD S. CARMICHAEL N. J Vet Intern Med 2005. ROSSER EJ. NELSON RW. Comparison of ultrasonographic charac. REFSAL KR. KAPTEIN EM.23: 113. Thyrotropin-stimulated DNA synthesis and thyroglobulin expression in normal and hyperthyroid feline thyro- 98. 95–101. medium-. KOOISTRA HS. HORSPOOL.146: 104. Secondary hypothyroidism following head trauma. Endogenous TSH in the diagnosis of hypothyroidism in dogs. 118. RIJNBERK A. VAN GEFFEN C.80:491–498. DUCHATEAU L. REESE S. BRÖMEL C. MOORE GE. J Vet Pharmacol Therap 2008. Vet Surg 2006. DAVID- SON AP. GERBER H. ACHENBACH SE. 100.54: 2091–2098.60:88–93. Domest Anim Endocrinol 2008. Tertiary hypothyroidism in a dog. Am J Vet Res 2006. JEFFERY ND. urinary corticoid /creatinine ratios in cats with hyperthyroidism. MOL JA. POLLARD RE. KOOISTRA pin receptor. HOFMANN-LEHMANN R.67:2012–2016. J Clin In- sis of dogs with induced primary hypothyroidism. J Vet Intern Med 2001. PETER HJ. SHIEL RE. Etiopathologic findings of hyper- 100–107. 116. SAMII VF. RIJNBERK A. Assessment of thyroid function in dogs with low ME. DIAZ ESPIÑEIRA MM. terisitics of the thyroid gland in healthy samll-. BORETTI FS. J. Carbimazole therapy roid gland in healthy. thyroid function in dogs suspected of having hypothyroidism. 97. GALAC S. BEVERS MM. 101. Vet Intern Med 2004. hypoprolactinemiea. Ultrasonographic evaluation of the thy. 117. Vet Rec 1992. Vet Clin North Am Small Anim Pract 2007. PEETERS STRA HS. STUDER H. perthyroid feline goiters transplanted onto nude mice. Evalu. BEHREND EN. MOL JA. PEETERS ME. VAN DEN INGH TSGAM. Can Vet J 2000. MOONEY CT. DIAZ ESPIÑEIRA MM. FERGUSON DC.41:215–219. thyrodism in cats. Thyroid 2005. 112. SYME HM. MOL JA.155: 531–539.7:135–139.15:299.131:257–264. HAUPTMAN 183–188. REUSCH CE.19:499–506.35:287–293. Vet Clin North Thyroxine and triiodothyronine distribution and metabolism in Am Small Anim Pract 2001. TIMMERMANS-SPRANG EPM. KOOISTRA HS. Schweiz Arch Tierheilkd 2004. Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism. 96. PEDERSOLI WM.21:25–32. CASSIDY JP.31: dogs. PETERSON ME. LJI. HS. Perspectives from a testing laboratory. RIJNBERK A.18:152–155. Historical. hypothyroid.12:571–575. BORETTI FS. HERRTAGE ME. Vet Clin Small Anim Pract 2007. 103. LUTZ H. Effect of storage of reconstituted rec. cytes in monolayer culture. 114. FAVROT C. thyroidism. DE LANGE MS.15:114–120. GOPAL MS.20:812–817 1997. J Feline Med ation of recombinant human thyroid-stimulating hormone to test Surg 2005. J Small Anim Pract 1992. High 102.35:98–111. ELLIOTT J. Am J Vet Res 1993. PEETERS ME. ed. PETERSON ME. Thyroid to salivary ratios determined by technetium–99M per. PETERSON ME. SARGEANT J. SCHENCK PA. PETERSON ME. JESSEN CR. 20–22 (and personal communications). Vet Derm 2005. Vet Radiol Ultrasound 2006. HOBBS JM.47:507–509. 3 136. BARTHEZ PY. DANIEL GB. Atlas of roidism. 143. Vet Radiol Ultrasound 2006. ADAMS W. NIECKARZ JA. Clin Tech Small Anim Pract 2006. J Am Vet Med Assoc 2001.54:351–355.37:799–821. KIRKBY R. RIJN- noma that had previously undergone surgery. Response to high- dose radioactive iodine administration in cats with thyroid carci- 126. Thyroidectomy. Nuclear imaging and radiation 2007. CHUN R. PAGE RB. Predictors of responses to radioiodine therapy in hyperthyroid cats. POLLAK YWEA.37:693–708. SCHAER M. Quanti- methimazole or both: 167 cases (1996–2003). thyroidism in cats. SCOTT-MONCRIEFF CR. 141. 146. RIJNBERK A. SMITH K. Calcinosis involving multiple foot radioiodine treatment in 91 hyperthyroid cats. Medical Management of hyperthyroidism. thyroidism in cats J Vet Intern Med 1990. NICHOLS R. J Am Anim Hosp Assoc 1998. J Fel Med Surg 2003. 127. POLLAK YWEA. Res Vet thyroid uptake of pertechnetate and radioiodine in normal cats. thyroidal disease. In: van Sluijs FJ.67:1362–1366. Vet Radiol Ultrasound 131. HUBBLE LJ.11:165–170. cats. 1992. Multimo.5:77–82. 142. DYKES NL. BHATTI S.43:374–382. ARMBRUST LJ. Efficacy of parathyroid gland autotransplantation in maintain- serum concentrations of free thyroxine. 137. Relation- ship between selected echocardiographic variables before and after 121. J Am Vet Med tative thyroid scintigraphy as a predictor of serum thyroxin con- Assoc 2006. DECLERCQ J. Vet Clin Small Anim Pract 2007.46:506–513. WAKELING J. 123. 139.42:448–457.21:22–28.4:233–238. sound 2005. 144. DENICOLA DB. SCHAAFSMA IA. DYKES NL. YOHN SE.2:150–157. J Am Vet Med Assoc BERK A. SYME HM. Identifying removable radioactivity on dality image fusion to facilitate anatomic localization of 99mTc. POLLAK YWEA. TREPANIER LA. DYKES NL.21:34–39. Questions incidence of postreatment hypo- technetate imaging in thirty-two euthyroid cats. ANDERSON KL. Vet Radiol Ultrasound 2002. Small Animal Surgery.34:21–324. SCRIVANI PV. LEVY JK. HOFFMANN G. centration in normal and hyperthyroid cats. MARKS SL. ERB HN. LIKEN GA. Quantitative aspects of thyroid scintigraphy with per- 1995. DANIEL GB. WEDEKIND KJ.37:723–743. 145. Vet Clin Small Anim Pract 2007. J Am Vet Med Assoc 2005. Subclinical hyperthyroidism in cats: a spontaneous model of subclinical toxic nodular goiter in humans? Thyroid 138. Vet Radiol Ultra- sound 2002. Vet Radiol Ultrasound 2001. Investigation 148. Transdermal methimazole treatment in cats technetate scintigraphy in suspected hyperthyroid cats. Ultrasound 2007.218:529–536. sound 2005. FEENEY DA. WEICHSELBAUM RC. Vet Radiol Ultra- paws in a cat with chronic renal failure and in a cat with hyperthy- roidism. SHARP DS. ROMATOWSKI J. LEATHERS CW. SHERMAN A. HOSKINSON JJ. New York: Churchill Livingstone. GARRETT LD. NACHREINER RF. Accuracy of increased thyroid activity during pertechnetate scinti- graphy by subcutaneous injection for diagnosing hyperthyroidism 147. 129. POLLAK YWEA.16:74–78. Radioiodine treatment of hyperthyroidism. Vet Radiol with hyperthyroidism. J Vet Intern Med 1988. MELIÁN C. WARDROP 122. J Vet Intern Med 1994. SYME H. TOBIAS KM. 2006. ERB HN. ELLIOTT J.227:32. Effect of Association of the risk of development of hypothyroidism after four sedative and anesthetic protocols on quantitative thyroid iodine 131 treatment with the pretreatment pattern of sodium scintigraphy in euthyroid cats.17:1201–1209. SCRIVANI PV. 262 cats with hyperthyroidism. Vet Radiol Ultra. NIECKARZ JA. VAN DEN BROM WE. 132. 134. 135. WOLFSHEIMER KJ. .8: 302–303. NYKAMP SG. Calcium homeostasis in thyroid disease in dogs and cats. NAP AMP. Cardiovascular and renal manifestations of hyperthy. GUPTILL L. 125. SCRIVANI PV. Clin Tech Small Anim Pract 2006.47:503–506.48:383–387. SCASE T. PETERSON ME.47:206–211. GRAVES TK. BLEVINS WE. SCHAAFSMA IA. pertechnetate 99m uptake in the thyroid gland in cats with hy- perthyroidism: 162 cases (1990–2002). HOBBS JM. FEENEY DA. MIL. KINTZER PP. CHANNELL CD. SCARLETT JM. Sci 1993. KIRK CA. HOSKINSON JJ. GAMBLE DA. and total ing serum calcium concentrations after bilateral thyroparathyroid- triiodothyronine in cats with hyperthyroidism and cats with non. Comparison of the disposition 131. Am J Vet Res 2006. PADGETT SL. MILNER RJ. Triiodothyro- nine (T3) suppression test: An aid in the diagnosis of mild hyper. References 89 119. HOSGOOD GL. 2005. Sur- vival times for cats with hyperthyroidism treated with iodine 131. technetate (99mTcO4-) in cats.46:521–523. 133. Vet Clin Small Anim Pract 2007. total thyroxine. Measurement of KJ. of two methods for assessing thyroid-lobe asymmetry during per. J Am Vet Med Assoc 130. The effect of methimazole on of carbimazole and methimazole in clinically normal cats. CHALMERS HJ. Vet Quart 1989. VAN DEN BROM WE. HENRIKSON TD. PETERSON ME. TABOADA J. DYKES NL. ERB HN. Methimazole treatment of in cats.226:1671–1675. PAGE RB. therapy in canine and feline thyroid disease. 124.43:587–591. Thyroidal radioiodine uptake in hyperthyroid 140. ectomy in cats. JANOVITZ EB.207:1055–1058.228:559–563. SJOLLEMA BE. 128. BARTHEZ PY. the surface of cats during the first week after treatment with iodine pertechnetate uptake in the feline head. ZARFOSS MK. 120. AUCOIN RP. eds. Associations between lymphocytic thyroiditis. Cancer Res 2008. J Am Anim Hosp Assoc 1994. SWIFT NC. Acta Endocrinol 1991. BIZZARRI 2006. DORIS P. HORNOF WJ. VOS JH. OHOKA A. VASSART G. HORNOF WJ. GR. DE VIJLDER JJM.123:291–298. Utiger RD. medullary thyroid carcinoma and thyroid adenocarcinoma in dogs: ules after percutaneous ethanol injection in patients subsequently a retrospective study of 38 cases. WINTER Leipzig (Tumors of the thyroid gland in dogs – a local character- EA. SLENSKY KA. 170. VERSCHUEREN CP. istics. Thyroid tumors in dogs and cats. Schilddrüsen- tumoren beim Hund – eine regionale Besonderheit im Raum 150. CORVILAIN B. SJOLLEMA BE. the cranium and pituitary gland in two dogs. STEPHENS LC.37:755–773. LEAV I. LONG C. J Small Anim Pract 1991. Anticancer Res results suggesting hyperadrenocorticism. G. PAGE RL. Vet ethanol injection for treatment of unilateral hyperplastic thyroid Pathol 2005. TESKE E. 165. KAPATKIN A.223:1602–1607. FELDMAN EC. 167. WARE WA. KURVERS IAPG. PETERSON ME.218:1298–1302. GUGLIELMI R. DUH Q-Y. VOS JH. Thyroid lymphography of the dog. In: Braverman LE. SIPERSTEIN AE. Use of percut. Flow-cytometric DNA ploidy analysis in primary Hyperthyroidism due to an intrathoracic tumour in a dog with test and metastatic canine thyroid carcinomas. GOLDSTEIN RE. RINALDI R. MALLERY KF. LARSSON C. 174.37: 591–593. Carbimazolzalf ter behandeling van hyper. J Am Vet Med Assoc 158.48:237–239. HORNOF WJ. RUTTEMAN GR.110: 172–176. Efficacy and safety of transdermal methimazole Anim 2007. J Vet Intern Med 2004. Thyroid carcinosarcoma in a dog. MAULDIN EA. ANGLETON GM.29:1173–1182. 166. FELDMAN EC. NYLAND TG. KOOISTRA HS. WELLS AL.218:1293–1297. Clinical character- 2039–2046. BIANCHINI A. ACTON DS. tion treatment in benign thyroid lesions: role and efficacy. DEVILEE P. RUTTEMAN 176. BARBER LG. LEGG MA. J Am Vet Med Assoc 2001. 155.14: CLARK OH. 164. LEE AC. 8th ed. Histologic changes in thyroid nod. MERKLEY DF. DE BRUIN TWA. 161. STERNS EE. BUIJTELS JJCWM. GRUBOR B. TAMURA Y. VAN 2003.30:20–23. COR. NELSON RW. Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. MELIÁN C. GALAC S. AUPPERLE H. . CARVER JR. Percutaneous 168. RODAN I. operated due to new focal thyroid lesions. POLLARD RE.21:468–476.48:283–287. PACELLA CM. and a comparison of staging systems. Tijdschr Diergeneeskd 2006. BERGER R. Horner’s syndrome associated with a Med Assoc 2003. MALLINCK- 151. PATNAIK AK. VAN DIJK JE. J Small Anim Pract 2007. RIJNBERK A. FELDMAN EC. J Am Vet Med Assoc 2006. POGGI M. RUTTEMAN GR. ESPINOSA DE LOS MONTE- heat ablation for treatment of hyperthyroidism in cats.42:84–87. DUMONT JE. 2004. Adenomas and carcinomas of the canine and feline 172. Am J Path 1976. SCHILLER AL. 175. DER KIN- DEREN PJ. LONG CD.132:461–468. BENJAMIN SA. HÖPPENER JWM. thyroidism. PALMA E. J Endocrinol dium iodide I 131 treatment of dogs with nonresectable thyroid 1992.131: 133–180. Percutaneous ultrasound-guided radiofrequency 171. SIL- thyroid. DIJK JE. NELSON RW. VERSTEIN D. Philadelphia: Lippincott 486–494. LEE JJ.18:651–655. Multiple metastases of thyroid cancer in thyroid nodules. HÖÖG A. Intracardiac thy- with thyroid carcinoma. LUI WO. BARTOS M. MOL JA. VERSCHUEREN CP. functional thyroid carcinoma in a dog.88:1139–1148. Dtsch tierärztl Wschr 2003. UCHIDA K. A comparison of 152. roid tumor in a dog: Diagnosis and surgical removal. SAUNDERS WJ. J Am Vet ROS A. prognostic factors. VAN LEEUWEN IS. GOLDSTEIN RE.11:1755–1762. Anticancer Res 1994. Cancer 2000.14:125–131. VOLK SW. KUIPERS-DIJKS- HOORN NJ. SCHOON H-A. STASSEN QEM.83:61–122. HAMILTON BF.33: Werner & Ingbar’s The Thyroid. TAMURA S. KROLL MM. SJOLLEMA BE. NELSON RW. NELISSE CJ. 163. SUZUOKA N. tumors: 39 cases (1990–2003). Int J Oncol 153. GRAZIANO FM. VAN DIJK JE. VAN GASTEREN CJR. CORNELISSE CJ. TREPANIER LA. 157. VON EULER H. RIJNBERK A. POMORSKI L. in the treatment of cats with hyperthyroidism.110: 3 thyreoïdie bij de kat (Transdermal carbimazole for the treatment of feline hyperthyroidism). KEBEBEW E. Thyroid FRANKLIN DS. Acute severe hemorrhage secondary to arterial in- vasion in a dog with thyroid carcinoma. J Am Vet Med Assoc 2001. JM. 478–482. 162. VOESTEN A. SCHWARZ T. So- plastic (primary and metastatic) canine thyroid tissue. VERSCHUEREN CP. A dog pedigree with familial medullary thyroid cancer. SARTOR LL. Vet Surg 1995. istic in the area of Leipzig). treatment. PETRUCCI L. Toxic adenoma RODT CH. BURKE BP. NYLAND TG. RIEDESEL DH. Circulating thyro- globulin measurements by homologous radioimmunoassay in dogs 173. Vet Pathol 1996. Williams & Wilkins 2000. 2007. SELMAN PJ. GLIESCHKE K. 156. 169. hypo- and toxic multinodular goiter.229: 542–548. Medullary thyroid carcinoma. TOSCANO V. LIPS CJM. Percutaneous ethanol injec. Thyrotropin receptors in nomral and neo. APMIS 2002.24:315–319.223:649–653. MCENTEE MC. MORALES M. ITUARTE PHG. VAN VEELEN W. Cancer 1968. 90 Thyroids 149. PAPINI E. 154. 160. VOS JH. and thyroid neoplasia in beagles. TURREL. J Small Anim Pract 1996. VOS JH. HASE- aneous ethanol injection for treatment of bilateral hyperplastic GAWA T. 159.564–572. Vet Clin Small CHALLONER L. nodules in cats. VOORHOUT G. HAYNES JS.68:1329–1337. 193. WORTH AJ. Treatment of thyroid carcinoma in dogs by surgical Clinico-pathological and endocrine aspects of canine thyroid resection alone: 20 cases 1981–1989). HAMDY NA. ADAMS WH. In: Verschueren CPLJ. BREARLEY MJ. SAUNDERS JH. Nat Clin Pract 2005. BIONDI B.51–53. MURPHY S. DICKINSON KL. THÉON AP. eds. POWERS BE. Utrecht University. LIPTAK JM.11–25. BAIER M. J Am Vet Med Assoc 2000. De- tern Med 2007. 188. 1995. Geneva: World Health 190. 184. HOCKING M.195:1606–1608. Thesis. The dium iodide I131 treatment of dogs with nonresectable thyroid tu. 2000. BURKE BP. VAN DIJK JE.42:471–474. Endocrine Glands. 181. 195. come. 8th ed. DANIEL GB. VERSCHUEREN CP. RUTTEMAN GR. Treatment of differentiated thyroid carcinoma in 7 dogs utilizing 131I. 1992. UCHIDA K. effects of thyrotropin-suppressive therapy on bone metabolism in mors: 39 cases (1990–2003). Radioiodine and other treatment and out- 183. 191. LUMSDEN JH. surgically-treated canine thyroid cancer. Thyroid 542–548. Evalution of some prognostic factors in STRAW RC.21:673–684. Philadelphia: Lippincott Williams & Wilkins. excision alone. ed. In: Owens LN. . PAGE RL.36:417–424. Fine needle aspiration cytology in the diagnosis of canine thy.229: patients with well-differentiated thyroid carcinoma. 3 PB. Aust Vet J mone therapy and thyroid cancer: a reassessment. Clin Tech Small Anim Functional thyroid gland adenoma in a dog treated with surgical Pract 2007. J Am Vet Med Assoc 1989. Surgical excision of ectopic thy. PACK L.83:208–214. FELDMAN ES. LITTLE Vet Radiol Ultrasound 2001. LEBOULLEUX S. TRAVALI J-P. OWENS LN.61:299–310. J Am Vet Med Assoc 2006. 187. 178. PEREMANS K. NIBE K. SALISBURY SK. 180. SCHLUMBERGER M.904–929. FRANKEN HCM. Thyroid-hor- therapy for the treatment of canine thyroid carcinoma. DOOKWAH HD. OGILVIE GK.48:761–763. MCENTEE MC. GRIFFEY S. 192. TURRELL JM. Canine thyroid carcinoma. KOJIMOTOT A. JH. External beam radiation Organization. SCHLUM. ROMIJN JA. ZUBER RM. SMIT JW. radiation therapy for invasive thyroid carcinoma in dogs: retrospec- tive analysis of survival. J Vet In. STIRTZINGER T. 189. MAYER MN. Clin Endocrinol nostic factors and patterns of treatment failure in dogs with unre- 2004. 179. WITHROW SJ. ITOH T. DAWSON SD. 2006. Radioiodide (131I) 194. In: Braverman LE. Can Vet J 2007. ROBERTS RE. WALKER MA. 1980. FILETTI S. Prog- BERGER M. COOPER MF. sectable differentiated thyroid carcinomas treated with megavolt- age irradiation. Vet Radiol Ultrasound 1995. Werner & Ingbar’s The roid carcinoma involving the base of the tongue in dogs: three Thyroid. therapy for thyroid cancer in the dog.69:61–63. LANTZ GC. HIROKI S.206:1007–1009.216:1775–1779. Thyroid imaging in the dog: Current status and future directions. BAUDIN E. Hypofractionated roid carcinoma. Medullary thyroid carcinoma. TNM clas- sification of tumours in domestic animals. CURTIS CR. Utiger RD.1:32–40. VOS 182. HAYES AM. finitive radiation therapy for infiltrative thyroid carcinoma in dogs. MARKS SL. TAEYMANS O. PETERSEN MG. Endocrinol Metab 2005. 185. MACDONALD VS. LEGENDRE AM. cases (1980–1987). THOMPSON EJ. HEEMSTRA KA. KLEIN MK. References 91 177.22:75–81. So.16:583–591. J Am Vet Med Assoc cancer.40:206–210. J Small Anim Pract 1999. 186. MAZZAFERRI EL. J Vet Med Sci 2007. Can Vet J 1980:21:186–188. This page intentionally left blank . E = capsule. lipid-poor cells are scattered beneath the adrenal cap- mone (ACTH) secreted by the pituitary gland. but ment have been identified. (2) zona fasciculata. . D = zona glomerulosa. cuata). (B) Similar section from a dog that received injections of progestagens. The cells are relatively large and contain much kidneys.1). In recent years several factors involved in adrenal develop. basic fibroblast growth factor (bFGF). Kooistra Ad Rijnberk 4 4. 4. It consists of col- umns of cells extending from the zona reticularis to the zona The adrenals are paired glands situated craniomedial to the glomerulosa. giving the cells a vacuolated appearance for which gland consists of coalesced chromaffin cells of neuroectoder. As ACTH is sule. They produce mineralocorticoids (primarily aldoste- not a growth factor per se. B = zona reticularis. The adrenal cortex are influenced by adrenocorticotropic hor. The medulla of each sections. Reusch Hans S. for which they are called »compact cells«. and (3) zona reticularis (fig. small. It functions together with the zona fas- factors are responsible for the differentiation of adrenal stem ciculata as a single unit. This zone produces androgens such as androstenedione. They do not have significant lipid content but have densely granular cytoplasm. at least some of its trophic actions rone) and are deficient in 17a-hydroxylase activity (see are modulated by locally expressed growth factors such as below) and therefore cannot produce cortisol or androgens. In this zone glucocorticoids (cor- mal origin that secrete epinephrine and norepinephrine. 93 4 Adrenals Sara Galac Claudia E. but it remains unknown which also glucocorticoids. resulting in complete atrophy of both the zona fasciculata and the zona reticularis.1: (A) Histological section of the adrenal gland of a healthy dog: A = medulla.1 Introduction The zona fasciculata is the thickest layer. The cells of the zona reticularis form anastomosing columns. surrounding cortex arises from mesoderm and histologically three zones can be distinguished: (1) zona glomerulosa (or ar. insulin-like growth factor (IGF)-II. while the zona glomerulosa remained intact. cells into cells of specific zones of the fetal adrenal cortex.2. Each consists of two functionally distinct endocrine cytoplasmic lipid. This is lost during processing of histologic glands of different embryological origin. epidermal growth fac- tor (EGF). The tisol and corticosterone) and androgens are produced. C = zona fasciculata. and trans- forming growth factors. they are called »clear cells«. Their intrinsic glucocorticoid effect suppressed endogenous ACTH secretion. In all mammalian species the growth and function of the fetal The zona glomerulosa lacks a well-defined structure.1 Some of the genes encoding these growth factors (particularly IGF-II) are similarly overex- pressed in fetal adrenals and adrenocortical carcinomas of hu- mans.3 A B Figure 4. 1 Synthesis and secretion of plasma is bound with high affinity to corticosteroid-binding corticosteroids globulin (CBG).2: Basic structure of adrenocortical steroids.1: Nomenclature for adrenal steroidogenic enzymes and their plasma cortisol concentration. In this pregnenolone molecule the four rings are identified by letters. 4. IUPAC-IUB 1967). similar to (type II isoenzyme) the free fraction.20 lyase CYP17 ingly used as noninvasive technique to investigate stress 21-Hydroxylase CYP21A2 responses in studies of welfare and of human-dog interac- 11b-Hydroxylase CYP11B1 tions. Individual carbon atoms are numbered. mone that is potentially available to tissues is determined by although cholesterol is also synthesized from acetate within the combination of free and bound fractions. the amount of hor- the LDL serves as the starting compound in steroidogenesis. which catalyzes the 17a-hydroxylation of pregnenolone and progesterone as well as the side-chain cleavage at C17 of 4 17-a-hydroxy C21 steroids. In dogs and cats the cortisol:corticosterone ratio in adrenal venous blood range from about 3:1 to 7:1. These capacity of CBG is diminished in dogs with portosystemic enzymes are membrane-bound hemoproteins that catalyze encephalopathy. 11-deoxycortisol. Figure 4. which converts deoxycorticosterone via corticosterone to aldosterone. The mitochondrial cytochrome P-450 enzyme aldosterone syn- thase. The physiological role of the circulating binding proteins is most probably buffering. in the dog estimated to range from 6 to density lipoproteins (LDL). 94 Adrenals The difference in hormone production between zones is re- lated to differences in two cytochrome P-450 enzymes. corticosterone.11–13 Up to four minutes can be taken to collect a saliva sample from a dog without the effect of handling being re- Aldosterone synthase CYP11B2 flected in its cortisol concentration.5–7 is biologically active.14 Of the devices tested. This absorb light at a wavelength of 450 nm after reduction. which are therefore secreted immediately after biosynthesis. the adrenocortical hormones are largely bound to plasma proteins. and fig. 11-deoxycorticosterone.1. a .4 4.3). Approximately 75 % of cortisol in 4. (Recom- mendation of the International Union of Pure and Applied Chemistry. The CBG-binding capacity is P-450 enzymes are responsible for most of the enzymatic higher in female dogs than in males.1. They restrain the flux of active Table 4. Steroidogenic cells cannot store the hormones. and aldosterone are derived entirely from adrenocortical se- cretion. Cytochrome fractions are in equilibrium. They are named for the ability of their heme group to are predominantly bound with low affinity to albumin. explains the low plasma concentrations of these hormones. which prevents rapid variations in Table 4. including oxidative cleavage of the precursor mol.20-lyase). An additional 12 % of total cortisol in blood is bound with low affinity to albumin and erythrocytes. Free cholesterol liberated from 14 %. whereas the other steroids are derived from a combi- nation of adrenocortical and gonadal sources. 4. Enzyme name Gene Cholesterol side-chain cleavage (SCC) (desmolase) CYP11A1 Unbound steroids readily diffuse into the salivary glands and the cortisol concentration in canine saliva is equivalent to 3b-Hydroxysteroid dehydrogenase (3b-HSD) HSD3B2 7–12 % of the total blood cortisol concentration. Only The adrenal cortex is rich in receptors that internalize low the free fraction. is only found in the zona glomerulosa. because these the gland (fig. The characteristic enzyme in the other two zones is the microso- mal cytochrome P-450c17 (17a-hydroxylase/17. However. thesis in the compromised liver. The other steroidogenic enzymes occur in all three zones.2 Transport and metabolism Following secretion.10 Measurement of salivary cortisol is increas- 17a-Hydroxylase / 17. table 4.1: genes cortisol to the target organ and also protect it from rapid metabolic breakdown and excretion. Cortisol.9 Androgens and aldosterone ecule. probably as result of decreased CBG syn- oxidation.8 The cortisol-binding conversions from cholesterol to steroid hormones.1.2. 3: Major biosynthetic pathways of adrenocortical steroid biosynthesis. scc = cholesterol side-chain cleavage.4).18 One to two per cent of the total cortisol se- metabolism. 11 = 11b-hydroxylase. 21 = 21-hydroxylase. cortisone by 11b-hydroxysteroid dehydrogenase (11b-HSD) is the most important pathway quantitatively. which inactivates them and increases their water cretion is excreted unaltered in the urine. The conversion of cortisol to the inactive cortisol production (chapter 12. most of the inactivated and conju- collection of canine saliva.15. In several . 3b = 3b-hydro- xysteroid dehydrogenase. as does subsequent conjugation with glucuronide this urinary »free« cortisol gives an integrated reflection of or sulfate groups. Introduction 95 4 Figure 4. whereas in the cat the excretion is largely as sulfates The liver and the kidney are the major sites of corticosteroid via the bile. Measurement of solubility. 17 = 17a-hydroxylase / 17.4. hydrocellulose eye sponge seems to be the best material for species including the dog.17.16 gated metabolites are readily excreted as glucuronides by the kidney. 20 lyase. 6). CLIP = corticotropin-like inter- mediate lobe peptide. There is considerable amino acid sively controlled by the plasma concentration of ACTH (see sequence homology of ACTH between species and canine . b-LPH = b-lipoprotein. and the processing of POMC in the anterior lobe and pars intermedia of the pituitary. 96 Adrenals 4 Figure 4. A B Figure 4.3 Regulation of glucocorticoid also fig. Compared with the anterior lobe (AL) and pars intermedia (PI) of the dog (see fig. there are few ACTH-positive cells in the PI but there are abundant MSH-positive cells. MSH = melanocyte-stimulating hormone. 4.1.4: Structure of the canine proopiomelanocortin (POMC) gene. gether with ACTH (fig. 1. together with several peptides that are released to- middle and inner zones of the adrenal cortex are almost exclu.5: Sections of the pituitary gland of a cat immunostained with anti-ACTH (A) and anti-a-MSH (B). 2. It is synthesized in the anterior lobe of the pitu- secretion itary gland from the precursor molecule proopiomelanocortin Synthesis and release of glucocorticoids and androgens by the (POMC). its mRNA. ACTH = adrenocorticotropic hormone.10). 4. J PEPTIDE = joining peptide. ACTH is a single-chain peptide of 39 amino acid residues. b-END = b-endorphin.4). 24 a-MSH regulates the activity of tyrosinase.8). and (4) immuno- logical factors (fig.29 Central nervous system events regulate both the number and responses to stress.7). the release of a-MSH is 4 pulsatile.36–38 In cats. including control of body weight and anti-inflam- matory effects.22 PI secretory activity is under almost permanent inhibitory con- trol by dopamine (fig. 4. Secretory profiles of a-MSH. (2) response to stress.6).21.32 afraid of gunshots responded to this noise by an increase in plasma cortisol. In contrast. as occurs in humans.7). ranging in the dog from six to neurogenic stresses did not stimulate secretion of ACTH or twelve per 24 h period.3. Introduction 97 ACTH differs from that of other species by only one amino acid in the carboxy-terminal part of the molecule. only those known to be concentration in plasma or saliva. 4. 4.1). eumelanin (brown / black color) and pheo- melanin (yellow/red color). ACTH. 2.35 However.4.19 In dogs and cats the PI contains two types of cells that can also synthesize POMC.23. (3) feedback inhibition by cortisol.21. for complete hypophysectomy does not lead to striking coat color changes (chapter 4. In laboratory dogs several emotional or magnitude of ACTH bursts. The Figure 4. a-MSH is now known to also have several other biological activities. the stress of intro- onset of stress such as anesthesia and surgery.3).25.26 Mel- anocyte function does not seem to be fully dependent upon a-MSH of PI origin.33. in a 1. responsive to the stress of physical restraint and b-adrenergic stimulants (fig. A loss-of-function mutation in the receptor (MC1R) to which a-MSH binds on the plasma melanocyte membrane is responsible for the coat color of the yellow Labrador retriever and the golden retriever.6: VP in portal blood is derived primarily from CRH-contain.34 Stress duction into a novel kennel or exposure to veterinary pro- responses originate in the central nervous system and increase cedures is reflected in elevated urinary corticoid:creatinine the release of hypothalamic hypophysiotropic hormones such ratios. thereby being pulses are indicated by asterisks. As for all ade- nohypophyseal hormones in the dog. 4. the rate-limiting melanocyte enzyme necessary for the synthesis of the two coat pigments.28 ACTH secretion by the AL is regulated by the hypothalamus and central nervous system via neurotransmitters that release the hypophysiotropic hormones corticotropin-releasing hor- mone (CRH) and arginine-vasopressin (VP) (fig. the PI in cats is ac- tively secreting.14 Among privately-owned dogs. In this neuroendocrine control four mechan- isms can be distinguished: (1) episodic secretion.31. ACTH is cleaved into ACTH1–14 (pre- cursor of a-MSH) and corticotropin-like intermediate-lobe peptide (ACTH18–39 or CLIP) (figs 4. Adminis- tration of an a-MSH analogue leads to darkening of the coat color. Significant nucleus and project to the median eminence.27 Apart from its classic role in pigment regulation.7). 4. albeit in only a few pulses per 24 h (fig.20 One is similar to the corticotropic cells of the anterior lobe. 4.5-year-old healthy beagle. on the other hand. ing parvocellular neurons that originate in the paraventricular Blood samples were collected at 10 min intervals for twelve hours. Dogs and cats seem to differ in their ling and intradermal skin testing causes impressive increases in . mild stress such as hand- as CRH and VP. and cortisol.6). In the other.30 The episodic secretion in dogs a-MSH13 and only profound stress such as long-term immo- and cats does not seem to increase in the early morning hours bilization consistently resulted in elevations of plasma corti- to the extent of a demonstrable circadian rhythm of cortisol sol.5). in that it reacts with anti-ACTH (fig. using urinary cortisol as a ACTH and cortisol are secreted within minutes following the measure of integrated cortisol production.21 fully separated from the VP involved in water homeostasis (chapter 2. Blood was collected via previously placed jugular ca- theters..7: Regulation of adrenocortical secretion of glucocorti- coids and androgens. (Adapted from Willemse et al. 1993). The melanotropic and corticotropic cells of the pars intermedia are largely under dopami- nergic (DA) inhibitory control.8: Plasma concentrations of cortisol. The activation of the hy- pothalamic-pituitary-adrenocortical axis as evoked by challenges to the immune system is shown on the right. 98 Adrenals 4 Figure 4. ACTH. Central nervous system afferents (episodic influences and stress) are mediated by hypo- physiotropic hormones such as CRH and AVP to stimu- late ACTH release from the anterior lobe of the pitu- itary. Figure 4.23 . ACTH stimulates the cells of the middle and inner zones of the adrenal cortex to produce chiefly cortisol. and a-MSH in six cats after intradermal skin testing between t0 and t5 and reading of the skin reactions at t15. which inhibits the secretion and influence of the hypo- physiotropic hormones on the corticotropic cells of the anterior pituitary. of which two have been un. are also associ. a group of polypeptides released from colonies of activated im- mune cells. sep- terior lobe being about twice as high. Inhibition of basal secretion of derived factors (neuropeptides. hormone kinetics have revealed asynchrony in ACTH and ticoid-preferring receptor (MR) and a glucocorticoid-prefer. RAS keeps the circulatory blood volume constant by promot- tokines are exerted predominantly at the level of the hypotha. 4.e. such as interleu. Studies of pulsatility and structurally different receptor molecules.2. Thus a bidirectional communication exits between the neuroendo- The third major regulator of ACTH and cortisol secretion is crine system and the immune system. 4.3) tivate the hypothalamic-pituitary-adrenocortical axis. a mineralocor. which not only im- clinic were considerably higher than those in urines collected pair the hypothalamic response to cytokine activation but also at home (chapter 12. enabling direct effects on cortisol release in health and more evenly distributed in the brain. Although other cytokines. i. neurotransmitters.43 feedback inhibition. ing aldosterone-induced sodium retention during periods of lamus. The dog brain and pituitary contain very regulation can influence release of corticosteroids.1. The MR has a 20-fold higher affinity influence cortisol secretion (fig. plasma ACTH concentrations (chapter 4. hormones. and a-MSH hypothalamic-pituitary-adrenocortical axis are also subject to (fig. Adreno- high levels of MR.4 Regulation of mineralocorticoid kin(IL)-6 and tumor necrosis factor a (TNFa). 4. ACTH.44 Multiple systemically- than the GR for cortisol.39 block cytokine production in macrophages (fig. hypovolemia and by decreasing aldosterone-dependent so- lamic response. In recent years it has become clear that apart from these four equivocally identified being the neurons in the hypothalamus ACTH-dependent mechanisms. The inhibitory action of glucocorticoids is exerted at multiple target sites. adipokines) and intra-adrenal paracrine pancy of the MR. The two main regu- lators are angiotensin-II and potassium (K+). Potassium . The feedback response of the highly sensitive adrenocortical stress system actions of glucocorticoids are exerted through at least two appropriately to physiological needs.4). or cytokines may give rise to hypercortisolism with suppressed Challenges to the immune system by infections invariably ac. indicating that signals other than ACTH ring receptor (GR).41 It The two primary mechanisms controlling aldosterone release is released from activated macrophages in the periphery and are the renin-angiotensin system (RAS) and potassium. 4.7). the highest being in the septohippocampal cortical cells express a great variety of receptors for these fac- complex and the anterior lobe of the pituitary. Introduction 99 Figure 4. IL-1 particularly activates the hypothalamic-pituitary-adrenocortical axis. factors. and inflammation. The latter GR is mainly ticemia. ceptors for neuropeptides. secretion ated with the responsiveness to stress. neurotransmitters. ACTH-independent mech- that produce corticotropin-releasing factors (CRH and AVP) anisms also have a role in fine tuning and modulating the and the corticotropic cells in the anterior lobe. there may be disorderly basal cor- involved in the feedback effect of glucocorticoids released as a tisol release independent of ACTH..9). the plasma concentrations of cortisol. cortisol responses.23 Corticoid:creatinine ratios in urines collected in a feedback regulation by glucocorticoids. These cytokine-mediated activations of the dium retention during hypervolemia (fig.45 Overexpression of re- result of stress-induced ACTH secretion.8).40 The GR is tors. disease.9: 4 Regulation of aldosterone secretion by the zona glomerulosa of the adrenal cortex. 4. The also produced in the brain.42 The regulatory actions of the cy.2.6). the amounts in the an. where CRH is the major mediator of the hypotha. In several disease states. including critical illness. cytokines. growth ACTH by glucocorticoids appears to be mediated via occu. These responses are mediated by proinflammatory cytokines. 10: Three major pathways of interaction of angiotensin-II with one of its receptors (AT1 receptor).)46 AT2R. ions directly regulate aldosterone secretion.11). Figure 4. ACTH is the classic representative of the group. Angiotensin-II has multiple effects on cardiac tissue (fig. of the membranes of the zona glomerulosa cells. AT1R and liams. and al- dosterone production (fig. Vascular renin biosynthesis and secretion (fig.12: counteracted by the direct inhibitory action of AT1Rs on Regulation of renin release from the juxtaglomerular cells of the kidney. this being partially Figure 4. adjacent to the regulates the glomerular filtration rate and renal blood flow afferent arteriole. Angiotensin-II elevates vas- cular resistance and blood pressure. its action is not sustained and it is not necessary to maintain normal glomerulosa cell function. ACE = angiotensin converting enzyme. and hypokalemia inhibits it by repolarization.10). 4. Angiotensin-II receptors in the afferent arteriole stimulate renin secretion in response to reduced renal perfusion pressure. natriuretic peptides.11: VR = vascular resistance. senses distal tubular Na+ delivery. 2005. but AT2Rs may have a counterregu- . 4.46 The vast majority of the physiological actions of the RAS are mediated by angiotensin-II and one of its receptors (AT1R). (Modified after Wil- Angiotensin-II synthesis and its interaction with two receptor subtypes. independently of the RAS. cell growth. LVH = left ventricular hypertrophy. Hyperkalemia stimulates aldosterone secretion by depolarization. 4. by constricting the efferent and afferent glomerular arterio- les. aldosterone secretion is influenced by several other factors (ACTH.10). and a variety of neurotransmitters). The macula densa in the distal tubule. Thus aldos- terone secretion is regulated by negative feedback loops for both potassium and the RAS. They include arteriolar vasoconstriction. 100 Adrenals 4 Figure 4. The actions of angiotensin II mediated by AT2R are less well understood. They also have the common feature of usually responding to stress. none of which is directly or indirectly connected to a negative feedback loop. While it is a very potent acute aldosterone secreta- gogue. In addition to these two regulatory mechanisms. 52 In a study of the (fig. a transcription monitored by the cells of the macula densa and low sodium factor that regulates the expression of several cytokine path- levels trigger communication between the macula densa and ways. have the highest homology with the comparable enzymes in sin-converting enzyme (ACE) converts the inactive decapep. generating active cortisol from the the fasted state. thereby exerting multifaceted effects to inhibit the im- the juxtaglomerular cells. In- cells of the distal tubule near the end of the loop of Henle hibition of gene expression is a key component of glucocor- and intimately associated with the juxtaglomerular cells ticoid action. such as pyruvate carboxylase.54 In recent years insight into this diversity of actions has been further extended by the notion that glucocorticoids Tissue-specific actions of glucocorticoids are not only deter. and fructose-6-phosphatase. These stretch re.11).1. glucocorticoids contribute to the mainten- . The response to reduced renal perfusion pressure. The type 2 dition.47.12). generating cortisol from inactive cortisone in. Studies in humans sug- tides. in immune cells GR inhibits the (fig.50 Among the species studied. activation of AT2R leads to suppression of renin bio. Introduction 101 Figure 4. latory role opposing AT1R-mediated vasoconstriction.13).48 get tissues such as the kidney (chapter 4. mune response (chapter 4. Stimulation of renal baroreceptors The cortisol-activated receptor interacts with specific DNA is the most potent mechanism for its release.49 duction of cortisone.6-diphosphatase. ubiquiti- nation) are thought to account for the wide array of actions of 4. a group of modified tional coactivators and corepressors recruited by the GR.51 In dogs the tissue distribution of both 11b-HSDs is tide angiotensin-I to the active octapeptide angiotensin-II similar to that in humans and rodents. sequences on target genes. transcription of target genes is also influenced by transcrip- lation is provided by the macula densa.3. Central to the metabolic effects of glucocorticoids is the syn- xysteroid dehydrogenase (11b-HSD). corticoid receptors (GRs). ACE-inhibiting compounds are used clinically to species-specific variability of the catalytic efficiency in the re- disrupt the RAS.1. 4. In the circulation angiotensinogen is cleaved by renin and adipose tissue. sue-specific action of glucocorticoids. 4.5 Glucocorticoid action cortisol. inactive glucocorticoid cortisone (fig.6).53 The proteolytic enzyme renin is synthesized in the juxtaglo- merular cells of the kidney. but also direct nongenomic mined by their production rates and the activation of gluco. gonad. Additional regu. The angioten.1. This enzyme occurs in thesis of mRNAs which lead to synthesis of key enzymes two isoforms. and adipose tissue. In ad. cortisol is metabolized at a prereceptor level by the enzyme 11b-hydro. feline 11b-HSDs other enzymes to release angiotensin-I. 4. resulting in changes in mRNA ceptors in the afferent arteriole stimulate renin release in synthesis and subsequent synthesis of specific proteins.6). In peripheral tissues. 1. the dog was found to have the lowest ac- tivity. including angiotensin-II. for example. Sodium concentration in the tubular lumen is action of nuclear factor-kappa B (NF-kB).13: Bidirectional conversion of cortisol and cortisone by 4 isoenzymes (type 1 and type 2) of 11b-hydroxysteroid dehydrogenase (11b-HSD). Angiotensinogen is produced gest that 11b-HSD1 can facilitate glucocorticoid action by mainly in the liver from its precursor preproangiotensinogen. in gluconeogenesis. enzyme is predominantly expressed in mineralocorticoid tar- synthesis and release. These mechanisms together with the presence of GR splice variants and tissue-specific posttranslational modifications (phosphorylation. effects (chapter 1. In vivo it acts pre. Type 1 is widely distributed in many tissues. as in the treatment of heart failure. humans. not only exert genomic effects. For example. resulting in renin release. Especially in dominantly as a reductase.3). in. fructose- cluding liver. Expression of both isoenzymes of 11b-HSD is important in controlling tis- Angiotensinogen is the precursor of several angiotensin pep. glucocorticoids affect almost all tissues and many pro. In the distal convoluted tubule aldosterone and DOC increase the reabsorption of sodium 4.6 Mineralocorticoid action and the excretion of potassium. which is controlled initially by increased insulin secre- tion. In the classic aldosterone targets (kidney. gradient is established that facilitates the passive transfer of po- xysteroid dehydrogenase type 2 (11b-HSD2). These ef- fects are mediated by the binding of aldosterone and /or Through these effects on intermediary metabolism and other deoxycorticosterone (DOC) to the mineralocorticoid recep- effects. Aldosterone and DOC have approximately equal affin- Most of these effects are clinically relevant and will be dis. which converts tassium from tubular cells into urine. fig.2). but the latter two hormones circulate at amiloride-sensitive epithelial sodium channels in the apical much higher concentrations than that of aldosterone. but aldosterone is quanti- tatively more important because much more of it circulates as free hormone (chapter 4. The widespread mineralocorticoid receptors (MR) have Once the hormone-receptor complex has reached the nu- equal affinity for aldosterone and the glucocorticoids cortisol cleus. 4. increases active sodium reabsorption. 11-keto analogs (chapter 4. aldosterone has two import- the hyperglycemia-induced hyperinsulinemia that promotes ant actions: (1) it regulates extracellular fluid volume and (2) it the opposite.e.1. cortisol and corticosterone.5. roughly similar concentrations. ance of normoglycemia by gluconeogenesis and by the pe. colon. As aldosterone by cortisol. including blood cells and immunologic functions. tor in the cytosol of epithelial cells. it initiates a sequence of events leading to activation of and corticosterone.55 tion. ney. This in turn causes increased lipogenesis. but not aldosterone. increased sodium influx stimulates the raised the question how the MR is protected from activation Na+K+-ATPase in the basolateral membrane.14). 4. However. Increased gluconeogenesis leads to hyperglycemia. These analogs can- creased glucose uptake and metabolism and decreased protein not bind to MR. ities for the mineralocorticoid receptor and circulate at cussed in sections on adrenocortical disease.13). Thus the end result of glucocorticoid excess is the catabolism of peripheral tissues such as muscle and skin to deliver the substrate for increased gluconeogenesis and lipo- genesis.1. In addi. predominantly in the kid- cesses. lipogenesis and fat deposition (fig.. Thereafter. is a major determinant of potassium homeostasis.1.14: Effects of cortisol excess on intermediary metabolism. i. 102 Adrenals 4 Figure 4. receptor. Thus potassium is not . lipolysis is stimulated in adipose tissue. This has membrane. to their ripheral release of substrate. thereby enabling aldosterone to occupy this synthesis leading to increased release of amino acids. an electrochemical salivary gland) this is accomplished by the enzyme 11b-hydro. The latter is achieved via de. in situ- ations of glucocorticoid excess the latter may be overruled by As the major mineralocorticoid. 1).15: Electrolyte transport in the distal renal tubule. insufficiency dothelial cells and on cardiac tissue contribute to blood press- ure homeostasis. colon. Their clinical manifestations are primarily determined reabsorption of sodium. Pathogenesis dione (fig. despite high levels of aldosterone. Conversely. adrenocortical androgen production site. there is mini.2). Aldosterone also activates potassium channels and Na+. dehydroepiandrosterone (DHEA) and androstene. 4. as in the presence of severe vol- ume depletion. and IGF-I. which must involve 90 % tional »cortical androgen-stimulating hormone« (CASH). Na+. do not develop dermal or behavioral symptoms of androgen mal is receiving a diuretic that blocks part of the proximal excess.2 Adrenocortical Actions of aldosterone. ization of aldosterone as an electrolyte-regulating hormone is too narrow. causing even more sodium to reach by the glucocorticoid excess.1. In addition to these conditions of absolute smooth muscle cells.7 Adrenal androgens 4. Adrenocortical insufficiency 103 Figure 4. If almost all sodium is reabsorbed more lacking. destruction of the adrenal cortices.58 ciency.K+ATPase. aldosterone has major actions on other epithelial and nonepithelial tissues. and atrial natriuretic peptide 4 (ANP). in tissues such as heart and kidney (see hormone deficits. renocortical insufficiency due to insufficient ACTH release angiopathies with fibrosis and proliferation of endothelial and by the pituitary. excreted in direct exchange for sodium. and salivary gland. Po- tassium leaves the cell through conductance channels.1 Primary adrenocortical insufficiency ACTH stimulates the secretion of the adrenocortical an- drogens. on en. Hence. but definite proof is sodium (fig. 4.59 proximally in the nephron.3. or more of the adrenocortical tissue before it causes symp- . prolactin.3).4. but rather in a Many putative CASHs have been proposed. (1) primary adrenocortical insufficiency due to lesions or With regard to the nonepithelial actions.K+-ATPase in the basolateral membrane is a major driving force for electroneutral cotransport by keeping intracellular Na+ low and the cell interior negative. a high sodium intake will in. there can be relative adrenocortical insuffi- also chapter 4. occasionally sex ste- the distal reabsorptive site. In addition to its effects on classic epithelial tar- gets such as kidney. probably in part nongenomic. including manner that depends directly on the active reabsorption of POMC derivatives. dogs and cats with increased androgen se- the distal tubule.3). chapter 4. driven by a concentration gradient. cretion accompanying ACTH-dependent hypercortisolism crease potassium excretion.15). does not meet physiological requirements (chapter 8. 4. it should be added disease processes in the adrenal cortices and (2) secondary ad- that long-term mineralocorticoid excess may lead to micro.2.56 roid production by an adrenocortical tumor leads to physical and behavioral changes due to androgen excess (see also In recent years it has become clear that the classical character. Aldosterone acti- vates sodium channels. This is particularly true if the ani. amiloride. 4. In mal potassium excretion in the absence of sodium delivery to contrast to humans.57 It appears that aldosterone may increase The term adrenocortical insufficiency includes all conditions blood pressure through two main mechanisms: (1) miner. Its two major forms are: fluid volume and (2) increased total peripheral resistance. Discrepancies between adrenal androgen and Primary hypoadrenocorticism results from progressive glucocorticoid secretion have led to the proposal of an addi. However. little sodium reaches the distal reabsorptive In the absence of gonads. which can be inhibited by thia- zide diuretics. in which the secretion of adrenal steroid hormones falls below alocorticoid-induced expansion of plasma and extracellular the requirement of the animal. 16). with 21-hydroxylase being typical or classic primary hypoadrenocorticism.20-lyase. toms and signs (fig.63 . This may Addison’s disease. All three zones of the cortex have completely disappeared.61 to include mineralocorticoid deficiency within months after the initial diagnosis. ciency. 104 Adrenals 4 B A Figure 4. in absolute deficiencies of glucocorticoids and mineralo- struction. The destruction may also be confined to the the result of tuberculosis. 4. pronounced negative feedback to the hypothalamus and pitu- scribed the syndrome in man. A B Figure 4.16: Cross-section of an adrenal of a healthy dog (A) and a dog with Addison’s disease (B) in which the adrenal medulla is only surrounded by the capsule. 1. resulting in what been reported in most human patients with nontuberculous is known as atypical primary hypoadrenocorticism. The atrophy that is often found The immune-mediated destruction typically terminates (fig. 17a-hydroxylase/17.62 In a minor- the most common. 4. (B) Lymphocytic adrenalitis throughout the cortex (HE. corticoids. Lymphocytic adrenalitis is probably an immune-mediated process that destroys the adrenal cortex with the end result as shown on the left.17) is probably the end result of immune-mediated de. the main determinant of the symptoms and signs of rol side-chain cleavage enzyme. for it is easily reaction with the adrenocortical autoantibodies include overlooked because of the absence of mineralocorticoid defi- 21-hydroxylase. together with high plasma levels of ACTH due to after Thomas Addison. Adrenocortical autoantibodies have middle and inner zones of the adrenal cortex.62 There has also been one reported case of isolated hyperreninemic hypoaldosteronism in a dog. a physician who in 1855 first de. The condition is also termed Addison’s disease. The major autoantigens involved in the be more common than is generally appreciated.60 Primary hypoadrenocorticism in dogs ity of cases. and choleste. The adrenal medulla is only surrounded by the fibrous capsule. atypical primary hypoadrenocorticism progresses was first described in 1953 by Hadlow. which at that time was usually itary (fig.8).17: (A) Section of an adrenal of a dog with primary adrenocortical insufficiency. x10). familial oc- currence has been documented.66.3. corticism than dogs of other breeds. and soft coated wheaten ter.66 Great Danes. metastatic disease. the mode weakness. The initial symptoms may have been very mild or scarcely tuguese water dogs.64 Con. frequently primarily young to middle-aged dogs (mean four years) with the animal is presented as an emergency in a state of severe de- a predilection for females.72. Finally. ano- Primary hypoadrenocorticism is an uncommon disease of rexia.70. homeostasis has been passed. Nova animal has been able to cope with the hormone deficits until Scotia duck tolling retrievers. mented in dogs as young as eight weeks. Hypovolemia is clearly evident in the microcardia and the poor filling of the caudal vena cava and pulmonary vessels. no sex predilection has been observed. type I diabetes mellitus. Genetic studies have shown that in Portuguese may be part of a polyglandular deficiency syndrome. pression. a critical threshold in the maintenance of fluid and electrolyte riers have a higher relative risk of developing hypoadreno. Moreover. gastrointestinal disturbances. and species. Although this can be the case. fungal infection.67–69 Despite the breed Although glucocorticoid deficiency may cause some lethargy.65 but they appear to be rare. standard poodles.1.p'-DDD or trilostane may reported cases of primary hypoadrenocorticism in cats due to deliberately or unintentionally destroy the adrenal cortices to infiltration of the adrenals by malignant lymphoma. and Nova Scotia duck tolling current endocrine gland failure may include primary hypo.3.18: Lateral (A) and dorsoventral (B) radiographs of a two-year-old male dog that arrived in a hypovolemic crisis due to primary hypoadrenocorticism.71 thyroidism. weakness. and mild nonregener- of inheritance of hypoadrenocorticism is undetermined in ative anemia. There have been two ment of hypercortisolism with o. one might expect an in- Clinical manifestations sidious onset of slowly progressive weakness.1). single autosomal recessive locus. fatigue. and hypotonic dehydration (fig. and primary hypopara. retrievers it is an inherited disorder under the control of a thyroidism. In cats hypoadrenocorticism is also a disease of young to Other possible causes of primary adrenocortical insufficiency middle-aged animals but it appears to be very rare in this include adrenocortical hemorrhage. 4. and vomiting.18). bearded collies. Por.73 In the limited number of cases reported thus far. water dogs. As mentioned in chapter 3. Adrenocortical insufficiency 105 4 A B Figure 4. all of which will certainly contribute to the . West recognized by the owner except in retrospect. primary hypoadrenocorticism most breeds. treat. Apparently the Highland white terriers. As the disease is usually caused by gradual autoimmune destruction of the adrenal cortices. predisposition and occurrence in certain families.64 The disorder has been docu.74 the extent that iatrogenic hypoadrenocorticism ensues (chapter 4. Rottweilers. standard poodles. Leonbergers. Initially the differentiation tion of the patient should alert the clinician for the possibility may pose problems. The early symptoms and signs are often vague and mimic toms and signs (table 4. paper speed 25 mm/s). Hyperkalemia vanced stage of the disease – rapidly worsening depression. nostic work-up and especially the prompt response to treat- cardia and /or the heart rate is increased by the sympathetic ment usually supports the suspicion of hypoadrenocorticism. contributes to the problems by affecting neuromuscular func. paper speed 25 mm/s). 4.2) can be related to hypotonic dehy. II. acute gas- A low heart rate that is inappropriate for the physical condi. Many of the symp.8 mmol. but. particularly leading to cardiac conduction disturbances. 4.19: 4 ECG recordings (leads I. and III) of a four-year-old dog with primary hypoadrenocorticism (calibration: 1 cm = 1 mV. and vomiting – evoke only a few differ- tion. troenteritis. and III) of a three-year-old female beagle with primary hypoadrenocorticism (cali- bration: 1 cm = 1 mV. ential considerations: ileus. II. but the cardinal features of the ad- dration due to the loss of sodium (fig. (A) Before treatment (Na+ = 131 mmol/l.18). but the heart rate may not be very associated with electrolyte disturbances. anorexia. Figure 4.19). clinical manifestations. A B (B) After treatment the R-waves became normal and the polarity of T-waves was reversed. or acute pancreatitis.20). weakness. as these conditions are occasionally also of hyperkalemia (fig. 4. renal insufficiency./l) the R-waves (lead II) were low and the T-waves were high and spiked. 106 Adrenals Figure 4. . (A) Before treatment (Na+ = 137 mmol/l. drive resulting from the hypovolemic shock (fig. K+ = 6. further diag- low if plasma potassium is not high enough to cause brady.20: ECG recordings (leads I.75 the manifestations are primarily Differential diagnosis caused by mineralocorticoid deficiency. those of other diseases.7 mmol/l) there was extreme bradycardia and no P-waves. A B (B) Treatment more than doubled the heart rate and P-waves reappeared. K+ = 8. 4.2.. For these reasons and because of concerns about the aldosterone concentration (PAC) is low in dogs with com. a Na:K ratio 쏝 27 270–690 nmol/l after ACTH.64. Hypothermia weight loss Neuromuscular Lethargy /depression. A re- diagnosis. the adrenocortical reserve capacity is necessary to establish the ACTH:cortisol ratio and the aldosterone:renin ratio.2. 4. weakness fascicular muscle contractions. tests two specific diagnoses: primary hypocortisolism and pri- cularly and blood is collected immediately before and at mary hypoaldosteronism. phosphatemia. and hyperkalemia. together with a conclusions. low R wave. cortical insufficiency it usually increases 쏝 50 nmol/l above adrenocorticism. megaesophagus Cardiovascular Dehydration / hypovolemia First-.84 Measurement of these ratios in a single blood sample or tetracosactrin) is administered intravenously or intramus.81. mary hypoadrenocorticism there is also no significant rise in betes mellitus. Basal levels of cortisol in urine and plasma are low in pri. wide QRS complex. weak pulse. diarrhea Melena. and it can also be PAC following ACTH administration.80 but they may also be low for stimulation test usually does not include measurements of other reasons (chapters 4. Diagnosis In healthy dogs. there may be little doubt about term glucocorticoid therapy or pituitary disease. In the ACTH-stimulation test. Furthermore. acidosis hypercalcemia Hematological Hypoplastic anemia (usually Lymphocytosis. However. and gastrointestinal disease.21).21: Results of an ACTH-stimulation test in healthy cats (blue area) and in a cat with primary hypoadrenocorticism (solid line). synthetic ACTH (cosyntropin 4. Adrenocortical insufficiency 107 Table 4. hypoglycemia. plasma cortisol concentration rises to From a pathophysiologic point of view.2: Clinical manifestations of primary hypoadrenocorticism System Common Less common Metabolic Poor appetite /anorexia. .4. such as after long- good response to treatment. hyponatremia.76 However. Similarly. Chronic ACTH deficiency. These are based on changes in the re- dogs without hypoadrenocorticism. hyper. its consequence is lifelong treatment to severe atrophy of the glucocorticoid-producing zones of and therefore it should always be secured by a confirmative the adrenal cortices and consequently to hyporesponsive- test. 4. second-.22. hyperkalemia. the ACTH-stimulation test (fig.urine SG. block ECG: wide or absent P wave. ness to ACTH administration. but may also be low in have been developed. cent study found that these ratios in dogs with Addison’s disease did not overlap those in healthy dogs (figs.81. In dogs with typical pri- in several other conditions. and high T wave Gastrointestinal Anorexia. restlessness.82 caused by EDTA contamination of the sample.e. availability and high cost of injectable ACTH. Shaking /shivering. i. dia. abdominal pain Renal & plasma Prerenal azotemia.82 Therefore a test of lations of the relevant endogenous hormones. the ACTH- mary hypoadrenocorticism.6). may lead the diagnosis. In dogs with primary adreno- may be regarded as pathognomonic for typical primary hypo. or third- 4 (10–15 % of body weight)..1). degree atrioventricular hypotonic veins. including renal insufficiency. such a low ratio may be found the low basal value (chapter 12.77–79 In some cases the results of an ACTH-stimulation test using Given the characteristic biochemical findings of prerenal measurements of plasma cortisol may lead to erroneous azotemia. 60 min after the injection for measurement of plasma cortisol. vomiting. basal plasma PAC.e. hypo. Inappropriately low biochemistry natremia. masked by hemoconcentration eosinophilia due to dehydration) Figure 4.83 alternatives plete primary hypoadrenocorticism. i.23).3. mine whether adjustments are needed in the doses of miner- alocorticoid and salt. Usually repeated in two to three weeks to determine whether the dogs begin to eat on the following day. If the salt causes vomit- overlap those in healthy dogs. 4. 108 Adrenals 4 Figure 4. The first fol- core of the protocol is the correction of hypovolemia and that low-up examination is made two to three weeks later. However. and the aldosterone:renin ratio (ARR) in 60 healthy dogs and 22 The box represents the interquartile range from the 25th to 75th percentile.2). without the addition of salt to glucocorticoid and miner- volemia and electrolyte imbalance by fluid therapy and corti. treatment to avoid a too rapid increase that can damage 쎱 If sodium is normal and potassium is abnormal. 4.72 The oral maintenance therapy (see also thickness of the adrenal glands as determined by ultraso. At discharge the importance of accuracy in administering the renocorticism is removed. The atrophy of the adrenal cortices reduces the length and despite treatment. dose of salt must also be changed.1).85 ing directly after the meal.76. lethargy. Plasma this and the corticosteroids will not be harmful in hypovol. alocorticoid substitution.2. it can instead be added to the drinking water or given in tablet form. alocorticoid (see chapter 13.24). but dimensions in dogs with hypoadrenocorticism coid. a mineralocorti- nography. of fludrocortisone is changed and the measurements are corticism improve rapidly after treatment is started. activity (PRA). horizontal bar through the box indicates the median. These adjustments are made as follows: The initial treatment scheme for an acute crisis of suspected 쎱 A slight increase or decrease in sodium combined with a primary hypoadrenocorticism consists of fluid therapy and normal potassium is corrected by adjusting the dose of salt parenteral administration of a glucocorticoid and a miner. and salt (mixed with the food).22: Figure 4. it is reassuring to know that the substitution therapy is explained to the owner. See also legend for fig. tenance therapy can be started.1) consists of a glucocorticoid. alone.89 costeroid administration (fig. If the hyponatremia is 쎱 If sodium is low and potassium is high. plasma renin sol:ACTH ratio in 60 healthy dogs and 22 dogs with primary hypoadrenocorticism.2. Client instruction and follow-up oratory analyses (table 4. it has been reported that dogs do well waiting for laboratory results. In cats the signs of weak- ness. If later the suspicion of hypoad. plasma sodium should be monitored during initial the dose of fludrocortisone is changed.86–88 Most dogs and cats with primary hypoadreno. Including salt in the Treatment treatment provides flexibility in the adjustment of the miner- Animals presented in hypovolemic shock and suspected of alocorticoid dose based on plasma electrolyte values (see having primary hypoadrenocorticism are treated without below). and anorexia may persist for three to five days . chapter 13. so that oral main.22. blood and urine are collected for routine lab. or vice versa.23: Box-and-whisker plots of plasma cortisol and ACTH concentrations and the corti. The dogs with primary hypoadrenocorticism. Box-and-whisker plots of plasma aldosterone concentration (PAC). sodium and potassium concentrations are measured to deter- emic shock due to other causes. and the whiskers represent the main body of data. only severe. Outlying data points are shown by dots and open circles. the dose the CNS. The aim is to correct the hypo. Just prior to starting fluid administration. or gastroen- teritis with fluid loss. Prognosis With satisfactory replacement therapy.2. follow-up examinations are made twice yearly.8). increasing the cortisone dose by four to six times may provide sufficient mineralocorticoid activity. zona fasciculata and zona reticularis (fig. polyphagia). together with appropriate syringes and needles (chapter 13. The owner is provided with an injectable glucocor- ticoid preparation and if available also an injectable miner- alocorticoid preparation. Adrenocortical insufficiency 109 Adjustment of the dose of glucocorticoid is mainly guided by the history at follow-up. a period of tassium were compatible with primary hypoadrenocorticism and were reversed by relative or absolute hypocortisolism will ensue. anesthesia). If the exo- nized primary hypoadrenocorticism with fluid therapy alone. which usually gives rise to multiple pi- tuitary hormone deficiencies (chapters 2. and decreased if there are signs of hypercortisolism (polyuria. injuries.1). No treatment was given from day –3 to day 0. 3. Via negative feedback Figure 4. as described in man.2). costeroid withdrawal several months may be required for full recovery of adrenocortical responsiveness to ACTH and re- . Second- ary hypoadrenocorticism may also be associated with cranio- cerebral trauma. such as after intra-abdominal surgery or major trauma. It should be emphasized to the owner that the injectable medi- cations should definitely be started when two successive oral doses have been missed. If an injectable mineralocorti- coid is not available.6.64 In its spontaneous and complete form the condition is rare. inappe- tence). A good rule is to double the dose during periods of minor illness and to increase it by two to four times 4 during periods of major stress.2 Secondary adrenocortical insufficiency In secondary adrenocortical insufficiency there is hyposecre- tion by the middle and inner zones of the adrenal cortices as a result of ACTH deficiency (fig. The iatrogenic form of secondary adrenocortical insuffi- ciency due to long-term corticosteroid therapy is much more common than the spontaneous disease. 4.91 has not yet been reported in dogs or cats. After corti- treatment on days 1 and 2.2. creatinine. The losses of sodium and fluid and the retention of po- genous steroids are discontinued for any reason. The dose is increased if there are symptoms and signs of hypocortisolism (lethargy. sodium.1). and potassium concentrations and fluid and synthesis and secretion. 1. it may become necessary to give them by injection.24: this therapy causes chronic suppression of CRH and ACTH Plasma urea. The dose of glucocorticoid is increased during situations of stress such as fever.2. and as a consequence atrophy of the electrolyte balance in a six-year-old cocker spaniel that recovered from unrecog. If the animal is unable to take the medications orally (vomit- ing. It may be caused by a large pituitary tumor.89 Once therapy is stabilized. 4.3.90 Isolated ACTH deficiency due to an autoimmune hypophysitis. primary hypo- adrenocorticism has an excellent prognosis in both dogs and cats. surgical procedures. insufficiency tisolism may give rise to severe chronic hypoglycemia.2). and its duration all de. 110 Adrenals covery of pituitary ACTH release.4. an imbalance between adrenal output and cortisol demand.6. The resulting hypercortisolemia is lems such as lethargy or alopecia.2.5–1.92 Several factors.3.4). such as trauma. hypocor. adrenocortical insufficiency its dramatic features. In dogs with primary adrenocor- tical insufficiency. gastrointestinal disturbances. as it is primarily regulated 3. The Pathogenesis absence of a response can be the result of a longstanding The underlying mechanisms of relative adrenocortical insuf- ACTH deficiency. the this disorder is called relative adrenocortical insufficiency or basal plasma cortisol level will be low and the response to critical illness-related corticosteroid insufficiency (CIRCI).1.3.1. ACTH levels are low ment of resistance to glucocorticoids at the tissue level. there remains the possibility of ficiency are largely unknown. ACTH deficiency (chapters 2.1). and in those situations the glucocorticoid dose not the tendency to hypotension and shock that gives primary should be increased to prevent a crisis (chapter 4. It is characterized by insuffi- primary adrenocortical insufficiency with selective atrophy of cient corticosteroid-mediated down-regulation of inflamma- the zona fasciculata and zona reticularis but with little or no tory transcription factors. In an ACTH-stimulation test (chapter 12.6.0 mg/kg or prednisolone acetate is given Clinical manifestations in a daily dose of 0.4) in the absence of hyponatremia and hyper. the pituitary pend on the dose of the corticosteroid that has been given. ACTH will be (1) normal or somewhat impaired or (2) ab.1.2. and the schedule and dur. The former response excludes primary hypoadrenocor.15 mg/kg. The condition is also be discussed in chapter 4.2). it must be regarded as lesion. The animals are especially at risk dur- by extrapituitary mechanisms (chapter 4. for a response might still be present soon after onset of the condition.1). in. sis is highly dependent upon the development of the causative tention for a long time. However. it is a consequence of both inadequate circulating glu- between these possibilities further studies are required.1). and challenges to the Thus it may happen that the condition is recognized more or immune system by infections.2. treatment of other deficiencies (see chapters 2.3 Relative adrenocortical tation is given (see also chapter 4.7). its area should be visualized to search for a lesion causing the intrinsic glucocorticoid activity. Comparable to diabetes mellitus involvement of the zona glomerulosa.2) may be required. anorexia. Treatment Although dogs seem to be able to live reasonably well in spite Another iatrogenic form of the disorder is ACTH deficiency of cortisol deficiency.4. activate the hypothalamic-pi- less incidentally during routine endocrine studies for prob. The likelihood of adreno. production is virtually unaffected. fig.1).1.1–0.95 ticism but not secondary hypoadrenocorticism.2. In addition. stasis and enhance survival (chapter 4. ation of its administration.3. 3.97 and nonresponsive to stimulation with CRH. although glucocorticoid deficiency may result in Prognosis slight depression. level. potentially dangerous because of the animal’s inability to cope with stress by activating the pituitary-adrenocortical system. TNF-a impairs CRH-stimulated .75 For differentiation type 2. An inade- quate response is potentially fatal. spontaneous secondary hypoadrenocorticism. Cortisone acetate is given in a 4 daily dose of 0. the progno- mild nonregenerative anemia.62. 4. cocorticoid and resistance to glucocorticoids at the tissue cluding measurements of plasma ACTH and a CRH-stimu.2. 13. and As in secondary hypothyroidism (chapter 3. its magnitude.96 lation test (chapter 12.1.93 These cytokines have also been implicated in the reversible dysfunction of the hypothalamic-pituitary-adrenocortical axis during critical illness. creases activity and alertness.3. severity of the illness of a patient. or that a pituitary tumor has an essential part of the stress response required for adequate been diagnosed and subsequent studies of pituitary function adaptation to these noxious stimuli in order to restore homeo- reveal ACTH deficiency. Hence there is ing stress. Once there is biochemical certainty about the presence of cortical insufficiency. In addition to a glucocor- In secondary adrenocortical insufficiency mineralocorticoid ticoid. In dogs with terleukin-1 have been shown to be involved in the develop- secondary adrenocortical insufficiency. oral glucocorticoid administration in- due to hypophysectomy (chapters 4. CIRCI is defined as inadequate corticosteroid activity for the sent. Major surgery or trauma might cause a crisis and /or failure to recover from anesthesia unless glucocorticoid supplemen.3. the condition may escape at. surgery. kalemia. tuitary-adrenocortical axis. basal plasma ACTH concentration is high Cytokines such as tumor necrosis factor-a (TNF-a) and in- and there is an exaggerated response to CRH. Nevertheless. In critically ill humans the Diagnosis secretory capacity of the adrenal cortices is commonly insuf- Suspicion of secondary adrenocortical insufficiency is raised ficient to compensate for the increased demand for cortisol.3.94 by finding a low urinary corticoid:creatinine ratio Because it is not an absolute deficiency of cortisol but rather (chapter 12. On the contrary.1).6. 4. due to hyper- require vasopressor treatment. those with relative adrenocortical insufficiency generally have normal Prognosis to elevated plasma cortisol concentrations. relative adrenocortical insufficiency. The duration of corticosteroid therapy should be guided by the duration of Diagnosis the underlying systemic inflammation. Consequently. TNF-a has been shown steroids to patients with critical illness is inadvisable. but a blunted Following recovery from the critical illness the dysfunction of response in an ACTH-stimulation test. ness.102 secretion by adrenocortical tumor (chapter 4.100–102 With regard to interpretation. matory response without causing excessive immune paresis. higher likelihood to other cases the disease is ACTH-independent. treatment with corticosteroids in critically-ill patients with systemic hypotension refractory to fluid loading and a sub- Clinical manifestations normal response to ACTH administration. al. The cocorticoid excess is essentially hypercortisolism.100. Glucocorticoid excess 111 ACTH release.106 The risk:be- fusion and microvascular disease resulting from disseminated nefit ratio of corticosteroid administration should therefore intravascular coagulation may also contribute.105 Several studies in humans have used an intravenous dose of 250 µg. pendent (chapter 4. ACTH dependent (chapter 4.101 . than those with an increment 쏜 83 nmol/l. and may even be assessed in each patient. Identical symptoms and signs are elicited by exogenous glucocorticoids Results of two recent studies indicate that relative adrenocor.1). cal stress-dose. been case reports of two other forms of hypercortisolism. companion animal patients with critical illness.6). Unlike patients with classic hypoadrenocorticism. severe trauma.102. In these cases. what con- stitutes a normal adrenal response to critical illness is un. the neurosurgeon remains somewhat elusive at this time. Prolonged latter is especially hindered by the lack of a test that quantifies exposure to inappropriately elevated plasma concentrations of glucocorticoid activity at the tissue level. In most incidence of systemic hypotension.1). It seems reasonable to initiate result in long-term adrenal dysfunction. indicating that delta cortisol concentrations as sole variable to assess the se- cretory capacity of the adrenal cortices should be viewed with caution. the relative glucocorticoid deficiency may inter.98–102 In addition.3. the pressor responsiveness and survival in septic humans with expression of these receptors is modulated by glucocorticoids. as is the amount of cortisol that is required or is op. the free cortisol leads to symptoms and signs often referred to as endocrine diagnosis of relative adrenocortical insufficiency Cushing’s syndrome. ACTH and interpretation of the test results. after Harvey Cushing.100. disease entities is preceded by a description of the common dogs with babesiosis having an increment in plasma cortisol denominator of the clinical manifestations.3. renals in dogs and cats (chapter 4.3. the 4 Systemic hypotension refractory to fluid loading and requi. and studies in humans and dogs have revealed Treatment inappropriately low plasma ACTH levels in some patients Routine administration of pharmacological doses of cortico- with critical illness.e. glucocorticoid 쏝 83 nmol/l had a significantly higher cortisol:ACTH ratio excess. there is much the hypothalamic-pituitary-adrenocortical axis generally re- controversy concerning the appropriate dose of synthetic solves spontaneously.4) and the other ACTH inde- though the increment in plasma cortisol after ACTH admin. both dogs and cats the disease is the result of excessive ACTH thetic ACTH administration was associated with increased secretion by a pituitary adenoma (chapter 4. one strated in dogs with critical illness due to canine babesiosis.2).3 Glucocorticoid excess 250 µg/dog.103 Adrenal hypoper. it does not improve outcome and enhances the risk of com- tions of ACTH on adrenocortical cells.104 The systemic hypotension may be due to Low doses of hydrocortisone have been reported to improve down-regulation of smooth muscle adrenergic receptors. corticosteroids should ideally be administered in a physiologi- ring vasopressors is a common manifestation of relative adre. because to reduce cortisol synthesis by inhibiting the stimulatory ac. There have Relative adrenocortical insufficiency could not be demon.3. In dogs the ACTH dose has ranged from 5 µg/kg to 4. or gastric dilatation-volvulus.5). However.1. The discussion of these different istration tended to be lower than in control dogs. However. and decreased survival. i. Thus endogenous glu- timal for a given critical illness in an individual patient. of studies on the effects of low doses of corticosteroids in fere with catecholamine production. who in 1932 first described the syndrome in man. in long-term therapy (chapter 4.3. a dose sufficient to suppress the proinflam- nocortical insufficiency in humans and dogs with critical ill. plications associated with the use of steroids. Cortisol is the principal glucocorticoid released by the ad- known.107 There are no reports In addition.. tical insufficiency is common in critically-ill dogs with sepsis. whereas others have used a total dose of only 1 µg per adult human. An increment of In about 80 % of cases of spontaneous hypercortisolism in 쏝 83 nmol/l in the plasma cortisol concentration after syn. in Cushing’s syndrome due to adrenocortical tumor the namely.28). back.1. . and thighs. increased gluconeogenesis and lipogenesis at the ex.5) in visceral fat. expression of this enzyme is not increased in omental adipose pense of protein.109 An alternative explanation for the abdominal fat accumulation might be in the autonomic nervous system. particularly of the abdomen. In addition to the generalized alopecia and calcinosis cutis on the neck and shoulder. whether this concept holds true for the dog. In dogs the cardinal physical features are tissue. Clinical manifestations The abdominal fat accumulation has been related to over- Many of the symptoms and signs can be related to the actions expression of 11b-HSD1 (chapter 4.25: Figure 4.108 It is also questionable central obesity and atrophy of muscles and skin (table 4. A B Figure 4. excess. there is atrophy of the temporal muscles and muscles of the shoulder.3. in which most. 4. liver.14.27: A nine-year-old female dachshund with hypercortisolism. figs.28). (B) The skin around two nipples showing keratin accumulation in atrophic hair follicles.26: A ten-year-old female mongrel dog with classic signs of hypercortisolism: alopecia A nine-year-old female mongrel dog with severe manifestations of glucocorticoid and truncal obesity. 112 Adrenals 4 Figure 4. but of glucocorticoids presented in chapter 4. arm.25–4. and lordosis accentuating the pendulous ab- domen (see also fig.1. 4.5 and fig. splanchnic cortisol production occurs in the dominating features. (A) The coat on the enlarged abdomen is thin and the atrophic skin readily bunches up into thin folds. as it is in human obesity. Polyuria and polyphagia are also frequently if not all. 4. to which the suppression of AMPK. 4. Glucocorticoid excess 113 4 A B C D Figure 4. In the hypothalamus glu- vations in rodents and humans that glucocorticoid excess cocorticoids increase the AMPK activity. together with the abnormal hepatic cell number in a compartment-specific manner. (C) Erythema and calcinosis cutis in the lumbosacral area of a nine-year-old male mongrel dog.28: Various manifestations of calcinosis cutis in dogs with hypercortisolism. primarily by Glucocorticoid excess causes inhibition of adipose tissue inhibiting protein synthesis. (B) Close-up above the shoulder of the dog in fig.112 (AMPK). lipogenesis. a sensor of cellular energy status and regulator of enzymes in lipid metabolism. growth hormone secretion must contribute (see also . and fat ceral fat tissue and. (D) Gray plaques of calcinosis cutis in areas of skin easily traumatized and bleeding in an eleven-year-old male boxer. Palpation revealed irregular firm plaques extending caudally to the lumbar area. contributes to the development of fatty liver.26. AMPK activity. bolic puzzle may have been largely resolved by recent obser. and insulin resistance. (A) Calcium deposits in the skin on the dorsal midline above the shoulder of an eight-year-old female boxer. Calcinosis cutis occurs not only on the dorsal midline but also on the ventral abdomen and inguinal areas. Glucocorticoid excess leads to muscle atrophy.110 This meta. which leads to in- changes the activity of AMP-activated protein kinase creased hunger. dyslipidemia.111. which may explain the accumulation of lipids in vis. which is known to modulate lipolysis. in a tissue-specific manner. How. leaving the cat with a full thickness skin de- ive tissue include reduced proliferation of keratinocytes and fect. alopecia. abdominal wasting). hypercholeste. increased ALT. Weight loss (muscle hepatomegaly. Probably related to the glu. Elevated hematocrit climb. in such a patient it is also possible that the hyper- ever. 4. lymphopenia. and some thinning of the coat to alopecia and a thin and the reported cases of hypercortisolism in cats. The continuous overextension makes walking very thyroxine (dogs). 2. 4. elevated value. However. lack of regrowth of clipped cocorticoids and diabetes mellitus has been present in most of hair.113. (see also chapter 3.7).3. This state of hypercoagulability is in part due to elevation of procoagu- . hyperlipidemia fig. hypercortisolism has often arisen specifically because of insu- cocorticoid-induced alterations in bone metabolism lin resistance encountered in the treatment of diabetes melli- (chapter 9. rolemia.28). full thick- 4 hair follicles ness skin defects (cats) Respiratory / Panting at rest Congestive heart failure Cardiovascular Pulmonary embolism Urinary Polyuria and polydipsia Urinary tract infection Glucosuria (cats) Glucosuria (dogs) Proteinuria (usually mild) Neuromuscular Lethargy.3. are also due to a generalized de. Very rarely dogs with glucocorticoid In dogs the polyuria of glucocorticoid excess is known to be excess are presented as an emergency in respiratory distress. muscular weakness. cultures. Cats are the duration of glucocorticoid excess. 4. disturbed metabolism of extracellular matrix pro.118 It is no The disease usually begins insidiously and progresses slowly exaggeration to say that an adult animal with demodicosis until the combination of symptoms and signs can be recog- should be suspected of hypercortisolism or hypothyroidism nized as the syndrome of glucocorticoid excess. especially in the beginning.117. due to both impaired osmoregulation of vasopressin release This might be due to the combination of intolerance to a hot and interference with the action of vasopressin (chapter 2. 114 Adrenals Table 4.1). weight gain. uria /polydipsia much less readily than in dogs and may only teins.3: cats System Common Less common Metabolic Polyphagia.3: Clinical manifestations of glucocorticoid excess in dogs and Table 4. difficult. calcium can be deposited in the dermis.31). Urinary tract infections.31). hair follicles. thin skin Hyperpigmentation. How- crease in skeletal muscle Na+K+-ATPase.114 The decreased exercise tolerance and inability The situation in cats is somewhat different from that in dogs. hyperglycemia myotonia (persistent muscle contraction) resulting from a degenerative myopathy. glucocorticoid excess results in poly- fibroblasts. jump. well-known symptoms The cutaneous manifestations may initially give the impres- of hypercortisolism in dogs. in some cases the skin is very fragile and tears during glucocorticoid excess on the skin.29: Glucocorticoid excess usually results in muscle weakness (decreasing ability to Hematology and Eosinopenia.27). there may be only one or two symptoms (fig. causing tus. symptoms are rare and the urinalysis may be normal. hypernatremia.30). this eight-year-old female in dogs). sion of being less pronounced than in dogs (fig. Skin atrophy and immune suppression velop overt diabetes mellitus. Suspicion of easily-wrinkled skin (fig. routine handling. increase susceptibility to skin lesions and skin infections such as mycobacterial panniculitis and demodicosis. alkaline phosphatase (isoenzyme (dogs).115 The effects of ever. environment and impaired ventilatory mechanics because of fig. 4. with keratin plugs in atrophic calcinosis cutis. intolerance to enlargement hot environment Skin and hair Thin coat. low hypokalemia poodle being a severe example. and connect. are common in dogs with hypercortisolism.121 Only about 10 % of dogs with hypercortisolism de- skin lesions (fig. the changes in dogs more susceptible than dogs to the diabetogenic effects of glu- range from cessation of shedding. and walk) and muscle atrophy. 4.120 Furthermore. particularly in the hind legs.29).119 cortisolism is complicated by pulmonary embolism.2.116 Depending on become obvious when diabetes mellitus develops. and disturbed synthesis of skin lipids. to climb stairs and to jump into a car. Very rarely there is hypertrophy due to biochemistry hyperglycemia (cats). Myotonia muscular atrophy Reproductive Absence of estrus Testicular atrophy Figure 4. Affected dogs walk stiffly. However. detected by positive urine the physical changes (muscle wasting and enlarged abdomen). but is often superfluous. most diseases begin as only slight deviations in health and it alopecia and muscular weakness in the hind legs. On a lateral radiograph of the abdomen.125 often distended. are the imaging techniques now most frequently used. particularly in dogs lature.2). pression is decreased. weeks duration.133.30: Figure 4. For example.e. rather than due to hyposecretion (chapter 3. there was features. Differential diagnosis Among the routine laboratory data (table 4. radiography can help to paint the mineralocorticoid hypertension (see also chapter 4. but abdominal radiography is of little use blood pressure and the highest values are found in dogs with in the diagnostic work-up of dogs suspected of hypercortisol- severe hypercortisolism. and meta. without physical changes. Ultrasonography. polydipsia.123 Glucocorticoid excess has also physical changes that can be associated with glucocorticoid been reported as a factor predisposing for the rarely occurring excess. namely.124. in dogs with hypercortisolism. this nine-year-old male boxer had hypercortisolism × 10–6). and magnetic resonance imaging (MRI) paired. distribution.2).1.128 This picture.134 In humans phenobarbital induces liver . larged (4 mm wide). symptoms mimicking those of mild hypercortisolism.129 In principle hypertension is a risk especially in the search for the location and characterization factor for congestive heart failure.1 mg dexamethasone per kg body weight due to an adrenocortical tumor but was presented only because of polyuria of four the UCCR decreased to 9 × 10–6.130 In cal features. Diagnostic imaging may help to complete the picture of the agulant factor antithrombin. In summary. Glucocorticoid excess 115 4 Figure 4. Basal UCCRs on two consecu. tical function in dogs have not been reported to be affected by this treatment. the reader is referred dogs this is mainly due to the induction of an isoenzyme hav.132 Dystrophic calcifications in the skin and vere hypercortisolism all available cortisol cannot be inacti. which is aortic / iliac thrombosis in dogs. subcutis may also be visualized in the areas of predilection for vated to cortisone and thus spills over onto the MR. bronchial and interstitial mineralization. illustrations are included in this book to depict pronounced diabetes mellitus.122 After three oral doses of 0.131 Thoracic radiographic abnormalities may include by a variety of mechanisms involving the kidneys and vascu. In contrast consequence of altered transport. for in humans with renal disease 11b-HSD2 ex. tomography (CT).126. In addition. lant factors and a decrease in the naturally occurring antico. tests of adrenocor- bolism of T4.31: A 17-year-old castrated male cat. In most dogs with hypercortisolism plasma T4 is decreased as a polyphagia.4). Anticonvulsant therapy with phenobarbital may cause therefore easily measured by a routine laboratory procedure. and a slight gain in weight. computed may be particularly important when renal function is im. However. referred because of problems in controlling its As in most textbooks. there is usually good contrast due to the ab- dominal fat. to cause calcinosis cutis.1. and including substrate saturation of 11b-HSD2. CT revealed the pituitary to be moderately en. with hypoxemia. polyuria. to chapter 14. to tests of thyroid function (chapter 3. polyuria and alopecia.3) a consistent For the differential diagnoses concerning the two main clini- finding is elevation of plasma alkaline phosphatase (AP). where algorithms for these problems are pres- ing greater stability at 65 °C than other AP-isoenzymes and ented. and weight loss. but this complication is rare of the source of the hormone excess.127 This hypertension is mediated ism. may take several months before the classic changes affecting muscle and skin be- tive days (73 and 88 × 10–6) were above the upper limit of the reference range (42 come apparent.. In addition to polyuria. hepatomegaly and a distended Endogenous and exogenous glucocorticoid excess increases bladder may be seen. i. In se. In occurrence of pituitary-dependent hypercortisolism and cor- .4.142 In cats the disease is rare. The combined contribute significantly to the laboratory measurement.88 and that of a negative test result is to cause neurological symptoms.6.18) with mild hypercortisolism. as described in the previous two consecutive days and the UCCRs in these two samples section.6.01 mg dexamethasone per kg body weight is administered intravenously in the morning. fig.3. These are pression is tested by administering a synthetic glucocorticoid called »invasive adenomas«. Clinical manifestations that it is of pituitary origin are are averaged (chapter 12. The uncertainty can be resolved by small nests of hyperplastic corticotroph (or melanotroph) cells measuring the UCCR in urine samples collected on ten con. and (2) slight predilection for small breeds such as dachshunds and decreased sensitivity to glucocorticoid feedback.4.138 4. whereas only the exceptional in a dose that discriminates between healthy animals and ani. than in humans and has been reported to be one to two cases vides an integrated assessment of the secretion of cortisol over per 1000 dogs per year. and rarely the sphenoid bone. miniature poodles.32: the entire protocol is carried out by the owner at home The urinary corticoid:creatinine ratio (UCCR) in three Pomeranians (see also (chapter 12.3 × 10–6) found in 88 healthy pet dogs (horizontal line). This is line) all values were above the reference range (mean UCCR 16. inappetence. 4.32).2.20. tumors with extracranial metastasis are considered to be car- mals with hypercortisolism. whereas in dogs and cats with hyper- cortisolism it remains high or has escaped from initial suppres- sion (chapter 12.137 The iv-LDDST can have a false positive result due to the stress of the hospital visit and the blood collection (chap- ter 12. The sensitivity of the pituitary-adrenocortical system to sup.4.2). and mental dullness (see ation in the UCCR.137 In some dogs there is considerable day-to-day vari. The predictive value of a positive test result (plasma cortisol 욷 40 nmol/l at 8 h) is 0.1 × 10–6). dura mater.7 × 10–6 and only one value exceeded the upper limit of the reference range When hypercortisolism has been confirmed it is necessary to (8. consisting of lethargy.2). 4.59.135 In both dogs and cats pituitary-dependent hypercortisolism is a disease of middle-aged and older animals.1. 0. some pituitary adeno- mas infiltrate surrounding tissues such as the cavernous sinus.0 × 10–6). (fig. a period of time and adjusts for fluctuations in plasma levels caused by the pulsatile release of cortisol (fig.146 Corticotroph adenomas may coexist with dexamethasone is used so that the dose will be too small to somatotroph adenomas (chapter 2.6).143 0. Pituitary-dependent P-450 cytochrome enzymes. These are often vague.144 As discussed in chapter 2.4).2. although it can Diagnosis occur in dogs as young as one year.34). whereas collections on other days might have revealed one or The pituitary lesions producing excess ACTH range from two elevated UCCRs. secutive days (fig. In dogs there is no pro- The biochemical diagnosis of hypercortisolism depends on nounced sex predilection.1). 2.4. 4. brain. which in mild forms of hypercortisolism also chapter 2. The incidence is much higher in dogs ment of the urinary corticoid:creatinine ratio (UCCR) pro.136 Measure.2. Blood for measurement of cortisol is collected 8 h later.139 In another dog (blue distinguish between the different forms of the disease.6) to adenomas (fig.2).140 In this o-LDDST Figure 4. In dogs the predictive value of a only observed when a pituitary tumor becomes large enough positive test result is 0.145. This can be avoided by the use of UCCRs and oral administration of dexamethasone.98.5).141 It occurs in all dog breeds with possibly a of the condition: (1) increased production of cortisol. In one dog (green line) the mean UCCR was 4. 4.33) and large tumors (figs. For the The physical changes and the routine laboratory findings are routine test the owner collects a morning urine sample on those of glucocorticoid excess. 2. leading to increased steroid hypercortisolism clearance and falsely positive dexamethasone suppression tests in patients with Cushing’s syndrome. and discussed in the following sections. but in cats most reported cases have the demonstration of two principal characteristics of all forms been in females. A potent glucocorticoid such as cinomas.92 and that of 4 a negative test result is 0. in the third dog (red line) the UCCRs fluctuated around the upper limit of the ref- erence range (mean UCCR 8.4. In healthy animals plasma cortisol concentration is still suppressed at this time. 116 Adrenals this dexamethasone screening test or low-dose dexametha- sone suppression test (iv-LDDST). occasionally leads to UCCRs just within the reference range. 2. 151.35).162 Cortico- ation.157 dexamethasone. to complete resistance even to high doses of tribute to tumorigenesis. troph adenomas in the AL become less sensitive than normal genes. In about one-fourth to one-fifth of ported.148 Pituitary-dependent hypercortisolism may in both lobes. mediate lobe (PAS-Alcian blue orange-G stain). As mentioned briefly in chapter 2. in the LDDST. These deficiencies may also con.33: Figure 4.155.4).1 it was explained that in dogs and cats both the pituitary anterior lobe (AL) and pars intermedia (PI) have Resistance to glucocorticoid feedback is significantly corre- cells that can synthesize POMC. albeit with different post. transcriptional repression.150 also because of the specific hypothalamic control of hormone synthesis in the PI. and for ras proto-onco.165 Not only translational processing.154 In addition.152 Ex- pression and mutation analysis has been performed in dogs However. the possible role of hypothalamic corticotroph cells to the suppressive effect of glucocorticoids. such as Tpit (see fig. resistance to the GR – is caused by loss of nuclear proteins involved in glucocorticoid feedback ranging from scarcely demonstrable.4 this is the functional gated. This loss of suppressibility can be thought of as to glucocorticoid feedback regulation of the POMC gene by being on a sliding scale in both dogs and cats. principally tonic dopami- tumors from corticotroph or melanotroph cells is regarded a nergic inhibition. both the AL and the PI.163. to differentiate normal animals from those with hypercorti- ticotroph adenomas in dogs.153. This explains why pituitary-dependent proto-oncogenes involved in hormone production and /or hypercortisolism of PI origin is resistant to suppression by cell proliferation and possibly also in tumor suppressor genes. Thus ACTH excess may originate in do large tumors tend to be more resistant to the suppressive . as has the combination with pheochromocytoma cases there is an adenoma in the PI. in the high-dose dexamethasone suppression test (HDDST. the As with several other tumors. Glucocorticoid excess 117 4 Figure 4. The enlarged pituitary compresses the anterior lobe. dexamethasone.164 In chapter 4. tisol-producing adrenocortical tumor has also been re. lated with the size of the pituitary (fig. separated by the hypophyseal cleft. As mentioned in chapters 4. hallmark of pituitary-dependent hypercortisolism that is used sight into the molecular pathogenesis of the formation of cor. hypothalamus but not sufficiently to cause neurological symptoms. as with pituitary-dependent hypercortisolism for factors in. On the right.147. hormones and intrapituitary growth factors has been investi.158.144 but neoplasia.160 which suppresses the expression of glu- multistep process requiring more than one mutation in the cocorticoid receptors.161 An inherited aberration may be the earliest step. 2. is the neurointer.5).1. pituitary lesions causing hypercortisolism do not maintain the volved in pituitary organogenesis and corticotroph differenti.67). 4.159 This is of clinical interest not only because also be a component of a syndrome of multiple endocrine the PI tumors tend to be larger than the AL tumors.3 and 12. 4. this is not an absolute difference from AL lesions. regulation characteristics of the lobe of origin.156 These studies have not provided conclusive in.149.34: Histological section of the pituitary of an eight-year-old female miniature poodle Cross section of the ventral two-thirds of the brain of a nine-year-old male boxer with pituitary-dependent hypercortisolism due to an adenoma (on the left) in the with pituitary-dependent hypercortisolism. There is now evidence that the solism in the low-dose dexamethasone suppression test hallmark of pituitary-dependent hypercortisolism – resistance (LDDST). but tumors may also occur (fig. chapter 12. the development of pituitary PI is under direct neural control. 118 Adrenals 4 Figure 4.35: Figure 4.36: Significant correlation (r = 0.72; P = 0.001) of the pituitary height / brain ratio Three daily UCCRs in a 13-year-old female poodle are shown at the left. After the (P/B) and the percentage of dexamethasone resistance of the plasma ACTH con- second urine collection the owner administered three doses of 0.1 mg dexame- centrations (ACTH, % from baseline) in 67 dogs with pituitary-dependent hyper- thasone per kg body weight at 8 h intervals. The horizontal band is the reference cortisolism.163 ACTH (% of baseline) represents the plasma ACTH concentration range for basal UCCRs measured in 88 healthy pet dogs (0.3–8.3 × 10–6).139 The 4 h after intravenous administration of 0.1 mg dexamethasone per kg body two basal UCCRs are elevated and the UCCR is then suppressed by more than weight as percentage of the plasma ACTH concentration before dexamethasone administration. effect of dexamethasone, they also release ACTH precursors differentiation between different forms is combined in one (POMC, pro-ACTH; fig. 4.35) more often than do small test using UCCRs and oral dexamethasone administration corticotroph adenomas.166,167 Dogs with high plasma levels of (fig. 4.36). the PI-peptide a-MSH have higher plasma levels of the pre- cursors than do those in which plasma a-MSH is not ele- When there is 쏝 50 % suppression, the hypercortisolism may vated.166 The release of incompletely processed or unprocessed still be pituitary dependent, due to a pituitary ACTH excess POMC by dedifferentiated corticotroph macroadenomas may that is extremely resistant to dexamethasone suppression. result in high plasma levels of POMC peptides without excess Further differentiation requires measurements of plasma ACTH and consequently without hypercortisolism.168 A cat ACTH. In animals with hypersecreting adrenocortical tu- with a melanotroph PI adenoma and extremely high plasma mors, basal ACTH concentration is usually suppressed. If in- concentrations of a-MSH was found to have no evidence of terpretation of ACTH values is uncertain, as may occur with ACTH-dependent hypercortisolism.146 the simultaneous occurrence of both entities, further studies are required: a CRH-stimulation test (chapter 12.1.1) and Diagnosis visualization of the adrenals and the pituitary. It may also be When hypercortisolism has been confirmed it is necessary to helpful to measure plasma a-MSH; high values occur distinguish between pituitary-dependent hypercortisolism especially with PI tumors, which are often dexamethasone and other forms. Despite decreased sensitivity to suppression resistant and rather large (chapter 4.3 and fig. 4.37). by glucocorticoids, ACTH secretion in most animals with pituitary-dependent hypercortisolism due to a corticotroph As mentioned in chapter 2.2.3, dogs with skin atrophy in adenoma in the AL can be suppressed by a ten-fold higher breeds such as the miniature poodle and Pomeranian have dose of dexamethasone, resulting in decreased secretion of been found to satisfy two criteria of hypercortisolism: in- cortisol. In the other forms of glucocorticoid excess the hy- creased cortisol production and decreased sensitivity to glu- persecretion of cortisol is not dependent on pituitary ACTH cocorticoid feedback.138 The routine tests for hypercortisol- and is therefore not influenced by the high dose of dexame- ism (chapters 12.4.2, 12.4.4) are often negative, but serial thasone (see also fig. 1.9). Two procedures are used, one em- measurements of the UCCR for ten days may demonstrate ploying plasma cortisol and the other employing the UCCR the presence of mild and fluctuating hypercortisolism (chapters 12.4.3, 12.4.4). In both, a decrease of 쏜 50 % from (figs. 4.32, 4.38). Following treatment for hypercortisolism baseline values confirms pituitary-dependent hypercortisol- the hair coat returns (fig. 4.39).169 ism. Often the test for diagnosing cortisol excess and for the Glucocorticoid excess 119 4 Figure 4.38: Two dexamethasone suppression tests using UCCRs, in a seven-year-old male miniature poodle with longstanding and gradually progressing alopecia; they were interpreted as indicating suppressible normocorticism. However, when the UCCR was measured daily for ten days, it was found to fluctuate between normal and elevated values (see also fig. 4.32 and legend to fig. 4.36). Figure 4.37: Results of an iv-HDDST test (chapter 12.4.3) in a ten-year-old female standard schnauzer. Dexamethasone-resistant hypercortisolism was indicated by UCCR values (basal 39 and 66 × 10–6 and after dexamethasone 31 × 10–6). Plasma con- centrations of cortisol and ACTH did not decrease in the iv-HDDST, which together with elevated plasma a-MSH levels, was compatible with a pituitary tumor orig- inating in the PI. Diagnostic imaging revealed both a pituitary tumor and bilateral adrenal tumors.149 A B Figure 4.39: A seven-year-old male miniature poodle with mild pituitary-dependent hypercortisolism (fig. 4.38), only manifested by gradually progressing alopecia, before (A) and seven months after destruction of the adrenal cortices with o,p'-DDD (B). 120 Adrenals Figure 4.40: Transverse dynamic CT image through the pituitary fossa at the moment of maximal contrast enhance- ment of the arterial cerebral circle in a 6-year-old York- shire terrier (A) and a 7-year-old Maltese dog (B) with 4 pituitary-dependent hypercortisolism. (A) The pituitary is not enlarged and the pituitary flush (arrow) is dis- placed dorsally and to the right indicating an adenoma ventrally and to the left. (B) The pituitary gland is not enlarged. Treatment at the pituitary level Spontaneous recovery is rare (fig. 4.41) and life expectancy in severe cases is usually less than one year if the disease is left un- treated. Death may ensue as a result of complications such as heart failure, thromboembolism, or diabetes mellitus. In mild cases with apparently little progression the course of the dis- ease can be followed by measurements of the UCCR (fig. 4.36). The treatment of pituitary-dependent hypercortisolism should be directed at eliminating the stimulus for cortisol pro- Figure 4.41: duction, i.e., the pituitary lesion causing excessive ACTH UCCRs (averaged duplicates on two consecutive days) in a seven-year-old cas- secretion. In the last decade experience has been gained trated male dachshund with alopecia, lethargy, and weight gain due to pituitary- with microsurgical transsphenoidal hypophysectomy in dependent hypercortisolism. Especially because the symptoms and signs were dogs and cats with pituitary-dependent hypercortisolism mild, the owners decided to postpone treatment and to follow the course of the (fig. 4.42).173,174 With appropriate short-term and long-term disease by UCCR measurements. The dog gradually recovered, became more substitution therapy (chapter 13.1.1) this is an effective treat- lively, and lost weight. After about twelve months the hair coat had fully regrown. ment (fig. 4.43). It can only be performed in specialized Such exceptional cases have also been observed in man and have been ascribed to spontaneous necrosis of a pituitary corticotroph adenoma.172 See also legend institutions with intensive perioperative care, and where to fig. 4.36. imaging techniques such as CT and MRI can be used to de- fine the location and size of the pituitary prior to surgery. When the surgeon has acquired the necessary experience, the results compare favorably with those of chemotherapy with When biochemical findings confirm pituitary-dependent hy- o,p'-DDD. The main advantage for long-term survival, com- percortisolism, the pituitary is visualized by computed to- pared with therapy at the adrenal level (discussed below), is in mography (CT) or nuclear magnetic resonance imaging avoiding the neurological problems that could eventually (MRI) (figs. 2.27, 2.28). This visualization is imperative if occur as a result of an expanding pituitary tumor.175 Survival either hypophysectomy or pituitary irradiation is to be used and disease-free fractions after hypophysectomy are higher in for treatment.170 The surgical landmarks for hypophysectomy dogs with nonenlarged pituitaries than in dogs with enlarged are best visualized by CT while the zones for intense pituitary pituitaries. Also, prolonged central diabetes insipidus is a radiation with a linear accelerator must be outlined by MRI. more frequent complication after hypophysectomy in dogs Dynamic contrast-enhanced CT facilitates contrast enhance- with enlarged pituitaries than in those with nonenlarged pi- ment of the neurohypophysis and the adenohypophysis. tuitaries.176 UCCRs higher than 5 × 10–6 and the presence of Absence of the pituitary flush indicates atrophy of the pulses in plasma ACTH at six to ten weeks after surgery are neurohypophysis due to compression by a pituitary tumor. risk factors for recurrence.177,178 Displacement or distortion of the pituitary flush in the early phase of dynamic CT can be used to identify and localize Several attempts have been made to reduce pituitary hyperse- microadenomas originating from the AL or PI in dogs cretion of ACTH medically, but now that the disease is (fig. 4.40).171 known to be of primary pituitary origin it is understandable Glucocorticoid excess 121 4 A B Figure 4.42: Transverse CT images of the head of a nine-year-old female Bouvier-cross with pituitary-dependent hypercortisolism, before (A) and three months after hypophysectomy (B). Prior to surgery contrast enhancement revealed a pituitary tumor 7.3 mm high and 8.3 mm wide, but no pituitary tissue could be visualized after surgery. In this dog the hypercortisolism was characterized as dexamethasone-resistant because the UCCR after dexamethasone suppression (23 × 10–6) was 쏜 50 % of the average of the two basal UCCRs (33 × 10–6). The high basal plasma ACTH (238 and 240 ng/l) and a-MSH (185 and 235 ng/l) concentrations suggested that the tumor originated from melanotroph cells of the pars intermedia. After surgery the UCCR on two consecutive days was 쏝 0.5 and 1.1 × 10–6. The dog lived for five more years and died from an unrelated condition at the age of 14 years. A B Figure 4.43: (A) Six-year-old castrated male affenpinscher with signs of glucocorticoid excess (polyphagia, alopecia, weight gain, and lethargy) and elevated UCCRs (25 and 13 × 10–6; ref. range: 0.3–8.3 × 10–6) and basal plasma ACTH (56 and 50 pmol/l; ref. range: 0.4–21 pmol/l). CT revealed an enlarged pituitary and dynamic CT revealed a pituitary adenoma (see fig. 4.40). Four months after hypophysectomy (B) there was good regrowth of the hair coat and UCCRs were 0.5 and 0.4 × 10–6. 122 Adrenals 4 A B Figure 4.44: An eight-year-old male miniature poodle with pituitary-dependent hypercortisolism and diabetes mellitus before (A) and six months after (B) destruction of the adrenal cortices with o,p'-DDD. In addition to the recovery from hypercortisolism, the insulin demand decreased considerably and remained stable and low. A B Fig. 4.45: A nine-year-old castrated male dachshund with pituitary-dependent hypercortisolism (basal UCCRs 42 and 48 × 10–6; after three oral doses of 0.1 mg dexametha- sone/kg: 6 × 10–6). The dog’s ravenous appetite was of greatest concern to the owner, illustrated by the empty can which the dog had tried to eat (A). Following destruction of the adrenal cortices with o,p'-DDD and replacement therapy the dog and owner resumed a normal life (B, photograph seven months after initiation of treatment). Glucocorticoid excess 123 that neuropharmacological approaches with an antiserotoni- cases in which selective destruction is the aim, there are one nergic drug and a monoamine-oxidase inhibitor were unsuc- or more relapses of hypercortisolism during treatment.190 In cessful.179–181 The medical treatment of pituitary-dependent order to circumvent these complications a treatment schedule hypercortisolism of PI origin, characterized by high plasma has been devised with the aim of complete destruction of a-MSH concentrations, was aimed at increasing dopaminer- the adrenal cortices and substitution for the induced hypo- gic inhibitory tone with the dopamine-agonist bromocrip- adrenocorticism (figs. 4.44, 4.45).191,192 This nonselective tine. Although a short-term effect was observed, the drug did destruction has been reported to be associated with fewer re- not prove to be efficacious in lowering UCCRs.182 currences than with selective destruction.193 Since the intro- duction of trilostane for the medical management of pitu- In the interests of new medical therapies the expression of so- itary-dependent hypercortisolism, o,p'-DDD is seldom used 4 matostatin receptor subtypes (mainly subtype sst2) and dopa- for this purpose. Its main use now is for the treatment of ad- mine receptor subtypes (subtype D2 modestly expressed) has renocortical tumors (chapter 4.3.2). been identified on canine corticotroph adenomas.183 The D2-agonist cabergoline has been reported to decrease plasma Trilostane is a competitive inhibitor of the 3b-hydroxysteroid ACTH and a-MSH concentrations and UCCRs in slightly dehydrogenase / isomerase system which is essential for the less than half of dogs with pituitary-dependent hypercortisol- synthesis of cortisol, aldosterone, progesterone, and andros- ism.184 Investigators in the same clinic also tested retinoic tenedione (fig. 4.3). Trilostane also inhibits other enzymes acid, a ligand for the nuclear receptor peroxisome prolifer- involved in steroid biosynthesis, such as 11b-hydroxylase and ator-activated receptor-g (PPAR-g), that arrests pituitary possibly 11b-hydroxysteroid dehydrogenase.194,195 tumor growth in a nude mouse model. They observed im- provement in both the physical changes and the endocrine In dogs with pituitary-dependent hypercortisolism (PDH), variables in all dogs treated.185 In both studies it is difficult to trilostane has the potential of significantly reducing basal and evaluate the reported recovery, for the UCCRs were lowered ACTH-stimulated plasma cortisol concentrations.196–201 The but remained around the relatively high upper limit of their resulting loss of negative feedback, leads to increased plasma reference range and the reduction in size of the pituitary ACTH levels.197,202,203 Very high plasma ACTH may indicate tumor was not completely convincing. trilostane overdosage.203 As discussed in chapter 2.2.6.2, the main indication for radio- Trilostane treatment also causes a slight decrease in plasma therapy is to reduce the size of a pituitary tumor that is com- aldosterone concentration and although it usually remains pressing the brain. Since it usually does not reduce sufficiently within the reference range,197,199 the decrease leads to hypo- the hypersecretion of ACTH, additional therapy at the ad- volemia and activation of the RAS (chapter 4.1.4, fig. 4.9), renal level (see below) is required. often with significant increases in plasma renin activity.203 Treatment at the adrenal level Trilostane is absorbed rapidly from the gastrointestinal tract. This consists of eliminating the glucocorticoid excess by bi- Administration with food significantly increases the rate and lateral adrenalectomy or by medical therapy. Total adrenalec- extent of absorption. There is marked variation in the optimal tomy achieves a complete cure of the hypercortisolism and dose and to avoid adverse effects due to overdosage, treatment the prognosis with glucocorticoid and mineralocorticoid re- is started at a relatively low oral dose of 2 mg/kg once daily. placement (chapter 4.2.1) is good unless or until expansion The dose is then adjusted according to the clinical response of the pituitary tumor causes neurological problems (chap- and the results of ACTH-stimulation tests (chapter 13.2.2). ter 2.2.6.2). The perioperative and postoperative medication The efficacy of treatment is also monitored by clinical signs is described in chapter 4.3.2. In the absence of alternatives, and measurements of plasma sodium, potassium, urea, creati- bilateral adrenalectomy has also been used in cats, but with nine, liver enzymes, and ACTH.203 complications such as sepsis, thromboembolism, and poor wound healing.186,187 Presurgical treatment with metyrapone, It has been reported that the UCCR cannot be used as an al- an inhibitor of steroid synthesis (see below), together with ternative to the ACTH-stimulation test to determine the op- perioperative administration of antimicrobials and heparin timal dose of trilostane.198,204 In more than half of the dogs can aid in preventing these complications.188,189 with pituitary-dependent hypercortisolism in a recent study the UCCR did not decline below the upper limit of the ref- For many years the most common form of treatment of pitu- erence range within two months after the dose of trilostane itary-dependent hypercortisolism in dogs has been use of the was considered to be satisfactory. However, in those that de- adrenocorticolytic drug o,p'-DDD. Some treatment sched- veloped hypocortisolism, based on clinical manifestations and ules aim at selective destruction of the zona fasciculata and an ACTH-stimulation test, the UCCR was below the upper zona reticularis, sparing the zona glomerulosa. However, in limit of the reference range several weeks before hypocorti- 5–6 % of the dogs in which this is attempted, the zona glome- solism was diagnosed. Consequently, in long-term follow-up rulosa is also destroyed to such an extent that iatrogenic hy- the UCCR may serve as an early indicator of hypocortisol- poadrenocorticism develops. Also, in more than half of the ism.204 124 Adrenals 4 A B Figure 4.46: (A) An eight-year-old male dachshund with polyphagia, polydipsia, polyuria, and alopecia. The basal UCCRs were 47 and 44 × 10–6 and the UCCR was reduced to 13 × 10–6 after high oral doses of dexamethasone. CT revealed mild contrast enhancement in a normal-size pituitary. Both adrenals were slightly enlarged. (B) Treatment with trilostane 30 mg once daily resulted in complete recovery. Within about a week on an appropriate dose of trilostane there Overdosage of trilostane results in cortisol deficiency and is a clear reduction in water intake, urine output, and appetite, sometimes even mineralocorticoid deficiency.201,203,212,213 In followed by improvement in the coat and skin, reduction of addition, necrosis, apoptosis, and hemorrhage in the zona central obesity, and increased physical activity (fig. 4.46). Tri- fasciculata and zona reticularis may cause life-threatening hy- lostane’s inhibiting effect on aldosterone secretion may cause pocortisolism.211 If hypoadrenocorticism occurs trilostane plasma potassium to increase slightly.196,197,199,201 Its short dur- must be stopped immediately and corticosteroid substitution ation of action may be responsible for the lack of improvement started (chapter 13.2.1). In most cases adrenocortical function in some hyperadrenocorticoid dogs.200,205 This may be re- recovers sufficiently within a few weeks and substitution can medied by twice daily administration, beginning at 1 mg/kg be stopped, but some dogs require long-term substitution per dose. therapy.201,203 Trilostane can be used in cases of hypercortisolism due to The median survival time for treatment with trilostane once functional adrenocortical tumors if neither adrenalectomy daily (662 days) is similar to that for selective adrenocorti- nor destruction of adrenocortical tissue with o,p'-DDD colysis with o,p'-DDD (708 days).214 The median survival (chapter 4.3.2) is an option.206 It can also be used as palliative time for treatment with trilostane twice daily (900 days) is treatment in cases of metastasis of a functional adrenocortical also comparable to that for nonselective adrenocorticolysis tumor.207 It holds promise for cats with pituitary-dependent with o,p'-DDD (720 days).193 In both studies, body weight hypercortisolism,208,209 but there is as yet little actual experi- and age at diagnosis were negatively correlated with survival. ence with its use in cats and more studies are needed before this can be generally recommended.209 Another therapeutic option could be the inhibition of adre- nocortical steroidogenesis by ketoconazole, a synthetic imida- Treatment of pituitary-dependent hypercortisolism with tri- zole analogue used as a broad-spectrum antifungal agent re- lostane may produce distinct changes in the ultrasonographic sulting from its binding to yeast and fungal cytochrome appearance of the adrenal glands. In most trilostane-treated P-450. At high concentrations, ketoconazole also affects cer- dogs there is a clear increase in the thickness of the adrenal tain cytochrome P-450 enzymes in microsomal and mito- glands, due to the continuing stimulation by ACTH. Long- chondrial fractions of mammalian cells.215 It has been used in term trilostane treatment may result in adrenal glands with an dogs in the treatment of both pituitary-dependent hypercor- irregular shape and a nodular appearance.197,210,211 tisolism and hypercortisolism due to adrenocortical tumor. The initial dose is 5 mg/kg twice daily for seven days and adrenal tumor discovered incidentally during diagnostic tuitary lesion does not expand to cause neurological signs. 4. Hypercortisolism due to twice daily to control hypercortisolism.220 Increased mRNA expression of 11-deoxycortisol to cortisol (fig. then 10 mg/kg twice daily. but bilateral tumors occur in about 10 % of cases. 4.223 Most adreno- cortical tumors are unilateral solitary lesions.221 Data on the expression tisolemia prior to bilateral adrenalectomy.147 Whether adrenocortical carci- noma develops from adrenocortical adenoma or occurs as a Aminoglutethimide. The atrophic ad- renal cortex is visible as a small rim surrounding the medulla at the caudal pole. cations that in humans adrenal tumorigenesis is a multistep but low efficacy and adverse effects limit its use.44–4.48).218 Metyra. another inhibitor of steroidogenesis.224. but this may have ad- verse effects such as anorexia. Figure 4.3. Most animals can continue satisfac. adrenocortical tumor These may be resolved by administering ketoconazole with Histologically adrenocortical tumors can be divided into food and temporarily reducing the dose. diarrhea.47) and carcinomas (fig.120 of genes involved in adrenal tumorigenesis in dogs and cats are still lacking. a distinction tations in using ketoconazole in dogs are adverse effects and that is by no means always straightforward. Glucocorticoid excess 125 4 Figure 4. imaging for reasons unrelated to adrenal pathology is referred Because of this possibility hypophysectomy is preferred where to as an incidentaloma.219 Microscopic failure of some dogs to respond. examination of a seemingly benign tumor may reveal its ex- conazole is the only legally available drug for veterinary use. process progressing from normal to adenomatous cells and ul- pone reduces cortisol synthesis by blocking the conversion of timately to malignant cells. The tumor was surgi- cally removed from a ten-year-old female miniature schnauzer with hypercortisolism. it IGF-II is one of the dominant transcriptional changes in has been used for controlling the harmful effects of hypercor. diagnostic imaging of the abdomen for other purposes. Silent tumors may be found during be satisfactory controlled. 4.216 The major limi.222 Adrenocortical tumors causing possible. hypercortisolism can or hormonally active.2. Prognosis With the above methods for either destruction of the adrenal Adrenocortical tumors can be either endocrinologically silent cortices or inhibition of steroidogenesis.48: Large adrenocortical tumor removed at autopsy from a nine-year-old male boxer with hypercortisolism. An torily for several years (figs 4. human adrenocortical carcinoma.225 The clinical findings are those of . and icterus. but there are indi- been used in dogs with pituitary-dependent hypercortisolism.147.147. Some dogs require 15 mg/kg 4. Tumor tissue protrudes into the longitudinally opened vena cava.3).47: Cut surface of a small adrenocortical tumor in the cranial pole of the left adrenal.217 In some countries keto. As mentioned above. hypercortisolism occur in both dogs and cats in middle and old age with no definite sex predilection. has separate entity has yet to be determined. pansion into blood vessels. vomiting. adenomas (fig.46). provided that the pi. the two glands being affected about equally. because plasma ACTH should be low and if it is not.5). adrenals. ter 4. plasma ACTH and if necessary a CRH-stimulation test renocortical tumors.1). basal Androgen hypersecretion may reflect dedifferentiation of ad. The preferred procedures for visualization of the adrenals are related symptoms and signs caused by metastases or non. rexia. and so it is tumor thrombi of the caudal vena cava (fig.237 Diagnosis Some dogs with adrenocortical tumor have only moderate cortisol excess and thus moderate symptoms and signs.242 i.49). adrenocortical tumors may also pro. needed. It provides a good estimate of tumor are rare consequences of adrenocortical tumor.226 or often used first even though it is more difficult to perform and hemo(retro)peritoneum secondary to rupture of an adrenal to interpret than CT or MRI. but suspicion is aroused by the finding that it 4 is not suppressed by dexamethasone. guish between macronodular hyperplasia and adrenocortical duce other adrenocortical hormones in excess. Whatever is used. In these cases the UCCR is often around the upper limit of the reference range. Basal urinary corticoid:creatinine ratios (UCCR) in dogs with hypercortisolism and resistance to sup- pression of these values (쏝 50 % suppression) by Hypercortisolism due to adrenocortical tumor can be dif- three eight-hourly administrations of 0. When the presence of an adrenocortical tumor has been con- cal tumors being unable to carry steroidogenesis efficiently to firmed. During abdominal ultrasonography for identification cortical tumors have also been reported in dogs.9).3.233–236 of the adrenals the liver should also be examined for meta- . 126 Adrenals Another interesting feature of adrenocortical tumors is that they may occur together with pheochromocytoma (chap- ter 4. readily detected by ultrasonography..238 In some dogs with a cortisol- secreting adrenocortical tumor.227–229 the size of the tumor and may reveal information about its ex- pansion (fig. In addition.224. i. graphy (CT) (fig. the neo- plastic transformation results in lower function per unit of volume (fig. magnetic resonance imaging (MRI) and computed tomo- specific features of malignancy such as weight loss and ano. 4. the tumor tissue is often only moderately active. Hypersecre. 4. an adrenocortical tumor is often renocortical tumor (AT) were based upon measu. dexamethasone adminis- tration causes a paradoxical rise in both the UCCR and Figure 4. ferentiated from nonsuppressible forms of pituitary-depend- methasone/kg body weight. cortisol.49: plasma cortisol. 4. Hypersecretion of cortisol by adrenocortical tumors cannot be suppressed by administration of dexamethasone (fig. with steroidogenesis proceeding to its (chapter 12.e. and does not require anesthesia.241 It is sometimes difficult to distin- In addition to cortisol. A palpable abdominal mass. Although adrenocortical tumors usually greatly exceed the size of the normal gland.4). final product. Note that in several cases of AT the UCCR measure plasma ACTH and perform ultrasonography of the were only moderately elevated and that the highest ratios were found in dogs with PDH. The diagnoses of ent hypercortisolism by measuring plasma ACTH (chap- pituitary-dependent hypercortisolism (PDH) and ad.51).240 Ultrasonography is less expensive. the findings should be interpreted tical tumors has been reported to be quite common. resistance to suppression by a high dose of dexamethasone is with about equal probability due to adrenocortical tumor or dexamethasone-resistant pituitary- dependent hypercortisolism.232 Mixed cortisol.149. There may also be mass. As measured by either plasma cortisol concentration or the UCCR (chapter 12.48). 1.230. 4. Hence it is common rements of plasma ACTH and visualization of the ad.148.1.231 in conjunction with those of biochemical studies. vascular obstruction by requires less time.1 mg dexa.50).and aldosterone-producing adreno. practice in cases of nonsuppressible hypercortisolism to renals.e. tumor by ultrasonography and so CT or MRI may also be tion of adrenal sex hormones by cortisol-secreting adrenocor.3). in hyperplastic and well-differentiated benign adrenocortical tissue but dedifferentiated adrenocorti. sidered. the possibility of distant metastases should be con- term..239 glucocorticoid excess (chapter 4. If an adrenocortical tumor is found it is still useful to have ACTH measurements.1). further studies are warranted to determine whether there is also pituitary-dependent hypercortisolism. effects of o.51: Contrast-enhanced CT image of the abdomen of a nine-year-old male German Transverse ultrasonogram from the right lateral intercostal region.p'-DDD in both humans and animals.p'-DDD treat- corticoid substitution is needed initially. Glucocorticoid excess 127 4 Figure 4. Successful removal of the affected adrenal will result drugs destroy adrenocortical cells and thereby reduce steroid in complete recovery without the need for lifelong medi. thereby minimizing the chance of tumor spillage.5 mg hy. Adrenocorticolytic surgery. destruction (chapter 4.1). it should be removed by renocorticolytic or adrenocorticostatic. tution with a glucocorticoid and a mineralocorticoid is required. Because of the potential of toxic medicine. whereas adrenocorticostatic drugs interfere with cation. ment should be complete destruction of all adrenocortical thesia. Administration of the adrenocorticolytic drug o. Although the hypercortisolism per se due to adreno- Because of the atrophy of the nontumorous adrenocortical cortical tumor may be treated successfully by selective tissue due to the longstanding glucocorticoid excess.1). When diag.p'-DDD/kg body weight per day. and the right kidney (3). owners cess because it provides maximal exposure of the tumor and must be given careful instructions on how to recognize and vessels.147.243–246 In humans ad. At the time of anes.248 but most surgeons still prefer transabdominal ac.1). gradually reduced and then stopped six to eight weeks of the thorax should be made to exclude metastases in the after surgery. The lumen of the caudal vena cava is echo- genic due to the presence of a tumor thrombus.147 After bilateral adrenalectomy lifelong substi- lungs. Thoracic radiographs or a CT scan daily.247 Laparoscopic adrenalectomy may recurs after adrenalectomy. immediately shepherd dog with a well-demarcated mass between the aorta (1). o. the caudal cranial to the right kidney. a household in which there is a pregnant woman or young child. Lateral to the aorta (1) and dorsal to the caudal vena cava (2) an adre- nocortical tumor is visualized (arrows). Drugs for this purpose are classified as ad- there is a resectable unilateral tumor.249 the aim of o. with a paracostal extension of the incision when needed. according to the treatment protocol for primary Treatment hypoadrenocorticism (chapter 4.p'-DDD doses up to 100 mg/kg per day . If possible metastases are found. The treatment protocol for complete adreno- administration over a period of 6 h. Adrenalectomy can be performed via a ventral midline steroidogenesis without cell damage.2. when intravenous fluid administration is started. celiotomy. 5 mg cells and substitution therapy for the induced adrenocortical hydrocortisone/kg body weight is added to the first bottle for insufficiency.p'-DDD is renalectomy is now often performed by laparoscopy. gluco. and in particular of tumor thrombi in the caudal vena respond to them. cortical destruction consists of 25 days of oral administration drocortisone/kg is administered subcutaneously at 6 h inter. Hypercortisolism due to adrenocortical tumor can also be nostic imaging has revealed no metastases and it is likely that treated medically. V = vena cava (2).p'-DDD should preferably not be used in cava. stases.50: Figure 4. of an eight-year-old miniature poodle (D = dorsal. or via a paracostal approach. Treatment has two objectives: removal of the adrenocortical tumor and containment of hypercortisolism. Subsequently 0. ventral). ultrasound-guided will consist of 1 mg cortisone acetate/kg body weight twice biopsy can be performed.3.2. consistent with an adrenal tumor. with often the treatment of choice in dogs in which tumor tissue lower perioperative morbidity and mortality than by open cannot be completely removed surgically or when the disease transabdominal surgery. of 50–75 mg o.191 In dogs of vals until oral medication is possible (chapter 13. This low body weight o. It is also used in cases of metastas- also become the surgical procedure of choice in veterinary ized adrenocortical tumor. synthesis. 128 Adrenals 4 Figure 4. with good instructions should be started (chapter 13.p'-DDD.p'-DDD is then continued for at range indicate glucocorticoid excess and o. The systemic availability of this are the values on two control days and after three oral doses of dexamethasone. all divided into at least two por. but is always doubled for one or two days animal’s appetite and water intake have increased. injectable medications poadrenocorticoid crisis. ination is made.p'-DDD is again least three months at the same dose once weekly (fig.p'-DDD concentrations in plasma of six dogs given the drug as intact tab. o.53: Mean o.1 mg/kg. substitution and to contact the veterinarian. If a loss of ap- chloride (0.5– causing the owner to contact the veterinarian because the 1. After 25 days of o.0 mg/kg per day. However. Treatment was discontinued for a few days be- cause of the dog’s inappetence and was then resumed once weekly for three months. who may in- fludrocortisone acetate (0.2. petite is ignored and o.52). to continue adrenocortical hormone therapy is begun with cortisone acetate (2 mg/kg per day).p'-DDD therapy there were no signs of re- currence of hypercortisolism.p'-DDD is given least once weekly and whenever questions or problems arise. substitution with equal emphasis. the dog may tions. 4. A written instruction for this is rare and usually the o. daily for the first five days. On the left lets without food (blue line) or with food (red line). 0. refuse substitution therapy. Owner compliance is essential for successful chemotherapy with o.1 g/kg per day). UCCRs exceeding the upper limit of the reference (see also chapter 4.53). On the third day. The doses of fludrocortisone and salt are omitting cortisone and fludrocortisone on the preceding adjusted by measurements of plasma sodium and potassium evening. If for any reason the dog cannot take or retain the tab. but possible recurrence should be investigated by re- UCCRs in morning urine samples collected after omitting peating UCCR measurements. Despite this treatment with o. tered with food (fig.8 kg.p'-DDD administration can be owners is presented at the end of chapter 13. lipophylic drug is very poor when intact tablets are given without food but ordi.p'-DDD.1).p'-DDD three times daily was monitored by nary dog food seems to contain sufficient fat to facilitate good absorption. Two morning urine samples the cortisone and fludrocortisone administration on the are collected at an interval of four to five days. The cortisone dose is reduced to 0.p'-DDD is continued.1).0125 mg/kg per day). thereafter on alternate days. a follow-up exam. Omitting in the event of anesthesia. The The owner is also instructed very clearly to stop giving daily dose is divided into three or four portions and adminis. o. and develop a hy- lets and salt two times in succession.p'-DDD if partial or complete inappetence develops.2. Two years after the start of o. resumed after a few days without further problems. and sodium crease the cortisone substitution temporarily. weekly measurements of the UCCR after cortisone and fludrocortisone were omitted on the preceding evening.52: Figure 4. UCCRs in an eleven-year-old female mongrel dog weighing 24.p'-DDD administration. may be required for complete destruction. given daily for 25 days and then once weekly for at least half a year or even lifelong. but. or injury. Treatment with 500 mg o. severe physical stress. 4. each time preceding evening. During the first month the owner reports at . begin to vomit. o. there are recurrences. the cortisone substitution may ameliorate the symptoms tem- Complete adrenocortical destruction results in very low porarily. The abdominal ultra- sonogram (A) can be compared with the CT image (B) in lateral recumbency. This often and can also be used as palliative treatment in case of meta. although mainten- . the hypercortisolism had recurred. Glucocorticoid excess 129 4 A B C AD Figure 4.53) and ultrasonographic examinations may reveal that the size of the tumor has decreased considerably.p'-DDD four times daily for 35 days and corticosteroid replacement was started. Dogs with irresectable adre- lostane can be used. A large tumor of the right adrenal gland is shown between the aorta (1). o. the adrenocorticostatic drug tri. One year after surgical removal of the tumor.250 Prognosis Even lung metastases may disappear (fig.54: Diagnostic images in a ten-year-old castrated female miniature pinscher of 8 kg with hypercortisolism due to a tumor of the right adrenal cortex. and right kidney (3). This is true for bilateral as well as unilateral tumors. leads to complete and permanent remission of the hypercor- stases of a functional adrenocortical tumor.207 tisolism (fig.p'-DDD according to the above schedule. The prognosis is excellent after complete surgical resection of adrenocortical tumor that has not metastasized. in which there was microscopic expansion into blood vessels. after bilateral adrenal resection. If adrenalectomy or adrenocortical destruction with ance therapy for induced hypoadrenocorticism is required o.54). caudal vena cava (2). The expiratory radiograph of the thorax of this obese dog (C) revealed several nodular densities (arrows) consistent with pulmonary metastases.p'-DDD there was no evidence of recurrence of hypercortisolism or lung metastases (D). It has been used successfully in a dog with nocortical tumor or recurrence after resection can be treated hypercortisolism due to a functional adrenocortical tumor206 with o.5 years and two years after the start of o. 4.p'-DDD is not an option.p'-DDD was continued once weekly for 1. 4. The dog was given 125 mg o. or MRI (chapter 4.1). Plasma con. topic hormone receptors. The condition may not be extremely cat was associated with bilateral alopecia. This is most pronounced in neu.253 Endocrine test.2). 130 Adrenals 4.3) and in exceptional severe cortisol excess exceeding the capacity of 11b-HSD2 cases also cause hypercortisolism. These are often malignant tumors originating membrane-bound receptors functionally coupled to steroido- from cells of the diffuse neuroendocrine system (chap.2 mmol/l). and metastases in the liver.232 but seems to be was not discovered.3. CT of the abdomen re- high plasma LH concentrations due to the neutering causes vealed a tumor in the region of the pancreas and laparotomy excessive secretion of androstenedione.252 formed and histological examination revealed a neuroendo- crine tumor with metastasis in the lymph node.262. the neoplastic adrenocortical tissue expresses Both the UCCR (1518 and 2176 × 10–6) and plasma ACTH functional LH receptors. including regression of penile spines.6). genesis have been reported. Nevertheless. Hypersecretion of sex hormones This condition has been documented in an eight-year-old German shepherd dog.5 Food-dependent glucocorticoid excess 4. and LH tumors. 17a-hydroxyproges.259 cortical tumor should be considered in neutered animals with newly developed physical and behavioral sexual changes such Thus ectopic ACTH secretion should be suspected when as urine spraying and aggression in neutered male cats.260 In a dachshund with hypokalemia an extrapitui- tumor.264 (chapter 4. rare. and gastrointestinal peptide (GIP). and these values may increase following responsible for severe hypercortisolism with persistent hypo- stimulation with ACTH. Consequently the clinical manifestations cessive secretion of androstenedione. catecholamine. In humans. a 3 cm metastasis in terone. A sex steroid hormone-secreting adreno. in which excessive secretion of sex hor. In another Ger- tenedione. and symmetrical alopecia. They may be small and therefore difficult to locate. The clinical manifestations centrations of cortisol and ACTH are usually not affected. in which this diagnosis has been proposed. including severe hypokalemia (2.231. Diagnostic imaging may reveal a ated adrenocortical carcinoma in a castrated male Himalayan neuroendocrine tumor. pancreatic. recurrence of sexual behavior in neutered pancreatectomy and extirpation of the lymph node were per- male ferrets.263 As mentioned in chapter 4. the dog did well for more rare in both species. 17-hydroxyprogesterone. Partial tered female ferrets. its expansion. These than cortisol or aldosterone.3. Hypersecretion of progesterone by a well-differenti.1.3. than two years on treatment with trilostane. and include thymic. vasopressin.251 exacerbated. findings were initially interpreted as being consistent with pi- tered pet ferrets. the glu. serotonin. including gastric inhibitory poly- ter 10. from noncortisol-secreting adrenocortical tumor has also probably because of additional metastatic tumor tissue that been reported in cats253–257 and dogs. activated LH Plasma ACTH concentrations and cortisol secretion rates can receptors on adrenocortical tumor cells in ferrets cause ex- be extremely high. leading to vulvar swelling in neu.3.3. 17a-hydroxyprogeste- can be very pronounced. The second Increased secretion of progesterone or other sex hormones surgical intervention did not alter the course of the disease.3. However. The UCCRs (236 and 350 × 10–6) by adrenocortical tumor and plasma ACTH concentrations (159 and 188 ng/l) were Adrenocortical tumors can produce various hormones other very high and not suppressible with dexamethasone.258 .2). solism may be due to expression of ectopic or hyperactive eu- cocorticoid excess is the result of ACTH secretion by nonpi. revealed a 5 mm nodule in the pancreas. as there have been two more reports of individual cases ing may reveal elevated plasma concentrations of andros.5) plasma ACTH concentrations that are not suppressible with whereas the castrated female develops hyperplasia of the high doses of dexamethasone and in the absence of a demon- vulva. estradiol. Activation of these receptors by the (281 ng/l) were further increased. and /or estradiol252 (chapter 4. 4. testosterone. man shepherd dog a primary hepatic carcinoid was held and /or progesterone. no tumor was found and there was some suppression of the plasma cortisol concentrations in the LDDST. an adjacent lymph node.261 Adrenalectomy is the treatment of choice and usually results in resolution of clinical manifestations. physectomy revealed no adenoma.231 Information about the size of the kalemia. histological mones by unilateral or bilateral adrenocortical tumors is the examination of the tissue removed by transsphenoidal hypo- most common form of hyperadrenocorticism. ACTH-independent hypercorti- In about 15 % of humans with Cushing’s syndrome. CT. and /or estradiol.3. receptors. including hypokalemia due to the rone. tuitary-dependent hypercortisolism. strable pituitary tumor.4 Ectopic ACTH syndrome In addition to autonomous cortisol secretion by adrenocorti- cal tumors (chapter 4. The there is very severe hypercortisolism and highly elevated castrated male cat develops spines on the penis (fig 8. 4 In this species. and the presence of metastases can be tary ACTH-producing microadenoma was considered. various adrenocortical tuitary tumors.3. but obtained by ultrasonography.3. Glucocorticoid excess 131 Food-dependent hypercortisolism. Esterified microcrystalline suspensions are slowly absorbed from the subcutaneous or in- tramuscular injection site. Ingestion of a meal resulted in signifi- cant increases in plasma cortisol concentration and the UCCR. In addition.2. 4. which increases tissue exposure.4). Binding to a receptor protein (chapter 4. 4. Cortisone and prednisone can be used for systemic. The duration of action of a glucocorticoid is not solely deter- mined by its presence in the circulation. Cortisone and prednisone are 11-ketocom- pounds (fig.55: liver (fig. obviating the need for biotransformation. The increased glucocorticoid ac- tivity is due to increased affinity for the GR and delayed plasma clearance of the hormone. the pharmaceutical formulation of in- jectable preparations plays a role.267 Hydroxylation at C-11 is required for glucocorticoid activity (figs. 4.6 Iatrogenic hypercorticism and iatrogenic secondary hypoadrenocorticism Alterations in the chemical structure of glucocorticoids have resulted in synthetic compounds with greater glucocorticoid activity than the natural hormones cortisol. and corticosterone (fig. not topical.1. for glucocorticoid activity. cortisone. The dog was treated suc- cessfully with trilostane.265 In this dog with clinical manifestations of hypercortisolism and slightly ele- vated UCCRs. The chemical modifications intro- duced to enhance glucocorticoid activity are shown in green. respectively.266 administration of 4 3 µg octreotide per kg body weight completely prevented the meal-induced hypercortisolemia. All glucocorti- coid preparations marketed for topical use are 11b-hydro- xylcompounds. but diagnostic imaging revealed no adrenocortical tumor. was re- ported recently in a six-year-old vizsla. Consistent with the diagnostic criteria for food-de- pendent hypercortisolism in humans. basal and CRH-stimulated plasma ACTH concentrations were low. presumably due to adre- nocortical expression of functional GIP receptors. This conversion by 11b-HSD1 occurs predominantly in the Figure 4. 4. therapy. administered two hours before meals. disease. By this modification of the phenotypical expression of the genetic information the glucocorticoid may continue to exert an effect after it has disappeared from the circulation.5) produces a glucocorticoid-receptor complex that modifies the process of DNA transcription.3.262.55). Many of these synthetic glucocor- ticoids have negligible mineralocorticoid effects and thus do not result in sodium retention and hypokalemia (table 4.13) and is only moderately impaired by liver Structures of commonly used glucocorticoids.56) and therefore must be converted to cortisol and prednisolone. 4.267 . thereby altering – via RNA translation – the rate of synthesis of specific proteins. Thus topically applied prednisolone is effective but topically applied prednisone is not. 4.3). 132 Adrenals Figure 4.56: The anti-inflammatory action of glucocorticoids. Corti- sol binds to the cytoplasmic glucocorticoid receptor 4 (GR). Conformational changes in the receptor-ligand complex result in dissociation from heat shock proteins (HSPs) and migration to the nucleus. There it binds to specific glucocorticoid-response elements in associ- ation with the activator protein-1 (AP-1), comprising c-fos and c-jun. The anti-inflammatory effects of gluco- corticoids are mediated via (1) Induction of the in- hibitory protein 1kB, which binds and inactivates the transcription factor NF-kB, (2) binding of the GR-glu- cocorticoid complex to NF-kB, thus preventing initi- ation of an inflammatory process, and (3) competition of both GR and NF-kB for the limited availability of coactivators. (Modified from Stewart, 2008).54 4.3.6.1 Glucocorticoids as pharmacological agents The side effects of glucocorticoid therapy are not confined to Glucocorticoids are used for substitution in adrenocortical in- the manifestations of glucocorticoid excess, which may in- sufficiency (chapter 4.2.1) and for the diagnosis and differen- clude diabetes mellitus.268,269 Suppression of the immune tial diagnosis of hypercortisolism (chapter 4.3). However, this response may precipitate fatal infections.270 In addition, there constitutes only a small part of their application in practice, is increased risk of complications such as pancreatitis, and gas- where they are widely used for the treatment of various aller- trointestinal hemorrhage, ulceration, and perforation.271 gic, autoimmune, inflammatory, and neoplastic diseases. There is no simple mechanism of action underlying the many 4.3.6.3 Iatrogenic secondary hypoadrenocorticism effects of glucocorticoids on inflammatory and immune Both systemic and topically applied corticosteroids cause responses. Many hundred glucocorticoid-responsive genes prompt and sustained suppression of the hypothalamic-pitu- have been identified (chapter 4.1.5). Two particular transcrip- itary-adrenocortical axis (chapter 4.2.2).272–274 Depending tion factors seem to be important in mediating anti-inflam- on the dose, the continuity, the duration, and the preparation matory effects of glucocorticoids. Activator protein-1 (AP-1) or formulation, this suppression may continue for weeks is a proinflammatory transcription factor induced by cyto- or months after cessation of corticosteroid administration kines. The GR-ligand complex can prevent interaction with (fig. 4.58).275 AP-1, thereby mediating inhibitory effects of glucocorti- coids. Similarly, functional antagonism exists between the GR An animal may appear to be healthy during corticosteroid and nuclear factor kappa B (NF-kB). NF-kB is a widely ex- therapy, but nevertheless it lacks the ability to increase cortisol pressed transcription factor that activates a series of genes in- secretion sufficiently in response to stress. If stressed, it may volved in lymphocyte development, inflammatory response, develop signs of acute adrenocortical insufficiency, such as host defense, and apoptosis.54 hypotension, weakness, anorexia, and vomiting. It may not recover from surgery without additional glucocorticoid supplementation. Similar long-lasting suppression of the hy- 4.3.6.2 Iatrogenic hypercorticism pothalamic-pituitary-adrenocortical system occurs in dogs As in spontaneous hypercortisolism, the development of signs treated with progestins.276 Also in cats, where progestins are and symptoms of glucocorticoid excess depends on the sever- used in the treatment of various dermatologic and behavioral ity and duration of the exposure. The effects vary among in- disorders, the affinity of the GR for these compounds may dividual animals and initially seem to be less pronounced in cause a similar suppression of the pituitary-adrenocortical sys- cats. Within days after the start of glucocorticoid adminis- tem.277 tration polyuria /polydipsia and polyphagia develop. After several weeks of glucocorticoid therapy, the classic physical During prolonged glucocorticoid treatment, tests of pitu- changes such as centripetal obesity, muscular weakness, and itary-adrenocortical reserve function (chapters 4.2.2, 1.2.4.1, skin atrophy develop (fig. 4.57). fig. 4.58) are not needed. A test is indicated when the gluco- Glucocorticoid excess 133 4 A B Figure 4.57: (A) A three-year-old female mongrel dog that was treated for six months with injections of 9F,16-methylprednisolone and 6-methylprednisolone for pruritus due to an underestimated flea infestation. Note the obesity and the thin coat. (B) With antiparasitic treatment and omission of the corticosteroids the dog regained its normal shape and a thick hair coat. corticoid administration has been reduced to replacement le- vels or stopped, and the recovery of the integrity of the system is questionable. This applies especially to animals that need an increase in the corticosteroid dose to cover stressful events such as general anesthesia and surgery. When secondary hypo- adrenocorticism is to be expected or has been demonstrated and the animal is at risk, a glucocorticoid should be given at four times the maintenance dose (chapter 4.2.1), i.e., 1 mg cortisone/kg body weight four times daily or an equivalent dose of another glucocorticoid (table 4.4). Table 4.4: Actions of commonly used glucocorticoid preparations Table 4.4: (the glucocorticoid potency of cortisol is set at 1 for Table 4.4: comparison) Name and duration Glucocorticoid Mineralocorticoid of action potency activity Short acting Cortisol (hydrocortisone) 1 Yes Cortisone 0.8 Yes Prednisone 4 No Prednisolone 4 No Intermediate acting Figure 4.58: Methylprednisolone 5 No ACTH-stimulation test results in a reference population of dogs (blue area) and in Triamcinolone 5 No the dog in fig. 4.57 at first admission (red line) and three weeks after stopping the prolonged glucocorticoid treatment (blue line). Long acting Bethamethasone 25 No Dexamethasone 30 No 134 Adrenals 48 h. The aim is to retain the therapeutic benefits while mi- nimizing the adverse effects. Thus it is an attempt to prevent the development of Cushing’s syndrome and secondary hypo- adrenocorticism. Although it is not known whether alter- nate-day administration definitely yields a better overall risk:benefit ratio than a once-daily dose, it is common prac- tice to use the alternate-day schedule when glucocorticoids are administered over a long period. 4 To induce remission of a fulminant autoimmune or immune- mediated inflammatory process, treatment is begun by ad- ministering the glucocorticoid once daily. When there are signs of improvement an attempt is made to reduce the dose. The following schedule is an example for oral administration of prednisolone: 쎱 Days 1–3: 2–4 mg/kg once daily. 쎱 Days 4–6: 1–2 mg/kg once daily. Figure 4.59: 쎱 Days 7–14: 1–2 mg/kg on alternate days. Longitudinal section of the left adrenal of a ten-year-old castrated male German shorthaired pointer with primary hyperaldosteronism. At the cranial end (left) there is an aldosteronoma about 7 mm in diameter.279 The dose is lowered further at weekly intervals if there are no exacerbations of the disease. Usually the final dose cannot be lower than about 0.5 mg/kg every 48 h. In some diseases it may be necessary to administer a higher dose or even to re- sume full daily doses temporarily. 4.3.6.4 Withdrawal from glucocorticoids Discontinuance of glucocorticoid therapy may not only result in exacerbation of the disease that is being treated but also in 4.4 Mineralocorticoid excess symptoms and signs of the corticosteroid withdrawal syn- drome. As mentioned above, the patient may even develop Reducing the effective arterial blood volume activates the secondary adrenocortical insufficiency. renin-angiotensin system (RAS), which in turn persistently stimulates aldosterone synthesis. Conditions in which this oc- The cardinal features of glucocorticoid withdrawal are ano- curs include chronic edematous diseases such as heart failure, rexia, lethargy, and weight loss. The lethargy may be the re- and hypoproteinemia due to hepatic cirrhosis, the nephrotic sult of what humans experience following glucocorticoid syndrome, and protein-loosing enteropathy. Despite the high withdrawal: myalgia, arthralgia, headache, and postural hypo- levels of renin and angiotensin and the secondarily increased tension. These symptoms occur in patients in whom the dose plasma aldosterone concentration, fluid volume remains re- has been tapered to a normal glucocorticoid maintenance duced and blood pressure is low-normal. The effect of aldos- dose and are due to the sudden cessation of the glucocorti- terone can be blocked by administering spironolactone, a coid-induced inhibition of prostaglandin production. Many nonmineralocorticoid steroid that competes directly with al- of the features of the corticosteroid-withdrawal syndrome can dosterone for binding to the mineralocorticoid receptor. be produced by prostaglandins.267 This pathophysiological mechanism that is activated in re- The dose should therefore be reduced gradually, as in the sponse to hypovolemia is called secondary hyperaldoste- transition from spontaneous hypercortisolism to normocorti- ronism; i.e., high-renin hyperaldosteronism. In primary cism (chapter 4.3.2), in which initially at least twice the mineralcorticoid excess there is low-renin hyperaldosteronism maintenance dose is given. The recovery of pituitary-adreno- due to autonomous hypersecretion of aldosterone by tumor- cortical function is not promoted by administering ACTH. It ous or nontumorous adrenals. is not the ACTH secretion but rather the hypothalamic hy- pophysiotropic stimulation that recovers last and administer- ing ACTH will only retard this recovery and that of the pitu- itary corticotroph cells.278 4.4.1 Primary mineralocorticoid excess In dogs and cats excessive activation of mineralocorticoid re- 4.3.6.5 Alternate-day glucocorticoid therapy ceptors can be the result of hypersecretion of aldosterone by In alternate-day glucocorticoid therapy a short-acting gluco- an adrenocortical tumor. In cats hyperaldosteronism due to corticoid (prednisone or prednisolone) is given once every nontumorous adrenocortical hypersecretion has also been re- Mineralocorticoid excess 135 4 Figure 4.60: Histological sections of adrenals stained with neuron- specific enolase (NSE). In the healthy cat (left), the staining of the cortex (C) is confined to the zona glomerulosa with only slight staining of the outer part of the zona fasciculata. In the cat with primary hyperal- dosteronism (right), the cortex consists of multiple hy- perplastic nodules, staining positively for NSE. Staining of the adrenal medulla (M) is similar in the two sec- tions. Bar = 200 µm. ported. In addition, adrenocortical tumors secreting the Clinical manifestations mineralocorticoid deoxycorticosterone (DOC) have been re- As noted in chapter 4.1.6, mineralocorticoid excess causes ported in dogs and cats. two abnormalities: (1) increased sodium retention, and (2) in- creased potassium excretion. The initial sodium retention is There have been two case reports of primary hyperaldoste- followed by natriuresis, so sodium balance is reestablished and ronism in dogs, one with a small aldosteronoma (fig. 4.59) edema does not develop. This is called the »escape phenom- and the other with a large adrenocortical carcinoma and he- enon«, meaning the escape by the renal tubules from the so- patic metastases.279,280 The occurance of primary hyperaldo- dium-retaining action of aldosterone. Natriuretic peptides steronism has also been mentioned for in three other dogs, (chapter 10.2) play an important role in this phenom- one with an adenoma and two with adenocarcinomas.281 enon.294,295 Symptoms and signs that might be compatible with primary hyperaldosteronism were attributed to bilateral adrenocortical Nevertheless, mineralocorticoid excess tends to be associated hyperplasia in another dog.282 Plasma aldosterone and renin with extracellular fluid expansion, hypertension, and in- are suppressed by elevated levels of DOC, as observed in a creased cardiac output.296 This is probably responsible in dog with hypersecretion of DOC by an adrenocortical car- part for the main presenting symptoms of hyperaldosteronism cinoma.283 Dogs with physical and biochemical features of in dogs: polyuria and polydipsia. In canine hyperaldosteron- both glucocorticoid and mineralocorticoid excess have in all ism the release of vasopressin following an osmotic stimulus is reported cases been found to have adrenocortical carci- delayed, and there is resistance to the action of vasopressin noma.284–286 (figs. 2.34, 2.36), similar to that in hypercortisolism (chap- ters 2.3.2, 4.3). Primary hyperaldosteronism seems to be less rare in cats than in dogs. About 20 cases have been reported in which the dis- The progressive depletion of potassium and the development ease was due to usually unilateral adrenocortical tumors of of hypokalemia affect several organ systems, but become par- varying degrees of malignancy, ranging from well-capsulated ticularly manifest in the neuromuscular system by affecting adenomas to carcinomas with growth into the caudal vena the polarization of nerve and muscle membranes. Muscle cava and distant metastasis.287–291 Not only plasma aldosterone weakness is likely to occur at plasma potassium concentrations may be elevated but also some of the precursors, such as pro- around 2.5 mmol/l, and areflexic paralysis may develop with gesterone.292 In addition to cases due to adrenocortical tumor, more severe hypokalemia. there has been a report of eleven cats with »idiopathic« pri- mary hyperaldosteronism caused by bilateral adrenocortical As in dogs, mineralocorticoid excess in cats occurs in middle hyperplasia (fig. 4.60).293 and old age. The main presenting symptoms are changes in neuromuscular function. Affected cats have episodic weakness 136 Adrenals 4 Figure 4.61: The main routes for development of hypokalemia. Figure 4.62: Changes in plasma renin activity (PRA) and plasma aldosterone concentration (PAC) that can occur in hypokalemia developed via the renal route. The congenital con- ditions described in humans but not (yet) in dogs or cats are marked with an asterisk. Mineralocorticoid excess 137 and a characteristic ventroflexion of the neck, in some cases leading to flaccid paresis with hyporeflexia and muscle hypo- tonia. In other cats the presenting physical features are domi- nated by signs of arterial hypertension, i.e., loss of vision due to retinal detachment and retinal and intravitreal hemor- rhages. The most consistent routine laboratory finding is hypokale- mia. Mineralocorticoid excess also favors increased acid se- cretion by a variety of mechanisms, leading to (usually mild) 4 hypokalemic metabolic alkalosis.297 In addition there may be hypophosphatemia and hypomagnesemia, as well as elevation of plasma alkaline phosphatase (in dogs) and creatine kinase. Particularly in cats idiopathic hyperaldosteronism is often as- sociated with slowly progressing renal insufficiency, probably due to aldosterone-induced arteriolar and glomerular scler- osis, tubular atrophy, and interstitial fibrosis (see also chap- ter 4.1.6). Even in end-stage renal failure, there is a tendency to hypophosphatemia rather than to hyperphosphatemia.293 Differential diagnosis Figure 4.63: For polyuria in dogs there is the well-known list of differen- Plasma aldosterone concentration (PAC), plasma renin activity (PRA), and the tial diagnoses given in chapter 2.3.3.4 (for the algorithm see PAC:PRA ratio (ARR) in eleven cats with nontumorous (idiopathic) primary hy- peraldosteronism. Grey areas represent reference values in healthy cats.293 chapter 14.2). The main routes for development of hypokale- mia are given in fig. 4.61. The possibilities for the renal route are specified in more detail in fig. 4.62. Diagnosis In primary mineralocorticoid excess, the plasma concen- Control populations of both dogs and cats have been studied. tration of aldosterone (or DOC) is characteristically high and In dogs the ARR ranged from 0.1 to 1.5, and both PAC and plasma renin activity (PRA) is immeasurably low. In hyperal- the ARR were slightly lower in spayed than in intact female dosteronism due to adrenocortical tumor plasma aldosterone dogs. In cats the ARR was 0.3–3.8, being somewhat higher concentration (PAC) is usually highly elevated. In cats with in neutered than in intact cats. The ARR was higher in cats idiopathic hyperaldosteronism PAC is usually only slightly 욷 5 years of age than in younger cats. Blood samples were elevated or within the upper limit of the reference range. As collected with the animals in various positions and sampling hypokalemia is a predominant factor in lowering PAC,298 in was associated with a wide variety of stress responses. Never- the presence of hypokalemia moderately elevated aldosterone theless, the reference ranges were similar to the relatively nar- values can be regarded as inappropriately high. The PRA row range obtained in humans under standardized conditions. must also be taken into account. The combination of a high- PRA and PAC are much higher in blood collected from hu- normal or elevated PAC and low PRA indicates persistent al- mans in the upright rather than in the supine position. This dosterone synthesis in the presence of little or no stimulation physiological response to rapid pooling of blood in the lower by the renin-angiotensin system. In humans the PAC:PRA extremities and to shifts in plasma fluid in surrounding tissues ratio (ARR) is considered to be a very useful aid in diagnos- is a less important factor in small quadrupeds such as ing primary hyperaldosteronism. This also seems to be true cats.301,302 for cats with idiopathic hyperaldosteronism (fig. 4.63).293 An alternative diagnostic approach may be measurement of The ARR is elevated in 10–20 % of human patients with ar- the urinary aldosterone:creatinine ratio (UACR). Cats ex- terial hypertension and most of these have excess aldosterone crete smaller quantities of aldosterone and its 18-glucuroni- production from both adrenal cortices.299 The diagnostic dated metabolite in urine than do humans or dogs, but never- value of the ARR is principally determined by the sensitivity theless the UACR can be determined.303 This would allow of the renin assay and interpretation should rest upon com- the development of a dynamic test, such as employing a sup- parison with an appropriate control population. The ARR is pressive agent that would reduce the UACR in healthy indi- currently regarded as the most reliable means of detecting pri- viduals but have little or no effect in those with primary hy- mary hyperaldosteronism, but the measurements should be peraldosteronism. In 42 healthy cats the upper limit for the repeated if the initial result is inconclusive or difficult to in- UACR was 46.5 × 10–9. The administration of sodium chlor- terpret because of suboptimal sampling conditions.300 ide did not significantly lower the UACR but administration of fludrocortisone (0.05 mg/kg body weight) reduced it by 138 Adrenals 4 Figure 4.64: Figure 4.65: Serial measurements of urine osmolality (Uosm, see also chapter 12.2.1) in a ten- Biosynthesis of catecholamines. The conversion of tyrosine to DOPA (dihydroxy- year-old castrated male German shorthaired pointer with primary hyperaldoste- phenylalanine) by tyrosine hydroxylase (TH) is the rate-limiting step. Aromatic ronism (see also fig. 4.59) during the administration of three different doses of the L-amino acid decarboxylase (AADC) converts DOPA to dopamine. Dopamine is mineralocorticoid-receptor antagonist spironolactone: 25 mg thrice daily (쏍), hydroxylated to norepinephrine by dopamine b-hydroxylase (DBH). The enzyme 50 mg twice daily (앬), and 50 mg thrice daily (앪). The dose was increased at phenylethanolamine N-methyl transferase (PNMT) catalyzes the conversion of monthly intervals. The line at the top (쑿) depicts Uosm values after left-sided ad- norepinephrine to epinephrine. Glucocorticoids enhance the expression of the renalectomy. gene encoding PMNT. 44–97 % (median 78 %). In a cat with an aldosterone-produc- of hypercortisolemia due to adrenocortical tumor (chap- ing adrenocortical carcinoma the UACR was within the ref- ter 4.3.2), temporary fludrocortisone therapy could also be erence range and was not lowered by fludrocortisone admin- considered. However, in the reported cases such postsurgical istration.304 This test may prove to be a practical noninvasive measures have not been necessary and their omission does not diagnostic tool, but further evaluation is required, particularly seem to have had deleterious effects. with regard to its discriminatory power in diagnosing idio- pathic hyperaldosteronism. If surgery is not possible or if the adrenocortical disease is bi- lateral, medical treatment is possible with the mineralocorti- Subtype classification – differentiating between tumorous and coid-receptor antagonist spironolactone and oral supplemen- nontumorous mineralocorticoid excess – requires diagnostic tation with potassium gluconate. The initial doses are 2 mg imaging. Ultrasonography and computed tomography have spironolactone/kg and 0.5 mmol potassium gluconate/kg, been used in dogs and cats to identify and characterize adrenal twice daily. Persistent arterial hypertension can be treated tumors.279,305 As in humans the findings are not always im- with the calcium blocker amlodipine (1–2 mg/kg). In cases of mediately conclusive.306 The visualization of a small aldoste- adrenocortical tumor medical treatment may lead to reso- ronoma may pose problems while nodular hyperplasia might lution of symptoms and signs such as the myopathy in cats and be interpreted as microadenoma.279,293 the polyuria in dogs, but complete normalization may not be achieved (fig. 4.64).279,291 Particularly plasma potassium tends Treatment to remain below the reference range, despite increasing doses Unilateral adrenalectomy is the treatment of choice for con- of both spironolactone and potassium. Doses of spironolac- firmed unilateral primary hyperaldosteronism. There have tone 쏜 4 mg/kg may cause anorexia, diarrhea, and vomiting. been several reports of successful surgical treatment,279,288,291 These side effects may be due to interference by spironolac- including the successful excision of an adrenocortical tumor tone with aldosterone action on transepithelial electrolyte and the associated caval thrombus.307 Preoperatively and peri- transport in the distal colon.308 operatively hypokalemia should be controlled as well as pos- sible, by oral and intravenous supplementation. Postoperative Experience is very limited, but medical treatment appears to intravenous fluids can be confined to 0.9 % sodium chloride be preferable in cats with hyperaldosteronism due to bilateral solution without potassium chloride, unless plasma potassium adrenocortical hyperplasia. The hyperaldosteronism is usually remains below 3.0 mmol/l. In principle during the first few somewhat milder than in cases due to tumor and normokale- weeks after surgery a generous dietary intake of sodium can mia may be maintained for a long period with spironolactone be provided to avoid hyperkalemia that could develop from alone or together with low doses of potassium.293 hypoaldosteronism due to chronic contralateral adrenocorti- cal suppression. Analogous to the postoperative management together with various other substan.310 All of the epinephrine in the circulation is derived subgroups (a1. hypovolemia. surgery. syn. lary catecholamine synthesis is not essential for survival. however.311 Catecholamines include epinephrine (adrenaline). sympathetic nervous system.291. and categories: a. They may also be inactivated in the liver by lation (fig.310 Most of the blood supply of the adrenal medulla is via a portal Figure 4. in viscera. metanephrine. 4. and dopamine. The effects of catecholamines de- . conjugation with sulfate or glucuronide. and within sympathetic gan- glia. which comprises approximately one- fourth of the adrenal mass. cise.4. whereas circulating norepinephrine same affinity for norepinephrine and epinephrine. Catecholamines are stored within the chromaffin cells in Catecholamines bind to receptors in the plasma membrane.e.1). The cells of the adrenal me- dulla. for this treatment will not abolish the 4 mineralocorticoid excess as definitely as surgery may do.5 Adrenal medulla 4. affinity for epinephrine. and hypoglycemia. which are further divided into CRH. Two enzyme systems are involved: COMT (cate- high concentrations of glucocorticoids. Secretion of catecholamines is part of the activation of the nephrine (noradrenaline). see also chapter 10).and b-receptors.66: system from the adrenal cortex. The prognosis may not be as favorable in cats with idiopathic hyperaldosteronism treated with spironolactone. The a-receptors have about the from the adrenal medulla. They are innervated by preganglionic fibers of the sympathetic nervous system that induce the release of catecholamines into the bloodstream. i. Examples for stimuli are exer- ticosteroid production by the adrenal cortex.309. They are metabolized to the inactive cholamines fill the need.66). can be re- garded as modified postganglionic sympathetic neurons lack- ing axons.293 Successful removal of the tumor will probably prevent further progression of al- dosterone-induced arteriolar sclerosis and interstitial fibrosis in the kidneys (chapter 4. 4. the prognosis can be excel- lent. Adrenergic receptors are of two broad apophysin. enkephalins. enzyme phenylethanolamine N-methyl transferase (PNMT) that is responsible for the conversion of norepinephrine to epi- nephrine (fig. Catecholamines are synthesized compounds normetanephrine. With these features the adrenal medulla be.5. b2. Some extra-adrenal chromaffin tissue is also present adjacent to the aorta.65). urine (fig. In contrast to cor. b1. somatostatin. place via G-proteins.1 Introduction The adrenal medulla.65). and vanillyl- from tyrosine by a process of hydroxylation and decarboxy. b3). perceived danger. ACTH. Some of the chromaffin cells.310. mandelic acid. from which signal transduction to intracellular sites takes ces such as chromogranin-A. a2. These induce the chol-O-methyl transferase) and MAO (monoamine oxidase). very short (1–3 min). re- ceive direct arterial blood supply bypassing the adrenal cortex. so that the medulla receives Metabolism of catecholamines. In both forms the disease may be associated with renal insufficiency. called pheochromocytes or chromaffin cells. adrenal medul. Adrenal medulla 139 Prognosis After complete removal of a unilateral nonmetastasized min- eralocorticoid-producing tumor. These cells contain predominantly norepinephrine. hypotension. norepi. 4. cursor uptake decarboxylase system. Excretion is via the longs to a system previously called APUD system (amine pre. develops during fetal life as part of the autonomic nervous system. without any medication. cytoplasmic vesicles. vasoactive intestinal polypeptide. whereas is mostly from postganglionic sympathetic neurons and only b-receptors (in particular b2-receptors) have a much higher to a small extent from the adrenal medulla. The plasma half-life of catecholamines is after bilateral adrenalectomy extra-adrenally produced cate.. 4. in the carotid bodies. ascites. hyper- paragangliomas have thus far been described in only a few case tension might be detected in a higher percentage of patients reports. arrhythmias. bone.5).314 Inherited multiple endocrine (fig. pend on the density of the different subtypes of receptors pacing. due to the difficulties not pathognomonic for pheochromocytoma. no pattern of echo- endocrine tumors and as such be part of a multiple endocrine genicity or architecture is specific for pheochromocytoma neoplasia syndrome. they should be considered potentially malignant tumors. In most dogs the pheochromocytoma is of suf- are both adrenal glands affected. azotemia.148. lung. scess. Tumor size varies greatly. and all veins Clinical manifestations 4 Bronchial muscles b2 Relaxation Pheochromocytomas occur most often in older dogs. or the urinalysis. 4. There is Gastrointestinal tract b2 Decrease in motility no apparent sex or breed predilection. hematoma. in diagnosing pheochromocytoma. 316–321 may be dilated while others remain unchanged.. Additionally. and hypoalbuminemia. Hormone secretion is sporadic and unpredict- glucagon secretion able and the clinical presentation is highly variable. ACTH-producing pituitary tumors (fig.2 Pheochromocytoma nosis of pheochromocytoma is challenging. However. as the blood pressure increases the heart rate is slowed and cardiac output tends to Large tumors may cause abdominal distension. collapse. Pheochromocytomas may ficient size to be visualized by ultrasonography. panting.149. infrequently. only occasionally and 쏜 10 cm. nephrine and norepinephrine (table 4.322. chemistry. coronary compression of vessels by large tumors also occurs. In up to Organ / tissue Receptor type Effect 50 % of cases the tumor is locally invasive and extends into Cardiovascular system b1 Increase in heart rate. vomiting. but even so it is and even less frequent in cats. liver. and decrease. and metastasis.314. ocu- lar hemorrhage. Symptoms Liver b2 Increase in glycogenolysis are often episodic and may only recur after weeks or months and gluconeogenesis or may appear several times per day. variable. muscle tremors. Eye a1 Mydriasis 쎱 Related to the cardiorespiratory system and /or to hyper- tension: tachypnea. Pheochro- increase in contractility mocytomas may metastasize to lymph nodes. 140 Adrenals Table 4. diag- 4. spleen.317 arteries. tachycardia.5.312 Diagnosis Since clinical manifestations are nonspecific.310.67). weight loss. pancreas. or other surrounding tissue and vessels. blood bio- Pheochromocytomas are catecholamine-producing neuro. Ultraso- coexist with glucocorticoid-producing adrenocortical tu. Due to its episodic nature.313 Most tumors are derived from the adrenal medulla. neutrophi- endocrine tumors arising from either chromaffin cells of the lia. quite a few may be over- looked and therefore the prevalence may be higher than gen.316. They may be dramatic Adipose tissue b2 Increase in lipolysis and life-threatening or they may be unapparent.309.323 The differential diagnoses for an adrenal mass neoplasia syndromes (MENs) known to occur in humans315 include nonfunctional lesions such as myelolipoma. nography also enables identification of tumor invasion of mors. Symptoms and signs Pancreatic islets a2 Decrease in insulin and result from secretion of excessive amounts of catecholamines. acute blindness. on specific organs and on the relative concentrations of epi. . increased liver enzymes. so that one vascular bed neal hemorrhage due to tumor rupture. There are no consistent abnormalities in routine hematology. it is detected in only approximately 50 % of dogs by gliomas. a2 Vasoconstriction kidney. However.314. gingival-. These effects are abdominal pain. Extraluminal b2 Vasodilatation in skeletal muscle arterioles. from the space-occupying or invasive nature b2 Increase in insulin and of the tumor. cyst. pale mucous membranes. 쎱 Miscellaneous: polyuria /polydipsia. disease. detrusor The symptoms and signs can be categorized as: 쎱 Nonspecific: anorexia. ab- have thus far not been identified in dogs or cats. and hypersecretory tumors. heart. glucagon secretion or.g. nasal-. There may be anemia. adrenal medulla or extra-adrenal paraganglia. the time of examination. lethargy. the lumen of adjacent vessels and other tissues. anxiety.68). Urinary bladder a2 Increase in sphincter tone b2 Relaxation of M. The latter are Although arterial hypertension is one of the hallmarks of the referred to as extra-adrenal pheochromocytoma or paragan.5: Catecholamine receptor types and subtypes Although pheochromocytomas tend to grow slowly. e. Most tumors are unilateral. diarrhea. or rarely intra-abdominal or retroperito- plays an important integrative role. 쎱 Related to the neuromuscular system: weakness. and easily explained by disturbances of other organ systems. modulated by reflex mechanisms. Pheochromocytoma is considered to be rare in dogs by repetitive blood pressure measurements. from a diameter of a few millimeters erally assumed. seizures. 4. the central nervous system (CNS) hind-limb edema. and CNS. specificity. In a preliminary study the urinary concentrations of maceuticals have similarities to norepinephrine and accumu. The risks and disad. 4. The largest diameter of the mass was 5.69). This higher sensitivity may be explained by the fact that although CT and MRI are more sensitive than ultrasonography in pheochromocytomas produce catecholamines they do not al- identifying adrenal masses and characterizing the extent ways release them but rather their metabolites. in which most tumors contain less epinephrine than the normal medulla. in dogs with pheochro- weighed against the potential benefits. On rare occasions both diseases occur simultaneously. information on the diagnostic value prising in light of the fact that epinephrine (which is meta- of fine-needle aspiration (FNA) is scarce.e. Other advanced diag. nondiagnostic metabolized to normetanephrine) is the main secretory prod- samples.to anechoic areas. norepinephrine.328 Stress associated with the hospital . Andreas Pospischil. plastic and there is a pheochromocytoma in the adrenal medulla. normetanephrine. sensitivity than measurements of 24 h urinary metanephrines. The adrenal cortex is moderately hyper. Dr. pheochromocytoma.) producing cortisol or a cortisol precursor. all related to creatinine concentration. they do not provide a definitive controversy concerning the preferability of testing blood or diagnosis.67: Figure 4.324. University of Zurich. nostic imaging procedures such as scintigraphy with 123I-la. pheochromocy. Anesthesia and contrast media may provoke a urine. However. misinterpretation) of FNA have to be carefully uct of the adrenal medulla.4 cm. but their specificity may be lower. measurements of plasma or 24 h urinary catecholamines. but were determined in healthy dogs and in dogs with pheochro- they have only been described in a small number of dogs and mocytoma. Institute of Pathology. be more specific for the diagnosis of pheochromocytoma. i. The normetanephrine:creatinine ratio had the no data on sensitivity. and vanillylmandelic acid. The work-up of human patients with a suspected pheochro- toma.. and predictive values are highest discriminating power (fig. late in the adrenal medulla. are by far the most common hypersecretory adrenal tumors measurement of urinary catecholamines and their metabolites and the clinical manifestations may be similar to those of metanephrine. begun. Plasma metanephrine measurements may have a higher hypertensive crisis and arrhythmias. epinephrine. plasma and 24 h urine are reported to be more sensitive than further complicating the work-up. Hence it may be necessary to rule out Measurement of free metanephrines in plasma and urine is a hypercortisolism due to an adrenocortical tumor in some more recent test. Vetsuisse Faculty.325 Similarly. normetanephrine. or even none. arrhythmias. However. The parenchyma is irregular due hypercortisolism and pheochromocytoma. dopamine. mocytoma the situation may be similar to that in humans. Adrenal medulla 141 4 Figure 4. There is some of local invasion.325.68: Histological section of an adrenal gland from a dog with both pituitary-dependent Ultrasonographic image of a pheochromocytoma. (Courtesy of Prof.326 beled metaiodobenzylguanidine (123I-MIBG) and positron emission tomography with p-[18F]fluorobenzylguanidine Evaluation of these variables in veterinary medicine has just ([18F]MFBG) take advantage of the fact that these radiophar. and aldosteronoma. In dogs cortisol-producing tumors mocytoma routinely includes biochemical testing. These techniques may therefore and metanephrine. to various hypo. Measurements of free metanephrines in cases. bolized to metanephrine) and not norepinephrine (which is vantages (hypertensive crisis.327 This may be sur- available. acidification. No studies of 0. EDQVIST 4. by DNA microarray analysis.5 mg/kg is reached. MISEK DE. 142 Adrenals Figure 4. TOUTAIN PL.329–331 tial hypertensive crisis and arrhythmias requiring professional References 1. formed as soon as possible. . Close collaboration with the laboratory is necessary for provi. in the hospital following the physical examination. the surgery can be extremely de. Res Vet Sci 1992. avoidance of light. hypovolemia) and to minimize perioperative complications. free cortisol in plasma in the dog by ultrafiltration /dialysis. ALJUNDI RT. LIZYNESS M. advanced stage disease. SAMANS B.69: 4 Urinary normetanephrine:creatinine ratios in healthy dogs and in six dogs with pheochromocytoma. PETERSON ME. 8. TAYLOR MJG. GIORDANO TJ. and cooled or frozen storage. Am J Path 2003. and day –7.314 The aim is to reverse and urine processing require certain conditions. Endocrinol 1996. Treatment hypotension. The patients carry a high anesthetic risk due to poten.52:682–686. Urine collection should therefore take place at started immediately after diagnosis and given for at least one home after adaptation to the procedure. Bio. cortisol concentrations in dogs with hyperadrenocorticism. hyperadrenocorticoid and healthy dogs. including the effects of excessive adrenergic stimulation (hypertension. RAMAS. Eur J Endocrinol 2006. DIEHL SM. rence. KEMPNÁ P. FACKLER L.25 mg/kg BID should be gradually increased every few days plasma metanephrine measurements in dogs have been until signs of hypotension or adverse drug reactions such as published and it may well be that they are less suitable in dogs vomiting occur or the maximal dose of 2. hypertension. SMITH AL. FLÜCK CE. THOMAS DG. mortality rate compared with untreated dogs. BARTSCH DK. 363–366. 2.162:521–531. 6. at home seven days prior to and one and seven days after the hospital visit.13:35–45. Domest Anim Endocrinol 1993. Phenoxybenzamine is used most often. 5. Potential complications after surgery include hemorrhage. * Indicates significant difference. Domest Anim arrays of gene expression patterns of human adrenocorticoal tu. Am J Distinct transcriptional profiles of adrenocortical tumors uncovered Vet Res 1991. mors.22:77–93. ROTHUIZEN J. and day 7. viving this initial period may live for several years. BAMBERG-THALÉN B. even with geon. THOMPSON NW. Adrenal gland development and defects. An a-adrenergic blocker should be excretion. 3. day 1. In the healthy dogs urine was collected at different times: day 0. MEYER HP. In the dogs with pheochromocytoma (Pheo) urine was collected once. Plasma free GAUGER PG.154:587–598. ZIELKE A. Determination of the percentage of Best Pract Res Clin Endocrinol Metab 2008. ALVINERIE M. SLATER PE. visit and the urine sampling increases urine catecholamine perioperative monitoring. 7.52: chim Biophys Acta 1968. HANASH S. If the tumor has invaded adjacent Dogs pretreated with phenoxybenzamine have a decreased vessels and other tissues.314 Animals sur- manding and should be performed by an experienced sur.327 Sample collection to two weeks before adrenalectomy. Interspecies vari- WAMY A. KUICK R. LANGER P. ations of corticosteroid-binding globulin parameters. because of the adverse influence of hospital-associated stress. pink circles = dogs of staff. SARTIN JL. Perioperative mortality is approximately 20–30 %. GAYRARD V. Analysis by cDNA micro.164:453–486. arrhythmias and tumor recur- Adrenalectomy is the treatment of choice and should be per.10:45–53. KEMPPAINEN RJ. NYBERG L. IUPAC Commission on the nomenclature of organic chemistry and LE. Blue circles = dogs of clients. SANDERS D. The initial dose of sion of reference ranges and technical assistance. Cortisol binding capacity of corticosteroid binding globulin in IUPAC-IUB Commission on on biochemical nomenclature. Evidence for episodic but not vary cortisol measurements in dogs. J Vet Intern Med 1998. BEERDA B. MOL JA. Affiliative and disciplinary VINE N.66: hormone concentrations in cats before and after physical restraint 63–67. ine with circadian variation in plasma a-MSH concentrations. JORDAN SA. COLURSO GJ. JANSEN J. Harvey JW. HADLEY ME. dogs. J Appl Anim Welfare Sci low coat colour. LENTJES 29. LE- 13. ocortin in the dog. and catecholamine ocyte-stimulating hormone secretion from the pars intermedia of measurements for a noninvasive assessment of stress responses in domestic cats. Hormonal and 2000. JANSSEN NSCRM. Chronic stress in tin 1 receptor variation in the domestic dog. concentrations during a 24-hour period in dogs. HAUBENHOFER DK. SMITH T. COX RE.31:194–199. immunological responses. and pain of open ovariohysterectomy versus a simple method of laparoscopic-assisted ovariohysterectomy in dogs.152: reactions to fear provocation in dogs.143:602–609. LINDNER DL. METALLI- 11. PETERSON ME. Methods of collection for sali. antiinflammatory and protective effects in vitro and in Sources of sampling variation in saliva cortisol in dogs. Physiological arousal a premature stop codon in the melanocyte-stimulating hormone re- for companion dogs working with their owners in animal-assisted ceptor gene (MC1R) in Labrador and Golden retrievers with yel- activities and animal-assisted therapy. TRANSQUILLI WJ. KEMPPAINEN RJ. DORR RT. chemistry. BEERDA B. Changes in salivary cortisol ed. Changes Fast resolution of hypercortisolism in dogs with portosystemic en. KEMPPAINEN RJ. VAN NOS DL. OLSON WA. complications. Psychoneuroendocrinol 2007. BARSH GS. LUGER TA. MEYER HP. and a-melanocyte-stimulating cephalopathy after surgical shunt closure. Melanocor. Am J Vet Res 1993. 17. RIJNBERK A.32:1144–1148 Raven Press.30:272–279. SCHILDER MBH. VOORHOUT G. 2nd ed. 16. ABELS C. J Endocrinol 2004. 6th 32. MIKLÓSI Á. RIJNBERK A. stile secretion of a-melanocyte-stimulating hormone (a-MSH) by the pars intermedia of the pituitary gland and the differential effects 35. Duration. BUTLER KL. MOL JA. Bruss ML. DRESCHEL NA. JACKSON IJ. J Endocrinol 1997. HOLMES NG. GREVEN SH. . Am J Vet Res 1994. Horm Behav 2008. VAN WOL- FEREN M. 25. 66:243–254. KWANT MM. Regulation of a-melan- The use of saliva cortisol. Ass 2005. DEVITT CM. sol concentrations in opposite directions. VROOM MW. eds. HYDBRING-SANDBERG E. GRUBB TL. Horm Behav 1996. VOS MH. Horm Metab Res 2003. HAILEY JJ. DE WEERTH C. inflammatory diseases. GOOSSENS MMC. STERCZER A. SCHILDER MBH. in dogs. HORVÁTH Z. J Endocrinol 1984. GRANGER DA. 22. Coat color darkening in a dog in response to behavior of human handlers during play with their dog affects corti. cortisol and thyroxine in dogs. ROTHUIZEN J. 26. SARTIN JL. KEMPPAINEN RJ. 2006. Physiological adrenocorticotrophic hormone in dogs. PETERSON ME. DAWSON BV. MAITIMU I. HRUBY VJ. The adrenal gland. WILLEMSE T. 10. sodic variation in plasma concentration of adrenocorticotropin. EVERTS RE. MOL JA. Acta Endocrinol 1991. SVARTBERG K. MOL JA. RIJNBERK A. Science 1981. SPRANG 31. In: James VHT. New York 1992:131–158. a-Melanocyte-stimulating hormone and related tripeptides: Bio- 14. ROTHUIZEN J. 18. Perioperative stress response in the dog: Effect of pre-emptive 20. MEIJ BP. The control of EGWM. in plasma cortisol. ed. SWENSON L.211: 34.11:24–30. corticotropin. BERNADINA W. KOOISTRA HS. II. DÓKA A.12:431–435. 439–448. MOL JA. Res Vet Sci vivo. Eur J Endocrinol 1996. 30. Res Vet Sci 1998. and intradermal testing. peradrenocorticism in cats. MAASER C.55: circadian activity in plasma concentrations of adrencorticotrophin. Physiol Behav 1999. WILKIE AL. Mammalian Genome dogs subjected to social and spatial restriction. LOXLEY HD. Clinical Biochemistry of Domestic Animals.29:581–602. VAN MANSFELD DM. The gene encoding proopiomelan. a potent melanotropic peptide.227:921–927. In- release by the canine pars distalis and pars intermedia. ACTH secretion. Amsterdam: Elsevier. MEYER HP.17:18–27. cortisol and thyrox- 355–362. HE L. HALMI NS.12: a-melanocyte-stimulating hormne (a-MSH). SARTIN JL. MOL JA. 24. Front Horm fluence of veterinary care on the urinary corticoid:creatinine ratio Res 1987. Domest Anim Endocrinol 1995. KOBELT AJ. NEWTON JM. 23. BÖHM M. DE VRIES HW. BRZOSKA T. Identification of 12. 163–168. urinary cortisol. KOYAMA T. KEMPPAINEN RJ. VON WALTER IW. Pul. A new device for collecting saliva for cortsiol determi. VAN SLUIJS FJ. Am J Vet Res 1999. Horm Behav 2009. Anim Genetics 2000. 28.29:85–91. and future perspectives for the treatment of immune-mediated 2003.9:165–172. administration of medetomidine. Differential regulation of peptide 36. VANIO O.75:157–161. KIRCHENGAST S. 4 HOOFF JARAM. Endocr Rev 2008.103:219–226.180: 113–121. BARNETT JL. HEMSWORTH PH. Adrenocortical function. KOOISTRA HS. 27. J Am Vet Med 21. THURMON JC. 19. VAN OOST BA. Domestic cats show epi- EPM.54:69–72.54: 107–114. 2008:605–622. BENSON GJ. Urinary excretion of glucocorticoids in the diagnosis of hy. PETERSON ME. BUCKINGHAM JC. 72–74. 15. In: Kaneko JJ.60:245–249. 33. JOHNSON PD. Vet Surg 2000.55:1593–1596. VAN VONDEREN IK. OMATA Y. SAITO A. NEFF-DAVIS C. FORKMAN B. Pituitary intermediate lobe in dog: Two cell types and high bioactive adrenocorticotropin content.125(Suppl 1):77–83.35:355–357. nation. KRIEGER DT. ROTHUIZEN J. LIOTTA AS. References 143 9. stress. HÖGLUND of dexamethasone and haloperidol on the secretion of a-MSH and K. STEPHEN JM. REUL JMHM. CONNELL JMC. 49. Aldosterone and vas- cular damage. ENGELAND WC. In: Becker KL. The new biology of aldosterone. MACKIE J. TOMLINSON JW. WOOD P. 60. DUNN AJ. Contemporary endocrinology: 44. Cytokine activation of the HPA axis. Ox- 42. eds. Feldman EC. ROTHUIZEN J. ROONEY NJ. PETERSON ME. JOHN CD. WILLIAMS GH. Textbook of Veterinary Internal Medicine. The adrenal cortex. ford University Press. Assoc 2007. Humana Press Inc. 62. 59. 11th edition. EHRHART-BORN. Science 1988. LOBETTI RG. Semin Reprod Med 45. REUSCH CE. mediated. Pretreatment clinical 50. Elsevier Saunders. In: Griffin JE. HADLOW WJ. CORRY DB. 5th edition. To- ACTH concentration-dependent drive of pulsatile cortisol secreion towa NJ 2007:111–126. Front Neuroendocrinol 2009. HAVELOCK JC. WILLIAMS GH. Dissociation of ACTH and glucocorti- coids. 48. J Clin Endocrinol Metab 1999. SCHUSTER D. New York 2004:319–348. 41. In: Carey RM. MELI ML. STEWART PM. not receptor. Melmed S. LEDGER RA. St Louis 2005:948–972. Textbook of Endocrine Physiology. Am J Pathol 1953. adelphia 2001:764–772. DRAPER N. nary cortisol in kennelled dogs. HUGHES AM. 64. BANNASCH DL. Curr Opin Pharmacol 2003. Angiotensin AT2 receptors: control of Comparison of classic hypoadrenocorticism with glucocorticoid- renal sodium excretion and blood pressure. FURMANIAK J. Philadelphia 2008: 40. PADIA SH. Trends Endocrinol Metab 2008. 445–503. BORETTI FS. Principles and Practice of Endocrinology 61.19:84–87. REUSCH CE. FAMULA TR. ADLER GK. FREY FJ. Williams Textbook of En- docrinology. Adrenal-cortex autoantibodies and 46. 52. GAINES SA. and laboratory findings in dogs with hypoadrenocorticism: HOLDER G.29:353–357. ROTHUIZEN J. ODERMATT A. 47.145:323–328. alocorticoid action: Target tissue specificity is enzyme. J Am Vet Med Assoc 1996. WOUTERSEN-VAN 66. Aldosterone biosynthesis. SPEE B.84:618–622.10:7–13. AUCHUS RJ. SCHWEIZER RAS.87: 65. KASS PH. SMITH R. SIEBER-RUCKSTUHL NS. Phil. Hyperreninaemic hypoaldosteronism in a dog. YIRMIYA R.231:407–412. 51. 58. ed. Quantitative real-time 2006. J Am Metab 2008. The adrenal glands. ed. 2004.208:85–91 phenotype in a patient with Cushing’s disease due to defective cor- tisone to cortisol conversion. J Am Vet Med chim Biophys Acta 2004. GOSHEN I. 43. FINK-GREMMELS J. Characterisation of Clinical features and heritability of hypoadrenocorticism in Nova 11b-hydroxysteroid dehydrogenases in feline kidney and liver. Cytokines: regulation of the hy. Endocrinology 55. KEENAN DM. Untersuchungen zum Kortisol. in the human. disease: comparison with immunofluorescence and immunopre- cipitation assays.35:89–101. CAREY RM. FUNDER JW. Heart Failure Rev 2005. Interleukin–1 (IL–1): A central regu. 56. regulation. glands in domestic animals. eds. DAVIES E.87:911–916 PCR for the measurement of 11b-HSD1 and 11b-DSD2 mRNA levels in tissues of healthy dogs. Behavioral and 548–554. BORNSTEIN SR. KADEREIT B. Metastatic tumors to the adrenal 57–62. NIJNANTEN F.22:279–280. Elsevier Saunders. SCOTT-MONCRIEFF JC. ed. J South Afr Vet Assoc 1998. Behav 2007. J Endocrinol 2005. 144 Adrenals 37. Therapy of heart failure. 6th edition. A longitudinal evaluation of uri. In: Ettinger 63. The rise in ad- renal androgen biosynthesis: adrenarche. JOHNSON AP. nase type 1 from six species. SISSION DD. RAINEY WE. In: Kronenberg HM. LUTZ H. VAN SLUIJS FJ. 3rd edition. CHEN S. STEIN M. ROELFSEMA F. BETTERLE C. Miner- 1990.287: E652-E661.186:1–20. Vet Med Assoc 2007. Lippincott Williams & Wilkins. PEARCE PT. ANDERSON JD.69:33–35. RIJNBERK A. Schweiz Arch Tierheilk 54. JOFFE HV. Endogeneous Hypertension and hormone mechanisms. PEDINI B. J Mol Endocrinol 2005. J Clin Endocrinol Metab 2002.230:1190–1194. DE COCK HEV. BALAZS Z. Comparative enzymology of the 11b-hydroxysteroid dehydroge- 39. HERMAN JP. ARAMPATZIS S. . STEWART PM.30:30–45. BULMER BJ.3:78–84. KINTZER PP. LABELLE P. Horm Metab Res 2007.917–608–617. Polonsky KS. LANGER T. SCHIPPER L. BRADSHAW JWS.127:907–915. and classical steroid-producing cells autoantibodies in patients with Addison’s mechanism of action. Canis familiaris.39: 38. glucocorticoid responses of dogs (Canis familiaris) to kennelling: Investigating mitigation of stress by prior habituation.1688:68–77. 2003. Trends Endocrinol deficient hypoadrenocorticism in dogs: 46 cases (1995–2005). PARKER KL. VOLPATO M. DE KLOET ER. Binding characteristics of mineralocorticoid and glucocorticoid receptors in dog brain and pituitary.92:847–854.42:52–58. ZIMMER C.19:175–180. Physiol 53. 57. cases. lator of stress responses. Am J Physiol Endocrinol Metab 2004. Vet Pathol 2005. Physiol Behav GÖNCZI E. NELSON RW. Ann N Y Acad Sci 2000. Absence of Cushingoid 225 cases (1979–1993). Renin-angiotensin system and aldoste- rone. REES SMITH B. 4 Kreatinin-Verhältnis in Urin (UCC) bei gesunden Katzen (Urinary cortisol /creatinine ratio in healthy cats). TUCK ML. pothalamo-pituitary-adrenocortical axis. Larsen PR.242:583–585. Adrenal cortical atrophy in the dog: report of three and Metabolism. SMITH AL. Scotia duck tolling retrievers: 25 cases (1994–2006). VELDHUIS JD. RAINEY WE. Ojeda SR. THOMPSON AL. Bio. SJ. BUCKINGHAM JC. 321–338. adrenal glands in six dogs with hypoadrenocorticism.224:198–199. MCLAUGHLIN CD. JAVADI S. 4 adrenocorticism in bearded collies.215:222–225. Low ratios of sodium to potassium in the serum of BOUDOU P. ROTH L.35:117–122. BELL R. MAXIME V. TASKER S. ovine corticotropin-releasing hormone on plasma concentrations of immunoreactive adrenocorticotropin.11:43–49.and glucocorticoid receptor a. cortical insufficiency. Hypoadrenocorticis as the primary mani- trauma in a dog. J Vet Intern Med 1989. DEYSS EM. A. Effects of in dogs.2:121–125. Inheritance of hypo. LECHAN RM. ANNANE D. GALAC S. PETERSON ME. 74. References 145 67. Hypoadrenocorticism in young nocorticotropic hormone ratios in healthy dogs and in dogs with related Nova Scotia duck tolling retrievers. LOTHROP CD. GRECO DS.53:421–425. BELANGER JM. GRAHAM J.39:348–351. REUSCH CE. 90. WARD JH. Hypoadrenocorticism in a cat. Aldosterone-to-renin ratio and cortisol-to-adre- SHAW D. MARIK. Containing cost of ACTH-stimulation test. 84. RAN XZ. 1988.mediated mechanisms in the regulation of systemic 81. J Am Vet Med Genetic evaluation of Addison’s disease in the Portugese Water Assoc 1999. Myelinolysis after correction of hyponatremia in two ity and complex segregation analysis of hypoadrenocorticism in the dogs. PLATT SR.2:15–21. J Am Anim WAGNER DR. 1997. . BELANGER JM. Am J Vet Res 1992.174:1319–1326. Hypoadrenocorti. J Vet Sci 2000. Nuclear factor-kappab. standard poodle. SYME HM. festation of lymphoma in two cats. KRITZMAN J. REFSAL K. HUTCHINS RG. DELAY J. Ultrasonographic evaluation of the 69. 88. MOSES LS. J Vet Intern Med 2006. WILLARD MD.44:490–492. WACK O. 97. HOLMES A. BENEMANN KS. Evidence for inflammation-induced target tissue in clinically normal dogs and in dogs with various diseases. Chest 2009. BOER P. MUTHIAH MP. 79. LIU DH. alpha-melanocyte-stimulat- 78. 89. PETERSON ME.214: 1208–1211. ABE E. OBERBAUER AM. Isolated adrenocorticotropin defi- 75. BELANGER JM. BRADY CA. KOOISTRA HS. PETERSON ME. LENNON EM.38: primary hypoadrenocorticism. PAK S-I. SCOTT-MONCRIEFF JC. ELTORKY M. SU YP. PETERSON ME. NEIGER R. FAMULA TR. NEL- 70. ADLER JA. SOMERVILLE C. ORTH DN. POWELL LL. NIELSEN L. nocorticism in ten cats. Chronic hypoglycemia in electrolyte concentrations in dogs with hypoadrenocorticism. PARNELL NK. 87. OBERBAUER AM.42:186–190. Critical illness-related corticosteroid insufficiency. Neurologic complications following treatment 72. Treatment and long-term fol- 73. CLEMMONS RM.70:1391–1397. Vet Rec 2008. Can Vet J 2003.20:556–561. KENHEUER AJ. BOYLE TE. KEMPPAINEN RJ. J Am Vet Med Assoc J Am Vet Med Assoc 2004. Severe neurologic seque- 71. MELLOR DJ.8:40–48. SHAKER E. HANNA P. J Am Vet Med Assoc 2007. RAMSEY I. cism in a family of Standard Poodles. 94. GAO JS. BURTON S. LIFTON SJ. lae in a dog after treatment of hypoadrenal crisis. THACKER E. BISSETT SA.48:1713–1718. and cortisol in dogs with naturally acquired adreno- dogs. 77. HOHENHAUS AE. CORREA MT. SAUTER NP.44:8–12. BELL JS. VITE CH.63:643–647. rived peptides. 68. Changes in glucocorticoid and mineralocorticoid 1988.30:623–627.12: Res 1987. STONEHEWER J. MEDURI GU. 86. HESS RS. BIR. LU SF. EYE J. J Vet Intern Med CHENG TM. PETERSON ME. The clinical implication of sodium-potassium ratios in ing hormone. SON MJ. of canine hypoadrenocorticism. HOERAUF A. J Clin Endocrinol Metab 1990. Hosp Assoc 1999. Pract 1998. GOLDEN DL. CARRATU P. 82.209:2076–2081. Use of basal serum or plasma cortisol concen- trations to rule out a diagnosis of hypoadrenocorticism in dogs: 96. ZOIA A. BMC Vet Res 2006. KING LG.1:61–65. 123 cases (2000–2005). COVERT SJ. TESKE E. A retrospective study of aldoste. Can Vet J 1997. FRIEDENTHAL 95. 83. J Am Vet Med that is not adrenocorticotropin or other proopiomelanocortin-de- Assoc 1996. PE. PATNAIK Secondary hypoadrenocorticism associated with craniocerebral AK. KROLL RA. rone secretion in normal and adrenopathic dogs. 85. J Small Anim Intern Med 2007.11:60–64. low-up of 205 dogs with hypoadrenocorticism. Dog. ZHANG W. Diagnosis of adrenal insufficiency in severe sepsis and 238 dogs. receptors of liver and kidney cytosols after pathologic stress and its regulation in rats. DROBATZ KJ. ciency associated with an autoantibody to a corticotroph antigen poadrenocorticism in dogs: 18 cases (1986–1995). IBRAHIM F. JOHNSON GC.192:1091–1092. 76. FAMULA TR. J Small Anim Pract 2003. Heritabil. Neuroimmunomodulation 2005. Am J Vet resistance to glucocorticoids. MACMILLAN KL. CHRISMAN CL. Evaluation of low sodium-potassium ratios 93. TYLER RD. J Am Anim Hosp Assoc 1999. 231–234.21:1168–1173. OBERBAUER AM. septic shock. J Vet a hunting dog due to secondary hypoadrenocorticism. DROBATZ KJ. J Vet Intern Med 1994.3:55–58. Evaluation of plasma and pulmonary inflammation during sepsis and acute respiratory aldosterone concentrations before and after ACTH administration distress syndrome. PAPICH MG. ZERBE CA.35:214–218. Crit Care Med 2002. J Vet Diagn Invest 1999. Primary hypoadre. FAMULA TR. J Vet Intern Med J Small Anim Parct 2001. J Am Vet Med Assoc 1999. CHROUSOS GP. 80. ORTH DN. Abnormalities of serum 92. TONI R. ALVAREZ JC. Glucocorticoid deficient hy. Am J Respir Crit Care Med 2006. HURVITZ AI. O’BRIEN DP. PETERSON ME. KINTZER PP. Am J Vet Res 2002.162:431–435.135:181–193. 91. ROBBEN JH.231:413–416. metyrapone to treat pituitary-dependent hyperadrenocorticism in a cat with large cutaneous wounds. BOSCARO M. TURNILL D. Eur J Endocrinol 2006. 112. MINNECI PC. Alterations in EN. HICKEY KC. Tumor necrosis factor as a potent in. the brain in type 2 diabetes. cretion in critically ill dogs. . mechanism in Cushing’s syndrome. ASADULLAH K. SCOBIE IN. HERR LG.21:226–231. WHITE RN. dose ACTH-stimulation test and the cortisol-to-adrenocortico. Meta-analysis: the effect of steroids on survival 559–563. KEMPPAINEN nase mediates glucocorticoid-induced metabolic changes: a novel RJ. Splanchnic cortisol production in dogs occurs urinary corticoid /creatinine ratios in cats with hyperthyroidism. AMP-activated protein ki- 99. GALAC S. GROSSMAN AB. BRYDEN SL. 117. SCHÄCKE H. N Engl J Med 1996. JÄÄTTELÄ M. GROSSMAN AB. Evidence for substantial hepatic specific J Vet Intern Med 2004. SAUERWEIN HP. Clin Endocrinol 2008.141:47–56. FOX PR. J Endocinol 1997. Mycobacterium 105. RONCONI V. GIAC- CHETTI G. LOLLI F. AJODHA S. GAILLARD RC. MOSER VR. anterior pituitary function of dogs with pituitary-dependent hy- adrenal function in dogs with acute critical illness. GRÄF KJ. Clin Tech Small Anim Pract 2007. 122. BUIJS RM. PRALONG F. MULLER AF. J Small Anim Pract 2000. MATERO F. KOLA B. pituitary gland to hypothalamic releasing factors. BERNANTE P. FORRESTER SD. CHRIST-CRAIN M. CHRIST-CRAIN M. J Vet Intern Med 1999. ILVESMÄKI V. NELSON RW. J Vet Intern Med M. 2007. CHIARAMONTE D. MEIJ BP. UMPLEBY AM. FREI U. Adrenal insufficiency. Feline adrenal disorders. critical illness: limitations of current assessment methods. ECK. Use of Crit Care Med 2005. KOLA B. SAKSELA E. BURKITT JM. SINGH RJ. Endocrinology 2006. KORBONITS 4 100. 118. HERRTAGE ME. 115. 956–960.202: 108. MARTIN LG.41:109–114.33:2457–2464. HUFFMAN JW. Relative adrenal insufficiency in dogs with sepsis. FELDMAN EC. High RIZZA RA. GIACCHETTI G.15: 104. 1990. BARCKOW D. GIACCHETTI G. ORTEGA T. NACHREINER RF. SCHOTANUS BA. DALLEY 106. Endocrinol Metab 2006. BOSCARO M. SCHINDLER R.K+-ATPase content in skeletal muscle of dogs MAN UH. BURROWS AK.13:557–560. ARDT KU. SAPPINO P. METTENLEITER TC.18:152–155. DE LANGE MS. KAP YS. Na+. INGEN C.91:3725–3745. ARAFAH BM. Gluco- corticoid therapy-induced skin atrophy. GOSSELIN R. DUNSTAN RW. BENN JJ. Domest Anim hibitor of adrenocorticotropin-induced cortisol production and Endocrinol 2006. RILLI S. FEKETE C. SCHICK RO. CHERRINGTION A. ARNALDI G. JB. DEANS KJ. SEBOEK Tumor necrosis factor alpha inhibits the hormonal response of the D. IGREJA SC. EVERTS ME. AUBERT G. ARNALDI G. KALSBEEK A. Assoc 2008.39:591–598. Adipose tissue 11b-hydroxysteroid dehydrogenase type 1 expression in obesity 121. 1993. 11b-hydroxysteroid dehydrogenase type 1 activity. Changes in adenosine 5'-monophosphate-activated protein ki- nase as a mechanism of visceral obesity in Cushing’s syndrome. FELTRIN D. BEHREND 114. Retrospective evaluation of urinary tract infec- 107. VOS IHC. EDGERTON DS.220: 615–619. DALTON MN. PRITTIE JE. KREIER F.55:3013–3019.154:505–512. MÜLLER B. VAN HEIJN. Endocrinology 1991. 101. POWERS RD. VOUTILAINEN R. KOOISTRA HS.233:87–95. 116.190: NATANSON C. BOSWOOD A. MARINIELLO B. HUSUNG C. SCHOEPE S. BARTON LJ. LAMB CR. 123. FASEB J 2008. J Am Vet Med Assoc 2002. 120. LOWY C. with pituitary-dependent hyperadrenocorticism. Aortic and iliac liver and pancreas: A neuroanatomical framework for the role of thrombosis in six dogs.335: 406–420. O’HARA AJ. BOENISCH O. Hyperadrenocorticism in a cat.93:4969–4973. HASKINS SC. FLIERS E. MAY E. SCHOEMAN JP. OPPERT M. KUNO G. MOL JA. 102. Ann Intern Med 2004. 124. FLETCHER DJ. primarily in the liver. GRECO DS. STEN.15:331–338. ROMIJN JA. Vet Parasitol syndrome before and after successfull treatment. KOOISTRA HS. and Cushing’s syndrome. J Am Vet Med Assoc 1987. 103. LOLLI F. KORBONITS M. 1206–1212.22:1672–1683.128:623–629.30:320–332. 119. steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. TRIP MRJ. Arch Surg 2001. J Am Vet Med Assoc 1993. Endocrinology HARVEY-WHITE J. KASS PH. WITTMANN G. J Clin Vet Derm 2004. Hypothalamic-pituitary adrenal function during gondii infection in a dog with concurrent hyperadrenocorticism. J Am Vet Med peradrenocorticism. DALEY CA. HOLTZMAN G. TROY GC. BOSCARO M. ZERBE CA. SÖNKSEN PH.147:1140–1147. OWINGS JT. J Clin Endocrinol Metab 2008. Exp Dermatol 2006.136:1003–1007. Pituitary. 146 Adrenals 98.22:26–31.155:435–441. ZERBE CA. Biochemical basis for the hypercoagulable state 110. Leucine metabolism in patients with Cushing’s trophic hormone ratio in canine babesiosis. and shock during sepsis depends on the dose. OELKERS W. BEVERS MM. Diabetes 2006. BANKS SM. Tracing from fat tissue. BASU R. seen in Cushing syndrome. 111. 109. GROMAN RP. VAN DER VLIET J. PETERSON ME. JACOBY RC. Pituitary ACTH and adrenocortical se.154:205–213. K. OFFERMANN tion in 42 dogs with hyperadrenocorticism or diabetes or both. BOWES SB.127:101–106. EICHACKER PQ. MEIJ BP. Adrenal response to the low 113. KEMPPAINEN RJ. RIJNBERK A. DE BRUIJNE JJ. STRITZEL S.22:273–281. TAKA. TESKE E. GASCHEN FP. RIJNBERK A. HOUT G.231:1081–1085.14:157–164.125:12–14. Vet Rec 151. Vet Quart 1995. Intra- HASHI K. MOL JA. 148. 4 127. KOOISTRA HS. 139. RIJNBERK A. J Am STEWART PM. bilateral adrenocortical tumours. MILLER J. GROSSMAN tumour. Multiple endocrine neoplasia type–1–like syndrome in two cats. drogenase type 2 is decreased in patients with impaired renal func- tion. not have neurologic abnormalities: 157 caes (1989–2005). SATTA MA. CERUNDOLO R. SCHOLTEN-SLOOF BE. References 147 125. Aust Vet J 2000. Vet Quart 1998. Diagnostic imaging findings and endocrine test results in dogs 129. REUSCH CE. SJOLLEMA BE. HALMI NS. PORT. SCANZIANI E. GENTILINI F. nol 1992. Vet Pathol 2005.153:291–299. Systemic arterial blood pressure and urine pro. Immunocytochemical study of the hypophysis in 25 dogs 130. . VAN SLUIJS FJ. BESTETTI GE. BOUJON CE. WILLITS N. 126. ORTEGA TM. VAN DEN INGH 132. VOOR- 19–23. QUINKLER M. HARADA Y. KLEINSCHMIDT S. with pituitary-dependent hyperadrenocorticism that did or did MOORE JS. clinical hyperadrenocorticism in dogs (canine Cushing’s syn- drome). RIJNBERK A.22:26–31. VAESSEN MMAR. of canine hypercorticism. YOGO T. Hypertension and the cortisol- cortisone shuttle.70:487–491. The effects of anti-convulsant drugs on adrenal function. HEWISON M. with pituitary-dependent hyperadrenocorticism. cases (1982–1992). Horm Metab Res 1998. Effect of pheno. term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. RIJN- BERK A. Vet Rec WOHLSEIN P.41:491–495. HURLEY KJ. VON DEHN BJ. and pheocytochroma. MÜLLER PB. GLAUS TM.160:393–397. TAGAWA M. atinine ratios and resistance to glucocorticoid feedback. 150. RIJNBERK A. VAN SLUIJS FJ. Vet Rec 1989. LLOYD DH. 137. J Vet Intern Med 2000. KOOISTRA HS. 36 dogs with hyperadrenocorticism caused by adrenocortical tu- GOOD G. Corti. with pituitary-dependent hyperadrenocorticism. COCKWELL P. Alopecia in pomeranians and miniature poodles in association with high urinary corticoid:cre. DISTL O.20:56–61. FELDMAN EC. NISHIDA K. RONDENA M. Expression of renal 11b-hydroxysteroid dehy. FAVERZANI S. 146. RIJNBERK A. cism. SCARPA P. Melanotroph pituitary ade- quency of pulmonary mineralization and hypoxemia in 21 dogs noma in a cat with diabetes mellitus.42:92–97. STEWART PM. FLIK G. Vet Rec 2004. and interindividual variation in urine osmolality and urine specific OSAMURA RY. FELDMAN EC.101:15–24. MOL JA. WOLFSHEIMER KJ. GRIFFEY SM. J Vet Med Sci 1997. TOBOADA J. ROCCABIANCA P. KOYAMA H. MOL JA.11:30–35. J Am Vet 518–521. TSGAM. Cushing’s dis. HUGHES SV.30:389–397. Multiple endocrine neoplasias in a dog: corticotrophic 135. 144. DRUCKER WD. TESHIMA T. FOSTER SF.14:151–156. Pheochromocytoma and hyperadrenocorticism in dogs: six 134. Clin Techn Small Anim Pract 2007. METTLER M. Med Assoc 1996. MELLOR D. barbitone on the low-dose dexamethasone suppression test and the urinary corticoid:creatinine ratio in dogs.88:2384–2392. ACQUA V. STOCK KF.155: tein-creatinine ratio in dogs with hyperadrenocorticism. Endocrinologist 1994. J Vet Intern Med ease complicated with thrombosis in a dog. carcinoma.207:322–324. RITZ U. TERAMOTO A. UERLING MR. J Am Anim Hosp Assoc 1982. PETERSON ME. low-dose dexamethasone suppression tests. MISCHKE R. The effect of hydrocor- tisone on systemic arterial blood pressure and urinary protein ex. UBBINK G. QUINKLER M. Epidemiological aspects of cretion in dogs.78: 149. The biochemical diagnosis of hypercorti. A clinico- 131. J Comp Path 1991. Assessment of two tests for the diagnosis of canine hyperadrenocorticism. MEIJ BP. Effects of long. MOL JA. KALTSAS GA. 1988. WOOD FD. RIJNBERK A. Berl Münch Tierärtzl Wochenschr 2008. J Vet Intern Med 2000.4:7–14 NIATTI M. KRIEGER DT. 147. 2008. Familial canine pituitary- 2007. 142. mour. SULLIVAN M. POLLARD RE. CHURCH DB. NEZU Y. Fre. FELDMAN EC. SCHWARZ T. HAWKINS EC. NELSON RW. PRIESTER WA. 140. 152. PARTINGTON BP.105:353–365. Vet Pathol 2006. WATSON ADJ. STÖRK CK. 141. Pituitary-dependent hyperad- renocorticism in a family of Dandie Dinmont terriers. PHILIPP U. VAN DER VLUGT-MEIJER RH. RIJNBERK A. TAODA T. ZEHNDER D. LEPENIES J. VOORHOUT G. NELSON RW. J Am Vet Med Assoc 1995.18:717–724. 143. AB. Urinary corticoid:creatinine ratios in healthy pet dogs after oral COWGILL LD. J Endocri- 138. Eur J Endocrinol 2005. Feline adrenal disorders. ROSSI GL. HARA Y. J Small Anim Pract 2000. Acta Endocrinol costeroid-induced alkaline phosphatase isoenzyme in the diagnosis 1982. POC- 136. 145. GRECO DS. dependent hyperadrenocorticism in wirehaired Dachshunds.209:1724–1729.122:178–180.135:535–542. J Clin Endocrinol Metab 2003. VAN DEN INGH TSGAM. PUTIGNANO P. KNOL BW. BERRY CR. CA- solism. VAN DER LINDE-SIPMAN JS. J Vet Intern Med 2008. PALTRINIERI S.43:345–352. MIDDLETION DJ. Results of adrenalectomy in 133. KOOISTRA HS.121:349–358. pathological study of canine Cushing’s disease caused by a pituitary teopenia and other radiographic signs in canine hyperadrenocorti. SCHELLENBERG S. VAN WEES A. ROTHUIZEN J. CRAPO L. VAN VONDEREN IK. MANN R. gravity in healthy pet dogs of various ages. MONCE K. CHIARAMONTE D. Vet Med Assoc 2007. WILLEBERG P. HOS. PETRELLI MD. MOL JA. Os. MOL JA. KOOISTRA HS. THURÓCZY J. VAESSEN MMAR.17:113–116. 128. RIJNBERK A. VOORHOUT G. J Endocrinol In. vasopressin pro-opiomelanocortin-producing pituitary tumor not causing hy- and insulin-like growth factor-I on proliferation of and adrencor. 166. VAN DEN INGH 158. peradrenocorticism. CROUGHS RJM. hyperadrenocorticism in dogs and cats. 173. J Vet Intern Med 2005. MOL JA.20:1–7. Immunocytochemical study of the hypophysis of 25 dogs tomography of the pituitary gland in dogs with pituitary-depend- with pituitary-dependent hyperadrenocorticism. melanotrophin and cor. Transsphenoidal hypophysectomy for treatment of KOOISTRA HS. RIJNBERK A. crinol 2002. LEEGWATER PAJ. KOOISTRA HS. 164. MEIJ BP. corticism. SPRANG EPM. Transsphenoidal hypophysectomy for treatment of dogs and dogs with Cushing’s syndrome: Diurnal rhythm and re. 162. MEIJ BP. BERK A. LLOYD DH. LUTON JP. 148 Adrenals 153. MOL JA.19:687–694.118:271–277. VAN WIJK PA. MOL JA. Plasma immuno. Ef. Progress in transsphe- fects of bromocriptine on corticotrophin. SPRANG EPM. WOLFSWINKEL 156. 154. DRUCKER WD. hyperadrenocorticism. MEIJ B. GRANGER N. VOORHOUT G. PETERSON ME. 2001. VAN DER VLUGT-MEIJER RH. VAN DEN INGH TSGAM.15:285–293. KRIEGER DT. RIJNBERK A. J Vet Intern Med 2003.130:469–471. 175. VOORHOUT G. RIJNBERK A. SARTIN JL. Domest Anim Endo- vest 1997. ent hyperadrenocorticism. Mol Cell Endocrinol nocorticism. MEIJ BP. VOORHOUT G. J Endocrinol 1988. ABECASSIS JP. VOORHOUT G. VAN DEN INGH TSGAM. HANSON JM. HANSON J. FIGA.19:23–28. ROSENBERG D.30:72–86. Plasma concentrations of ACTH precursors correlate screening for somatic mutations in corticotropic adenomas of dogs with pituitary size and resistance to dexamethasone in dogs with with pituitary-dependent hyperadrenocorticism. BERTAGNA X. KWANT MM. KOOISTRA HS. RIJNBERK A. VOORHOUT G. Treatment of canine Alopecia X with trilostane. J Endocrinol 1997.17:18–27. Central diabetes insipidus in a dog with a MOL JA. DRUCKER WD. BOSJE JT. MEIJ BP. 4 155. VOORHOUT G. Results of transsphe- tide release by the canine pars distalis and pars intermedia. RIJNBERK A. RIJNBERK A. 1982. A. VOORHOUT G. Efficacy of transsphenoidal the size of the pituitary gland in dogs with pituitary-dependent hypophysectomy in treatment of dogs with pituitary-dependent hyperadrenocorticism.101:15–24. and pituitary adenoma size in cerebrospinal fluid of dogs with pituitary-dependent hyperadreno. BATISTA D. BERTHELET F. hormone and adrenocorticotropic hormone concentrations in pro-adrenocorticotropin hormone. Expression and mutation analysis of Tpit in Correlation between impairment of glucocorticoid feedback and the canine pituitary gland and corticotroph adenomas. STRATAKIS C. hyperadrenocorticism. 2002. MOL JA. ORTH DN. ticotrophic hormone secretion by canine corticotophic adenoma cells in vitro. 167. CHAVEZ FT. BRUE T. Correlation between impairment of glucocorticoid feedback and TESKE E. Plasma pro-opiomelanocortin.152:387–394. DROUIN J. Acta Endocrinol ent hyperadrenocorticism. MEIJ BP. KOOISTRA HS. Effects of corticotropin-releasing hormone. VAN DEN INGH TSGAM. VOORHOUT G. 163. Vet Surg 1998. EVANS H. BONNIN 159. Dynamic computed NS. HAZE- 160. J Endocrinol 1997. Vet Surg transsphenoidal hypophysectomy in dogs with pituitary-depend- 2001. PETERSON ME. HALMI NS. J Neurosurg 2007. Front noidal hypophysectomy in 52 dogs with pituitary-dependent hy- Horm Res 1987. CROUGHS RJM. 174. 172. HALMI TSGAM. 168. concentrations. Genes Dev 2006.197:81–87. DELISLE F. MEIJ BP. RIJNBERK A. HANSON JM. MEIJ BP. LENESTOUR E. Vet Surg sponses to various stimuli. 165. CAUVIN A. 177. VOORHOUT G. MOL JA.34:217–222. MOL JA. Endocrinology 1992. RIJN. BILODEAU S. peradrenocorticism. pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1995. DRUCKER WD. Prognostic factors for outcome after pituitary-dependent hyperadrenocorticism in 7 cats. RIJNBERK A. VOOR. DROUIN J. CERUNDOLO R. pituitary-dependent hyperadrenocorticism in 7 cats. GAUTHIER Y.30:72–86. VAN ’T HOOFD MM. VAN DER VLUGT-MEIJER. Endocrinology 1988. BILODEAU S.27:246–261. 170. noidal hypophysectomy for treatment of pituitary-dependent ticosteroid secretion in dogs with pituitary-dependent hyperadre. MOL JA.131:2659–2662. dogs with Cushing’s disease. ORTH DN. DE FORNEL P. GALAC S. Corticotropin-releasing S. PETERSON ME. Plasma immu. Eur J Endocrinol 1998.9:361–365. VAN WIJK PA. ZIELINSKI AC.20:2871–2886. J Vet Intern Med 2005. TESKE E. CROUGHS RJM. VOORHOUT G. Dermatol 2004. TESKE E. VALLETTE-KASIC S. MEIJ BP. HANSON JM. 161. WINKEL HAW. MEIJ BP. PERSECHINO A. .107:830–840. Eur J Endocrinol and dogs with Addison’s disease and Cushing’s syndrome: Basal 1994. DEVAUCHELLE P.122:1250–1262. GOOSSENS MMC. Silent necrosis of a pituitary corticotroph adenoma DAVIS DR. MEIJ B.152:387–394. 169. Mol Cell Endocrinol 2002. RIJN- noreactive proopiomelanocortin peptides and cortisol in normal BERK A.119:720–730. MEIJ BP. Role of Brg1 and HDAC2 in GR trans-repression of Imaging of the pituitary gland in dogs with pituitary-dependent the pituitary POMC gene and misexpression in Cushing disease.22:201–210. CROUGHS RJM. Vet 157. 176. RELLA-BRANGER D. J.138:309–315. VAN WIJK PA. 171. RIJNBERK A.17:773–780. KOOI- VAN LEEUWEN IS. VOORHOUT G. MOL JA. LACROIX A. Differential regulation of pep. Endocrinology 1986. SEGOND HOUT G. hyperadrenocorticism. RIJNBERK A. Molecular STRA HS. revealed by timely magnetic resonance imaging: A cause of reactive proopiomelanocortin peptides and cortsiol in normal dogs spontaneous remission of Cushing’s disease. Domest the size of the pituitary gland in dogs with pituitary-dependent Anim Endocrinol 2008.197:89–96. KEMPPAINEN RJ. MOL JA. MEIJ BP. in dogs with pituitary-dependent hyperadrenocorticism treated SON ADJ. lective adrenocorticolysis with mitotane or trilostane for the treat- nocorticism. cortisol. CABRERA Am J Vet Res 2002. THEODOROPOULOU M. SIEBER-RUCKSTUHL NS. KWANT MM.10:600–607. cortisol. HANSON JM. ROBERTSON ID. J Vet Intern Med 1999.tvjl. KOOISTRA HS. Expression and functional analysis of dopamine receptor subtype 2 and somatostatin receptor subtypes in canine 197. HOFLAND LJ. ARENAS C. Study of hyperadrenocorticism in cats: 10 cases (1988–1992). Inefficacy of selegiline in treatment of canine pitu. J Endocrinol 1988. CLEMENTE M. BELSHAW BE. MASER-GLUTH C. Vet Rec 2007. WITT AL. a-melan. laboratory tests. 180. ZERBE CA. UITTERLINDEN P. cism. STALLA J. Retinoic acid as a 199.42:269–276. WENGER M. ARZT E. BORETTI FS.118:271–277. NEIGER R. . J Am Anim metyrapone to treat pituitary-dependent hyperadrenocorticism in Hosp Assoc 2006. NETT CS. Effect of trilostane on serum concentrations of al- ogy 2006. Res Vet Sci 2008. NEIGER R.p'-DDD in 129 dogs with pituitary-dependent hyperadrenocor- pituitary-dependent hyperadrenocorticism before and after hypo. PÁEZ-PEREDA M. 192.1016/j. 194. Cortisol. CROUGHS RJM.159:277–281. CASTILLO V. BRADDOCK JA. with trilostane.190:601–609. RAMSEY I. STOLP R.122:486–488. PETERSON ME. GALAC S. SCHICK RO. J Endocrinol 1984.217:691–694. HOLSBOER F. Aust Vet J 2004. 196. 184. renin-aldosterone axis in dogs with pituitary-dependent hypercor- ment of 200 dogs with pituitary-dependent hyperadrenocorti. J Smal Anim Pract 1998. 195. Aust Vet J 2003. GARCÍA JD. a cat with large cutaenous wounds. MOL JA. Vet Rec ticosteroid secretion in dogs with pituitary-dependent hyperadre. Long-term efficacy of trilostane administered twice daily in 188. 183. MORALES M. ment of dogs with pituitary-dependent hyperadrenocorticism. Hyperadrenocorticism in six cats. Adrenalectomy for treatment of 200. LAMBERTS SWJ. HURLEY KJ. DUESBERG CA. pendent hyperadrenocorticism treated with trilostane. HOERAUF A. ROBERTSON ID. KOOISTRA HS. physectomy.202: 956–960. ticism. GIACOMINI D. The efficacy of 4 L-deprenyl in dogs with pituitary-dependent hyperadrenocorti. REUSCH CE. TESKE E. 187.31:63–75. SIEBER-RUCKSTUHL NS. DEN HERTOG E. O’CONNOR J. ARENAS C. CHURCH DB. Trilostane treatment in dogs with pituitary-dependent 185.10. An alternative protocol for the coid /creatinine ratios in dogs with pituitary-dependent hypercor- management of canine pituitary-dependent hyperadrenocorti. BUIJTELS JJCWM. PEREZ ALENZA D. WENGER M. RIJNBERK A. HERRTAGE ME. aldosterone. MOORE LE.5:182–190. STEFFEN T. MEIJ BP. melanotrophin and cor. NELSON RW. LABEUR M. Vet Rec 1988. BORETTI FS. dosterone. Trilostane treatment of 78 dogs with pituitary- WAAIJERS AM. MCGROTTY Y. BELL R. androgen and endogenous ACTH concentrations 181. BUIJTELS JJCWM. MOONEY CT. WATSON PJ. REUSCH CE. RIJNBERK A. Serum concentrations of 182. MÜLLER C. CROUGHS RJM. REUSCH CE. REUSCH CE. KOOISTRA HS. KOOISTRA Plasma profiles of adrenocortitropic hormone.163:477–482. Urinary corti- 191. STALLA GK. RIJNBERK A. Results of clinical Cushing’s disease. Am J Vet Res 2004. tisolism during trilostane treatment. J Vet Intern Med 2009.007. GROSSMAN AB. MELIAN C. cortisol and cortisone in healthy dogs and dogs with pituitary-de- fects of bromocriptine on corticotrophin. OLSEN DE.82: 272–277. WAT. MASER-GLUTH C. MOL JA. J Endocrinol 2006. Ef.150:799–804. J Vet Intern Med 1991. References 149 178. cism. REUSCH CE. J Am Vet Med Assoc 2000. MELIÁN C. hyperadrenocorticism. and growth hormone in dogs with o. trations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. LALIA JC. RIJNBERK A.85:26–34. Domest Anim Endocrinol 2006. LUZ LOPEZ M. Results of non-selective adrenocorticolysis by ocyte-stimulating hormone.161:805–809. WAT- SON AD. 201. Hyperadrenocorticism trilostane therapy. Cushing’s disease in dogs: Carber- goline treatment. BLATTER MF. BRAAKMAN JCA. Vet J 2008. Vet Rec 2004. POWERS RD. 2008. Endocrinol. HS. itary-dependent hyperadrenocorticism. examinations. dependent hyperadrenocorticism.207:1066–1070. RUCKSTUHL NS. Results of cypro. 203. nocorticism. Ef- fects of trilostane treatment on the pituitary-adrenocortical and 190.65:1245–1250. doi:10.144:12–17. Vet Rec 1999. VADEN SL. PÉREZ-ALENZA MD. Vet Rec 2002.208. BILLER DS. DE BRUIN C. Endocrinology 2008.63:506–512. 186. CHURCH DB. FELDMAN EC. TESKE E. novel medical therapy for Cushing’s disease in dogs.p'-DDD) treat.147:4438–4444. DALEY CA. Adrenocorticotropic hormone levels in dogs with pituitary-dependent hyperadrenocorticism following 189.101:311–314. KOOISTRA HS. Comparison of non-se- heptadine treatment in dogs with pituitary-dependent hyperadre. treated with metyrapone followed by bilateral adrenalectomy in a cat. and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. BRADDOCK JA.154:399–400. tisolism.149:4357–4366. Use of dogs with pituitary-dependent hyperadrenocorticism. SIEBER-RUCKSTUHL NS. cor- tisol precursor. 204.13:291–301. ahead of print. KINTZER PP. 202. J Am Vet Med Assoc 1993. CASTILLO VA. NEIGER R. GÓMEZ NV. SCOTT-MONCRIEFF JCR.39:175–184. J Am Vet the effects of once daily doses of trilostane on cortisol concen- Med Assoc 1995. 193. HANSON JM. RAMSEY IK. and potassium in dogs with pituitary-depend- ent hyperadrenocorticism. WENGER M. Epub cism. 198. Vet Rec 2006. 179. GALAC S. Mitotane (o. DE ANDRÉS PJ. 210. VAUGHAN MA. Pharmacology and clinical uses of inhibitors of hormone secretion and action. YNA. OLIVER JW. NELSON RW. treatment with trilostane. of both adrenal glands in 15 dogs with functional adrenocortical itary-dependent hyperadrenocorticism treated with trilostane. Vet Rec 2008. HOERAUF A. 217. Secretion of sex hormones in dogs with adrenal dys- 349–352. 225. NICHOLLS PK. 219. BLEVINS WE. KUICK R. GAUGER PG. Indi- Evaluation of twice-daily. cators of malignancy of canine adrenocortical tumors: histo- tered orally in dogs with naturally occurring hyperadrenocorti. LE BOUC Y. Extensive venous thrombosis and hind-limb 212. GROOTERS AM. SYME HM. pituitary-dependent hyperadrenocorticism. REUSCH CE. BERNARD MH. MARSH 206. TAYLOR JM. MAUREY C. LABELLE P. MORAILLON R. HOSGOOD G.43:104–108. GLICKMAN NW.35:306–310. Endocrinology. LIEN Y-H. Hyperadrenocorti- cism in 5 cats. VAN TOOR AJ. 220. KOSHKO MA. 226. J Small Anim Pract 2003. LAMB CR.35:193–199. SCOTT-MONCRIEFF JC. VAN DEN INGH TSGAM. RAMSEY IK. Phila- pituitary-dependent hyperadrenocorticism in the dog. SNYDER PW. NELSON RW.88:998–1001. ELWOOD CM. In: DeGroot LJ. 218. J Small Anim Pract 2004. 1725–1728. HURLEY KJ. Trilostane ther- MISEK DE. ARCHER J. J Am Vet Med Assoc 1993. WHITTEMORE JC.86:491–495. cism caused by bilateral adrenocortical neoplasia in dogs: Four LUTZ H. HOAR BR. Current Veterinary Therapy XI. Aust Vet J 2008. NELSON RW. 2006:2353–2386. VOORHOUT G. eds. Histological evaluation cases (1983–1988). Haemorrhage from a canine adreno- HERRTAGE ME. Trilostane 223. 150 Adrenals 205.198:278–280. treatment of a dog with functional adrenocortical neoplasia. THOMAS DG. Use of ketoconazole for control 231. 209. THOMPSON MF.14:81–85. VAN DER therapy for treatment of pituitary-dependent hyperadrenocorti. GASTON V.219:329–333. NEIGER R.44:682–685.162: 521–531. ROSENBERG D. BENCHEKROUN G. LIZYNESS M.44:126–131. J Clin Pathol 2008. BUCH HN. Jameson LJ. A comparison of cortical tumour: a clinical emergency. renocortical tumor in two dogs. Vet Pathol 2004:41:490–497. FELDMAN EC. BROCKMAN DJ. PEIX JL. Philadelphia: Saunders 1992: OLIVER JW. management. REUSCH CE. 213. LINDE-SIPMAN JS. Adrenal incidentaloma: evaluation and cat. BOON GD. cism in four cats. HARDIE EM.160:219–224.163:190–192. PETRUS D. NOBLE A. MANTIS P. CAMUS AC. VANDENBERGH AGGD. POSPISCHIL A. HÉRIPRET D. BERGER N. BARKER EN. DE COCK HV. Vet Rec 1992. LENARD Z. J Clin Endocrinol Metab 2003. PRESTON CA. DELISLE F. ROBINSON BG. 227. EVANS K.131: the survival times of dogs treated with mitotane or trilostane for 539–540. GUERRERO B.44:269–272. HANASH apy for hyperadrenocorticism in three dogs with adrenocortical SM. VOS JH. Adrenal causes of hypercortisol- RAJA E.45: 307–310. 214.202:789–792.61:1168–1173. In: Furr BJA. PÉREZ ALENZA MD. 207. Use of trilostane for the treatment of pituitary-dependent hyperadrenocorticism in a 222. 5th ed. FARVER TB. KYLES AE. HUANG H-P. FELDMAN EC.226:556–561. GOMEZ E. TEBB AJ. JAFFE MH. eds. HILL KE. J Am Vet Med Assoc 2001. WENGER M. Trilostane DJ. IMMINK WFGA. 228. 232. 230. NEIGER R. Radiol Ultrasound 2003. GLICK- of canine hyperadrenocorticism. Hyperadrenocorti- 216. Anim Pract 2002. Ultrasonographic characteristics ultrasonographic appearance of adrenal glands in dogs with pitu. THOMPSON NW.219: J Am Vet Med Ass 2008. VAN SLUIJS FJ. SIDHU S. SMITH AL. . GIRALDI FP. Changes in 224. 229. LAFARGE 221. HOSGOOD G. SINGH PK. MELIÁN C. NEIGER R. Small Anim Pract 2003. WITT AL. Bonagura JD. Vet Rec 2007. FELDMAN EC. low-dose trilostane treatment adminis. DE FORNEL-THIBAUD P. BEGON D. J Am Anim Hosp Assoc 1999. J Am NEIGER R. KOWALEWICH N. ALJUNDI RT. RAMSEY IK. MAN LT. PARTINGTON BP. EASTWOOD JM. Wakeling four dogs. DE COSTER R. AE. CAVAGNINI F. 1987:288–307. function. J Am Vet Med Assoc 2008.233:1896–1901. London: Baillière Tindall. KELLY DF. CHAPMAN PS. pathology and proliferation index. Nontraumatic rupture of an adrenal gland 215. Hyperadrenocorti- 211. Use of ketoconazole to treat dogs with cism associated with excessive sex hormone production by an ad- pituitary-dependent hyperadrenocorticism: 48 cases (1994–2007). covered by DNA microarray analysis. RICHARDSON J. SKELLY BJ. In: Kirk RW. KYLES AE. J Am Vet Med Assoc 2001. AMERY WK. J A case report in favor of a multistep adrenocortical tumorigenesis. treatment of hyperadrenocorticism. SIEBER-RUCKSTUHL N. Use of aminoglutethimide in the treatment of ism. PEÑA L. VANDENBOSSCHE H. WHITE MR. J Am Vet Med Assoc 1991. J Am Vet Med Assoc 2005. cism. LUBBERINK AAME. Am J Pathol 2003. eds.18:160–164. J Small delphia: Elsevier Saunders. GICQUEL C. J Vet Intern Med 2005. 4 S. PERREN A. WITT AL.19:810–815. SANDERS D. Adrenal necrosis in a dog receiving trilostane for the Anim Hosp Assoc 1999. Phar. Persistent isolated hypocortisolism following brief tumor in a dog. tumor causing intra-abdominal or retroperitoneal hemorrhage in macology and clinical use of ketoconazole. Hemoperitoneum secondary to traumatic rupture of an adrenal IRWIN PJ. 208. FORD SL. FELDMAN EC. REID SWJ. GERMAN AJ. TEBB AJ.232:1321–1328. of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet tumors. NELSON RW. SCOTT-MONCRIEFF JC. Distinct transcriptional profiles of adrenocortical tumors un- metastases. Vet Quart 1992. CAMPBELL S. GIORDANO TJ. edema associated with adrenocortical carcinoma in a dog. J Vet Intern Med 2004. 254. KIKUMORI T. KEMPPAINEN RJ.223:654–662. JIMÉNEZ PELÁEZ M. SIEMS J. WEIGAND CM. REZNEK RH. NE- 244. POZZA C. VAN DEN MATHEWS KG. DE COCK HEV. drogen and estrogen concentrations in ferrets with hyperadreno- corticism. SCHOEMAKER NJ.and al. J Am Anim Hosp Assoc adrenocortical tumors in dogs. MOL JA. Evaluation of prognostic factors renin activity in healthy dogs and dogs with hyperadrenocorticism. RIJNBERK A. Med Assoc 1986. J Vet Med Sci 2008. J Am Vet Med lateral adrenalectomy. Vet Quart 1997. HERRERA M. KOVAK JR. Vet Surg 4 corticosterone. Results 257. TAKIGUCHI M. 259. Predictive factors and the effect of 484–487. J Am Vet Med Assoc 2008. Nephrotomography and ultrasonography for the production in a cat. (1999–2005). RIJNBERK A. FELDMAN 253. SCAVELLI TD. J Vet Intern Med 2008. VAN WAES SNYDER PW. NEIGER R. YOUNG DW.36:512–517. diagnosis. KASS PH. 256. HARDIE EM.214:666–669. BEHREND EN. OHIWA M. PASCOE PJ. ANDERSON CR. and results in seven dogs. UCHIDA E. BERGMAN PJ. JAVADI S. SCOTT-MONCRIEFF JC. Trilostane treatment of 241. hypertension. LUDWIG LL. 338–348. GRIFFIN C. KOMUREK K. CHURCH DB. MEHL ML. 243.p'-DDD). . J Clin Endocrinol Metab 2006. HOPPER BJ. WITHROW SJ.51:1280–1285. term follow-up.226:1662–1666. 245. KOOISTRA HS. J Am Vet Med Assoc 1990. Urinary corticoid /creatinine ratios in the differentiation between pitu. BELAND. MATTHIESEN DT.153:521–525. PETERSON ME. Plasma aldosterone concentrations and plasma MONETTE S.178:50–53. JENKINS PJ. Corticoid produc- tion by four dogs with hyperfunctioning adrenocortical tumours 237. kalosis and adrenal-dependent hyperadrenocorticism. J Am Anim Hosp pin syndrome: Clinical features.232:77–84. Laparoscopic 235. MILLARD RP. 250. MACHIDA T. phenoxybenzamine on outcome in dogs undergoing adrenalec- tomy for pheochromocytoma. Evaluation of plasma an- 1333–1339. FUNAHASHI KR. Progesterone secreting adrenal mass in EC. Mitotane treatment of 32 dogs 236. Med Assoc 1999. HIRAYAMA K. FOSTER SF.86:139–146. BRESHEARS LA. Assessment of survey radiography and comparison with JW.28: (1994–2001).234:505–508. FELDMAN EC. KOPROWSKI A.37:444–453. Aldosterone-. RIJNBERK A. Canine hyperadrenocorticism ronism in a cat with an adrenal cortical carcinoma. YOSHII K. LUMEIJ JT. MASE T. al. Assoc 1994. PERLIS J.196: 2000. BOUVY BM. IMAI T. Am J Surg 1999. COHN LA. VOORHOUT G. PETERSON ME. Domest Anim Endocrinol 2005. PETERSON ME. KERL ME. and long- Assoc 2001. tion of sex hormones in a cat with an adrenocortical tumor. ISIDORI AM. KASS PH. PARDO ID. SCHWARTZ P. VAN DEN bilateral adrenal enlargement and excessive sex steroid hormone INGH TSGAM. KYLES AE. REFSAL 247. Concurrent pituitary and adrenal tumors in a cat with clinical signs of hyperadrenocorticism. TESKE E. Med 2005.91:371–377. ANOTHAYANONTHA L. H. Corticosterone. 17–20. MONSON JP. Vet Rec 1992. MATSUDA K.and cortisol-secreting adrenocortical carcinoma in 2008. KALTSAS GA. 252. BOER P. VAN DEN BERG G. PETERSON ME. Hyperaldosteronism and hyperprogeste- 242. A case-controlled study of laparoscopic compared with open dosterone-secreting adrenocortical tumor in a dog. localization of hyperfunctioning adrenocortical tumors in dogs. Assoc 2005. KINTZER PP. KUNTZ CA. J Am cortical neoplasia in the dog: 25 Cases (1980–1984). RIA GA. POWERS BE. FELDMAN EC. ROSENTHAL KL. RIJNBERK A. WELLS KL. References 151 233.205:54–61. BOER WH.22: 251. Surgical treatment of ad. in the surgical treatment of adrenal gland tumors in dogs: 41 cases Vet Rec 2003. 248. BESSER GM. The role of luteinizing hormone due to adrenocortical tumour in the dog. J Am Vet Med O’HARA AJ. DAVIDSON AP. BIRCHARD AJ. 246. a dog: case report. STOLP R. The ectopic adrenocorticotro- renocortical tumors: 21 cases (1990–1996). MEIJ BP. PICKENS EH. Hypokalaemic paresis.70:317–320.209:1097–102. Mol Cell Endocrinol 2002. SJOLLEMA BE. management. DAVIES DR. J Am Vet Med Assoc 1996. VOORHOUT G. KOOISTRA HS. J Vet Intern Med 1991. 249. Excessive produc- of surgical treatment for hyperadrenocorticism caused by adreno. itary-dependent hyperadrenocorticism and hyperadrenocorticism THIJSSEN JH. MOL JA. J Vet Intern due to adrenocortical neoplasia.197:117–125 239. IRWIN PJ. TEERDS KJ. GALAC S. J Am Vet Med Assoc 2003. MOL JA. VOORHOUT G. J Am Vet Med dogs with hyperadrenocorticism: 17 cases (1978–1995). Austral Vet J 2008. adrenalectomy for treatment of unilateral adrenocortical carcino- mas: technique. TANIYAMA H.19:355–358. GROSSMAN AB. FRAJESE V. Am J Vet Res 1990. J Small Anim Pract 2004. VOORHOUT G. RIJNBERK A.131: MAN EC NELSON RW. REUSCH CE. DECLUE AE. RIJNBERK A.214:1349–1353. with cortisol-secreting adrenocortical neoplasms. J Am Vet Assoc 1999. BOAG AK. DUPRÉ GP. GRECO DS. Surgical management of adrenal gland tumors peradrenocorticism in a dog due to ectopic secretion of adreno- with and without associated tumor thrombi in dogs: 40 cases corticotropic hormone. 255. INGH TSGAM. ILKIW JE.5:3–10. STAUDTE KL. MOL JA.19: in the pathogenesis of hyperadrenocorticism in neutered ferrets. 238.37:93–97. 258. complications. WELL-PRICE J. J Am Vet Vet Med Asoc 2009. KOOISTRA HS. Hy- GREGORY CR. WHITLEY EM. ROSSMEISL JH.45:263–266. BOORD M. NELSON RW. during treatment with mitotane (o. 240.189:1360–1364. FELD. 234. WELLS A. OLIVER PFGM. 1799–1803. GALAC S. Hyperadrenocorticism and hyperprogesteronemia in a cat x-ray computed tomography for detection of hyperfunctioning with an adrenocortical adenocarcinoma. corticosterone. KLEY S. al- kalosis and adrenal-dependent hyperadrenocorticism. 280. Hypokalaemic paresis. J Am Vet Med Assoc 1986. J Am Vet Med Ass 1985.51:60–65. AXELROD L.177:141–143. BEHREND EN. TSCHUOR F. Domest Anim Endocrinol 2008. HELMAN RG. dogs. Remission of dia. TOMEK A. pituitary-adrenal axis response and liver function. FELDMAN EC. BORETTI FS. J Small Anim Pract 2007.1:117–122.74:1036–1039. Vet J 2008. St. ciples and practice of endocrinology and metabolism. 281. BOER WH. FULGHUM RE. ed. SCHOEMAKER NJ. 275. J Vet Intern Med 1999.53: 266. Recovery of responses to ovine corticotropin-releasing hormone after withdra- and subclinical ACTH-independent macronodular adrenal hyper. KR. Effects on the hypothalamic-pitu- itary-adrenocortical axis. BOER P. REINE NJ. ANSON LW. J Am Anim Hosp Ass 2005. LOTHROP CD. ZENOBLE RD. GELZER ARM. Austral Vet J 272. J Clin Endocrinol Metab plasia and aberrant hormone receptors. COLLINS LG. BELLAH JR. J Am Vet Med Assoc 2005. ZINI E. VAN VONDEREN IK.191:685–688. In: Becker KL. hypercortisolism and hy. CHURCHER RK.25: YOSHII K. GLAZE MB. and the occurrence of side effects attributable 262.188:145–150. SELMAN PJ. Hyperaldosteronism in a cat with metastasised adrenocortical 716–720. 276. Luteinizing JA. Aust Vet J 1999. GRAVES GM. Saunders. JEFFERS JG. HIRAYAMA K. J Am Vet Med Assoc 1989. MEUTEN DJ. WHITLEY EM. AK. 267. with polyuria as the leading symptom.23:38–43. N’DIAYE N. 268.86:139–146. Canine and feline endocrinology pression of ACTH. 152 Adrenals 260. RANDOLPH JF. MATSUDA K. 467–470. VOORHOUT G. Prin. dosteronism in a dog. LACROIX A. PATNAIK duced in a dog after administration of corticosteroids and methyl. SCHICK RO. RUTTEMAN GR. Corticosterone. Adrenocortical suppression 2008. HAMET P. BREITSCHWERDT EB. TAKIGUCHI M. 284. Diabetes mellitus in. . BOER P. CRAWFORD MA. SPARKES AH. SHANLEY KJ. 289. N’DIAYE N. HENRY CJ. MIDDLETON DJ. COOK CS. 1999. duced hypercortisolaemia in a dog. O’HARA AJ. 279. J Am Vet Med Assoc 288. FLOOD SM. GIP-dependent adrenal Cushing’s syndrome with incomplete sup. Corticosteroid therapy. 290. LACROIX A. VAN SLUIJS FJ. BRIGEEL DF. HOLT PE. REFSAL K. Endocr Rev 2001. Domest Anim Endocrinol 2001. CROWE DT. 271. GOTTSCHALK J. Fatal iatrogenic 285.131:422–430. 1662–1666. RIJNBERK A. acetate and prednisolone. J Vet Med A 2006. Eur J Endocrinol 1994. Ectopic to glucocorticoid excess. MOORE GE. Phila. IJZER J. 261. 282. DAVIES DR. 270. TURNQUIST SE. BURGENER IA.20:227–240. KOOISTRA HS. 265. wal of a short course of glucocorticoid. KARS VJ. VROONHOVEN TJMV.77:641–645. Vet Quart 2001. FANG VS. ABRAHAM G. DE HERDER WW. J Am Anim Hosp Assoc 1989. KUIJTEN AM. 283. 119–131. HOPPER BJ. VOORHOUT G. CRISTOPOULOS S. GREENFIELD CL.24:293–307. J Feline Med Surg 1999. FOSTER SF. WATSON ADJ. STOLL MR. Primary hyperaldosteron- ism in a dog with concurrent lymphoma. II. and reproduction. MOL JA. Evidence for ototopical glucocorticoid-induced decrease in hypothalamic. IJZER J. BOER matory doses of prednisone in dogs. NAFE LA. YOUNG DW.13:386–390. CAYWOOD DD. 269. J Am Vet Med Assoc 1987. Idiopathic hyperal- delphia: Lippincott William & Wilkins 2001:751–764. EGER CE. KIUPEL M. HOFLAND LJ. Primary aldos- teronism (Conn’s syndrome) in a cat. 3rd ed. KOOISTRA HS. STAUDTE KL. 673–676. by topically applied corticosteroids in healthy dogs. VOORHOUT G. Horm Res 2005.35:411–416. ZELLISSEN PMJ.192:73–75. MACKAY AD. WAARDEN RJM. HOENIG M. in cats during therapy with megestrol and abnormal hormone receptors in adrenal Cushing’s syndrome. CROUGHS RJM. Colonic perforation in corticosteroid-treated 286. PETERSON ME. Duration of pituitary and adreno.48:584–587. NELSON RW. Pro- pokalaemia in a dog. KEARNEY MT. HUXTABLE CR. MACHIDA T. Clinical 278.34:278–283. 4 263. Deoxycorticosterone-secreting adrenocortical carcinoma in a prednisolone pulse therapy. HOHENHAUS AE. 287. SIEBER-RUCKSTUHL NS. Louis 2004:352–353. Empty sella syndrome.22:1326–1332. J Clin Endocrinol Metab 2000.22:75–110. UCHIDA E. BONDY PJ. TREMBLAY J. 274. hypertension. JOHNSON KD. HW.64: 1992. tumour. J Vet Med Sci 2008.70:317–320. MCCAW DL. TOOMBS JP. hyperadrenocorticism and megaoesophagus in a 277. GEROLD A. Cushing’s syndrome in a dog. REFSAL OHLERTH S. a case report and review of 273. LACROIX A. KEMPPAINEN RJ. RIJNBERK A. Aldosternoma in a dog putorius furo).and cortisol-secreting adrenocortical carcinoma in a dog: case report. KOOISTRA HS. Ophthalmic corticosteroid therapy: Systemic effects in the dog. J Vet Intern Med adrenocortical tumor in a dog. NACHREINER RF. TANIYAMA H. VAN DEN hormone-dependent Cushing’s syndrome in a pet ferret (Mustela INGH TSGAM. MOL JA.53: WH. KONAR M. IRWIN PJ. WEIGAND CM.146:3163–3171. CATERSON dachshund. BOURDEAU I. HOWE CJ. treatment of a cat with primary aldosteronism. ACTH-independent hyperadrenocorticism due to mealin. Aldosterone-. REUSCH CE. RIJNBERK A. Suppression of cortisol responses to exogenous adrenocorti- cotrophic hormone. Am J Vet Res 1992. Successful surgical 1988.52:235–240. ROBINSON WF. Endocrinology Primary hyperaldosteronism in two cats. ROSENFIELD RL.199:77–80. Can J Vet Res 1987. MOL 264.226: 2008.and aldosterone-secreting betes mellitus in cats with diabetic ketoacidosis. GALAC S. Hepatic carcinoid. CASEY comparative aspects. VAN DER cortical suppression after long-term administration of anti-inflam. J Small Anim Pract 1983. VAN SLUIJS FJ. ID. dog. GALAC S.187:841–845. gestin treatment in the dog. UNGEMACH FR. GILSON SD. SAND O. 309. PESSINA AC. HARVEY BJ. 306. Primary hyperaldosteron. Pri- mary hyperaldosteronism. J Am Anim Hosp Assoc 2007.127:50–56. delphia: W. MANNELLI M. KASS PH. The Veterinary Clinics of North America. 2004: 439–477. 7th ed. FREEL AM. JS. 299. diagnosis. triuretic factor and sodium escape phenomenon in patients with aldosteronism.42:191–194. IRNATEN M. SYME HM. KB.185:448–454. Phila- R. J Small Anim Pract 2001.295: 310. DJAJADININGRAT-LAANEN SC. 313. MOL JA. Horm Res corticotropic hormone ratios in healthy dogs and dogs with pri. In: Green- 352–369. STOWASSER M. BOER P. KATAYAMA T. Role of atrial ectomy and caval thrombectomy in a cat with primary hyperaldos- natriuretic peptide in mineralocorticoid escape phenomenon in teronism. 2004:200–234. regulation of renin and aldosterone in humans. J Urol 1989. MURATA K. VAN LAAR KJC. drome associated with an adrenal phaeochromocytoma in a dog. Rapid responses to aldosterone 295. SAKAMAKI T. FLETCHER MGR. MARKS SL. KERL ME. 293. In: Kintzer PP. J Vet Intern Med 2006.48:202–208. Sand O. FOREMAN O. Proc Soc Exp Biol Med 1987. JAVADI S. Pheochromocytoma in 50 dogs. Am J Med Sci 1988. CONNELL JMC. HOVE K. Role of epinephrine-induced hypokalemia in the W. eds. 304. CAREY RM. BARTHEZ PY. J Nephrol 2008. Phaeochromocytoma. Pheochromocytoma in dogs and cats. TASKER S. SCHOEMAN JP. THOMAS W. 301. KATO T. RODRIGUEZ CO.142:13–18. VAN SLUIJS FJ. MACKENZIE SM. ROBBEN JH. WHEELER SL. Metabolic alkalosis. FRASER Small Animal Practice. 314. Nr. MEHL ML. JAVADI S. Vol.22: 1333–1339. in cats. STIDWORTHY MF. HARVEY AM. STUBBS AK. FERRARIO CM.20:556–561. Primary aldosteronism: Part II: subtype differentiation and treatment. OVERLACK A. ASH RA. J Vet Intern Med 2008. SYMIYA H. span FS. 2. YOUNG WF.108: SHIMAZAKI J. 311. J Nephrol 2006. GOMEZ-SAN- CHEZ CE. SMITH TA. BROSHNIHAN mals. quences of altered regulation of aldosterone production for car- diovascular function. Budd-Chiari-like syn- Small Anim Pract 2007. ICHIKAWA S. In: Kintzer PP. 1997:359–380.19(suppl 9):S86-S96. 315. DJAJADININGRAT-LAANEN SC.18:625–631. The effect of adrenal surgery on plasma atrial na. KOOISTRA HS. In: Sjaastad O. Aldosterone-to-renin and cortisol-to-adreno. 1997:173–186. MAHLER ER. BILLER DS.28:85–104. and alpha-melanocyte-stimulating 317. J Vet Intern Med 2004. ELLIOTT J. TAJIMA Y.B. THAKKER RV. KRUSE HJ.19:355–358. J Ster Biochem Mol Biol 2008. TESKE E. JAVADI S. patients with primary aldosteronism. FELDMAN EC. 2001. VOORHOUT G. 300.93:3266–3281. tomy for pheochromocytoma. 1283–1288. and treatment of pa.21: 4 VAN DEN INGH TSGAM. PYPENDOP BH. 316. SLINGERLAND LI. BEHREND E. MATTU 294. ALZAMORA R. eds. BOER WH. HERRERA M. 302. 297. Animal Practice. References 153 291. Adrenal Medulla. Predictive factors and the effect of tients with primary aldosteronism: An Endocrine Society clinical phenoxybenzamine on outcome in dogs undergoing adrenalec- practice guideline. cortisol. Hove K. LABELLE P. adrenocorticotropic hormone. in the kidney and colon. 27.22: 292. Domest Anim Endocrinol 2005. ed. Small 298. 307. NAKAMURA T. TWEDT DC. J Vet Intern 305. SJAASTAD O. 312. 303. DECLUE AE. Philadelphia: STUMPE KO. nary aldosterone to creatinine ratio in cats before and after sup- pression with salt or fludorcortisone. DAVIES E. NELSON RW. GALAC S. WITHROW SJ. Adrenal physiology. KOOISTRA HS. RIJNBERK A. a mediator of progressive renal disease 455–462. Uri- 173–182. J Clin Endocrinol Metab 2008. GOLDFIEN A. Measurement of aldosterone in feline. BOER P. 27. McENEANEY V. MANTERO F.7: BEECK SE. SECCIA TM.8: BOER WH.217:21–215. KEMPPAINEN RJ. A lifetime aldosterone excess: Long-term conse. FELD- MONTORI VM. EISENHOFER G. FITZGERALD PA. Hemodynamic and neurohormonal changes in the develop- ment of DOC hypertenstion in the dog. MOHARA O. Multiple endocrine neoplasia. Pheochromocytoma in dogs: 61 cases (1984–1995). ROSSI GP. . BRESHEARS LE. COHN LA. Saunders Company. MAT- hormone in healthy cats. MCNIEL EA. Physiology of Domestic Ani- 296. Adrenal Disorders. GALAC S. KHANNA A. KURTZMAN NA. BOER P. FURUTA H. Saunders Company. Adrenal Disorders. Plasma 228–232.29:133–154. PERLIS J. RIJNBERK A.43:209–214. MAN EC NELSON RW. FUNDER JW. ed. UENO Y. J Vet Intern Med 1997. BAILEY SR. J Feline Med Surg 2005. LENDERS JWM. J Lab Clin Med 1996. Adrenal- KOGURE M.11:272–278. The endocrine system. Vol. Use of abdominal ultra- Med 2005. VAN DE BEEK MG. NAKADA T. RUPPERT M. J Vet Intern Med 2008. KYLES AE. KOOISTRA HS. SATO K. J 318. sonography in the diagnosis of primary hyperaldosteronism in a cat. Hyperaldosteronism and hyperprogeste- ronism in a cat with an adrenal cortical carcinoma. Oslo: Scandinavian Veterinary Press. CAMMEL- ism in the cat: a series of 13 cases. KOOISTRA HS. Case detection. Endocr Rev 2008.B. MOORE LE. The Veterinary Clinics of North America. PASCOE PJ. WOO J. J Am Vet Med Assoc 2000. Gardner DG. PARDO ID. TEUCCI M. J Vet Intern Med 1994. canine and human urine. FARDELLA C. Lancet 2005. New York: Lang Medical Books/McGraw-Hill. KOLLOCH RE. ROSE SA.56:67–72 mary hypoadrenocorticism. 2.366:665–75. VAN DONGEN AM. renin activity and plasma concentrations of aldosterone. Nr. 308. 310–317. PACAK K. Basic & Clinical Endocrinology. complications. 1427–1434. YOUNG WF. J Am Vet Med Assoc 2001. SAWKA AM. 328. J Am Vet Med Assoc 2003. Radiol Ultrasound 1997. Fischer J. HARDIE EM. Urinary catecholamine and metanephrine to cre- atinine ratios in healthy dogs at home and in a hospital environ- 321. ALE. LOUVET A. GRE- for the diagnosis of a pheochromocytoma in a dog. NELSON RW. J Small Anim Pract 2005. London: McGraw-Hill In- ultrasonographic evaluation of adrenal lesions in 26 dogs. A com- EM. J Clin Endocrinol Metab 2003. SUAREZ ML. FELD. Aortic thromboembolism and retroperi- toneal hemorrhage associated with a pheochromocytoma in a dog. WALTHER MCCM. 88:553–558. VILA M. Bertagna X. 2001: 337–339. KYLES AE. GILSON SD. Biochemical diagnosis of pheo.17:164–169. PRESTON CA. HARDIE 326.34:52–55. and without associated tumor thrombi in dogs: 40 cases (1994– 2001). Groop L. EISENHOFER G. KOOK PH. and results in mocytoma. BORETTI FS.23:195–200. Use of iodine metaiodobenzylguanidine scintigraphy THEWS KG. 324. KASS PH. REUSCH CE.17:917–922. treated by en bloc resection including the suprarenal caudal vena chromocytoma. DENIS B. Vet ternational. ILKIW JE. COLE SG. In: Pinchera A. 2007. PENNINCK DG. ORTON EC. Surgical treatment 323. FELDMAN EC. ALWOOD AJ.287: cava in a dog. Which test is best? J Am Med Assoc 2002. LINEHAN WM. 331. Crit Care 2007. Wass J. Diagnostic imaging in canine pheochro. .41:499–506 six dogs. Nontraumatic rupture of an adrenal gland parison of biochemical tests for pheochromocytoma: measure- tumor causing intra-abdominal or retroperitoneal hemorrhage in ment of fractionated plasma metanephrines compared with the four dogs. J Vet Intern Med 2003. The adrenal medulla: basic concepts. PACAK K. FRIBERG P. WITHROW SJ. of pheochromocytoma: technique. MANNELLI M. WRIGHT KN. BROWN AJ. KEISER HR. ESPINO L. WHITTEMORE JC. BERRY CR. FELDMAN EC. 329. Serio M. Schoemaker J. GOLD. LENDERS JWM. 325. Vet Radiol Ultrasound 2000.223:654–662. LOPEZ M. SANTAMARINA G.21:388–393. Surgical management of adrenal gland tumors with Ultrasound 1993. KYLES AE. SINGH R. Vet Surg 1994. BRAVO EL. J Vet Emerg 327. BESSO JG. J Vet Intern Med 4 MAN N. HERSBERGER M. Endocrinology and Metabolism. 154 Adrenals 319. LAZARD P.46:591–596. 322.219:329–333. DE COCK HEV. ment and in 2 dogs with pheochromocytoma. ROSENSTEIN DS. Retrospective eds. MA- MAN JM. Phaeochromocytoma STEIN DS. combination of 24-hour urinary metanephrines and catechola- mines.38:448–455. GLAUS TM. GLIATTO JM. Malignant pheochro- mocytoma presenting as a bradyarrhythmia in a dog. Vet Radiol GORY CR. 320. JAESCHKE R. 330. BREITSCHWERDT EB. 2: pancreas. It is located in the epigastric and mesogastric segments of the abdominal cavity and con- sists of a thin. responsible for both diges- tion and glucose homeostasis. Schematic drawing of the ventral aspect of the pancreas. There are four major types of cells in the islets: b-cells (by showing its left (L) and right (R) lobes. The endocrine function of the pancreas is provided by clusters of cells known as the islets of Langerhans. 5. ACTH. and pancreastatin.5 The islets are highly vascularized and their capillaries are fe- nestrated. gastrin. Although some of these appear to participate in the regulation of islet-cell function. the apex of which lies caudo- medial to the pylorus (fig. In the adult animal they constitute roughly 1–2 % of the total pancreatic Figure 5. venous drainage is by vessels that terminate in the portal vein.6 The islets are innervated by sympathetic and para.1: mass and are scattered irregularly throughout the exocrine tis.2). their rel- evance is largely unknown. Reusch Joris H. Kooistra 5.4 Several other peptides and hormones have been identified in the islets by the use of immunostaining techniques including TRH. and PP-cells that produce pancreatic polypeptide. a-cells that produce glucagon. Blood is supplied by branches of the celiac and cranial mes- enteric arteries.2 Most textbooks state that b-cells are located in the center of the islet but several studies have shown that the distribution differs between species and that in dogs and cats b-cells are often located in the periphery of the islet (fig.1 Introduction 5. calcitonin gene-related peptide. slender right (duodenal) lobe and a shorter. In most dogs the pancreas has two excretory ducts. 155 5 Endocrine Pancreas Claudia E. showing an islet of Langerhans sympathetic fibers which influence the release of pancreatic surrounded by exocrine tissue. staining for amylin. . There is great variation in the pattern of the duct system within and between species. An islet-acinar portal sys- tem communicates between the endocrine and exocrine pan- creatic tissue.3. It is assumed that blood coming from the islets flows into the acinar capillaries before leaving the pancreas and that islet hormones have a role in regulating the exocrine Figure 5. sue.1. whereas in most cats only one duct persists. d-cells that produce somato- statin. thicker left (splenic) lobe. 5. increasing permeability. far the most abundant) that produce insulin and amylin. in con- formity with its origin from two different primordia.1). The form is that of a V.1. Robben Hans S. cholecystokinin. Histologic section of the pancreas of a healthy cat. which are united at the pancreatic body. b-cells (red) are shown by immunohistochemical hormones.1 The endocrine pancreas 5 The pancreas is an essential organ. while differing from canine insulin at the b-cells to insulin by removal of a peptide fragment called three positions (table 5. The synthesis of insulin begins in the rough endoplasmic reti- culum with the formation of preproinsulin. 5. mainly in the liver and kidney. Within the b-cells glucose is metabolized (phos.1). 5.7 blood glucose concentration and the insulin secretion rate (fig. but its measurement is mainly used in human medicine and for research purposes. Insulin and C-peptide are packaged and stored in secretory granules and released in equimolar amounts by the process of exocytosis.7 Insulin consists of two polypeptide chains. Circulating insulin is almost en. connected tirely unbound.3: Feline insulin is most similar to bovine insulin. so it does not appear in the circu- lation in appreciable quantities. The in the blood and there is a positive feedback relation between increase in cytosolic calcium then triggers insulin release.1. but in the circulation it is a monomer. The body has complex mech. 5. which allows rapid equili. 156 Endocrine Pancreas 5. C-peptide (connecting peptide). of which insulin is the most important. The increase in the ATP:ADP ratio is followed protein.3). The concentration of C-peptide in plasma is an indicator of b-cell function. It is followed by a slowly increasing second phase that is di- centrations. Proinsulin is further processed to insulin by removal of 5 another peptide.4). rectly related to the level to which glucose is elevated . formed insulin that is readily released from secretion granules. Insulin is the only hormone that decreases blood glucose concentration. meals as well as increased insulin secretion following meals. by closure of ATP-sensitive potassium channels in the b-cell anisms to ensure adequate basal insulin secretion between membrane. Proinsulin is processed in in only one amino acid. Insulin consists of an A chain of 21 amino acids and a B chain of 30 amino acids.3). which is con- verted to proinsulin by removal of a small peptide fragment. This in turn causes membrane depolarization and opening of The most important regulator is the concentration of glucose voltage-dependent calcium channels in the membrane. The first phase starts within a Glucose is transported into b-cells via the glucose transporter few minutes. and involves exocytosis of pre- protein GLUT 2 (chapter 5. has a half-life of 5–8 min. There is some uncertainty whether elevated fasting proinsulin levels and a change in the proinsulin:insulin or proinsulin:C-peptide ratio are early in- dicators of b-cell damage.2 Insulin synthesis and structure Glucose homeostasis is maintained by a complex system of regulating and modulating hormones and factors. connected by two disulfide bridges (fig. The insulin molecule has been highly conserved during evolution and the differences be- tween species are small. called C-peptide (connecting peptide) (fig. Proinsulin is largely con- verted before secretion.4). and is metabolized by two disulfide bridges. an A chain of 21 amino acids and a B chain of 30 amino acids. preventing potassium ions from leaving the b-cell. also differing Synthesis and secretion of insulin.3 Regulation of insulin secretion Continuous availability and moment-to-moment adjustment phorylation by glucokinase and production of pyruvate) to of insulin is essential for the normal control of carbohydrate. bration between extracellular and intracellular glucose con.1. Figure 5. Within the granules insulin coprecipi- tates with zinc ions to form hexamers and microcrystals. 5. and lipid metabolism.1. lasts 5–10 min. produce ATP. Canine insulin is identical to porcine insulin and differs in just one amino acid from human insulin. The secretion of insulin is biphasic following intravenous in- jection of a bolus of glucose. g.. sorbitol) Several other pancreatic hormones influence insulin secretion Amino acids directly or indirectly. Stimulation can be direct or potentiated by incretins. also called gastric inhibitory polypeptide (GIP). Several effects of amylin. (fig.1: Species differences in the amino acid sequence of insulin nounced insulin secretion than does glucose given intra- A8 A10 A18 B30 venously. amino acids and fatty acids also stimulate insulin secre- tion. In addition to glucose and other sugars. but it is not known whether these also occur in dogs and cats. where they interact with Feline Ala Val His Ala their receptors on b-cells to amplify insulin secretion. and delay of gastric emptying. modulation Glucagon of glucagon release. GLP-1. 5.2).5). cholecystokinin) tabolism.8 . which have been dem- onstrated in humans and rodents. Several other sugars Epinephrine. Canine Thr Ile Asn Ala Incretins are secreted by endocrine cells in the gastrointestinal tract in response to nutrients and are then carried in the Bovine Ala Val Asn Ala bloodstream to the pancreatic islets. are of physiological rele. In sev- eral species GLP-1 has additional effects. This phenomenon is due to the actions of so-called incretin hormones. In general terms. vated glucose concentration and inhibited by a low glucose concentration.5: Relation between insulin and glucose: insulin secretion is stimulated by an ele. Biphasic insulin response to an intravenous glucose injection. but its importance is still Stimulants of insulin secretion Inhibitors of insulin secretion unclear. Amylin (islet amyloid polypeptide. xylitol. Fatty acids IAPP) is a single-chain 37-amino-acid peptide cosecreted Incretins (e.2: Factors influencing insulin secretion fluence on islet hormone release. Orally administered glucose triggers more pro. The autonomous nerve system also exerts a modulating in. the most important being glucagon-like Human Thr Ile Asn Thr peptide-1 (GLP-1) and glucose-dependent insulinotropic Porcine Thr Ile Asn Ala polypeptide. such as reduction of glucagon secretion and stimulation of b-cell differentiation and proliferation. (gastrin. insulin secretion is stimulated by vagal nerve fibers and inhibited by sympathetic nerve fibers Glucose Somatostatin (table 5. Introduction 157 5 Figure 5.4: Figure 5. Table 5. Amylin Keto acids and its metabolic effects may play a role in the development of Acetylcholine human and feline type 2 diabetes mellitus.g. norepinephrine (e.. GIP) with insulin. Other intestinal hormones vance and contribute to the regulation of nutrient me. They include inhibition of food intake. Table 5. The »substrate« proteins phosphorylated by the insulin recep. and intestinal tract. the GLUT 4 mol- feeding as well as during food deprivation. and fatty acids as fat. The a-subunits are extracel. muscle. When insulin levels decrease. After food intake. glucose uptake is insulin-independent and occurs via other GLUT proteins. the so- food intake increases and blood glucose begins to decrease. such that insulin inhibits glucagon secretion and glucagon stimulates Glucose is a polar molecule and cannot diffuse across cell release of insulin. Dysregulation within the with insulin to maintain normal blood glucose concentration signaling cascade may lead to insulin resistance. amino acids. They are key mediators in the insulin signaling pathway and . the conversion of amino acids to glucose. availability of amino acids for gluconeogenesis. phosphofructokinase. tein. mainly affecting protein 5 largely controlled by the blood glucose concentration and to a and glucose metabolism. The main target tissues for insulin sues in which insulin mediates glucose uptake (such as muscle are liver. increases the activity of lipoprotein lipase. followed several hours later by de- lesser extent by the concentration of amino acids. GLUT 4 is the crine inhibitor of insulin and glucagon secretion. In various other tissues such as brain. cose transport in these two tissues by causing the translocation terrelations and there are certainly other hormones and effects of GLUT 4 molecules from the cytosol to the cell membrane.1. Its main function is ing to high-affinity cell surface receptors. As the interval after Within seconds after insulin binds to its receptor. Each the gastrointestinal tract. Insulin activates the enzymes pyru- proteins. They mediate their activity by transferring In adipose tissue insulin promotes the synthesis of lipids and phosphate groups to tyrosine residues on intracellular target inhibits their degradation. Inhibition of lipolysis is mediated by inhibition of hormone- tor are called insulin-receptor substrate (IRS) molecules. ecules are removed from the cell membrane. and phosphate. for insulin is embedded in the plasma membrane. motes protein synthesis in peripheral tissues. Insulin facilitates and adipose tissue) as well as in those in which it does not the oxidation of glucose to pyruvate and lactate by the induc- (such as liver. The insulin receptor belongs to the large group of tyrosine ki- nase receptors. How the intra- that glucagon disturbances play an important role in diabetes cellular signals lead to the final biological effects of insulin is mellitus. 5.6). kidney. It is a potentially important para. and prevents catabolism of nutrient stores. however. it is obvious that with which they fuse and function as pores for glucose entry the pancreatic islets finely tune metabolism during times of (fig. At tified in many tissues. named in order of their discovery. in the endothelium of capillaries of extrahepatic tissues. while the insulin decreases the activity of hepatic enzymes involved in b-subunits penetrate through the cell membrane (fig. In short. which promotes the entry of fatty acids into adipose tissue. and pyruvate kinase.7). GLUT 1–14. major insulin-responsive transporter and is found almost ex- clusively in muscle and adipose tissue. and adipose tissue (fig 5. 158 Endocrine Pancreas Glucagon. kidneys. Intermediate energy stores. Its transport is facilitated in several tissues by a family of glucose transporter (GLUT) proteins or (in the Somatostatin is a 14-amino-acid peptide that has been iden. which pro- mote the synthesis of fatty acids from acetyl-CoA. least 14 different GLUT proteins have been identified in hu- hibitory effect on absorption and digestion and on motility of mans.1 5. sensitive lipase. amino acids as pro- widely distributed throughout the body and are found in tis. It is a major catabolic hormone acting in concert the focus of very active research. paracrine signaling between insulin and glucagon. called rapid insulin actions lead to the cellular uptake of glu- glucagon is secreted to prevent hypoglycemia and to mobilize cose. brain. 5. and erythrocytes). It is a tetra. Additionally. liver. Insulin also Binding of insulin to the a-subunits triggers the tyrosine ki. intestine and kidney) by active transport with sodium. Insulin promotes glycogen synthesis in Like the receptors for other protein hormones. a single-chain peptide of 29 amino acids. membranes. tion of enzymes such as glucokinase. an enzyme located nase activity of the b-subunits.4 Actions of insulin Insulin is the most important anabolic hormone in the body Insulin regulates numerous metabolic processes through bind. but there is increasing evidence complex network of intracellular molecules. These receptors are to ensure storage of glucose as glycogen. potassium. molecules seem to play a major role. lation which activates the catalytic activity of the receptor. in which IRS by opposing many of the key metabolic effects of insulin. There is layed actions which mainly concern lipid metabolism. the receptor liver and muscle by increasing glycogen synthetase activity. has long act as docking proteins between the insulin receptor and a been a »neglected« hormone. Gluconeogenesis is decreased by insulin because insulin pro- meric protein. which are not yet known. leading to autophosphory. appears to have evolved for a specific task. vate dehydrogenase and acetyl-CoA carboxylase. Insulin stimulates glu- The hormones mentioned here have additional effects and in. Changes in the ratio of insulin to glucagon are actions occur within a few minutes. decreasing the units linked by disulfide bonds. Pancreatic somatostatin has an in.6). insulin secretion increases to conserve energy and to prevent hyperglycemia. composed of two a-subunits and two b-sub. lular and contain insulin binding domains. muscle. It is sulin-dependent and non-insulin-dependent diabetes mellitus currently assumed that diabetes in dogs is usually similar to (IDDM. as well as regulation of cell growth and expression of various genes. protein. This interaction allows growth and survival on diets of almost exclusively protein and fat. and lipid. Although there is still much to unravel.1 Classification Traditionally. Recent studies have provided evidence of the similarity of diabetes in hu- mans.10 than etiology and were therefore regarded as more confusing than helpful. Glucagon acts pre- dominantly on the liver. It is also a ke- togenic hormone. into two broad categories. Insulin and glucagon act in concert following ingestion of protein. diabetes mellitus in dogs and cats has been cat- egorized more or less according to the scheme used in human medicine. dogs. while glucagon counters the decrease in glucose by stimulating hepatic gluconeogenesis.2. and adipose tissue. increasing gluconeogenesis and gly- cogenolysis and decreasing glycogen synthesis.2 Diabetes mellitus 5.7: was justifiable. etiopathogenesis of diabetes in pet animals. Both are released when amino acids increase in the plasma. and cats. IRS (insulin receptor substrate) acts as a docking protein between 5 the receptor and a complex network of intracellular signaling molecules. The Expert Committee on the Diagnosis and Clas- sification of Diabetes Mellitus of the American Diabetes As- sociation. working in close collaboration with the WHO. Insulin causes a decrease in blood glucose and amino acids. due to its ability to enhance lipolysis. since they were based on treatment rather type 1 and diabetes in cats closely resembles type 2. 5. because of the scarcity of knowledge about the Effects of insulin in liver. The vast majority of human cases of diabetes fall The same committee has abandoned the long-used terms in. Diabetes mellitus 159 Figure 5. Insulin stimulates protein synthesis and inhibits protein degra- dation and thus promotes a positive nitrogen balance. NIDDM). Glucose binding to its receptor protein initiates activation cascades that result in translocation of GLUT 4 to the cell membrane. However. insulin action or both«. now named type 1 and type 2. de- fines diabetes mellitus in their latest report (2008) as »a group of metabolic diseases characterized by hyperglycemia result- ing from defects in insulin secretion. the human classification may be used in order to facilitate recognition and differentiation of the various forms of the disease. This facilitates glucose influx and the synthesis of gly- cogen. . it has long been uncertain whether this Figure 5.6: Simplified scheme of insulin action.9 The main antagonist of insulin is glucagon. is of 5 course with manifestation later in life (latent autoimmune little importance in dogs and cats. hepatic steatosis and hyperlipidemia. When the renal capacity for glucose reabsorption is and IL-6. Some of the latter.2. type 2 can usually be managed without insulin the lack of insulin lead to acceleration of lipid catabolism. A marker of the disease is the presence of circulating uals having a susceptibility to the disease. and protein metabolism (fig.2). which is largely identical to the previous NIDDM. the cause is an absolute deficiency of insulin secre. hypercortisolism. and various other mechanisms play a role. The loss of energy via glucos- Dysfunction of b-cells is essential for the development of type uria is compensated by increased food intake. In contrast to type 1 hydrate metabolism. e. muscle. such as adiponectin and pos. The extent of glucose humans. exceeded. but it may also have a slow and initially mild The fourth category in humans. This other than defined as type 1 or type 2. pose tissue. administration. There is a subgroup of type 1 dia. Type 2.8). 160 Endocrine Pancreas In type 1 diabetes. refers CoA. but eventually this is no longer possible.g. The increased availability of glycerol accelerates hepatic glu- toacidosis is much higher in type 1. such as TNF-a mones.2. . glutamic acid decarboxylase of type 1 diabetes with endocrine diseases that result from (GAD) autoantibodies. diabetes bodies. lation by the hypothalamus. not yet described in animals. relative lack of insulin has profound effects on carbohydrate. with diestrus in dogs can be considered its equivalent betes. Diabetes can develop secondary ketoacidosis. which is strongly inherited with no (chapter 2. It is characterized by 5. due to deficient glucose utiliz- cose-induced insulin secretion. certain drugs. lin resistance may be compensated by increased insulin secre- mans has a strong genetic basis and is promoted by obesity. hypersecretion of counterregulatory hormones very-low density lipoproteins (VLDL). The resulting osmotic ter 11). such the increased production of glucose. A number of genetic syndromes. although it is un. but the diabetes associated diabetes in adults. called mia is the unopposed production of glucose in the liver via adipokines. insu- are liver. and adipose tissue.2. The increased levels of NEFA are also trans- ported to the liver. at least for several years. but to a lesser extent. and administration of glucocorticoids or progestins. and erythrocytes.2 Metabolic disturbances two defects: insulin resistance and b-cell dysfunction. »Other specific types«.1). ation. The main sites of insulin resistance inadequate for the degree of insulin resistance. gestational diabetes. termed idiopathic. common autoimmune destructive processes. as do other stress hor- as NEFAs and proinflammtory cytokines. Intestinal absorption of glucose is unaffected. These disease islet-related autoantibodies such as islet-cell autoantibodies associations should be differentiated from the coexistence (ICA). Also. Hyperglycemia develops when insulin secretion is absent or is certain which is primary. as reflected by the worldwide fat. and diabetes is Another suggested factor is the deposition of amyloid in the sometimes regarded as a disease of lipid rather than of carbo- islets due to polymerization of amylin. in particular since the discovery that entry of glucose into brain. Hyperglycemia results recognition that the increasing prevalence of obesity parallels in part from the reduced entry of glucose into muscle and adi- the increasing prevalence of type 2 diabetes. and tyrosine phosphatase IA-2 anti. Glucagon contributes to sibly leptin. There is a genetic contribution and the autoimmune with hypothyroidism (chapter 3. coneogenesis. induce or worsen insulin resistance (see also chap. but others. as is ject of intense research. glucose is lost in the urine. Increased hepatic concentration of fatty acids to disorders of the exocrine pancreas (pancreatitis. Insulin resistance in hu. pancreatic also results in enhanced hepatic synthesis of triglycerides and carcinoma). The reasons for b-cell failure are largely unknown. evidence for autoimmunity. overt diabetes only develops in those individ- b-cells.4. 5. which can result in also relevant in dogs and cats. velopment of diabetes and its complications. kidney. which accounts for about 10 % of cases in are also included in this category. Absolute or physical inactivity. and high glucose levels. The intracellular deficits of glucose and diabetes. Hyperglycemia and hyperlipidemia can be Derangement of lipid metabolism plays a major role in the de- damaging (referred to as glucose toxicity and lipotoxicity). LADA). Obesity is of great importance. diuresis is compensated by increased water intake and the polydipsia may become severe. The disease is typically diagnosed in children and adolescents. may improve insulin sensitivity. poorly defined. the amount of which may exceed the need for ATP to diabetes that develops in association with diseases or factors production by further oxidation in the Krebs cycle.. The consequences are (hypersomatotropism. A characteristic feature is loss of first-phase glu. the risk of ke. hyperthyroidism). There they undergo b-oxidation to acetyl The third category of diabetes. Appetite stimu- 2 diabetes. intolerance varies widely and insulin therapy may or may tion due to T-cell mediated autoimmune destruction of the not be required. accounts for up to 90 % of human cases. insulin antibodies (IA). Initially.3. Some of these are causes a shift to ketone body production. paired. gluconeogenesis and glycogenolysis. The adipose tissue is an active organ releasing large amounts of second and potentially more important cause of hyperglyce- nonesterified fatty acids (NEFA) and various proteins. The second phase is also im.1) or Addison’s disease process is triggered by environmental factors that are still (chapter 4. tion. Both are usually present at the time of diagnosis. Obesity is a sub. risk of diabetes was shown to be associated with certain ucts. and lenses. called secondary diabetes) include pancreatic destruction due to acute or chronic pancreatitis or pancreatic neoplasia. The conse. and altered membrane per. There has been no though neuropathy is rarely recognized clinically in dogs. orders in dogs. Hu- meability. GAD65. Evidence for acute or chronic pancreatitis was reported in 13 % of dogs . skin. Protein metabolism shifts toward decreased protein synthesis 5. These in. dogs the disease is similar to human type 1 diabetes. The increased availability of amino acids further accelerates hepatic gluconeogenesis. type 1 diabetes termed latent autoimmune diabetes in adults most probably because of the shorter lifespan.14.12. Since most dogs are middle-aged to elderly at the time of diagnosis.15 In many and possibly cachexia.8: Overview of the effects of insulin deficiency. Diabetes mellitus 161 5 Figure 5.3–0. it is evidence that dogs develop an equivalent of human type 2 a common problem in cats. most likely not due to autoimmune destruc- neuropathies similar to those in diabetic humans. having a prevalence of 0. Antibodies against b-cells and several verely affect the quality of life and life expectancy.17 The observation that certain breeds of dogs are creased activity of the polyol pathway with accumulation of predisposed to diabetes18 recently led to genetic studies. process. Recent studies have shown that the activity of the enzyme aldose reductase in Dogs with diabetes may have concurrent endocrine diseases the lens is increased.2.25 Electron microscopic studies of peripheral nerves have re.16. dog leukocyte antigen (DLA) haplotypes. human autoimmune polyendocrine syndrome type 2.3 Diabetes mellitus in dogs and increased proteolysis. which leads to accumulation of sorbitol. Aldose reductase activity is low in the lenses of mans who carry a particular HLA genotype are at a higher older cats. and decreased antioxidant status. tion but to b-cell aplasia or abiotrophy. disease) and the nervous system. which may in part explain why cats have much less risk of diabetes.11 plotype in dogs. loss of muscle mass. and insulin resistance due to other diseases or factors. islet components (insulin. a combination which may be equivalent to swelling and rupture of lens fibers. Addison’s disease). a situation similar to the high risk DLA ha- serious diabetic cataracts. The hypo. The most com.19–24 mon diabetic complication in dogs is cataract. The sorbitol. suggesting that these antigens are involved in the autoimmune theses that have been proposed to explain these include in.6 %. IA2) have been demon- volve the vascular system (microvascular and macrovascular strated in the serum of dogs with newly diagnosed diabetes. there is an influx of water. Diabetes mellitus occurs occasionally in dogs less than twelve vealed that more than 90 % of diabetic dogs and cats have months of age.13 Al. Other forms of diabetes (a category previously and the underlying mechanism are unknown. which is caused by autoimmune destruction of b-cells in genetically In diabetic humans there are chronic complications that se. The reasons for this difference diabetes. increased formation of advanced glycation end prod. canine The serious chronic complications in humans – nephropathy type 1 diabetes seems to correspond best to the subgroup of and cardiovascular disease – are rare in diabetic dogs and cats. of possible autoimmune etiology (such as hypothyroidism and Because sorbitol is hyperosmotic. predisposed individuals. Diabetes mellitus is one of the most common endocrine dis- quences are negative nitrogen balance. (LADA). Administered progestins and /or Blood glucose concentration may also be increased by anxiety glucocorticoids may also induce diabetes. a cause and effect relation is not yet clear. Most diabetic dogs are not presented for veterinary sufficient b-cell function. Exocrine be obese. Remission of diabetes is possible. miniature schnauzers. and poodles (miniature and toy) are at increased risk for diabetes. Diabetes is diagnosed on the basis of appropriate symptoms ter 2. and vomiting (see in principle a physiological event. however.2. Tibetan. most being five or more years of age.15. dog with so-called uncomplicated diabetes is usually in relatively good physical condition. various terrier breeds (Australian. Glucosuria alone is insufficient for the di- agnosis of diabetes. Glucose intolerance and diabetes examination until blood glucose concentration exceeds the may also be induced by glucocorticoids.2).4.30 Due to the poten- tial danger of lens-induced uveitis. In most dogs with renal capacity for glucose reabsorption (~ 10 mmol/l) and hypercortisolism.31 The prognosis following early other. ease such as pancreatitis or infections.28. and rarely occurs in dogs 쏝 12 months of age. pan- creatitis may also cause such destruction of b-cells that dia. but this hyperglycemia is either mild or than in dogs. 162 Endocrine Pancreas Signalment and clinical manifestations Diabetes typically occurs in middle-aged to elderly dogs.9). and weight loss. Acromegalic features caused by the growth. Symptoms and signs other than cataract depend on the dur- betes ensues. beagles. Its haircoat may pancreatic insufficiency can also be a sequela of pancreatitis be dull and hepatomegaly may be palpable.29 This is lethargy. only about 10 % of the cases. as it is in cats. There are have been mild symptoms in preceding diestrus phases that no diagnostic criteria for diabetes in dogs. its cause (e. provided mans. If mild hyperglycemia (blood glucose 7–9 mmol/l) persists in an unstressed and otherwise unremarkable dog. blood glucose concentration is hence polyuria and polydipsia develop.g.25 The four typical symptoms of diabetes mellitus are polyuria. West Highland white). Overt diabetes develops in is not a relevant differential diagnosis in dogs. and while diabetes is a known risk factor for pancreatitis.2). It has also been hypothesized that b-cell antigens ation and severity of the diabetes and possible concurrent dis- released in the inflammatory process could stimulate an im.2. reduced water intake. of normal weight. Diagnosis and workup promoting effects of GH may also be obvious (chap. the eyes should be moni- tored closely during the course of diabetes. more often in cats and by other diseases.. a search for diseases causing insulin resistance. may be warranted. anorexia. persistent hyperglycemia. and glucosuria.9: unnoticed until the dog develops blindness due to diabetic Bilateral cataract in a dog with diabetes mellitus. In contrast. diabetes during this phase of the cycle due to the diabetogenic actions of GH. the and is occasionally seen in dogs with diabetes.23. polyphagia. The risk of cap- sule rupture appears to be particularly high in dogs with with diabetes mellitus in one study26 and 28 % of those in an.4. 5. or underweight. Before the onset of overt diabetes.27 However. The diabetic dog may mune reaction that exacerbates the destruction. such as hypercortisolism. rapidly progressing cataracts. German shepherd dog. About 50 % of diabetic dogs develop cata- ract within the first six months and about 80 % within 16 months after the diagnosis of diabetes. dogs with dia- The increase in progesterone levels during diestrus in intact betes complicated by ketoacidosis or the hyperosmolar non- bitches results in a rise in circulating levels of growth hor. cataracts (fig. and thus the blood glucose level signifying diabetes is that castration is performed promptly and that there is still imprecise.19 Samoyeds. but some dogs develop below). ketotic syndrome are usually presented with symptoms of mone (GH) originating from the mammary gland. head trauma32 or seizures) is readily apparent. The proportion of females has de- creased from more than 70 % to around 55 %. since it may also by caused by renal defects . and golden retriever ap- 5 pear to be at low risk18. most probably because of more frequent early neutering and the consequent decrease in diestrus-associated diabetes (chapter 2. as there are in hu- were overlooked. Otherwise. The boxer. Stress hyperglycemia normal or only slightly elevated. These are sometimes Figure 5. Preliminary genetic studies have sug- gested a genetic component for both susceptibility and resis- tance to diabetes. cairn. surgical intervention is usually good. there may and signs. polydipsia. or diabetogenic drugs? who follows a strict protocol (see chapter 13. fructosamine is usually 쏜 400 µmol/l and may be 쏜 1000 µmol/l. It is not necessary to maintain Further workup should answer the following questions: normal or near normal blood glucose levels. Glycated Treatment hemoglobin is another indicator of long-term metabolic con. thereby enabling the animal to have a good quality of life. reasons. and glucosuria. and bacteriuria with or tween glucose and amino groups on plasma proteins and it re. Testing for hypercortisolism should be delayed tosamine level at the time of diagnosis but diabetes of very until treatment of the diabetes is stabilized. and control of concurrent or underlying problems. ment of the diabetes? 쎱 Is there evidence for underlying disease /factors which Successful treatment requires that the owner be highly moti- could have caused the diabetes. without pyuria. but are usually about 200–350 µmol/l. tivity (cPLI). and urine culture should be performed..33 Measurement of fructosamine is not Routine hematology. Typical findings long-term management and an initial measurement provides include a stress leukogram.1). such as pancreatitis. dietary management. slight to moderate a reference point and is therefore recommended. (hypoglycemia and ketoacidosis). plasma or serum biochemistry. as is the aim in 쎱 How severe is the disease.e. ab- blood glucose concentration. and canine pancreatic lipase immunoreac- It is unusual for a diabetic dog or cat to have a normal fruc. Treatment consists of insulin therapy. There may be a trace of ketone bodies in the flects the mean blood glucose concentration in the preceding urine even in uncomplicated diabetes.10: Strength and duration of action of short-. for most diabetic dogs and cats appear to do well present? when the blood glucose ranges between 15 mmol/l before 쎱 Are there concurrent diseases such as stomatitis /gingivitis insulin administration and 5 mmol/l at the time of the glu- or urinary tract infection. proteinuria. vated and work in close collaboration with the veterinarian. measurement of trypsin-like immu- between laboratories.020 despite Fructosamine is the product of an irreversible reaction be. percortisolism.3. Diabetes mellitus 163 5 Figure 5. cose nadir (= lowest plasma glucose concentration). but it is useful in sis. polyuria. urinaly- required for the diagnosis per se in dogs. diestrus. but for technical reasons it is rarely used in veterinary of diabetes mellitus and prevent short-term complications medicine. daily exercise. It is not affected by short-term changes in procedures that may be indicated include radiographs. noreactivity (TLI). cessation of diabetogenic drugs. urine specific gravity 쏜 1. i. body weight reduction if the dog is overweight. All dogs with diabetes should be treated with insu- . Reference ranges differ slightly dominal ultrasonography.35 In a newly diagnosed diabetic dog. hyperlipidemia. which could hinder manage. and certain drugs. hy. is diabetic ketoacidosis humans. inter- mediate-.34 elevation of alanine aminotransferase (ALT) and alkaline phosphatase (ALP). The aims of therapy are to eliminate the symptoms and signs trol. and long-acting insulin. Measurement of short duration (쏝 5 days) or hypoproteinemia are possible circulating insulin concentration is not helpful in most cases. Additional diagnostic one to two weeks. in contrast to administered twice daily. Follow-up examin- To simplify treatment. and long-acting (fig. and After diagnosis of diabetes the dog may be kept in the hospital poor metabolic control. moderate.36. Intervet) licensed The owner must recognize the symptoms of hypoglycemia. the box represents the for one to two days to begin insulin therapy and to complete 25th to 75th percentile (= middle half of the data). control to be achieved. load a syringe without air bubbles. just before each dose of insulin. lin. lente-type insulin (Caninsulin® / Vetsulin®. 164 Endocrine Pancreas glycemic after castration and require insulin treatment. and ten to those that are obese. A high. eventually after one to three days of stabilization with insulin. During this time blood glucose concentration the main body of data. The owner must be able to mix the insulin correctly (gentle roll- Insulin preparations are categorized according to duration of ing.5 U/kg. and then approximately every 1 % reduction in weight per week. poly- dipsia. for use in dogs. The owner should also know that the mixture of 30 % short-acting amorphous and 70 % long-act. measurement of body dietary regimen. nurse teaches the technical aspects of the treatment. Most remain hyper- . The horizontal bar through the box is the median and the whiskers extending above and below the box represent the workup. dose of insulin reduced if blood glucose falls below 5 mmol/l. know how to deal with such problems as injection pain an intermediate-acting insulin. use of the progesterone receptor antagonist aglepristone is a reason- able alternative. polyphagia. Aglepristone may also be given to dogs which developed diabetes during progestin treatment. and measurement of blood glucose and fructosamine ment of diabetes. the meals should be reduced to achieve a twelve weeks after diagnosis. six to eight. In these box-and-whisker plots. Figure 5. but lifelong supervision and periodic fiber diet (쏜 8 % fiber on a dry-matter basis) is preferred. In ister an injection subcutaneously on the lateral wall of the dogs with uncomplicated diabetes. intermediate-.10).38.39 adjustment of therapy is usually needed. three. of hypoglycemia. concentrations. The initial workup and beginning of treatment may also be on an outpatient basis. PZIVet®. but insulin resistance can gradually decrease during days to weeks of treatment and complete remission of the diabetes may be achieved by close monitoring and appropriate adjustment of the dose of insulin. The presence or absence of polyuria. Concurrent severe disease four months.37 The diabetic patient should receive meals of constant composition and caloric content. In ations should be made at one. which is porcine-derived. insulin should be stored in the refrigerator in the up-right ing crystalline insulin. 5. it is necessary to prevent progesterone-induced hypersecretion of mammary-derived GH during subsequent diestrus and the resulting insulin resistance and disruption of treatment. Oral hypoglycemic drugs are ineffective for metabolic One of the most important periods in the owner’s care of a control. and symptoms of dia- Lente. All intact bitches with diabetes should be castrated. even if there has been no obvious temporal relation betweens diestrus and the onset of diabetes. In some countries. Insuvet® PZI. Lente insulin is a tation with the hospital. The examination includes assessment of the such as pancreatitis or renal failure usually requires a different owner’s observations of symptoms. betic ketoacidosis. fed at the It usually takes two to three months for reasonable glycemic same times each day.25–0. or bleeding and injection into the fur rather than the subcutis. The starting dose is 0. treatment is started with chest. because full action of insulin develops over a few days (so-called equilibration). weight. and weight loss are used to assess Intact bitches that have developed diabetes during diestrus the quality of metabolic control. 5 In the rare instance in which castration is not possible. which has priority over the dietary manage. Once-daily administration of a U-100 insulins for humans. lethargy. admin- action as short-.11: Fructosamine concentrations in plasma of diabetic dogs with good. other insulins (Insuvet® recurrence of polyuria and polydipsia. The reference should be measured three to four times over the day and the range (200–350 mmol/l) is shown in yellow. even though a-glucosidase inhibitors or chromium diabetic pet is the time during which the veterinarian or the may have slight auxiliary effects. dogs are fed two meals of equal size. Even though re- mission of the diabetes is not usually achieved by castration. and that only a U-40 syringe higher dose is not recommended because it increases the risk should be used. both Schering Plough. not shaking).40 should be castrated as soon as possible. It is not necessary to increase the dose of insulin if blood glu- cose remains high. position and that Caninsulin is a U-40 insulin. which in most cases is equal to the range. and understand that these require consul- IDEXX) are also available for veterinary use. Thus the finding of a normal fructosamine concentration (es- pecially in the lower half of the reference range) should raise concern about the possibility of prolonged periods of hypo- glycemia due to insulin overdosage.12). A difference of 6 mmol/l poglycemia or the Somogyi effect.11). It may be possible to im- would indicate satisfactory insulin efficacy in an animal re. stress. expensive and therefore probably not performed as often as it should be. insulin resistance.g. A lower nadir can be caused by an insulin the order of 10–25 %. for it is blood samples. and strenuous exercise. for which glucose is (A) Ideal curve. Capillary . poor insulin absorption. Fortunately. changing to an insulin with a different action profile is the dose is 쏜 1. short duration of insulin effect.m. should be obtained in animals with (B) Short duration of insulin effect. diseases causing insulin resistance. 5. because most owners are unable to collect venous possible. Diabetes mellitus 165 Fructosamine concentration increases when glycemic control worsens and decreases when glycemic control improves. and the Somogyi effect. and the du- ration of effect. 5 mine levels indicate poor control but do not help to identify the cause and thus all possibilities must be considered: insulin underdosage. Fructosamine levels of 350–450 µmol/l indicate good metabolic control. Even so. ser. and the counterregulatory phase of the Somogyi effect must also be considered. the results of such BGCs can be in- The duration of insulin effect is defined as the time from the fluenced by stress. and differences in the feed- injection through the glucose nadir until the glucose concen. The most important variables evaluated by the BGC are insulin efficacy. methods are now available that en- tration returns to 12–15 mmol/l. This indicates satisfactory control and additional ing insulin BID. (C) Somogyi effect with counterregulation after rapid decrease in blood glucose tosamine levels above 550 µmol/l. BGCs were almost always performed in veterinary already being treated with high doses. Insulin and food are given concentration. and weight loss. and technical problems of the owners (fig. the dose should be decreased by at least 50 %. that approach is time-consuming and necessary in order to correct the treatment.12: is found to be 10–15 mmol/l and fructosamine is 350– Representative blood glucose curves in animals treated with an intermediate-act- 450 µmol/l. lack mogyi effect. Since even well-controlled diabetic dogs are slightly to mod- erately hyperglycemic throughout the day. lack of exercise. ial blood glucose curves (BGC). persistence of polyuria. fructosamine does not usually become completely normal during therapy. High fructosa. ing routine. but if ceiving an insulin dose of 쏝 0. insulin resistance is also hospitals. prove the duration of action by manipulating the diet. 8–10 h. A small difference (e. Single measurements are sufficient when symptoms of diabetes have been resolved and blood glucose around the time of insulin administration Figure 5. As a rule of thumb. excessive overlap of insulin actions.5 U/kg. In the latter case. polydipsia.. the glucose nadir. 5. Depending on the results of the BGC. low. 3 mmol/l) is ac. glucose concentration in treated diabetic dogs and cats (15–5 mmol/l). and fruc. is required. which should be interpreted next. the counterregulatory phase of the Somogyi effect. at 8 a. Glucose measurements are required to characterize the prob- lem and evaluate the action of insulin. possible thereafter. In contrast. or insulin antibodies. A glucose nadir Changes should not be made more frequently than every five 쏜 9 mmol/l can be the result of an insulin dose that is too to seven days.m. The blue area is the preferred range of blood blood glucose measurements are unnecessary. It is very important to identify the cause. In an animal In the past. and 8 p. changes in the dose should be of ideally 5–8 mmol/l.5 U/kg but insulin resistance if not. at home and the BGC measurements are begun as soon as (D) Poor response due to technical problems. but following hypoglycemia or the So- dose that is too high. and other symp- ceptable if the highest blood glucose is 쏝 12 mmol/l but not toms of diabetes and if more than 14 h there is a risk of hy- acceptable if it is 쏜 17 mmol/l. technical problems indicated. polydipsia. In addition. there is usually polyuria. Insulin efficacy (= difference between the highest and the lowest glucose concentration) is interpreted with reference to the highest blood glucose concentration and the insulin dose. If the duration is less than able the owner to measure blood glucose at home. levels of 450–550 µmol/l indicate moderate control. and those above 550 µmol/l indicate poor control (fig. except in case of repeated hypoglycemia. the counterregulatory phase of the Somogyi effect. of food intake. measured every 1–2 h. a change in the insulin dose and sometimes a change in the insulin preparation is The glucose nadir. The dog remained hypergly- versity of Zurich. 5.14: Blood glucose concentrations in a collie bitch that developed diabetes during dies- In the Clinic of Small Animal Internal Medicine of the Uni. The blue area is the preferred range of blood glucose concentration in treated dia- structed to contact the clinic. he or she 10 weeks after castration. There may be con- siderable day-to-day variability of blood glucose concen- tration43 due to difference in insulin absorption and different . insulin was stopped and twice weekly and a BGC once monthly. Blood glucose levels decreased progressively and the measures the animal’s fasting blood glucose concentration dose of insulin was reduced after each curve. 166 Endocrine Pancreas 5 A Figure 5.5 U/kg lente insulin BID. Figure 5. At week 10. home monitoring of blood glucose (HM) can be an imposing challenge for the owner and every effort should be made to minimize the technical difficulties.41. The former serves to the dog remained in remission thereafter. Interpretation of the BGC fol- lows the same rules as used in the hospital. the dose of insulin was increased by 25 %. The owner should be provided with a PBGM that is simple to operate B and should have ready access to veterinary support whenever required.13: Obtaining a blood drop from the inner surface of the pinna of a diabetic dog. (B) Blood glucose curves determined at home by the owner at 4. treatment. 8. In either case. blood glucose concentration is measured before insulin injection (fasting) and then every 2 h until the next injection. detect morning hypoglycemia. using the slight suction created by a lancing device.13) and blood glucose con- centration is measured with a portable blood glucose meter (PBGM). After each curve. some owners can be trained to collect blood from a peripheral vein with a needle and syringe. 6. blood is obtained from the inner aspect of the dog’s pinna by means of a lancing device (fig. 5. in which case the owner is in. Alternatively. trus and was castrated immediately after diagnosis. HM is not begun before the third week of cemic postoperatively and was discharged on 0. and Once the owner is comfortable with the procedure. This allows the owner to become familiar with the (A) Blood glucose curves determined in the hospital at one and three weeks after castration. For determination of the BGC. disease and to gain experience with the injection of insulin.42 betic dogs and cats (15–5 mmol/l). When b-cells are healthy. 250x).46 Type 1 diabetes appears to Pancreatic islet of a cat with diabetes mellitus (H&E. but eventually the b-cell damage be- . position. the adaptive response to cats the disease resembles type 2 diabetes. This is the acterized in cats.53 It is important to note that although high blood glucose levels. glucotoxicity. physical inactivity. but the genetic factors have not yet been char.46 Additional risk factors include in. one of the major advantages of HM is that it enables the BGC to be measured frequently. Figure 5. but it is also a frequent find- ing in older healthy cats56 and hence it probably should be re- In humans it is now well accepted that adipose tissue is an im. and proinflammatory Glucose toxicity is the concept that prolonged hyperglycemia cytokines such as TNF-a and IL-6 (see also chapter 5.45. Amyloid deposition is found in greater risk for diabetes.57 Initially.43 %. b-cells and insulin have not been found in cats and lympho- cytic infiltration. obesity and insulin resistance is an increase in insulin secre- ical characteristics and islet histology.51 about 90 % of cats with diabetes.2 % in 1999. adiponectin levels decrease in obesity while leptin and tion ceases after three to five days of continuous induction of TNF-a levels increase. and obes. in which the fre.9 times hormone cosecreted with insulin from b-cells.44 In Australia the current hospital prevalence is 0. Diabetes mellitus 167 levels of stress and exercise.47. b-cell failure.54. producing various factors col.44.2. the most important risk factor in cats derived from amylin (also called islet amyloid polypeptide). It was recently reported that in the USA there was an increase in its prevalence in veterinary teaching hospitals from 0. which leads to increased cose- more weight than did female cats. a marker of immune-mediated destruction. 5. adiponectin.08 % in 1970 to 1. Individual curves may thus not re- flect the true glycemic situation. 5. male gender. regardless of whether they are obtained in the hospital or at home. It is assumed that amyloid deposition is accelerated have lower insulin sensitivity prior to the trial and gained in a state of insulin resistance. lin secretion capacity is reduced by 80–90 %. whereas the both factors.21 Type 2 diabetes is a tion. which might explain their cretion of insulin and amylin. second phase is delayed and often exaggerated.50 In healthy experimental cats an average weight gain amylin predisposes it to fold into b-pleated sheets. based on clin. sulin secretion and the progression to diabetes: amyloid de- glucocorticoid and progestin administration. the mental and genetic factors play a role in the development of first phase of insulin release is markedly reduced. as in hu. and /or lipotoxicity? Islet amyloid is ity. a is obesity and it has been shown that obese cats are 3.1). glucose tolerance is insulin action (insulin resistance) and b-cell failure. together with hydropic degener- be very rare in cats. which may be of particular importance in animals that are difficult to regulate or in which insulin re- sistance is likely to decrease and needs close supervision (fig.9 kg during a feeding trial was associated with a more deposited as amyloid in the islets. How- heterogeneous disease involving a combination of impaired ever.56 % and in the UK the prevalence in an in. The most convincing arguments for the threshold situation before the development of overt hyper- existence of genetic factors have been derived from studies in glycemia and symptoms of diabetes.52 impairs insulin secretion by the b-cells. so that normal glucose tolerance is maintained.55 quency of diabetes was shown to be about four times higher than in domestic cats. and it occurs when insu- Australia and the UK in Burmese cats. when there is b-cell dysfunction.48 It is currently assumed that in approximately 80 % of diabetic diabetes. garded as a contributing factor and not the primary cause of portant endocrine organ. Initially.49 As in humans. These are of 1.2. has only been described in a small number of cases. 5.15). Cats are more likely to develop diabetes than those of optimal among the few species in which the amino acid sequence of weight. The phenomenon can Preliminary studies in obese cats have shown that. Among them are leptin. being neutered.14). lectively termed adipokines that influence insulin sensitivity. in contrast to dogs. leading to loss of b-cells than 50 % decrease in insulin sensitivity.4 Diabetes mellitus in cats 5 Diabetes mellitus is a common endocrine disease in cats. Male cats tended to (fig.15: sured cat population is 0. There are massive amorphous deposits of amyloid (pink material). impaired and eventually type 2 diabetes results. Environ.45.46. the suppression of insulin obesity induces insulin resistance. Antibodies against ation of islet cells. be nicely demonstrated in healthy cats in which insulin secre- mans. It is not yet known what is responsible for the reduction in in- creasing age. However. not all obese cats develop secretion is reversible. and approxi.3). polydipsia. circulating insulin concentration at long been assumed not to develop diabetic cataracts.16: Figure 5. entiate from diabetes. Pancreatic lesions are tisolism. measuring fructosamine. Second. their entire stay in the hospital. 100 % of those with hypersomatotropism are diabetic. First. They were much less severe than in diabetic dogs. cats are prone to Signalment and clinical manifestations stress-induced hyperglycemia that may be difficult to differ- Diabetes occurs most often in middle-aged to elderly cats. and exposure to diabetogenic In cats with concurrent disease such as pancreatitis. such as hind limb cessive fatty acids on the b-cells. ketoacidosis. Fructosamine concen- uria. but a re- the time of diagnosis is usually low58 and thus measuring in.62 Stress hyperglycemia may be recognized cats are at risk. Lipotoxicity is the analogous effect of ex.60 The causes include pancreatitis. and none of the diabetes) in the cat account for approximately 20 % of cases. 35 % are of normal weight. comes permanent.61. About 10 % tration may also be normal when diabetes is of very recent . have serious usually presented with lethargy.17: Overweight cat (10 kg) with diabetes mellitus. unkempt haircoat are common. it can be mild but concentrations more than 95 % being older than five years. and plantigrade posture been shown as convincingly as with glucose. opacities that were more pronounced than in nondiabetic cats.59 but they are often mild and thus probably not the by ketoacidosis or hyperosmolar nonketotic syndrome are initiating cause of diabetes. normalities consistent with peripheral neuropathy. ated in cats with stress hyperglycemia. and weight loss. but no other breed has been reported to when repeated blood glucose measurements also reveal nor- be. important concepts because immediate treatment of diabetes Lethargy and a dry. anorexia. or hypersomatotropism. examination often reveals hepatomegaly and neurological ab- creases the probability of complete remission of the diabetes. but is not elev- Most diabetic cats have classical symptoms of diabetes: poly. other symptoms and signs often identified by ultrasonography or by islet histopath. decreased ability to jump. 5. although the damage has not weakness. This can be resolved by weight. Physical may reverse the adverse effects of glucose toxicity and in. however.2. reduced water in- pancreatitis. Some cats. hyperso- matotropism (acromegaly). cats was blind. which is above 400 µmol/l in dia- betic cats and may be as high as 1500 µmol/l. hypercortisolism. the renal mately 80 % of cats with hypercortisolism and presumably threshold is higher in cats than in dogs (cats ~ 15 mmol/l. but some cats have stress hyperglycemia during (fig. being Other specific types of diabetes (formerly called secondary detected only by ophthalmic examination. which could be the factor that triggers diabetic take. and vomiting (see below).16). Approximately 60 % of diabetic cats are overweight mal values. Burmese also be present. It is generally difficult to decide which of the two – diabetes or pancreatitis – is the cause and which is the Diagnosis and workup effect (see also chapter 5. have overt signs of diabetic neuropathy. cats but a few differences should be noted. and 5 % are under. dogs ~ 10 mmol/l) and thus glucosuria does not occur until blood glucose reaches a higher level. Cats have Due to glucose toxicity. Cat with plantigrade posture due to diabetic neuropathy. polyphagia. Glucocorticoids and growth The diagnosis and workup are generally similar for dogs and hormone have strong diabetogenic actions. 168 Endocrine Pancreas 5 Figure 5. There is a strong 쏜 15 mmol/l are not exceptional and thus glucosuria may sex predilection. 5. approximately 70 % being male. cent study of 50 diabetic cats showed that almost all had lens sulin does not help to predict whether remission is possible. Those with diabetes complicated ology. hypercor- hormones (progestins. There is rarely weakness of the front legs as well. may be more prominent.17). glucocorticoids). These are very (fig. At most intervals ficient residual b-cell function for eventual remission of the healthy cats had significantly higher insulin concentrations. mission occurred during the first four months of therapy (blue line) and those in lease of insulin. leading to partial or com- plete recovery of b-cell function. Cats can be more difficult for the owner mans and others are under investigation (table 5.. genesis. 5. inhibit glucagon secretion Amylin analogs Delay gastric emptying.3. apy may reverse glucose toxicity. Routine hematology. islets inhibit glucagon secretion. oral hypogly- control of the clinical features. 9.2 g/kg. which there was no remission (black line).18: Measurement of plasma insulin concentration (baseline or Insulin concentration before and at 2. and urine culture should be performed. chromium) action Incretin mimetics Stimulate glucose dependent Islets (e. in cats with newly diagnosed diabetes mellitus (blue line). due to the loss of b-cell function. further workup should clarify the severity of diabetes and the presence of concurrent disease or other contributing factors. urinalysis. regardless of whether remission is (B) Insulin concentration in newly diagnosed diabetic cats: those in which re- possible or not. 7. The plasma insulin concentration is usually centrations were not different.g. namely. after injection of an insulin secretogogue) does not help to (A) Insulin concentration (range and median values) in healthy cats (red line) and identify the type of diabetes or to predict whether there is suf.64 Treatment The aim of therapy is identical in dogs and cats.35. Figure 5. but the baseline con- disease (fig. 15. low at the time of diagnosis. increase satiety onset and when there is concurrent hyperthyroidism or hy- poproteinemia. This is usually achieved if cemic drugs may in theory be used. Except to treat and it is very important to provide sufficient for sulfonylureas.18). GLP-1 analogs) insulin secretion. Treatment found unsuitable for use as the sole agent (biguanide. Five classes of these drugs blood glucose is maintained between 15 and 5 mmol/l have been approved for treatment of type 2 diabetes in hu- throughout the day. muscle. they have either not been investigated in information on all relevant aspects of the disease as well as diabetic cats (meglitinide.63 As in dogs. and thus some residual b-cell function is required for them to .1). thiazolidinediones) or have been ready access to veterinary support when needed. Liver. may improve insulin Largely unresolved (vanadium. Insulin ther. with written instructions for the owner. good Since 80 % of diabetic cats have type 2 diabetes. Brain. and 30 minutes after ad- ministration of arginine 0. Diabetes mellitus 169 Table 5. plasma or serum biochemistry. as well as radiography and ultrasonography.3: Oral agents used in type 2 diabetes in humans Action (simplified) Predomination site of action Approved classes in humans Sulfonylureas Increase insulin secretion b-cells Meglitinides Increase insulin secretion. if in- dicated. Intestinal tract inhibitors hydrates Other agents (eclectic) Transition metals Various. Sulfonylureas stimulate insulin secretion chapter 13. The difference between the two groups was not significant.58.3). a-glu- should follow a precise and easily understood protocol (see cosidase inhibitors). Glucose toxicity contributes to the low re. 25. increase insulin adipose tissue sensitivity Thiazolidinediones Improve insulin sensitivity Muscle. 4. adipose tissue 5 a-glucosidase Delay absorption of carbo. b-cells in particular first-phase Biguanides Reduce hepatic gluconeo. 68 The initial dose of lente insulin is 1 U/cat twice daily for cats weighing 쏝 4 kg and 1. The twice-daily dose is increased in increments of 0. Intermediate-acting insulins are preferred in cats with un. In humans insulin glargine is still present. gine may be a suitable alternative for cats in which duration of action of lente insulin is too short for metabolic control. A porcine derived. The natural diet of wild fe- . In cats the ing glipizide in experimental trials.69 Glargine has recently gained may have negative effects on islets and accelerate b-cell loss.19: sulin analoga. the initial dose is no more than 1 U twice daily. Aventis) is currently the most frequently used long-acting insulin analog. it should only be used in cases in better with twice-daily than with once-daily injection. who are often well Increased amyloid deposits have been observed in cats receiv. and have at a slightly acidic pH but after injection small crystals precipi- only moderate symptoms and signs of diabetes. This makes the analog soluble for injection that are in good physical condition. The initial tate at the pH of the subcutaneous tissue.5–2.54 An sulins and it has been reported that once-daily injection of analogous limitation of sulfonylureas was found in recent glargine treatment is as successful as twice-daily injection of studies on human b-cell culture. in which sulfonylureas in.0 U at intervals of five days.5–1. causing erratic shown in blue (200–350 mmol/l). The reference range is problem is inconsistent absorption of insulin. PZIVet®. but to other types as well.70 In our experience the duration of action of creased b-cell apoptosis. The disadvantages of glipizide are that treatment thought to be absorbed steadily without peaks and to have a is successful in only 30 % of diabetic cats65 and that the drug duration of action 쏜 24 h. If blood glucose is 쏝 20 mmol/l at the time of diagnosis. both Schering Plough. 170 Endocrine Pancreas in many countries and is probably the insulin most widely used. Treatment of diabetes mellitus should be started as soon as possible after the diagnosis is confirmed. Another amino acid dose is 2. are not ketotic. increased to 5 mg twice daily after substitution at the end of the A chain improves the cohesion two weeks if there are no adverse effects and hyperglycemia is between insulin molecules.67. In some cats the duration of insulin action is 쏝 12 h. in- dependent of body weight. Two basic amino acids are substi- be effective.66 Since glipizide offers no medical glargine in cats is usually 쏝 24 h and glycemic control is advantage over insulin. number of published cases71. Glipizide is the member of this class that has been tuted on the C-terminal portion of the B chain to alter the used most often in cats. Intervet) is licensed for use in cats clearly from the omnivorous dog. It has been postulated that the remission rate is higher in cats trol reverses the effects of glucose toxicity and increases the treated with glargine than with other types of insulin but the probability of remission. It should only be used in diabetic cats isoelectric point. Satisfac- tory regulation is usually achieved in one to three months. popularity among owners of diabetic cats. finitive conclusion. Insuvet® PZI. long-acting in- Figure 5.72 is still too small to allow a de- ministration of insulin and management of the diet. The cat is a true carnivore. In humans this problem has led to the re- cent development of insulin analogs.5 mg twice daily. This problem is well recognized and applies not only to lente in- sulins. blood glucose levels. of which insulin glar- gine (Lantus®. Opinions on diets for diabetic dogs and cats have changed in complicated diabetes. Blood glucose is measured three to four times over the day and the dose of insulin is reduced if glucose is found to be 쏝 5 mmol/l. usually have to be given twice daily to cats. although designed for once-daily adminis- Decrease in fructosamine concentration in five cats in which remission of diabetes tration.0 U twice daily for those weigh- ing 쏜 4 kg. probably because glipizide duration of action of glargine is longer than that of lente in- stimulates the secretion of amylin as well as insulin. lente-type insulin recent years. which distinguishes it (Caninsulin® / Vetsulin®. There are additional preparations for veterinary use (In- suvet® Lente. The mainstays of treatment are ad. 5 The cat may be hospitalized for one to two days until the workup is completed. Glar- which the owner is unable to inject insulin. IDEXX) in some countries. Another was achieved during the first two months of insulin therapy. lente insulin. Good glycemic con. The initial workup and onset of treatment can also be man- aged on an outpatient basis. For example. informed via the internet and discussion forums. clinical control was better and there was a higher rate of remission of the diabetes. About lin overdosage. Scheduling of of referral. 13. In diabetic cats fed a diet low in carbohydrate and high in protein. Cat bodies.2.1). and a BGC for 12 h at least once a month. in which the carbohydrate content is up to 50 %. showing the Somogyi effect. Blood glucose measurements in the hyperglycemia. Most cats go into Figure 5. It is likely that the curve obtained in the hos- diabetic dogs. serious hypoglycemia may occur.75 The feeding schedule should. Diabetes mellitus 171 lids. contains less than 10 % carbohy- drate on a dry-matter basis. It is likely that the composition of manufactured cat food74 and physical inactivity contribute to the high prevalence of obesity in cats. raise blood glucose concentration so vigorously that marked hy- long-term basis. however. may be misleading. This is very different from many of the commonly used manufactured cat foods.20). and the aims of therapy are the same as in dogs (see are highly elevated and the differential diagnosis was: technical problems. Obesity decreases insulin sensitivity and is a major risk factor for diabetes. The cat weighed 6 kg and received 4 U lente insulin BID at the time but remission can occur after one year or more. The quality of metabolic control in cats receiving their meal at the same time as the in- sulin injection was not different from that in cats fed 45 min after the injection. and interference by insulin anti- dogs.3. Cats have a high protein requirement and the activity of hepatic enzymes responsible for phosphorylation of glucose for subsequent oxidation or storage is lower in cats than in omnivores. Since obesity-induced insulin resistance is nearly completely reversible and even slight to moderate weight loss improves metabolic control. insulin underdosage.19).77 . Reduction of the insulin dose resolves the even in BGCs performed at home and therefore a single curve problem. counterregulatory phase of the Somogyi ef- hospital are even more difficult to interpret in cats than in fect. 5. low-carbohydrate diet.73 The previous remission rate of ~ 25 % may be 5 increased to ~ 50 % when insulin therapy is combined with a high-protein. glucagon and epinephrine being 70 % of cat owners are able and willing to perform HM on a most important. be consistent from day to day: either two meals of equal size around the time of insulin administration or free access to food day and night. insulin resistance. due to cats’ susceptibility to stress hyperglycemia. Counterregulatory hormones. We recommend measuring fasting blood glu. because remission of diabetes may occur and if unnoticed and insulin administration is not ter- minated. such as mice and birds. gyi effect represents the physiological response to hypoglycemia induced by insu- poglycemia. weight re- duction should be strongly encouraged in overweight cats (approximately 1 % per week). interpretation of blood glucose (A) Blood glucose curve obtained in the clinic on the day of admission. Cats are metaboli- cally adapted to utilize primarily protein and fat.3. The preferred range for blood glucose concentration in treated diabetic dogs and cats is shown in blue (15–5 mmol/l). It should be stressed that variability is high perglycemia can occur for up to 72 h. lack of insulin absorption. The values values. The Somo- cose twice weekly. (B) Blood glucose curve obtained at home a few days later with the same dose of owners are introduced to HM in the same way as owners of insulin. In complicated cases. Follow-up examinations are essential during long-term man- agement. stress chapters 5. more than one curve can be obtained at home before a treatment decision is made (fig. follow-up examinations. and diets high in carbohydrate appear to be unfavorable.20: Blood glucose concentrations in a diabetic cat in which the disease was waxing remission during the first three months of therapy (fig. and waning. pital reflected the late counterregulatory phase of the Somogyi effect. In cats close supervision is of particular importance during the first months. 5.76. The timing of feeding relative to insulin administration does not seem to play an important role. both to keep in practice and to detect hy. weight loss) have usually occurred previously but have identified. chondria and oxidation to ketone bodies (acetoacetate. and volume depletion. Kussmaul respiration (a slightly in- Poor absorption of insulin can be considered in cats receiving creased. be a Somogyi effect or short duration of insulin effect. are then transported to the liver. Abdominal pal- may be worth trying insulin of a different species. and (dog). remission of the diabetes. Icterus is a frequent pres- enting sign in cats with DKA. and elevated plasma fructosamine. Mental depression (sopor. together with hyperglycemia. Confirm that the insulin used by owner is not outdated. inappetence. They are the technical errors it covers are frequent causes of problems eliminated via the kidney. any concurrent disease – inflammatory. Signs of a concurrent disease may also be present. perketonemia (with ketonuria). pancreatic neopla. shock. dehydration. vomiting. lethargy.0–1. Con. Increased plasma levels of liver enzymes are also common.2. hypercortisolism. or vomiting. Ob. and is Insulin deficiency and stress hormone excess cause the release mixed correctly before being drawn into the syringe. In at least two-thirds of cases there is a con- to seven days until it reaches 1. the fatty acids is impaired. deep breathing pattern) can be observed in severe cases PZI insulin and can be evaluated by changing to lente insulin. stupor. In principle. diestrus coma) can be due to dehydration. weakness. The pa- Circulating insulin antibodies can also be considered and it tient’s breath can have a fruity or acetone odor. current disease.5 U/kg twice daily. or neoplastic – may cause insulin resistance. Blood osmotic diuresis. due to respiratory compensation of metabolic acidosis. such as urinary tract infection or pancreatitis.2. polyuria. dehydration. elevated total protein and albumin. collapse. which may increase stress hormone release and trigger DKA. glucosuria. has not been diluted. Confirm that the initial workup and treatment time during treatment. but periodic adjustments continue to diabetes mellitus. lestasis. Hepatic reesterification of serve the owner’s method of mixing. in insulin sensitivity due to other disease. which exacerbates osmotic diuresis. pation may reveal hepatomegaly. Typical laboratory findings are ketonuria and metabolic aci- dosis (reduced blood levels of bicarbonate and total carbon dioxide. which firm that the syringe is for U-40 insulin and not U-100. and acetone). hepatic gluco- neogenesis and glycogenolysis are enhanced and peripheral Third step. motic diuresis together with insufficient water intake due to anorexia and /or vomiting. or even sia. Dehydration results from os- failure. Additionally. glucose should be measured at home every 1–2 h for at least 12 h. but it may also occur at any First step. It is frequently the initial pres- 5 enting manifestation of diabetes.79 Second step. hypersomatotropism (cat). usually develop. anorexia. Acetoacetate and b-hydroxy- This second step in problem-solving is often neglected. If no explanation for the problem has been gia. It may be the result of decreasing insulin resistance. polypha- Fourth step. and obesity. diseases causing insulin resistance should be con. drawing up. in favor of their entry into mito- ing the insulin. or pancreatic neoplasia causing extrahepatic cho- therapy. If symptoms persist in spite of insulin therapy. which causes hyperglycemia. TCO2). of large amounts of free fatty acids from adipose tissue. The pain. The symptoms depend on the stage at the time of presentation.3.6 Diabetic ketoacidosis (DKA) and regulation of diabetes in dogs and hyperglycemic hyperosmolar cats state (HHS) Most animals can be adequately stabilized within the first DKA and HHS are the two most serious complications of three months of therapy. and mental dullness most relevant possibilities are pancreatitis. Classical symptoms of diabetes (polydipsia. Hypoglycemia is always a potential problem during insulin pancreatitis.1. It results from a relative or absolute de- thus far have been according to the protocol in chap. and inject. severe acidosis. Perform a BGC to determine whether there may glucose utilization is reduced. crease in insulin together with an increase in glucagon and other ter 13. and electrolyte loss. twice daily administration of a long-acting insulin. prerenal azotemia. and hy- can be used. as in the case of further loss of b-cells or a change require immediate intense therapy. the following stepwise approach DKA is defined as hyperglycemia.78. frozen. As the metabolic sidered. or heated. Both are potentially life threatening and be needed. b-hy- droxybutyrate. metabolic acidosis. infection of oral cavity or urinary tract.5 Problems associated with the 5. 172 Endocrine Pancreas 5. but butyrate are acids that cause metabolic acidosis. been unnoticed or disregarded by the owner. As a result of the osmotic . situation deteriorates. Review the diet and exercise regimen. Then increase the dose of lente insulin every five stress hormones. in regulation. due to severe hepatic lipidosis. chronic renal hyperglycemia / hyperosmolality. and lactic acidosis. Hypovolemia can cause an elevated hematocrit. abdominal infectious. In most cases. supplementation should be reduced if potassium phosphate is Especially in sodiumfluoride-coated tubes hemolysis can be severe (centrifuge used for phosphate supplementation.3. may cause an ministration of glucose (or feeding).. Values below Hunger Ataxia 2. concurrent diseases contribute to the development of HHS. glycemia accompanied by symptoms that are relieved by ad- mia is also possible which. Regular insulin therapy Plasma or serum samples older than 24–48 h.3. To exclude artifact as the Hence the test for ketonuria may be only moderately positive cause of a low glucose values.5 mmol/l). and the lack of an energy substrate available to with a balanced electrolyte solution at a rate that will normalize the central nervous system (neuroglycopenia) (table 5.4: Causes of artifactual hypoglycemia deficits may be severe. and hypomagnesemia may be present. Hypophosphate. especially in cats. Concomitant potassium Hemolysis of the blood sample can interfere with the measurement technique. 쎱 insufficient application of blood. 쎱 blood samples with a high hematocrit value. Intermittent IM injection of insulin B. an accredited veterinary laboratory. Loss of consciousness Death Hence the hypoglycemic syndrome is not defined by hypo- . Since plasma phosphate le. Initially. DKA is one of the most complex metabolic emergencies and 5 its treatment is demanding. but values Polyphagia Seizures just below the lower limit of the reference range may not be. which is lower than in arterial blood. A low blood glucose value. The hydration in ~ 12 h. (Sodium fluoride inhibits glucose metabolism by blood cells. renal failure being particularly common.8 mmol/l are often accompanied by symptoms. without acidosis or ketonuria. 쎱 tendency of these devices to give lower than actual blood glucose values*. Collection and handling of the blood sample may be normal.4).3 The hypoglycemic syndrome Anxiety Generalized muscular weakness Polyuria /polydipsia Posterior paresis The hypoglycemic syndrome is primarily characterized by Cholinergic symptoms Visual impairment (»blindness«) a low circulating glucose concentration. be made in two or more separately-collected blood samples before undertaking an extensive diagnostic workup. but why some diabetic patients DKA capillary blood. severe hyperos- Error of other laboratory devices used to measure blood glucose. tube. should be started ~ 4 h after the beginning of fluid therapy and correction of electrolytes. It requires 24 h surveillance with The symptoms of hypoglycemia are due to activation of the au- frequent reevaluation of clinical and laboratory parameters tonomic nervous system.5: Symptoms and signs of hypoglycemia treatment are identical to those of DKA. hyponatremia. molality (쏜 340 mOsm/kg). may be an artifact (table 5. and profound dehydration. and correction must be started before treat- ment with regular insulin is begun. Rehydration should be started immediately renal medulla. particularly if blood is not collected in a sodium fluoride-coated vels may also be low or may decrease quickly with fluid therapy. HHS is much less common than DKA. tients with DKA die or are euthanized.) phosphate may also be supplemented.2). In most cases. The principles of Table 5. Potassium Table 5. eats and drinks. hypokale. neuronally-released transmitters and appropriate adjustments of therapy (see also protocol in as well as epinephrine and norepinephrine released by the ad- chapter 13. have severe hyperglycemia (쏜 30 mmol/l).e. despite »beep« given by device as an and does not vomit.5). an accurate measurement should in an animal with DKA. correction of hypovolemia will also restore the acid-base balance quickly and additional treatment with bicarbonate to correct metabolic acidosis is often unnecessary and can even be detrimental. The prognosis is guarded to poor and most animals die or are euthanized. glycemia alone. serious of a mmol per liter.2). The pathogenesis of HHS is * Note that glucose concentration measured by a PBGM is lower in venous blood than in similar to that of DKA. Fluid therapy can be tapered off and lente can give erroneously low glucose concentrations due to insulin can be started when the animal is stable. i.80 Autonomic symptoms Neuroglycopenic symptoms Adrenergic symptoms Lethargy Muscle twitching Behavioral changes Muscle tremors Confusion 5. should be reevaluated every 4–6 h. but are less accurate than measurements in but it is not detected in urine by most test strips for ketones. The hypoglycemic syndrome 173 diuresis and acid-base disturbances. especially if unexpected. PBGM devices measure glucose quickly b-hydroxybutyrate is the most abundant ketone body in DKA and conveniently. Measurement is used most often but constant IV infusion is also a good option Portable blood glucose meters (developed for human diabetes mellitus patients) (see chapter 13. The differences can be several tenths and others develop HHS is not known. Prolonged storage of blood (쏜 1 h) before separation of serum / plasma from the cell component. although the initially measured value A. electrolytes within 30 min after collection).81 acute hemolytic crisis (plasma phosphate concentration often 쏝 0. but – according to Whipple’s triad – hypo- mia. The prognosis is guarded and ~ 25 % of pa- indication of the opposite. Patients with HHS Incorrect use of other laboratory devices to measure glucose. glu- cagon. Apart from occasional ascribed to hypoglycemia. for in- ease. 5. In most dogs the diagnosis is made within five not related to it.5) and only rarely due to mass creased peripheral glucose utilization (demand-side hypo.5 cm in diameter. severe parenchymal liver dis. gastrin. secretion of the counterregulatory hormones 40–50 % of cases at the time of surgery. Initially.93–95 about two days of fasting. in adult dogs fasting leads to an appreciable ketosis after Slye and Wells. the brain cannot utilize free fatty derived amyloid deposits have been found in 25 % of primary acids as an energy source. of the disease.3. glucagon and growth hormone does not change signifi- cantly. This is an important clue. reports are confined to single plasma glucose concentration for a short period and after cases. garded by the owner. and polycythemia. in the latter disorders there are rarely symptoms of insulinoma. The blood glucose duce insulin despite the hypoglycemia they provoke. Highland white terrier. Long-term starvation (especially in young The associated proprioception deficits and depressed spinal individuals).89 Since then. with an average of about 8½ years. nohistochemical staining of these insulin-secreting PETs dividual variation and the underlying disease. pancreatic polypeptide. At the time of diagnosis the dogs’ ages vary Initially the glucose is derived almost exclusively from hepatic between 4 and 13 years.99 Apart from the hypoglycemia. PETs. can frequently be related to fasting. in insulin release. systemic shunting. and rarely in small breeds. glucose production in the liver and kid. The precursors for hepatic glucose synthesis 쏝 2.88 5 tone bodies. or exercise. and confusion.83 Secondly. but glycogenolysis can only sustain the Insulinomas are rare in cats.85–87 In addition.1 Insulinoma nadir: convulsions and loss of consciousness often occur when plasma glucose concentration is 쏝 2. Canine insulinomas are often solitary (~ 90 %) and usually neys is activated. primarily in regional lymph nodes and the liver.7). portosystemic shunting. The first case of insulinoma in a dog was reported in 1935 by over. which are metabolites of free fatty acids.82 Thus preservation of the function of the been diagnosed in many dog breeds. The symptoms occur intermittently and There are several. hypoadrenocorticism reflexes are the result of degenerative changes in the radial and (chapter 4.82 Clinical manifestations Symptoms related to insulinoma are almost always the result When these corrective mechanisms do not compensate in. Immu- threshold for symptoms of hypoglycemia also depends on in. excitement. mia. often critical. 5. hypoglycemia is often an inci. the changes in locomotion and behavior due glycemia) or decreased availability of glucose (supply-side to hypoglycemia are often subtle and are commonly disre- hypoglycemia).91 There is no pronounced breed or sex predisposition.2). other causes of the hypogly- such as sulfonylurea derivatives (chapter 5. or hypoadrenocorticism. no abnormalities are found by physical examination. liver glycogen stores are completely depleted. but they can only provide up to half of the energy requirement.97 In the dog they are often ma- and amino acids derived from muscle. The rate of Insulin-secreting pancreatic endocrine tumors (PETs). continue to pro- the severity of the symptoms and signs. sulinoma is one of the few diseases that can cause an increase dental finding and the clinical manifestations of the disease are in body weight. and juvenile hypoglycemia.92 glycogen (fig. In addition.98. nonpancreatic tumors associated with hypoglyce. Ten to 14 % of insulinomas are are glycerol released from adipose tissue and lactate /pyruvate multiple or grow diffusely. obesity. The following cemic syndrome are limited to nonpancreatic tumor. and polycythemia are examples of disorders ischiadic nerves. especially medium-to- central nervous system in postprandial or fasting states is large breeds. and /or growth hor- Glucose is the primary energy substrate for the brain. alone. glycemia is not severe (쏜 3. such as lethargy. hypoadrenocorticism. effects.8 mmol/l.0 mmol/l) and symptoms do not There may be weight gain if the owner has responded to the occur.84 An example in which the symptoms are solely due to hypoglycemia is increased utilization of glucose due to an Differential diagnosis overdose of exogenous insulin or oral hypoglycemic drugs In middle-aged and elderly dogs. porto- discussion is confined to disorders that are mainly character.96. insulin-secreting PETs have only days to weeks.2). of hypoglycemia (see table 5. such as the West mainly dependent upon increased production of glucose. hypoglycemia. more decrease and the duration of the hypoglycemia also determine commonly known as insulinomas (fig. illnesses in which the hypo. 174 Endocrine Pancreas severity of the symptoms and signs depends on the glucose 5. ized by symptoms and signs of the hypoglycemic syndrome: However.21). may also be related to other aspects Peripheral neuropathy is a rare occurrence with insulinoma. . often reveals that they are also positive for somatostatin. More. In mone. In the adult dog the lignant (쏜 95 %) and there are macroscopically visible meta- catabolic state of fasting is primarily the result of a decrease in stases. IAPP immunoreactivity and IAPP- contrast to other tissues. ness. the syndrome of hypoglycemia may occur. muscle weak. results of that rarely present with symptoms related to hypoglycemia routine laboratory investigation are usually unremarkable. animal’s increased appetite. In addition to glucose it can use ke. symptoms and signs that may be months of the onset of symptoms. In diseases such as sepsis.90. have been advocated to im. but if not.5 mmol/l and plasma insulin 쏜 10 mU/l (70 pmol/l) is severe hypoglycemia.96. If hypoglycemia is not found but there have been convincing symptoms of it. nography. The hypoglycemic syndrome 175 Diagnosis When a presumptive diagnosis has been made on the basis of the signalment and a detailed medical history but the plasma glucose concentration is not low. treated surgically may be longer and better than that of dogs ments. Plasma fructos- amine or glycosylated hemoglobin concentrations can be measured as complementary investigations. confirm the diagnosis of the hypoglycemic syndrome could be hazardous. (fig. transabdomi- outdated polyclonal antibody-based assay or radioimmuno. so that it is not necessary to provoke signs of hypoglycemia. localization. The chronic nature of this disease often results in few or no symp- toms at plasma glucose concentrations even 쏝 2. computed to- indirectly on plasma glucose concentration. centrations (chapter 5. The survival time and quality of life of dogs with insulinoma prove the diagnostic value of glucose and insulin measure. and presumed additional value of these ratios: staging of the primary tumor and metastases are essential for 쎱 Reference ranges vary between laboratories and assay the selection of appropriate candidates for surgery.1. glucose transporters (GLUT) (see chapter 5.103 insulinoma in humans.4).113–115 However. have been used in dogs with insulinoma.110 However. gestive of metastatic disease or neoplasia of nonpancreatic centration in human patents with insulinoma. a supervised fast can be undertaken. as in humans. and thus aging techniques [abdominal ultrasonography. such as the amended in- sulin-to-glucose ratio (AIGR). It has been postulated that patients with insulinoma have increased uptake of glucose by the brain via changes in the setup of these glucose transporters.104. such as the immunoradiometric assay (IRMA). in addition.102. with repeated measurements of blood glucose. More modern monoclonal antibody-based reports have described the use of transabdominal ultraso- assays. CT was best in detecting and localizing the primary sulin in the same sample will not necessarily reveal a direct tumor but often failed to identify metastatic lesions correctly causative relationship.1.21: triad to be fulfilled by the presence of symptoms in order to Insulinoma of a ten-year-old male Malinese shepherd during surgery. it requires a car- rier system consisting of membrane-associated glycoproteins. The simultaneous occurrence of blood glucose justify their routine use and.108.e. fasting is prolonged for up to 72 h. and somatostatin receptor scintigraphy for 40 min or longer. low plasma con.107 Hence measuring glucose and in. with varying results in detecting the primary pan- measure lower plasma insulin immunoreactivity than the creatic tumor (36 % and 75 %). Measurements of circulating C-peptide and proinsulin con- centrations of these may be indicative of prolonged hypo. Circulating insulin concentrations are typi..104 Insulin:glucose ratios.115 . origin. However. but could support the presumptive diagnosis and differentiate The hallmark of the diagnosis is the association of persistent exogenous hyperinsulinism. nal ultrasonography may be useful in detecting lesions in the assays (RIA) in dogs with insulinoma. (SRS)].22). 5. test. have not been developed for dogs. However. such as hypoglycemia and inappropriately high plasma insulin the intravenous glucose tolerance test and glucagon tolerance concentrations.109 Provocation tests. may persist mography (CT). i. cally within the reference range or higher despite hypogly.112 Accurate detection. 5 For glucose to pass the blood-brain barrier. In a recent comparative study of three diagnostic im- tion of insulin on the liver and peripheral tissues. A few methods.101 Hence requiring Whipple’s Figure 5.106 The ac. Fasting for 24 h is in most cases sufficient to re- veal hypoglycemia. they may provoke 쏝 3. the medical history and a low plasma glucose concentration are often sufficient.111. after fasting overnight.100.97 diagnostic. there are two major reasons that limit the treated medically. which are used in the diagnosis of glycemia in dogs with insulinoma.8 mmol/l.2).105 liver or peripancreatic tissues (regional lymph nodes) sug- 쎱 There are very erratic oscillations in plasma insulin con. it should be measured on two or more occasions before feeding in the morning. the value of these tests has been too limited to cemia. Most dogs with insulinoma appear to be comfortable even ing canine insulinomas.119 risk of a hypoglycemic crisis. surgery is the treatment of choice. Radioactivity accumulated in the kidneys. (fig. A third important initial step is Also. (B. (Modified from Robben et al. the described diag. of the organs of interest or by use of intravenous methylene formation on anatomical relations and the localization of blue infusion remain the standard for localization of primary lesions.115. 176 Endocrine Pancreas 5 A B Figure 5. thereby shortening the intervals between meals. Some radioactivity was detected in the intestinal tract. 3.114. with insulinoma often have micrometastases and that the hy- sualized with regular scintigraphy and even better with poglycemic syndrome frequently recurs after surgery because single photon emission computed tomography (SPECT) of growth of these functional metastases.117 SRS uses the 111In-labelled somatostatin possible. Whenever sulinoma tissues.)115 Transabdominal ultrasonography and CT provide in.. expression of four somatostatin receptor Treatment of hypoglycemia due to insulinoma consists of life- subtypes (SSTR1. and 5) was demonstrated in canine in. SRS provides more information on the nature of the tumors. The thus concentrated radionuclide can be vi. 2. 5.115–117 These scan results also could have predictive value for the effectiveness of treatment with octreotide or oc.22). 2005. for changes in diet composition have and staging of canine insulinoma by inspection and palpation not been proved to be beneficial and they carry the risk of . especially SSTR2 and to a lesser extent poglycemic syndrome. only option that can result in complete remission of the hy- tostatin receptors. Owners should be informed that dogs to SSTR5. other currently available techniques – endoscopic and to divide the dog’s food over five to eight meals per day. and in the pri- mary tumor (T) in the left lobe of the pancreas. and to a lesser extent. as ercise should be limited and excitement avoided to reduce the could the combination of different imaging techniques.121 lesion.120 To date. not normalization of plasma glucose concentration per se. and gastric fundus (F). Changes in noma detection. On the CT image the right kidney (K) and spleen (S) can be ident- ified. A better understanding of the use of with subnormal plasma glucose concentrations. nostic imaging techniques have a modest accuracy in detect. medical therapy.116 Treatment At the mRNA level.118 Currently. gall bladder (G). the intraoperative localization the diet are not advised. The goal of therapy should be alleviation of symptoms and treotide-based radiotherapy. because it is the analogue octreotide that binds with high affinity to soma. In vitro and in vivo studies have demonstrated that ca- nine insulinoma tissues express somatostatin receptors. Physical ex- CT and SRS in insulinoma could improve their accuracy. intraoperative ultrasonography – could prove useful in insuli. metastases. C) Corresponding transverse CT and SPECT images in the same C dog.22: (A) Ventral view of a three-dimensional reconstruction of a SPECT study performed 6 h after injection of [111In-DTPA-D-Phe1]-octreotide in a seven-year-old neutered female beagle with a solitary b-cell tumor in the left lobe of the pancreas. and /or surgery. style changes. The initial dose is 10 mg/kg body noma (fig. Doses as high as 60 mg/kg/ to a single subcutaneous dose of 50 µg octreotide. which will also re- duce the costs of therapy. 5. As an alternative.105 In contrast to humans. If side effects develop (ptyalism. 100 or 200 µg octreotide/ml) inhibits the Plough. If these measures fail to prevent hypoglycemic symptoms. and sur. Right panels: dogs with insulinoma. It also stimulates effect of a single dose of octreotide on plasma insulin and glu- hepatic gluconeogenesis and glycogenolysis. This is a benzothiadia. even these side ef- gain. vomiting. Schering. Bone marrow depression and dia- If these measures do not suffice. 2006. Chemotherapy dose of prednisolone is 0. Sandoz. combined with glucocorticoid therapy. Note the differ- ence in response to octreotide (thus far unexplained): In the healthy dogs a decrease in plasma insulin and glucagon concentrations coincides with a minor de- crease in plasma glucose concentration. day could be increased. * Significantly different from baseline values.23: Plasma concentrations (median and range) of glucose. tin®. Also note the wide range of basal plasma insulin concentrations in the dogs with insulinoma. Left panels: healthy dogs. day may be necessary to prevent symptoms of hypoglycemia the absence of high affinity somatostatin receptors can cause Adverse reactions may be prevented or postponed by slowly worsening of hypoglycemia due to inhibition of the release of increasing the dose to effect and by administering it with the counterregulatory hormones glucagon and growth hor- .. gery is not an option.23). (Adapted from Robben et al. lished. betes mellitus are rare side effects of diazoxide. in a dog with insulinoma. all dogs responded weight divided in two daily doses. Hence lower doses of diazoxide can be and should not be underestimated. Glucocorticoids interfere with the ac. If symptoms of hypoglycemia persist in diarrhea). and hypoglycemic crisis. but the clinical results have been variable and protocols high doses are needed. this can be increased gradually if needed. secretion of insulin by unaffected and neoplastic b-cells.122 The somatostatin analogue octreotide (Sandosta- ment can be started with diazoxide (Proglicem®.)105 gastrointestinal disturbances that could increase the risk of a food. and glucagon after a single subcutaneous in- jection of 50 µg octreotide at T = 0 min.0 mg/kg divided in two to with alloxan and streptozotocin has been tried to treat insuli- three doses. the total amount of food fed over the stopping the drug. without food for 4–6 h. in the dogs with insulinoma a decrease in insulin concen- tration without a significant effect on plasma glucagon concentration coincides with a significant increase in plasma glucose concentration. treat. Often noma. The hypoglycemic syndrome 177 5 Figure 5.5–1. However. In humans. 50. insulin. and inhibits cose concentrations has been reported in dogs with insuli- peripheral use of glucose. al- tion of insulin and promote gluconeogenesis. even though this could lead to weight necessitating a continuous intake of food. they can be stopped by reducing or temporarily spite of these measures. In contrast. 100 mg diazoxide /capsule). in comparison with the healthy dogs. The zide diuretic that inhibits insulin secretion. medical treatment can be undertaken to control hypoglycemia. These simple measures may stabilize the dog for months fects can be hazardous. fasted overnight. or no longer do so. which frequently give rise to the side to reduce the risk of nephrotoxicity have not been well estab- effects of iatrogenic hypercorticism. The initial daily ternative medical therapies can be considered. anorexia. 1). disease or the hypoglycemia (chapters 5. and spection of the abdomen for metastases. most often the latter. which may be of tumors with extensive hepatic metastases.126 Hypoglycemia may also result from a variety of tumors of both epithelial and mesenchymal origin. or even coma. one should be aware that the delayed rise in plasma glucose concentration in some dogs can be preceded by an initial decrease (fig. The prognosis is mainly determined of tumor removed but rather on the amount remaining. chapter 10. feeding regime (see chapter 5. mia. The able to accept them.3. which could ex.1). other differential diagnoses. leiomyosarcoma. plasma glucose concen. plain treatment failures in dogs with insulinoma. 178 Endocrine Pancreas mone.3. develop.131. These complications and /or nonresectable tumor mass lin concentration in dogs lasts only 3–4 h. by partial pancreatectomy. convulsions. great prognostic importance. drugs such as glucocorti- glycemia. Postoperatively.105 Hence it is preferable to 5. but should be followed suming the dietary measures and medication with diazoxide as soon as possible by additional measures to maintain an or prednisolone or both.130. intravenous glucose and medi. Surgery is undertaken not only to remove the tumor tissue. documented in a few cases of hypoglycemia in dogs (see also creatic b-cells. ing or shortly after surgery. any glucose infusion is gradually stopped. with hypoglycemia thermore. the success of surgery depends not on the amount coids are rarely necessary. Find- pression. They inhibit insulin mia in humans.127 Plasma glucose concentration is checked and corrected by infusion of Clinical manifestations and diagnosis glucose. may be reason for euthanasia. lymph node excision and partial hepatectomy glycemia: deranged tumor metabolism with excessive uti- may also be necessary. Postoperative hypoglycemia is usually presumptive diagnosis can be strengthened by exclusion of the result of incomplete removal of the tumor and /or meta. plastic syndrome. several mechanisms have been suggested to explain the hypo- ing surgery. Pancreatitis can complicate post. If octreotide is being considered. one of the few options to support the cause-effect relation be- operative stabilization. The effect of a slow-release formulation of octreotide has not yet been In most dogs. if necessary. Small bination of a low plasma glucose concentration and a nonpan- amounts of food and water are offered as soon as the dog is creatic tumor makes a paraneoplastic syndrome likely.1). The com- perglycemia. possible. fasting can be reduced to the final convincing evidence that incompletely processed insulin-like 6 h. Depending on its severity and the tween the tumor disease and the occurrence of hypoglycemia. if The most frequent nonpancreatic tumors are leiomyoma. and whether there is Resolution of hypoglycemia after successful treatment of the persisting hypoglycemia. Fur. For those If despite treatment such serious hypoglycemic effects as that benefit from surgery.3).3.23).2 Nonpancreatic tumors associated combine octreotide with other emergency measures. the animal may die from pancre- atitis or from neurological effects of uncontrolled hypoglyce- .124. A major concern is the perioperative lization of glucose.125 curs after surgery.3. The hypoglycemia can usually be treated by adjusting the stases at the time of surgery.132 a mechanism that has also has been release by postsynaptic a2-adrenoreceptor stimulation of pan.133 cogenolysis and stimulate growth hormone release. Dur. Only rarely is insulin therapy needed to bridge over ing increased plasma levels of insulin-like growth factors is this temporary deficiency. hypoglycemia due to insulin-secreting PETs re- studied in dogs.112 5 adequate plasma glucose concentration.3. Now there is 12–24 h before surgery.3. Medical treatment is of gluconeogenesis and glycogenolysis.123 The suppressive effect of octreotide on plasma insu. an emergency symptoms or the need for medication is 1–1. Depending on the findings dur. ectopic insulin pro- started preoperatively and if liquid diets are used in the final duction. associated vomiting and abdominal pain. tumor disease also supports the diagnosis of this paraneo- cations (see above) will be necessary. until the normal b-cells recover from sup. 5. parenchymal liver destruction with failure control of plasma glucose concentration. Prognosis Treatment and prognosis In about 40 % of cases there are macroscopically visible meta. which protocol should be started (see protocol in chapter 13. Finding a low plasma glucose stases. 5. Successful surgery is often followed by hyperglycemia concentration together with a low plasma insulin concen- for days or weeks. the mean survival time without ataxia. The symptoms can be the result of the underlying tumor tration is monitored closely and if there is euglycemia or hy. and inhibition of glucagon release. hepatocellular carcinoma. but also for thorough in.5 years. although they may also activate hepatic gly. tration can help to exclude insulinoma (chapter 5. can be extended (in some cases to three years or more) by re- This includes glucose administration. hepatoma.1). With regard to control of hypo. it is important to note that somatostatin has been shown to prevent the diazoxide-induced hyperglycemia in Pathogenesis healthy dogs.128–130 In the past. which suggests that most have metastasized before they are diagnosed and surgery is attempted. by the underlying tumor. The use of a2-agonists during surgery may be beneficial growth factors (pro-IGF-II and IGF-I) cause the hypoglyce- to control plasma glucose concentration. PETs. directly stimulating hydrochloric acid The blood glucose concentration may be extremely low.141 Gastrinomas are usually malignant Clinical manifestations and diagnosis and metastases can be found in more than 70 % of cases dur- The symptoms of juvenile hypoglycemia are not dissimilar to ing surgery.134 companion animals. conditions (chapter 5. Intermittent diarrhea is caused by maldigestion if there are neurological signs.4 Other endocrine tumors In puppies of miniature breeds such as the Yorkshire terrier associated with the pancreas and the Chihuahua. are not released under physiological conditions by a-.2 ml/100 g body weight.140 usually presented with lethargy or in coma. a ketogenic endocrine setting. There may also be Gastrinomas are rare in cats. Puppies of small breeds develop hypoglycemia within pancreatic tumors. and rarely somatostatin or pancreatic polypep- mal recessive inheritance pattern has been found in a family tide. oral rehydration is guided by blood electrolyte The animals are usually lethargic and in poor nutritional con- measurements. amounts of food are given at intervals of 2 h.4.136 If secondary to enzyme inactivation. respectively) is indicated weight loss. more than 70 % of dogs with a gastroen- the condition. i. teric gastrin-secreting tumor. although some of the elderly dogs with a mean age of about nine years.140 5 Pathogenesis Puppies have relatively high rates of glucose utilization. and PP cells under physiological cold) may cause hypoglycemia. There ap- symptoms may in part be due to the ketosis. and generalized con. It leads to death as a result of peri. gastrin being the one reported most frequently in cular degeneration. Some have symptoms of abdominal pain..3. there have been reports in dogs of PETs that secrete poglycemia due to a glycogen storage disease with an autoso. Gastrin is cagonemia.140.8 and 0. called gastrinoma. there may be polydipsia. PETs can produce hormones that of Norwegian forest cats. gastrointestinal disturbances. histamine from fundic enterochromaffin-like cells. The animals are pears to be no pronounced breed or sex predisposition. erosive esophagitis and gastroduodenal ulcers can lead to he- tered at regular intervals until the appetite returns. and trophic effects on the gastric mucosa. cases. Similar forms of juvenile hy. Perforating ulcers lead to symptoms and signs of acute abdomen and sep- The prognosis is good if hypoglycemia is corrected before tic shock.136 Clinical manifestations In some there are symptoms of an underlying disease such as The clinical features can be traced back to the main biologic congenital portosystemic shunt or severe intestinal parasitism.1). The risk of developing the syndrome of anemia and hypoproteinemia as a result of blood loss. vomiting. this is adminis. Hy. and inactivity due to produced by the a-. At admission most are in a good nutritional state and physical examination reveals no remarkable abnormalities. actions of gastrin. Nevertheless.142 vulsions.. and (0. Laboratory examination may reveal regenerative brain damage occurs. dition. hypochloremia. Leukocytosis probably reflects gastrointestinal erosion and inflammation.140 The development of the pup can take the glucose solution orally. b-. and relatively limited stores of 5. glucagon. d-. During fasting the hepatic glycogen stores are rapidly depleted and the possibly still immature glu.0 mmol/l.137–139 Furthermore. reports being confined to single muscular weakness. natal hypoglycemic collapse or late-juvenile-onset neuromus. . Profuse hypoglycemia decreases with increasing age and body vomiting can lead to hypokalemia. The hypersecretion of Treatment and prognosis hydrochloric acid and the hypertrophic gastritis resulting Intravenous administration of a 20 % or 50 % glucose solution from gastrin hypersecretion lead to anorexia.e. i. Gastrin comprises three biologically active 24 h of fasting. b-. Other endocrine tumors associated with the pancreas 179 5.141 The syndrome occurs in middle-aged and those of other forms of hypoglycemia. In 1955 Zollinger and Ellison were the first to describe a syn- coneogenesis cannot supply the large amounts of glucose drome in humans associated with hypersecretion of gastrin by needed. If tube feeding is needed. insufficient food supply of any cause Pancreatic endocrine tumors can secrete any of the hormones (starvation.135 bolic alkalosis. disproportionately large brains. ranging in size from 14 to 34 amino acids.3 Juvenile hypoglycemia 5. and meta- weight. or PP-cells. muscle twitching. peptides. This leads to hypoinsulinemia and hyperglu.1 Gastrinoma gluconeogenic substrate.e. d-. In addition. even mild muscle spasms. Then small matemesis and melena. even secretion by gastric parietal cells and indirectly by releasing 쏝 2. have a tumor mass in the pancreas. In addition to the insulin-secreting poglycemia have not been well documented in kittens.135 Underlying secreted by G-cells in the gastric and duodenal mucosa and diseases such as portosystemic shunting that cause anorexia or does not occur in appreciable amounts in the normal pan- impaired liver function may contribute to the precipitation of creas. Normal exocrine pancreas at the lower right. The histamine H2-receptor antagonists cimeti- dine (Zitac®. Famotidine (Pepsid. but reference values have not yet been established. (Courtesy of is a more potent H2-receptor antagonist. 180 Endocrine Pancreas Treatment and prognosis The ideal treatment of gastrinoma is surgical resection. but a parietal cell Dr.141 tric outlet obstruction. stomatitis. acid secretion stimulated by gastrin and other secretagogues.2 g/ml]. J. Nevertheless. hypoaminoa- ing of the primary tumor and metastases are essential to select cidemia. These include chronic treotide holds some promise for treatment of metastatic renal failure. Dogs undergoing surgery should receive medical therapy peri- operatively. hy. and in plasma amino acid levels is held responsible for the skin magnetic resonance tomography have not been evaluated for lesions: intravenous amino acid infusion can resolve the this purpose but the small size of these tumors would appear erythema. Astra Zeneca.5–1. and hyperglucagonemia. it directly decreases gastric pertrophic gastritis. of the reference range. treatment of gastrointestinal ulcer- ation with sucralfate (Ulcogant®. abdominal ultraso. GlaxoSmith- Kline.4. This has led to the thermore. and stag. liver disease.139. anorexia. Pfizer.140 Receptor-mediated radiotherapy of tu- and elevated circulating gastrin concentration in the absence mors with radiolabeled somatostatin derivatives such as oc- of other causes of hypergastrinemia. weight loss. a secretin provocative test can be used. Furthermore. 5–10 mg/kg every 6 h) and ranitidine (Zantac. vere liver failure such as hepatic cirrhosis. matitis is more often observed with diabetes mellitus and se- nography may be used to detect possible metastases. Ultrasonography. In humans. described in dogs. and gastric and /or duodenal ulceration. hyperglycemia (mild diabetes mellitus).5 of endoscopically collected unstimulated gastric Combination therapy appears to have the additional benefit juice can be indicative of acid hypersecretion. and Ba- senji enteropathy.) Na/K-ATPase or proton pump inhibitor such as omeprazole (Losec®. SRS has been used in veterinary medicine to de. mia. but this is rarely curative because of unresectable metastases. Therapeutic control of gastric acid secretion can be achieved by use of specific antagonists of the regulators involved. 250 ml suspension [0. Immunohistochemical staining for gluca. with gastrin release. Even without complete surgical resection of tumor tissue.144 and palpation of the organs of interest remains the standard for localization and staging of gastrinomas. and inhibition of gastric acid 5 secretion.140. and 40 mg omeprazole /tablet. 150 and 300 mg ranitidine /tablet. 10. medical therapy can be beneficial. circu.141 The long-acting somatostatin analogue octreotide binds to soma- Diagnosis tostatin receptors on the tumor cells and thereby interferes Suspicion may arise when endoscopy reveals esophagitis.5–1 g every 8 h). 0.141 mas is characterized by lethargy.2 Glucagonoma gastrinoma. 5.5–100× the upper limit term prognosis poor. Glucagon-secreting PETs or glucagonomas have rarely been tween hypergastrinemia and an endocrine tumor in the pan. 100 and 200 mg cimetidine /tablet. In the reported cases of gastrinoma. Note cytoplasmic staining for glucagon in tumor cells (left). 0. localization.143. A pH 쏝 1. gastrinoma. 0. The tumor is sur- rounded by a capsule. mild ane- As for insulinomas. The diagnosis can be confirmed by finding a 5. Merck.140 but it seems that intraoperative inspection for the skin. The high grade of malignancy of gastrinomas makes the long- lating gastrin concentrations were 1. Fur. 20. .7 mg/kg orally once daily) may be more effective. the reduction appropriate candidates for surgery. gas.J. Intervet. gastric wall thickening and large ulcers may also be suggestion that the common denominator for the skin lesions examined.140 A presump.24: may have little or no beneficial effect. accurate detection. chronic gastritis. van der Lugt. administration of H2-receptor antagonists. CT. is the liver failure leading to a deficiency of essential nutrients tect gastrinomas.0 mg/kg every 12 h) gon.138 The syndrome produced by glucagono- creas. Symptomatic measures concentrate on restoration of the fluid and electrolyte balance. although it has been suggested recently that im- munocytochemistry is necessary to confirm the relation be. 10 mg famotidine /tablet. It is noteworthy that superficial necrolytic der- to limit their usefulness. skin rash (necrolytic migratory erythema). Glucagonoma in the pancreas of a dog. 2 mg/kg every 8 h) Fig. that antisecretory drugs inhibit gastric acid secretion via a dif- tive diagnosis of gastrinoma is based on the clinical findings ferent mechanism. In cases in which gastrin is 쏝 10× the upper limit of the reference range. 4. TON GD. STURGES BK. CHRISTIE Immunohistochemical morphometry of pancreatic endocrine cells MR. 5. GUPTILL L. HERRTAGE ME. SAND O. SJAASTAD OV. guinea pigs.199–234. STABENFELDT GH. J Am Anim chester. Review of 14. FALL T. King GL. Antigens 2006.000 in- Moses AC. 20. 8. Islets of Langerhans: morphology and post. In: 253 dogs in the United Kingdom with diabetes mellitus.37:489–496. THOMSON W. LEE AC. 1. JOHNSON KH. OHTANI O. Vol. RISTIC JM.336–358. CATCHPOLE B. HENTHORN PS. DAVISON LJ. WARD CR. OLLIER WER. CATCHPOLE B. 3. Tierärztl Prax 1989. HOVE K. Williams & Wilkins. 25. FRET- WELL N.) 2003. VERNAU KM. Time trends and risk factors for diabetes mellitus in dogs: analysis of veterinary 5 Medical Physiology. BARNES A. DAHME E. West Sussex: John Wiley & Sons Ltd. Comparable myelinated nerve pathology in feline and Canine diabetes mellitus: from phenotype to genotype. STEINER JM. 2003. LE- cats. Zurich. GANONG WF. Klein BG. DAVISON LJ. J Vet Intern Med (abstr. costeroids should be avoided. APPLETON DJ. 17. HAFNER A. References 181 A presumptive diagnosis can be confirmed by finding an elev.. FRETWELL N..21:1209–1216. KENNEDY LJ. Diabetische 24. American Diabetes Association: Diagnosis and classification of dia- betes mellitus. J Vet Intern delphia: Lippincott. DAVISON LJ. Comparative analysis of insulo-acinar 19. WARD CR. New York: Lange Medical Books/ medical data base records (1970–1999). Sand O. The endocrine system. As with other PETs. HERRTAGE ME. and dogs. SHORT AD.38:235–238. KIMMEL SE. GLICKMAN N. RAND JS. poor. sured dogs: Incidence. 7. Medical ther- ated plasma glucagon concentration in the absence of hypo. HAYDEN DW. survival and breed disposition.48:1948–1956. CATCHPOLE 11. HEDHAMMER A. St. 23. 16. 15. Mol Cell Endocrinol 2002. NELSON RW. WILLIAMS DA. Canine and feline diabetes mellitus: nature or nurture? J Nutr 2004. KENNEDY LJ. ed. Corti- glycemia. O. DAVISON LJ. J antigens (GAD65 and IA–2) in newly diagnosed canine diabetic pa- Comp Path 1986. KENNEDY LJ.17:395. 2005. CATCHPOLE B. dogs.17:177–188. Assoc 2000. FLEEMAN LM.197:221–229. 2007. DeFRONZO RA. Breed distribution of dogs with portal system in rats. J Vet Intern man primates). Vet J 2003. Canine diabetes mellitus: can old dogs teach us new tricks? Diabe- tologia 2005. 9. nonhu. Med (abstr. 3rd ed. BONNER-WEIR S. Diabetes Care 2008. WEENINK SM. 13. Comparative aspects of diabetes mellitus in dogs and 21. 1997. Surgical resection is the first treatment option. Familial International Textbook of Diabetes Mellitus. Tissue Am J Vet Res 2002. SHORT AD. GRECO DS. DERER R. Neuropathie beim Hund und Katze – eine bioptisch-elektronen. SPIESS B. BARNES A. minipigs. Physiology of Domestic Ani. WANG QX. Vet Rec Sjaastad OV. Identification of susceptibility and protective major histocom- and glucose-related opacities in incubated lenses from dogs and cats. eds. KÄMPE natal growth. 2005.41–52. Hove K. Endocrine functions of the pancreas & regula- tion of carbohydrate metabolism. eds. JONES C.216:1414–1417. HANSSON HAMLIN H. . Presurgical diagnostic imaging and exploratory la. tients. 2003. WIECZOREK GA. Diabetes mellitus in a population of 180. JONES CA. EGENVALL. FLETCHER TF. apy with somatostatin analogues might be an option. 22. SHEL. DAVISON LJ. Study of 2. HESS RS.) 2003. Weir GC. McGraw-Hill. Anim Pract 2008. J Am Vet Med 1997. eds. SCHMIDT P. A comparative immunohistological study of CATCHPOLE B. Textbook of Veterinary Physiology. normoglycaemic glucose-intolerant and normal cats. Acta Neuropathol 2007. Phila. Hosp Assoc 2002. 2005. because most glucagonomas are malignant and dogs chemistry supports a definitive diagnosis (fig. Oslo: Scandinavian Veterinary Press. O’BRIEN TD. 14th ed.24). References 1. OLLIER WER.409–64.143 The long-term prognosis is and any metastases. 18. J Small human diabetes mellitus. CATCHPOLE B. Evidence of anti-insulin autoreactivity and pan- pancreatic islets in laboratory animals (rats. 10.165:240–247. patibility complex haplotypes in canine diabetes mellitus. DAVISON LJ. LECOUTEUR RA. KEEN H. ZIMMET P. MIZISIN AP. creatic inflammation in newly diagnosed diabetic dogs. Smith RJ.68:467–476. GUSCETTI F.17:738. Inaugural-Dissertation. FARROW HA. In: Ganong WF. J Hered 2007.113:431–442. immunohisto. 12. eds. FLEEMAN LM.49:4–10. RICHTER M. Louis: Saunders Elsevier. Microsc Res Tech diabetes mellitus admitted to a tertiary care facility. Aldose reductase activity B. GLICKMAN L. In: Cunnig- ham JG. REUSCH C. HERRTAGE ME. 5. OLLIER WER. 4th ed.156:467–471. KASS PH. Joslin’s Diabetes Mellitus. Autoantibodies to recombinant canine in diabetic. Chi.63:1591–1597. WILLIAMS DC.98:518–525.31:S55-S60.134:2072–2080. with this tumor are often seriously debilitated by the time of diagnosis. Med 2007. HOENIG M. BURGERS ML. mals. Analysis of candidate susceptibility genes in canine diabetes. insulin-dependent diabetes mellitus in Samoyed dogs. HESS RS. 21st ed. as development of diabetes mel- parotomy can help to localize the primary pancreatic tumor litus worsens the situation. Endocrinology. mikroskopische Studie.96:357–369. FERRANNINI E. 6. CATCHPOLE B. Jacobson AM. In: Kahn CR. MCCANN TM. in cats presented to veterinary teaching hospitals. Canine Feline Med Surg 2007.9:289–299. FAZILOVA VV. MASKELL E. HOENIG M. Efficacy and safety of a purified porcine insu. VAN WINKLE TJ. BEYNEN AC. SYRING RS. HABERER B. 182 Endocrine Pancreas 26. J Am Vet Med Assoc 2000. Beta cell and insu- lin antibodies in treated and untreated diabetic cats. and enrofloxacin on clinical laboratory measurements of urine glu- cose in dogs. J Feline Med Surg ing the luteal phase and mid-anoestrus in beagle bitches.217:48–53. Am J Pathol 2000. WESS G. WARD CR. Evaluation of the effect of cephalexin 1997. SAUNDERS HM. RAND JS.212: daemia and hyperbilirubinaemia. ALEJANDRO R.7:177–182. Influence of glucose dosage on interpretation of intravenous glu- NEAL LA. BRIGGS CE. 37. Small Anim Pract 2003.16:529–532. BASHAM CR.444:840–846. Vet J 2009. FERGUSON DC. Indoor confinement and physical 34. condition and disease in cats. J Am Vet Med Assoc 1998.193: toring of blood glucose concentration by owners of diabetic dogs. J Vet Diagn Invest 33. 41. J BRAS ID. RAWLINGS JM. JOHNSON K. SELMAN PJ.) 2003. diabetes mellitus and spontaneous lens capsule rupture: a retrospective study of 18 dogs. Time trends and risk factors for diabetes mellitus RIJNBERK A. 36. FELDMAN EC. Effect of insulin dosage on glycemic 51. 55. Pulsatile secretion pattern of growth hormone dur. FALLIN EA. FERGUSON DC. 48. HOENIG M. M.9:328–334.9:98–100.77:93–102. BEAM S. DEN HERTOG E.44:298–305. HESS RS. Nature tern Med 2005. OKKENS AC. KIMMEL SE. MOL JA. Domest Med Assoc 2000. SUNVOLD GD. J Am Vet in the dog originates in the mammary gland. 1725–1731. Vet Rec 2001. HALL G. Vet Ophthalmol 1999. agement of diabetes mellitus. CORREA MT. Activity and tissue-specific expression of naturally occurring insulin-dependent diabetes mellitus. azotaemia.222:317–321. REES CA. VOCHEZER R. KOOISTRA HS. J decreases with obesity. A new parameter for diagnosis and metabolic control in the development of feline type 2 diabetes mellitus.19:675–682.216:1076–1081. HÄSSIG M. 247–253. 52. DROBATZ KJ. DEMACKER soluble and soluble dietary fiber on glycemic control in dogs with PNM. GLICKMAN LT. J Am Anim Hosp Assoc 2002.119:217–222. WILKIE DA. HOYER M. TETRICK M. Pract 2002. LIEHS MR. GRAHAM PA.157:2143–2150. SHIENVOLD FL. OTTO CM. Vet Ophthalmol 2006. 45. Anim Endocrinol 2006. REUSCH CE. WESS G. GLAUS TM. population and a questionnaire-based putative risk factor analysis. inactivity rather than the proportion of dry food are risk factors in tosamine. 5 29. ing obesity to insulin resistance and type 2 diabetes. RIJNBERK A. KOOISTRA HS. Fertil 2000.30:333–344. RAND JS. RUTTEMANN GR. HOENIG M. dogs and cats with head trauma: 122 cases (1997–1999). HESS RS. APPLETON DJ. CASELLA M. 27. MICHEL KE. 54. GLICKMAN NW. 44.179: diabetic dogs and cats. J Feline Med Surg 2001. A retrospective-co. MINTZ D. J Vet Intern Med hort study on the development of cataracts in dogs with diabetes (abstr. FARROW HA. O’BRIEN T. SIMPSON KE. CATT MJ. Evaluation of fructosamine in dogs 50. SANTEN DR. McGOLDRICK JB.217:1166–1173. at greatest risk of glucose intolerance with weight gain.3:211–228.2:169–172. BUTT JA. ELLIOTT DA. HALL DG. KAHN SE. UTZSCHNEIDER KM. FELDMAN EC. feline diabetes mellitus in a feline private practice. Reliability of history and physical examination findings cose tolerance tests in lean and obese cats. KELLEY LC. PLANTINGA EA.148:370–376.216:217–221. GEMENSKY-METZLER AJ. J Am Vet lipases and tumor-necrosis factor a in lean and obese cats. HOENIG M. Home moni- results of islet transplantation. Effects of in. NASH AS. 49. J Am Vet Med Assoc 2000.9:351–358. REUSCH CE. GRAY ML. FLEEMAN LM. 1994. J 1050–1055. BARAL RM. WARD CR. JORDAN K. WARD CR. et al. 53 cases (1995–1998). Vet Immunol 32. J Vet In. NORRIS KN. J Am Vet Med Assoc 2004. Evaluation of day-to-day variability of E. RICHTER KP. RAND JS. Prevalence of 30. Associations between body and cats with hypo. J Small Anim induced islet amyloidosis. GUPTILL L.38: 239–245. REUSCH CE. Insulin sensitivity response in dogs with diabetes mellitus: 221 cases (1993–1998). 46. COLITZ CMH.224:1455–1458. A feline model of experimentally trol and quality of life in dogs with diabetes mellitus. LAXTON D. SHAW DJ. . J Vet Intern Med 1993.43:67–73. HENSON MARKWELL PJ. J Am Vet Med Assoc 2001. NELSON RW. 47. BOOTHE DM. J Vet Intern Med for assessing control of glycemia in dogs with diabetes mellitus: 2002. DONOGHUE S. FERGUSON D. MONROE WE. and lean cats with low insulin sensitivity are Am Vet Med Assoc 2000. DEBEER M. HULL RL. DAVIDSON MG.or hyperproteinaemia. ALEXANDER S. SCARLETT JM. Endocrinology Med Assoc 2003. 38. HESS RS. 28. J Am Vet Med Assoc 1988. Mechanism link- lin zinc suspension for managing diabetes mellitus in dogs. Measurement of capillary Concurrent disorders in dogs with diabetes mellitus: 221 cases blood glucose concentrations by pet owners: a new tool in the man- (1993–1998). Advances in canine diabetes mellitus research: etiopathology and 42. Lymphocytic inflammation of pancreatic islets in a diabetic cat.134:287–292. Feline dia- betes mellitus in the UK: the prevalence within an insured cat 31. SLINGERLAND LI. 40. J Reprod 2007. 2006. Fruc. 53. HOLSON J. Hyperglycemia in Immunopathol 2000.17:433–434. REUSCH C. REUSCH CE. Influence of a high fibre diet on glycaemic con. PETERSON ME. PRAHL A. VAN GARDEREN 43. KUONEN VJ. mellitus: 200 cases. hyperlipi.218:1124–1129. Progestin-induced growth hormone excess serial blood glucose concentration curves in diabetic dogs. 39. CASELLA M. MOL JA. cataracts. 35. 211:188–192. RIJNBERK A. HAESSIG M. GRECO DS. Treatment with glargine results in Endocrinol 2002. WOLFSWINKEL newly diagnosed diabetic cats. HAWKINS KL. REUSCH CE. 86. BEALE AB. FETTMAN MJ. 2006. Hypoglycemic seizures attributable to hypoadrenocorti- 68. J Am Vet Med Assoc 2001. O’BRIEN TD. REUSCH CE. J Am Vet Med Assoc 2004. REUSCH CE. 85. KIRK C. higher remission rates than lente or protamine zinc insulins in newly diagnosed diabetic cats. MARSHALL RD. Zurich. 81. CARR RD.) 2005. DROBATZ KJ. References 183 56. J Feline Med Surg 59. SM. 58. Acute stress hyperglycemia in cats is associated with 76. Hypergly- 50-week evaluation of glipizide administration in 50 cats with pre. MAEDLER K. Ann Surg 1935. SMITH CA. FELDMAN EC. Metabolism 1981. Vet 75. day-to-day variability of blood glucose curves and evaluation of IGF-1 levels in cats with diabetes mellitus. WILLIAMS DL. VISSER TJ. ALTSZULER N. NELSON RW. Day-to-day varia- retrospektive Studie über 4 Jahre. low fiber diet and a moderate carbohydrate-high fiber diet in the management of feline diabetes mellitus. BOSCO D.75:553–535. WHIPPLE AO.12:1–6. HUME DZ. Canine pancreatic endocrine tumors: immuno- betes mellitus.20:725–726.215: 78. FORD SL. ZINI E. FREEMAN L. cemic.98:641–650. REUSCH CE. MICHELS 83. NELSON RW. J Vet Intern Med 2002. BENNETT N. Serum fructosamine concentration in cats with overt hyperthyroidism. O’BRIEN TD. GERICH JE. BLACKSHAW J. Vet Rec 2007. J Am Vet Med Assoc 1997. NELSON RW. Diabetic ketosis and ketoacidosis in cats: 42 cases (1980–1995). DROBATZ KJ. J Am Vet Med Assoc 1994.19: 57. ROBBEN JH. sulinomas.24:308–314. FURRER D. DE BRUIJNE JJ. Br J Nutr 2007. CAVE NJ.20:31–37. betes mellitus: 26 cases (1999–2002). ROZANSKI EA. HESS RS. J Vet Intern Med (abstr. Gonadectomy and high dietary fat but not high dietary carbohydrate induce gains in body 60. J Vet Intern Med diabetic ketoacidosis: 127 dogs (1993–2003). MAHONY OM. J Am Vet Med Assoc 1997. VAN GARDEREN E.30:190–194. home monitoring of blood glucose concentrations in cats with dia- nephrine. NEY T. 65. CHAN DL. MARSHALL RD. RAND JS. SM. DONATH MY. RAND JS. 67. FELDMAN MS. BRUSKIEWICZ KA.18: J. TSCHUOR F. Sulfonylurea induced beta-cell apoptosis in cultured human islets.14:30–40. 69. GOOSSENS MMC. CAYWOOD DD. BORETTI FS. ALT N. REUSCH CE. ZUELLIG RA. GRIFFEY 1297–1300. Glycogenolysis in the fasting GM. J Am Vet Med Assoc 2007. J Vet MATHES M. PETERSON ME. HAYDEN DW. KLEY S. LALUHOVÁ D. FELDMAN EC. The effect of feeding time on the quality of metabolic con- Ophthalmol 2006. 5 of a cross-sectional study of 2000 normal animals. 63. Intravenous arginine stimulation test in cats with 79.161:88–94. O’LEARY TP. 772–777. DE KOSTER P. HEATH MF. Outcome of dogs with transient and non-transient diabetes mellitus. KEISLER DH. GRIFFEY 2006. HAMPSHIRE J. TOMSA K.230: 1011–1017. WAGNER-MANN CC. NELSON RW. NELSON RW.9:341–349. Vet Pathol 1987. WEAVER KE. GRIFFEY SM. Locally produced growth hormone in canine in- 401. Fat mobilization and plasma hormone levels in fasted dogs. 70. J Am Vet Med Assoc 1999. MARTIN GJ. Intensive 80. Mol Cell Endocrinol 2002. porcine insulin zinc suspension. ALT N. Insulin glargine and a high protein- low carbohydrate diet are associated with high remission rates in 87. 74. J Vet Intern Med (abstr. FELDMAN EC. unpublished data. sient clinical diabetes mellitus in cats: 10 cases (1989–1991).204:526–528. J Vet Intern Med 1998. Control of diabetes mellitus in cats with cism in a dog. SUMMERS BA. 84. insulinism. BACKUS RC. GERBER B. 2006. BER. RAND JS. CASELLA M. Evaluation of long-term struggling and increased concentrations of lactate and norepi.16:123–132. BAGLIONI A. Tran.) 2004.225:261–266. KUHAJDA FP. LALUHA P. histochemical analysis of hormone content and amyloid.210: 2001). KOENIG A. Inaugural-Disser- tation. HACKENG WH. 71. islet cell tumors in dogs. 50 cats with dia- betes and one hundred cats following dehydrational crises. Mol Cell 72. KLEY S. Vet Pathol 1987. hyperosmolar syndrome in feline diabetics: 17 cases (1995– viously untreated diabetes mellitus. mellitus in cats. MOL JA.90: 82.197:213–219. Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985–1995). Use of glargine and lente insulins in cats with dia. . J Clin Endocrinol Metab 2005. KINNAIRD E. Prevalence of feline cataract: results weight and fat of domestic cats.146:375–383. Adenoma of islet cells with hyper- 66. Comp Biochem Physiol B 1983. RAND JS. 64. 62. 61.) 2006. Schweiz Arch Tierheilkd bility of blood glucose concentration curves generated at home in 2004.20:547–555. cats with diabetes mellitus.218:38–42.8:73–84. Insulin glargine: long-acting basal insulin analog for Immunocytochemistry of normal pancreatic islets and spontaneous improved metabolic control. FRANTZ VK. 425. Comparison of a low carbohydrate- Intern Med 1999. J Vet Intern Med 2006. KING LG. 501–506. J Vet Emerg Crit Care 2004.13:28–35.101:1299–1335. 73. LYNN RC. KAUFMANN K. Pathogenesis of feline diabetes mellitus. Stresshyperglykämie bei kranken Katzen: Eine 77.24:170–179. J Vet Intern Med (abstr. PRIEST J. trol. LEVY JK. FELDMAN EC.20:234–238. DE BRUIJNE JJ. LUTZ TA. Curr Med Res Opin 2004. Efficacy of protamine zinc insulin for treatment of diabetes dog.197:187–195. JOHNSON KH. J Am ogy and Reproduction.329:834–839. BREARLEY MJ. eds. FELDMAN EC. 184 Endocrine Pancreas 88. MITRAKOU A. 111. UNZUETA A. FELDMAN EC. glucagon. Nelson RW. noma and subclinical peripheral neuropathy in two dogs. spective review of 16 cases. 2004. N Engl J Med 1995. MCMILLAN C. J Nucl Med 1997. VOORHOUT G. VENEMAN T.27:194–198. Louis. Effect of octreotide on plasma concentrations of glucose.215:226–230. O’BRIEN TD. munohistochemical evaluation. HARVEY HJ. Med 1993. J Clin Endocrinol Metab 1997. VAN DONGEN AJ. REUBI JC. JD. JOHNSON KH. POLTON GA. J Am Anim Hosp Assoc 1990. pathological and im. AMLING KA. Treat. and single-photon emission computed tomography for 1999. Hypoglycemia and irreversible neurologic compli. YEAGER AE. HOKARI M.and hyperglycemia revisited. GENTER P. Clinical loid polypeptide and calcitonin gene-related peptide immuno. J Am Vet imaging in vivo by planar scintigraphy facilitates the diagnosis of Med Assoc 1997. PATNAIK AK. and anemia. Pancreatic insulin-secreting 2899–2903. FELDMAN EC. SNEAD EC. JOHNSTON SD. . J Vet Intern Med 2005. WESTERMARK P.211:723–727. et al. J Am Anim Hosp Assoc 1985. VAN DEN INGH TSGAM. crine tumors. DEN INGH TSGAM. Res Vet Sci JM. BRYSON ER. J Vet In- tern Med 1987. FELDMAN EC. MOL JA. 113.26: 108.19:15–22. Vet Res reactivity in amyloid and tumor cells of canine pancreatic endo. 101. DUNN JK. 102. KEMPPAINEN RJ. Vet Med Assoc 1999. HEN. Insuli. LAMB CR. computed to- fects of hypo. and dogs with naturally developing diabetes mellitus. growth hormone. CAYWOOD DD. J Am Anim Hosp Assoc 2007. NORRIS AM.1:86–90. KRUTH SA. JACKSON KF. 109. 110. KIRPENSTEIJN J. Insulin-secreting islet cell tumors: establishing a diagnosis and the clinical course for 96.223: L. Glucose homeostasis during prolonged suppression of 93. KRAJE AC. 103. Improved survival in a retrospective cohort of 28 dogs with CAN M.616–643.19:168–176. LAMBERTS SWJ. FELIC P. St. JOHNSON KH. N Engl J canine insulinomas. J Small Anim Pract 2008. CHOU HF.82: DERSON RA.24:577–584. HERRTAGE ME. 91. Somatostatin receptor beta-cell neoplasia. MAHER F. Outcome of surgical versus medical treat- In: Feldman EC. SERVICE FJ. LUCROY MD. Reversibility of un. O’BRIEN TD. insulin. PERRIELLO G. J Vet Intern Med 2005. Gly- cosylated hemoglobin concentrations in the blood of healthy dogs 116. ROELS S. WHITE RN. RUTTEMAN GR. CARILLO and cortisol in healthy dogs and dogs with insulinoma. ROBBEN JH. J Am Vet Med Assoc 2003. VOORHOUT G. Islet amy.18:13–23. 5 and general management in 35 dogs. HAEFTEN TW. J Am Anim Hosp Assoc 1988. Missouri: Elsevier. DeFRONZO R. 107. NELSON RW.74:348–352. Vet Rec 1997. APPEL NM. insulinoma. WITHROW insulin concentrations in patients with insulinoma: mechanism for SJ. WELLS HG. TOBIN RL.43: 65–69. STEINER JM. Insulinoma in a cat. 1144–1152. ELLIOTT DA. Erratic oscillatory characteristics of plasma 92. KENNEDY PC. pancreatic McDONOUGH SP. Commun 2001. glucagon and insulin secretion by somatostatin. VAN HAM L. In CALDERONE S.181:54–58. WAHREN J. TOIVIO-KINNU. ROBBEN JH. BERMAN N. SLYE M. BRIGHT RM. VAN RIJK PP. RIJNBERK A.33:514–520. diagnostic.25:109–115. CASE LC. HENDLER R. BOSWOOD A. BOWSHER R. 95. GD. GARDEN OA. neoplasms: clinical. MACDOUGALL cations in a cat with insulinoma. SHERWIN RS.49:38–40. VAN West Highland white terrier. 11 cases. OKI J. Can Vet J 1999. 3rd ed. Beta-cell neoplasia: insulinoma. Vet Pathol 1990. Arch Pathol 1935. PUTCUYPS I. BRUYETTE DS. NELSON RW. BRAUND KG. ment of a dog with an insulinoma-related peripheral polyneuro- pathy with corticosteroids. Diagnosis of insulinoma in the dog: a study in a dog. O’LEARY TP.72:2382–47. SIMPSON IA. 106. RICHARDSON RC. pendent diabetes mellitus. Insulinoma in a dog with pre-existing insulin-de- 812–814. Tumor of islet tissue with hyperinsulism in WALKER MJ. 115. Canine and Feline Endocrinol. KLAUSNER JS. HEATH MF. 89. et al. TURNER TM.40:343–345. SIMPSON KW. PLATANISIOTIS D. IPP E. PEREZ M. NEAL LA. TESKE E. VAN 100. GREEN SN. 104. ROBBEN JH. EASTWOOD 98. FANELLI C. 94. Comparison of ultrasonography. VAN DEN BROM WE. Blood-brain barrier glucose transporter: ef. hyperadrenocorticism.21:607–612. HOLMAN BOROFFKA SAEB. BRAUND KG. U S A 1977.141:98–100. and prognostic features in 73 dogs. Proc Natl Acad Sci Pancreatic endocrine tumor in a cat: clinical. COX D. Comp 25 dogs. vitro and in vivo detection of functional somatostatin receptors in awareness of hypoglycemia in patients with insulinomas.38:1036–1042. Insulin-producing islet cell neoplasms: surgical considerations 2006. canine insulinomas. value of fructosamine measurements in non-healthy dogs. SIMPSON KW. J Neurochem mography. Ultrasonography of pancreatic neoplasia in the dog: a retro- 99. J Small Anim Pract 2007. NELSON RW. CORTEZ C. MATTHEWMAN LA. POLLAK YWEA. LOSTE A. Hypoglycemic disorders. Canine insulinoma.80:25–32.19:537–542. 112. ment of dogs with beta cell neoplasia: 39 cases (1990–1997). 114. Cont Educ Pract Vet 1996. VISSER-WISSELAAR HA. JM.137:65–68. J Am Vet Med Assoc 1982. MEHLKAFF CJ. PETERSON ME. MARCA MC. NORTON F. Vet Rec 1995. HOFLAND LJ. 90. Pancreatic insulin-secreting neoplasm (insulinoma) in a 105. STEISS JE. the detection and localization of canine insulinoma. unpredictable hypoglycemia. DYKES NL.48:151–156. ALLEN AL. WOOLDRIDGE 97. J Small Anim Pract 1992. COLEMAN ES.332: 453–457. EBERLE C. Octreotide acetate long-acting release in patients with metastatic neuroendocrine tu. HALL GM.30: 134. VENN RM. ZINI E.24:175–182.132:744–750. The pathophysiology of IGF-II hypersecre- Functional Characteristics [Thesis].54:242–247. with octreotide LAR. Utrecht: Utrecht University. Endoscopic ultra. 132. ARVIGO M. VAN DEN dogs. ROBBEN JH. POST GS. 1337–1355. J Vet Intern Med 1989. References 185 117. tion in non-islet tumor hypoglycaemia. tion of insulin-like growth factor-I. KOMMINOTH P. Philadelphia: WB Saunders Co. Treatment of gastroenteropancreatic neuroendocrine tumours 138. VAN HOE N. HAUSER B. Hepatocutaan syndroom. BARRECA A. HENRY CJ. Gastrinoma in dogs. ed. KIRCHER P. GALLI L.92:1616. WANG P.21:193–195. VAN WINKLE TJ.221:811–818. KWEK. DAUGHADAY WH. ORLANDINI C. type IV of Norwegian forest cats. POLLAK Y.3:178–182. NELSON RW. 139. BRYANT A. Eur J Endocrinol 1995. HOLT DE. ROBBEN J. ARNOLD P. Use of long-acting 137. KRISTAL O. 121. Diabetes Rev 1995. PAT- TERSON DF. J Am Vet Med Assoc 1985. sarcoma in 14 dogs. 144. VAN DER LUER R. KIUPEL M. endocrine and inflammatory responses in post-operative view of therapeutic options.26: 140. MATUS RE. GROUNDS RM. MINUTO F. N Z Vet J 2006. JENSEN RT.9: J Am Vet Med Assoc 2002.17:107–110. KRENNING EP.11:1127–1130.14: WOLFF C. Somatostatin receptor-targeted radio. A complex rearrangement in 120. 133. FERDEGHINI M. 130.48: ile-onset neuromuscular degeneration in glycogen storage disease 338–349. 127. COHEN M. Veterinary Therapy XIII. HOENERHOFF M. ANTONUZZO A. SMEAK D. GARDNER JD. KINTZER P. Gastrin-secreting neoplasia in a cat. J Am Anim INGH TS. 2007. VAN DER LINDE-SIPMAN JS. MOL JA. BODEI L. Metabolic epidermal necrosis-hepatocutaneous syndrome. growth factor type-II secreting hepatocellular carcinoma in a dog. VROOM MW. FYFE JC. McDONOUGH SP. On the mech- anism of diazoxide-induced hyperglycemia.3: 2004. J Comp Pathol 2004. HAWKINS MG. somatostatinoma in a 10-year-old Portuguese water dog. Tijdschr Dierge- REUSCH CE. Mol Genet Metab 2007. SANDERS NA. Dig Dis Sci 1989. 118. Experimental induction of Hosp Assoc 1988. Diabetes 1977. Transient juvenile hypogly- ment of pancreatic islet cell tumors in dogs: 17 cases (1989–1999). Part II: Clinical trials and results in four dogs. Vet Clin North Am Small Anim Pract 1999. SIMPSON KW. WENSING T. Hypoglycemia associated with nonislet cell tumor in 13 dogs. Vet Q 1987. NEUTEBOOM J. CONTE PF. SLAPPENDEL RJ. Intravenous methylen blue infusion for intraoperative identification of pancreatic islet-cell tumors in 135.32:133–140. HAMPSHIRE J. CORINALDESI R.132:920–922. caemia in a Yorkshire terrier and in a Chihuahua. MORARU E. Gastrointestinal leiomyo. Canine gastrinoma: a case study and literature re- vascular. KVOLS LK. 172–176. O’DORISIO TM. Pancreatic polypeptide and insulin-secret- cell tumors. ZERBE CA. 123. VAN DEN INGH T. J Vet Intern Med 2007. 125. WOLFRAM K. Concurrent gastrinoma and mors pretreated with lanreotide. Vet Quart 1991. 141. Vet Radiol Ultrasound 2007. BYRNE KP. PLETCHER somatostatin analog SMS 201–995 in patients with pancreatic islet JM. TOMASSETTI P. gastric wall producing an insulin-like growth factor II-like pep- Biodistribution of [111In-DTPA-D-Phe1]-octreotide in dogs: tide. Effects of dexmedetomidine on adrenocortical function. OGILVIE GK. Glucagon-producing 557–560.186:53–55. VALKEMA R. YUHKI N. WRIGHT JC. 126.130:313–318. GLAUS TM. J Clin Endocrinol Metab WELS S. PETERSON ME. HUGHES SM. DIROFF JS. Aliment Pharmacol Ther 2000. 2000. CLAUDE REUBI J. J Vet Intern Med 2006. GBE1 causes both perinatal hypoglycemic collapse and late-juven- sound of the canine abdomen. 136. Hypoglycemia due to paraneoplastic secre- KEBOOM DJ.34:28S–39S. GIGER U.86:650–656. Paraneoplastic hypoglycemia due to an insulin-like neeskd 2007. SMITH C. Semin Nucl Med 2002. BAKKER W. BOOSINGER TR. J Small Anim Pract 2000. HENTHORN PS. RASSNICK KM. KURZHALS RL. ing tumor in a dog with duodenal ulcers and hypertrophic gastri- tis. and the cardio. DE JONG M. Kirk’s 931–935. GASCHEN L. 142. Streptozocin for treat. . VEN- TUROLI M. J Vet Intern Med 2003. 122.90: 383–392. nuclide therapy of tumors: preclinical and clinical findings.13:16–23. RICCI S. PATNAIK AK. 63–72. ALTSZULER N.20: 128. BESTETTI GE. Ann Oncol 2000. neuroendocrine tumour associated with hypoaminoacidaemia and skin lesions. MIGLIORI M. Nucl Med Biol 2003. 1245–1247. MATON PN. HASKINS ME.29: 129. LEIFER CE. BOARI A.41:402–406. 124. BREEMAN WA. FINGEROTH J. patients needing sedation in the intensive care unit. uptake in the stomach and intestines but not in the spleen points towards interspecies differences. VOORHOUT G. ALLENSPACH K. fasting hypoglycaemia and fatty liver syndrome in three Yorkshire terrier pups. HAUSER B. 143. MINUTO F. VAN TOOR AJ. 617–621. PAU. JAMAR F. GRABAU JH. Br J Anaesth 2001. Hypoglycemia in a dog with a leiomyoma of the 119. GULLO L. In: Bonagura JD. Insulinoma in Dogs – Diagnostic Aspects and 131. DAUGHADAY WH. GLAUS T. 5 225–232. MOORE AS. Testosterone stabilizes the former Wolffian (or mesonephric) duct. Secretion of AMH by the fetal Sertoli cells is necessary to inhibit the growth and development of the Müllerian ducts into female internal genitalia. Dihydrotestosterone (DHT) is required for complete development of the external male genitalia and closure of the urethra. .1: Schematic representation of male and female differentiation and development from the undifferentiated state under stimulation and inhibition of sex steroids and regulatory peptides. 186 Gonadal Development and Disorders of Sexual Differentiation 6 Figure 6. The presence of a Y chromosome leads to male differentiation of the gonad with subsequent secretion of testosterone and Antimüllerian Hormone (AMH). Normal mammalian sexual development is a of expression of these genes.2 sex determination and steroidogenesis is DAX-1 (dosage-sen- sitive sex reversal-adrenal hypoplasia congenita critical region . comprising ovaries. expression of target genes essential for both male and female clude the Leydig and theca cells. a re. and kidney.1 Introduction 6. gonadogenesis. the Sertoli and granulosa cells. and the peritubular myoid and stroma cells. individuals having testicles and XX individuals having somes).1). These counterparts in. in birds and reptiles. Consequently. which mediate mosomal sex of the zygote after conception. the male gonadal sex in mammals is the expression of a domi. factors that are expressed in the gonadal ridge and are required for gonadal development and sexual differentiation – The bipotential gonads arise from the urogenital ridge. 6.7 WT1 may increase and oocytes).1 Establishment of the induction. known. The product of the SRY gene is a transcription factor (often called testes determining factor) that is thought to play a key role in initiating the cascade of gene regulations resulting in testicular 6.2 Establishment of the CS 17.1. of 39 chromosome pairs (78 chromosomes). 187 6 Gonadal Development and Disorders of Sexual Differentiation Heidi J.2. The cat has 38 chromosomes (19 pairs). Although the importance of the SRY gene for sex 18 pairs of autosomes and one pair of gonosomes. the germ cells (spermatocytes onset of the sex determination period. and GATA4 – presumably because they activate the the cell lineages of the adrenal cortex.1. induction of testes is only associated with SOX9 ex- distinguished and are therefore termed bipotential or indiffer.1. The structural homology of SRY to transcriptional ways has an X chromosome and the sperm has either an X or regulators of the high-mobility-group family led to the hy- a Y. it is the gonosome of the sperm that determines the chro. more than in the female. steroidogenic factor-1 gion adjacent to the mesonephros that ultimately determines (SF-1). WT1 is involved in uro- testes and ovaries have functional counterparts with corre. Thirty-eight normal development of the reproductive organs results in XY pairs are autosomes and one is the sex chromosomes (gono. which ceptor family and the onset of SF-1 expression signifies the support germ cell maturation. male and female gonads cannot be SRY. might very well initiate testis development by upregulating SOX9 (sex-determining region Y-box 9) expression because SRY expression begins at CS (Carnegie Stages) 16 in the dogs testis.3–5 In the presence of a Y chromosome. ent. The zygote will the conversion of the bipotential gonad into a testis. the levels of SF-1.6 The SOX9 structure is typical for a transcription fac- gonadal sex tor and upregulation of SOX9 is essential for testis develop- ment. They have bipotential genital ridges. Another gene that interacts with SF-1 in which form the connective tissue of the gonads. SF-1 is a member of the nuclear hormone re- ogenic compartment. pothesis that SRY activates downstream genes. The expression of essential target genes. Furthermore. pression. sex differentiation Sexual differentiation is dependent on the expression of sex requires not only the participation of a large number of genes determining genes and the production of hormones in the at different loci but also the correct timing and adequate levels fetal gonads. which comprise the steroid. nant genetic factor localized on the Y chromosome: the SRY opment of gonadal sex and phenotypic sex (fig. the exact mechanism by chromosomal sex of the conceptus is determined at the time which it induces male gonadal sex differentiation is still un- of fertilization. Wolffian and Mül- lerian ducts. a genital tubercle. Kuiper 6.1. Essential in the development of complex process that relies on successful completion of suc. gonad. a urogenital sinus. gene (sex-determining region of the Y chromosome). 6. followed by upregulation of SOX9 expression at 6. Because the ovum produced by the female al. 6. undifferentiated gonads always develop into testes.1). 6 cessive steps that determine chromosomal sex and the devel. such as Wilms’ tumor related 1 (WT1). and genital Recent studies have identified several other transcription swellings (fig. The determination is unquestionable.2). containing chromosomal sex an SRY gene.1 SRY have the gonosomes of either a female (XX) or a male (XY). while in the absence of the SRY gene or its gene prod- The complete chromosomal complement of the dog consists uct the gonads develop into ovaries (fig.1 Genes essential for gonadal development In the male. which do not have Prior to sex differentiation. genital development and has been suggested to regulate the sponding functions in reproduction. 188 Gonadal Development and Disorders of Sexual Differentiation Figure 6.2: Molecular events in mammalian sex determination. Genes believed to have key functions are depicted: WT1 = Wilms’ tumor gene; SF-1 = steroidogenic fac- tor 1 gene; LHX9 = LIM homeobox protein 9 gene; DAX-1 = dosage-sensitive sex reversal-adrenal hypo- plasia congenita critical region on the X chromosome; 6 GATA4 = GATA binding protein 4 gene; SRY = sex de- termining region of the Y chromosome; SOX9 = sex determining region Y-box 9 gene; DMRT1 = doublesex and mab-3 related transcription factor 1 gene; PAX2 = paired box gene 2; PAX8 = paired box 8 gene; EMX2 = empty spiracles homeobox 2 gene. on the X chromosome, gene 1), a transcriptional regulator male ducts. The proximal part of the Wolffian duct coils and that inhibits target genes.8 GATA4 encodes a transcription forms the epididymis and the distal part forms the vas defer- factor that promotes SRY expression in the XY gonad.7 The ens. The seminal vesicles develop from lateral outgrowths of LHX9 (LIM-homeobox 9) gene, encodes a homeodomain the caudal end of the vas deferens. transcription factor that has been described as essential for gonad formation in mice and gives rise to the development of In the absence of AMH and testosterone, female organo- both Sertoli and granulosa cells.9 DMRT1, the doublesex and genesis proceeds by regression of the mesonephric Wolffian mab-3 related transcription factor 1, is conserved among ver- ducts and stabilization of the Müllerian ducts (fig. 6.1). De- tebrates, is involved in testis differentiation in mammals, birds, velopment of the Müllerian ducts takes place in the cranio- reptiles, amphibians, and fish, and is associated with Sertoli caudal direction, to give rise to the female internal genitalia. cell maturation. The cranial portion of the Müllerian duct gives rise to the oviducts. The middle portion gives rise to the uterine horns, which fuse caudally to form the body of the uterus. The cau- dal portion gives rise to the uterovaginal plate with the par- 6.1.3 Development of the Wolffian ticipation of both Müllerian and Wolffian duct components, and Müllerian ducts to form the cervix and cranial vagina. The urogenital tubercle of the female undergoes limited growth and remains exposed The internal genitalia derive from the genitourinary tract, as a cleft into which the vagina and urethra open.11,12 The which is initially identical in male and female embryos Wolffian ducts recede in female mammals but remnants may (fig. 6.1). At the indifferent stage, male and female embryos be present in the form of an appendix vesiculosa, epoopho- have two identical sets of paired ducts: the Müllerian ron, paroophoron, or duct of Gartner.13 (paramesonephric) ducts and the Wolffian (mesonephric) ducts.1 Whether there is development of Wolffian ducts for the male or the Müllerian ducts for the female depends on 6.1.3.1 Genes essential for development of Wolffian autosomal genes that permit or prevent the production of and Müllerian ducts AMH (anti-Müllerian hormone or Müllerian inhibiting sub- Several genes are involved in the initial development of the stance (MIS)) in the Sertoli cells of the fetal gonad. AMH is Wolffian and Müllerian ducts. Thus, contrary to the older the first secretory product of the fetal testis and thus marks the view that fetal ovarian development is passive, female germ end of the testis induction period and the beginning of testis cell differentiation and normal fetal ovarian morphogenesis function.6 Müllerian duct regression in male dogs begins by require the expression and collaboration of various genes. day 36 of gestation and is completed at day 46.10 PAX2 (paired box gene 2), a transcriptional regulator of the paired-box family, is expressed in the epithelium of the me- When the Leydig cells in the male gonad begin to produce sonephric tubules as well as in the Wolffian and Müllerian testosterone, it determines the further development of the ducts. PAX8 is coexpressed with PAX2 and has additional Abnormal sexual differentiation 189 functions in urogenital development. WT1 is required for the formation of the caudal mesonephric tubules, but not the cranial tubules that later form the efferent ducts.13 The LHX1 (LIM-homeobox 1) gene is expressed in epithelium of the mesonephric tubules of the Wolffian and Müllerian ducts and is presumed to play a role in the formation or very early dif- ferentiation of both Wolffian und Müllerian ducts. EMX2 (empty spiracles homeobox 2) is also required for the formation of both pairs of genital ducts.13 The gene encoding the AMH glycoprotein is transcription- ally regulated by several genes, including SF-1 and SOX9. These work synergistically and stimulate AMH transcription in the gonad, while DAX-1 is inhibitory (fig. 6.2).14 Figure 6.3: 6 Androgen-mediated differentiation of the duct system and Detection of a 201 bp product specific for the canine SRY gene using PCR and the primers Dog_SRY_F 5'-AAG CGA CCC ATG AAC GCA TT-3' and Dog_SRY_R external genitalia also depends on the functional integrity of 5'-TTC GGG TAT TTC TCT CTG TG-3' (EMBL Accession No. L77494). The product the androgen receptor (AR) gene located on the X chromo- is present in the reference male (left) but absent in both the female (middle) and some. The AR protein is a ligand-dependent transcription the XX sex-reversed patient (right). A 100 bp ladder is shown as reference for the factor that regulates the transcription of specific genes by size of the PCR products. binding androgen-AR complexes to regulatory DNA se- quences close to target genes. Epithelial cells of the skin, the urethral plate in the glans, and the stroma and epithelium of the tubular urethra of the penile shaft are known to be In dogs and cats, the fetal testes migrate from the posterior strongly AR positive in man and are presumed to be so in poles of the kidneys and pass through the abdominal wall to other mammals, also.11 reach the scrotum. The descent is completed a few weeks after birth in these species (see also chapter 8). 6.1.4 Establishment of the phenotypic sex 6.2 Abnormal sexual differentiation Like the internal genitalia, the external genitalia derive from structures initially found in both sexes, including the genital Disorders in male or female development may result in an in- tubercle, urethral folds, the urethral groove, and the genital tersex individual or hermaphrodite. The latter term is derived swellings. While the urethral groove in females is open, part from Greek mythology, referring to Hermaphroditus, the of the urogenital sinus forms the vestibule. The labioscrotal issue of Hermes and Aphrodite, who was neither female nor folds form the vulva. In contrast to male sex development, male but at the same time both. Intersexuality or hermaphro- formation of a female phenotype does not require the ditism may be manifested in a variety of phenotypes, ranging presence of gonads and the hormones they produce.15 If the from mild forms of genital malformation to ambiguous exter- gonads are removed from an embryo that is still sexually in- nal genitalia with complete sterility, depending on the specific different, a female phenotype nevertheless develops.16 stage at which sex differentiation was disrupted. Individuals with both ovarian and testicular tissue are called true her- In males androgens are critical for virilization.1 Testosterone, maphrodites and must be differentiated from pseudoher- secreted by the Leydig cells through the activation of the maphrodites, in which chromosomal and gonadal sex agree 3b-HSD gene, is required for differentiation of the male duct and yet external appearance is that of the opposite sex. system. Dihydrotestosterone, a potent androgen produced from testosterone by one of the 5a-reductase enzymes within Intersexuality can originate from disorders of chromosomal the target cells of the urogenital sinus, is required for differ- sex, disorders of gonadal development, or disorders of pheno- entiation of the external genitalia. This includes closure of the typic sex. Hence, correct classification of intersexuality urogenital sinus, elaboration of the urethral and prostate requires identification of the subject’s chromosomal sex, glands, elongation of the genital tubercle and fusion of the gonadal sex, and phenotype. urethral folds over the urethral groove to form the penis and penile urethra, and relocation of the genital swellings poster- Identification of chromosomal sex requires cytogenetic ior to the genital tubercle prior to their fusion to form the examination, but the polymerase chain reaction (PCR) can scrotum (fig. 6.1).11,17 also be used to investigate specific regions of the Y chromo- some for the SRY gene (fig. 6.3) or the ZFY (zinc finger pro- 190 Gonadal Development and Disorders of Sexual Differentiation 6 Figure 6.4: Four male cats with the tortoiseshell coat color indicat- ing a chromosomal anomaly. The two at the top of the picture had the XXY syndrome and the two at the bottom were XX / XY chimeras. The latter two were presumed to be fertile because spermatogenesis was observed in some seminiferous tubules. tein, Y-linked) gene. Gonadal sex should be determined by Chimeras arise from fusion of two or more zygotes after con- histological examination of the gonads by a person experi- ception, while mosaics originate from a single zygote and the enced in this field; ultrasonographic examination is not con- chromosome abnormality usually results from a mitotic non- clusive. Phenotypic sex can be determined by physical exam- disjunction. Neither disorder is considered to be inherited. ination, diagnostic imaging of the abdomen, and hormone measurements. XX / XY chimeras have been described in several dog breeds. A uterus, cervix, and ovaries with follicles were found in a dachshund with a small prepuce and a scrotum lacking testes. The penis could not be extruded from the prepuce.20 An 6.2.1 Disorders of chromosomal sex XX / XY karyotype was also demonstrated in a Belgian shep- herd dog with male behavior, abdominal testes, and a 6.2.1.1 Chimerism and mosaicism of uterus.21 Ovotestes and a uterus were present in a schipperke sex chromosomes with an enlarged clitoris.22 An abnormal phenotype has been Errors in the constitution of the sex chromosomes can in- found in all of the reported cases of an XX / XY karyotype in fluence gonadal differentiation. The majority of animals with dogs. Cases of 78,XX / XY chimerism with both ovarian and sex chromosome abnormalities have few symptoms, the most testicular tissue are termed true hermaphrodites. common being primary anestrus in phenotypic females and infertility in phenotypic males.18 In some cases ambiguous Chimerism of sex chromosomes is also known in cats, occur- genitalia provide an impetus for further investigation.19 ring most often in fertile tortoiseshell (calico) colored tom cats (fig. 6.4). Most of these have both a 38,XX and a 38,XY In both chimerism and mosaicism of the sex chromosomes cell line.23–25 Among 38 tortoiseshell colored tom cats, 7 had the animal has two or more genetically different cell lines. the XX / XY karyotype.26 Some were fertile males or pre- Abnormal sexual differentiation 191 sumed to be fertile. A 38,XX /38,XY chimera with ovotestes The most prominent manifestation of gonadal dysgenesis is was reported by Leaman et al.27 The presence of an ovotestis is primary anestrus. The onset of puberty occurs at six to often seen in chimeras in other species, but this is the only re- 23 months of age in the normal bitch and at four to ported case in cats. 21 months of age in the queen, and in both species the diag- nosis of primary anestrus requires the absence of pubertal es- Chimerism in cats and dogs is usually whole body, i.e., in all trus by 24 month of age.35 For the diagnosis of gonadal dys- tissues. Blood chimeras, well known in freemartin cows, have genesis other possible causes of primary anestrus must be not been reported in cats or dogs and are unlikely because of excluded. These include mosaicism, chimerism, XX- or XY- the difference in placental structure. sex reversal syndrome, male or female pseudohermaphrodit- ism, oophoritis, and hypothyroidism. The plasma concen- The only reported case of mosaicism involving the sex chro- trations of LH and FSH will be elevated in the absence of mosomes in a dog was an infertile female toy poodle with a ovarian tissue. The final diagnosis should rest upon the cyto- 77,X0/78,XX karyotype and no signs of intersexuality.28 As genetic demonstration of X-monosomy. In addition, histo- in the X0 syndrome (see below), there was dysgenesis of both logical examination of gonadal tissue obtained by laparoscopy gonads. In addition to small ovaries, there was a relatively or at laparotomy can confirm the diagnosis of gonadal dys- 6 small uterus without a functional body. genesis. Karyotyping is necessary for the diagnosis of chimerism or In an unusual case in an Eskimo dog, there was persistent mosaicism in order to define the sex chromosome error. This proestrus which necessitated ovariohysterectomy,29 but in can be performed on peripheral blood lymphocytes or cul- most cases no therapy is required for there are no physical tured fibroblasts. changes that interfere with the health of the animal. Gonadectomy has been recommended when there is intra- abdominal testicular tissue, since this is associated with an in- 6.2.1.3 XXY syndrome creased risk of Sertoli cell neoplasia (see also chapter 8). Hys- Another chromosomal anomaly resulting in abnormal sexual terectomy has been recommended in true hermaphrodites development is the XXY syndrome (Klinefelter’s syndrome in because of the risk of endometritis. These risks must be humans), which is known to occur in almost all domestic ani- weighed against the morbidity and mortality associated with mals. The presence of the Y chromosome may lead to male abdominal surgery. gonadal differentiation with subsequent AMH and testoste- rone production, so that the individual is phenotypically male. The presence of an extra X chromosome (or several X 6.2.1.2 XO syndrome (gonadal dysgenesis) chromosomes) causes atrophy and hyalinization of the semi- In gonadal dysgenesis or the X0 syndrome the second sex niferous tubules together with Leydig cell abnormalities and chromosome is missing. Most often the paternal X chromo- decreased steroid secretion by the Leydig cells.36 some is lost during spermatogenesis or after fertilization. Germ cells are usually absent and the gonads consist mainly of Most humans with Klinefelter’s syndrome are described as fibrous tissue (streak gonads). In the absence of germ cells having atrophic testes, gynecomastia, and a hypoplastic penis. there is no gonadal steroid stimulation of the female genitalia There have been only three reported cases in dogs. One of and the individual is infertile. In humans the syndrome is these had a normal male phenotype, small testes, and no sper- termed Turner’s syndrome, but in mammals the term X0 syn- matogenesis.37 The second was initially thought to be a male drome should be used. pseudohermaphrodite, for there was a bicornuate uterus and testes, one of which had descended.38 The third dog was a There have been only a few cases reported in dogs. One af- one-year-old poodle with bilateral cryptorchidism and a fected bitch had a paradoxical pattern of persistent proes- 78,XY/ 79,XXY mosaicism demonstrated in lymphocytes trus.29 One was presented because of primary anestrus and a and in gonadal tissue cultures.39 small body size, and appeared to have small ovaries.28 Another had facial deformities.30 A six-month-old Doberman with Although the true incidence of the XXY syndrome in cats is this syndrome had ambiguous genitalia.31 The syndrome has unknown, it is the most commonly reported sex chromosome also been reported in two three-day-old kittens, of which one abnormality in this species. It is known to occur in several was found dead32 and the other was euthanized because of breeds of cats and in almost all reported cases it is associated spina bifida.33 The X0 syndrome was also diagnosed in a with a tortoiseshell or calico coat color (fig. 6.4).40,41 In cats 2.5-year-old Burmese cat which was smaller than its litter- the genes for orange and nonorange are X-linked alleles at the mates; it had primary anestrus and its ovaries did not respond Orange locus. The random inactivation of one X chromo- to gonadotropin stimulation and contained inactive germinal some in all somatic cells during embryogenesis in all XX fe- epithelium.34 males is then visible as either an orange or a non-orange coat color. Females heterozygous at the Orange locus develop ran- dom patches of tortoiseshell or calico color because only one 192 Gonadal Development and Disorders of Sexual Differentiation Figure 6.5: Karyotype of a cat with two X chromosomes and a Y chromosome (similar to Klinefelter’s syndrome 6 in man). Chromosomes are arranged according to a standardized system developed for the domestic cat. (Courtesy of Dr. A.A. Bosma, Department of Functional Morphology, Faculty of Veterinary Medicine, Utrecht University.) allele is expressed. The same situation occurs in tom cats with year-old Labrador retriever bitch with anestrus.47–49 The the XXY syndrome. Tortoiseshell tom cats often have a XXX syndrome has not been reported in cats, but one case of 39,XXY karyotype (fig. 6.5), but other observed karyotypes 37,X0/39,XXX mosaicism has been reported in a pregnant include 38,XX /39,XXY, 38,XX /57,XXY, 38,XY/ cat with one normal ovary containing follicles and one dys- 57,XXY, 38,XY/39,XXY/40,XXYY, and 38,XX /38,XY/ genetic ovary lacking corpora lutea or developing follicles.50 39,XXY/40,XXYY.26,42–45 Not all cats with the XXY syn- drome have the tortoiseshell coat color.46 They can also have a The reported dogs with XXX syndrome were examined be- single coat color, but it is the tortoiseshell or calico coat that is cause of infertility. There are several acquired conditions lead- usually the reason for cytogenetic investigation. The tortoi- ing to infertility in dogs, such as cystic endometrial hyperpla- seshell or calico coat color occurs not only in male cats with sia and hypothyroidism. In addition, mosaicism, chimerism, the XXY syndrome, but also in XX / XY or XY/ XY chim- XX or XY sex reversal syndrome, and male pseudoherma- erism. phroditism can also result in an almost normal female pheno- type with infertility. The final diagnosis should rest on cyto- All XXY cats are infertile. The testes descend but are small genetic demonstration of X trisomy. Patients with XXX and lack spermatogenesis. The cats have a normal male phe- syndrome require no special treatment, for the physical notype but are somewhat small. Most have normal male be- changes do not interfere with general health. havior. The diagnosis should be based on cytogenetic examination. In the reported cases of XXY in cats no therapy was necessary. 6.2.2 Disorders of gonadal sex In XXY dogs with a uterus, gonadectomy and hysterectomy may be required. Disorders of gonadal differentiation can result in a phenotype that is the opposite of the chromosomal sex. Individuals 6.2.1.4 XXX syndrome (X trisomy, triple X syndrome) whose intersex stems from disorders of gonadal differentiation This is a rare chromosomal anomaly that is probably the result are termed »sex reversed«. In affected dogs the sex of the of meiotic nondisjunction. Three cases have been reported in gonads does not, or only partially, agree with the chromoso- dogs: (1) an infertile four-year-old Airedale terrier bitch with mal sex. Animals with the XY sex reversal syndrome develop a small uterus, female phenotype, and ovaries without fol- ovarian tissue despite the fact that they carry a Y chromo- licles, (2) an infertile five-year-old mixbred bitch having some. Animals with the XX sex reversal syndrome have tes- ovaries of normal size, shape, and histological structure with ticular tissue despite the absence of a Y chromosome. Pre- corpora lutea and primary follicles, and (3) an infertile two- sumably due to mutated genes in the cascade of gene Abnormal sexual differentiation 193 6 Figure 6.6: Figure 6.7: Histological section of an ovotestis from a true hermaphrodite dog. There are Genital tract removed from an XX male dog. Although the gonads are in the seminiferous tubules (lower right) as well as ovarian tissue with a corpus luteum normal position of ovaries and connected to a juvenile uterus, histological (upper left). examination revealed their exclusively masculine composition, although lacking spermatogenetic elements. regulations that results in testicular induction, gonadal devel- special interest to dog breeders because monogenic autosomal opment is started or stopped independent of the presence of recessive inheritance has been demonstrated in the American an SRY gene. In XY sex-reversed individuals the cascade cocker spaniel and is most likely to occur in other affected stops even though testicular induction began in the presence breeds.54 The anomaly is known in several dog breeds, includ- of a Y chromosome, while in XX-sex reversed individuals ing the beagle, Chinese pug, Kerry blue terrier, Weimaraner, testicular induction begins even though no Y chromosome is German shorthaired pointer, West Highland white terrier, present. basset hound, Doberman, viszla, Walker hound, soft-coated wheaten terrier, Norwegian elkhound, Jack Russell terrier, German pinscher, cocker spaniel, and Komondor.55–59 6.2.2.1 XY sex reversal syndrome (XY SRS) The XY sex reversal syndrome has not been reported in cats, Even though there is no Y chromosome but – as in a female – and only once in a dog. This three-year-old Yorkshire terrier two X chromosomes, one or both gonads contain testicular with an enlarged clitoris, bilateral ovotestes, epididymis, and tissue. The most frequent combination in XX sex-reversed uterus had a male chromosome complement. There were two dogs is bilateral ovotestes (fig. 6.6). Less frequent are one ovo- types of X chromosome, one cell line being normal and the testis and one ovary, one ovotestis and one testicle, or both other having a translocation involving the X chromosome gonads completely developed to cryptorchid testicles. Rarely and an autosome. Thus the dog was presumably a mosaic with there is a testicle on one side and an ovary on the other. If a karyotype of 78,XY/ 78,XYrcp(X;autosome) and not both ovarian and testicular tissue are present, the individual is strictly sex reversed.51 a true hermaphrodite (hermaphroditismus verus). If only tes- ticular tissue is present, the individual is called an XX male In humans with XY SRS, both mutations in the sex-deter- (fig. 6.7). The underlying defect is a single etiologic form of mining SRY gene52 and mutations in other autosomal genes XX sex reversal in which the degree of gonadal masculiniz- of the cascade, such as in SF-1, WT1, and SOX9, have been ation may be partial or complete. The reason why some XX reported to be responsible for the XY sex reversal syn- sex-reversed individuals develop into true hermaphrodites drome.1,53 The mutations are presumed to interrupt the cas- and others become XX males is not known. Although in cade required for testes development. those with much testicular tissue the oviducts can be absent, the uterus is always present.60 The external appearance of XX sex-reversed dogs can be ambiguous. In a female phenotype 6.2.2.2 XX sex reversal syndrome (XX SRS) there may be an enlarged clitoris or abnormally large vulva, or The XX sex reversal syndrome occurs frequently in dogs but the anogenital distance can be altered. The degree of mascu- has not been reported in cats. This congenital anomaly is of linization in true hermaphrodites depends directly on the 194 Gonadal Development and Disorders of Sexual Differentiation nence. Some develop endometritis or pyometra and in the gonads neoplasms can develop. Hematuria, genital swelling, and attraction of male dogs may occur, presumably due to cyclic activity of the ovaries. Differential diagnosis A female phenotype with masculinization also occurs in male and female pseudohermaphrodites, chimeras, mosaics, and possibly XY sex-reversed dogs. A female phenotype without overt masculinization can also occur in X monosomy, tri- somy, cystic endometrial hyperplasia, and hypothyroidism (see also chapter 7). Diagnosis 6 Elevation of the plasma testosterone concentration after stimulation with hCG or GnRH provides a presumptive di- agnosis (chapter 12.5.1). Ultrasonography and retrograde Figure 6.8: contrast radiography can reveal female internal genitalia in Empty scrotum and hypoplastic prepuce and penis of a true hermaphrodite cocker dogs with a male appearance (fig. 6.10). Affected dogs cannot spaniel. The skin irritation has been caused by urinary incontinence. usually be differentiated from normal females during gonadectomy, because testicular tissue is usually in the center of the gonad and therefore not visible. A definitive diagnosis is based upon histological examination of the gonads by a path- ologist who is familiar with XX-SRS and upon cytogenetic demonstration of a female XX karyotype. Affected dogs have amount of testicular tissue in the gonads (fig. 6.8). In most a complete uterus and many have epididymes adjacent to the true hermaphrodites there is no visible difference in the phe- ovotestes or testes.56 notype. For example, Meyers-Wallen and Patterson found the external phenotype in 20 of 22 true hermaphrodites to be in- Treatment distinguishable from normal females.54 These animals are fer- Vulvar irritation caused by a protruding clitoris can be re- tile and mostly remain undiscovered in the dog population. solved by resection of the os clitoris. Gonadectomy has been recommended when there is intra-abdominal testicular tissue, In humans a translocation of the SRY gene to an autosome is which carries an increased risk of Sertoli cell neoplasia (see often responsible for the XX sex reversal syndrome, the indi- also chapter 8). Hysterectomy has been recommended in true vidual being termed SRY-positive. However, all of the re- hermaphrodites because of the risk of endometritis. These ported XX-SRS dogs have no SRY sequence and are thus risks must be weighed against the associated morbidity and SRY-negative.56 In dogs mutations in several of the autosomal mortality of abdominal surgery. genes leading to activation of the cascade of testis differenti- ation have been suggested to result in SRY-negative SRS and Prognosis attempts have been made to identify the mutation resulting in Local irritation of the vulva usually resolves after removal of XX-SRS in the American cocker spaniel. Candidate genes in the enlarged clitoris or the os clitoris. XX-SRS is an in- humans and goats – such as FOXL2, PISRT1, WT1, GATA1, herited disorder and breeding should be discouraged to pre- FOG2, Lhx1, SF-1, SOX9, and Lhx9 – have been shown not vent the homozygous fertile hermaphrodite from transmitting to be responsible for the XX-SRS in the American cocker the recessive trait. Heterozygous carriers resemble normal spaniel population.7,9,61–64 This supports the notion that there males and females and at present there is no practical means of are still unknown genes in the cascade responsible for testis identifying them. Because XX SRS is presumably a mono- differentiation. genic, autosomal recessive inherited disorder, it is likely that the male and female siblings of an XX sex-reversed dog are Clinical manifestations carriers of the disease allele or that the females may be true Several true hermaphrodites and XX males have a female hermaphrodites. phenotype with some degree of masculinization, ranging from a small clitoric protuberance with a small os penis up to a hypoplastic penis (fig. 6.9). Depending on the amount of ovarian tissue, affected dogs can have normal estrous cycles, be fertile (always as females), and be able to deliver normal litters.65 The symptoms and signs may include infertility, pri- mary anestrus, irregular estrous cycles, and urinary inconti- German pinscher.67–70 The administration of androgens to in- tact female dogs should therefore be discouraged. Abnormal sexual differentiation 195 6 Figure 6. All of the few reported cases in dogs have apparently been the result of administration of methyl testosterone orally or testosterone propionate parenterally during gestation. 6.3. and American cocker spaniel). uterus. than other forms of intersexuality in a survey of 52 canine cases. The masculinization ranges from an enlarged clitoris to male external genitalia (fig.71 Ovotestes were found in the six female offspring of an American Staf- fordshire Terrier bitch treated with oestradiol benzoate and .66 It develops as a result of exposure to exogenous or en- dogenous androgens.10: Retrograde cystourethrography in a true hermaphrodite cocker spaniel with hypo- plastic male external genitalia.2.56 There are male and female forms of pseudohermaphroditism. but the Fallopian tubes. 6. and cranial part of the vagina are not visibly altered.9: Rudimentary male genitalia of four unrelated XX sex reversed dogs of different breeds (Komondor. Note the male urethra and the accumulation of Female pseudohermaphroditism was found less frequently contrast material in the female genitalia.2.3 Disorders of phenotypic sex XY and XX sex reversal must be differentiated from pseudo- hermaphroditism.1 Female pseudohermaphroditism (pseudohermaphroditismus femininus) Masculinization of androgen-sensitive tissues in individuals having ovaries and an XX-karyotype is referred to as female pseudohermaphroditism.56 Figure 6. 6. in which chromosomal and gonadal sex al- ways agree but the phenotype is that of the opposite sex. mixbred.11) with in- ternal parts of a prostate gland. 12: Female pseudohermaphroditism in a dog as the result of administration of Surgical removal of the os clitoris from a male pseudohermaphrodite dog with fe- anabolic steroids to the dam during pregnancy.3. 6. but the genital ducts and /or external genitalia are 11b-hydroxylase required for adrenocortical synthesis of cor. male external genitalia. Low or undetectable plasma testosterone concen. Fallopian tubes. Like male pseudohermaphro. clitoris may require surgery (fig. in which it is inherited as an autosomal recessive Male pseudohermaphrodites have a male karyotype (XY) and disorder resulting in a deficiency of either 21-hydroxylase or two testes.72 surgically if it causes irritation. leading to internal and /or exter- tisol and aldosterone. karyotype.11: Figure 6. These dogs have a normally de- veloped penis with a prepuce and scrotum.(2) an amount of androgen exposure. Laparotomy revealed two ovaries. The persistent Müllerian duct syndrome (PMDS) is the A female phenotype with masculinization is also seen in sex most common form of male pseudohermaphroditism in dogs. synthetic androgens during pregnancy and thus they were If there is endometritis.73 This cat had a calico-colored coat and an XX duction of sex steroids in the adrenal glands. tation may not require treatment. Congenital adrenocortical 6. and a uterine body. In principle. uterus. and a fully formed penis.12). is responsible for the presence of oviducts. chimeras. and cranial vagina in otherwise completely dicate the absence of testicular tissue (fig. which results in endogenous androgen expo. trations before and after stimulation with hCG or GnRH in. error in the release or action of AMH.14).56. two uterine horns. 6. but the reason why of choice. incompletely masculinized. and scrotum. The low secretion of cortisol results in nal parts of the female genital tract. ent target tissues such as 5a-reductase deficiency and low or tritis. 196 Gonadal Development and Disorders of Sexual Differentiation 6 Figure 6. In less severe cases the irritation caused by the enlarged absent androgen receptor activity. cal hyperplasia. normal male dogs (fig. or (4) defects in the androgen-depend- symptoms suggesting lower urinary tract disease and endome. or (2) disturbances in androgen-dependent masculinization. reversed dogs. these maldevelopments can be The clinical manifestations depend on the duration and the result of: (1) defective testicular differentiation.13). administration of a glucocorticoid will reduce sure. pituitary ACTH release and consequently the excessive pro- maphrodite. male pseudohermaphrodites. has only been described in one cat. a female pseudoher. ovariohysterectomy is the treatment considered to be true hermaphrodites.74 Half of the . Male pseudohermaphro- high ACTH release and consequently increased secretion of dites can be classified as having: (1) defective regression of the adrenal androgens.38. Müllerian ducts.2. An enlarged clitoris or os clitoris may be removed they developed testicular tissue is unknown. but no palpable testes. Less severe cases of masculin- ization due to administration of androgens during ges- Congenital adrenocortical hyperplasia due to 11b-hydroxy. In congenital adrenocorti- lase deficiency. (3) an error in the syn- dites. female pseudohermaphrodites may be presented with thesis of testosterone.2 Male pseudohermaphroditism hyperplasia is the most common cause of ambiguous genitalia (pseudohermaphroditismus masculinus) in children. 6. cervix. prepuce. and A defect in AMH (MIS)-induced Müllerian duct regression mosaics. including the basset hound77 and gesting lower urinary tract disease.14: 6 Schematic representation of persistent Müllerian ducts in a male dog.81 laterally or bilaterally cryptorchid.78 and in two cocker spaniels with an enlarged clitoris the most common problem and may result in hematuria. Symptoms suggesting pected in a dachshund bitch with an enlarged clitoris and ab. Most of the affected dogs Thus defects at the receptor or postreceptor level. Both basal testosterone concen- tration and the response to stimulation depend on the amount of functional tes- ticular tissue. as shown by the different values in the two cases of true herma- phroditism.13: Schematic illustration of plasma testosterone concentrations before and after stimulation with hCG or GnRH (chapter 12. Note that the vasa deferentia terminate in the wall of the uterus. and a scrotum with undescended testes. bioactive in the critical period of Müllerian duct regression.79 Moreover.75 A single case in this and the epididymis is not affected by inflammatory changes. in which radiographic examination revealed a mal.59 PMDS was also sus. unlikely to think of endometritis (or even pyometra) in a oped penis. abdominal pain. a hypoplastic uterus. and systemic illness.1).5. and hypospadia of the glans dog that appears to be male.74 PMDS has not been reported in cats. This may cause severe delay in penis.15: Radiograph of a two-year-old mixbred cryptorchid PMDS dog with malformation of the os penis. Figure 6.74. are the most likely ex- planation. Endometritis is probably poodle. while the other half are uni. as demon- are fertile.76 PMDS has also been Animals with PMDS are often presented with symptoms sug- found in other dog breeds.15). lower urinary tract disease can be so prominent that the dominal testes. for the veterinarian is two-year-old mixbred cryptorchid dog with an underdevel. PMDS has been reported in a underlying condition is overlooked.56 .80 Studies in miniature schnauzers incidence of cryptorchidism may give rise to Sertoli cell neo- and basset hounds demonstrated that AMH is produced and is plasia.38. breed was diagnosed in Germany. affected dogs have scrotal testes. Figure 6. In miniature schnauzers the associated high formed os penis (fig 6. strated in comparable cases in humans. correct diagnosis. Abnormal sexual differentiation 197 Figure 6. PMDS was first described in the miniature schnauzer and an autosomal recessive mode of inheritance in this breed has Dogs with PMDS can be fertile if the testes have descended been proved by breeding experiments. the veterinarian zation.83 PMDS having unaffected testes and epididymes. duction and androgen dismantling are known in humans and some animal species. de. the persistent Mül. One dog Müllerian ducts regress and so that there is no uterus or with incomplete testicular feminization had a female pheno- cranial vagina. However. In addition to defective regression of the Müllerian ducts.18).17). Affected dogs derivates are present. Selective resulting in periscrotal hypospadias and the blind pouch that hysterectomy or vasectomy can be performed in dogs with resembles a vagina. Less severe mutations cause compromised mas- contribute to spreading of the defective allele in the dog culinization.56 A defect in the androgen receptor gene results in should inform the breeder about the inheritance and the fact partial or complete absence of androgen-dependent mas- that affected dogs with or without unilateral cryptorchidism culinization. be the result of: (1) defects in the production of luteinizing pearance. androgen insensitivity. In all animal species this is assumed to be have testes and female-appearing external genitalia with a an X-chromosomal recessive trait. the finding synthesis and in the LH receptor as well as in androgen pro- of a uterus provides the diagnosis of PMDS. CT. 6. The hound with persistent Müllerian duct syndrome (PMDS). or MRI. In dogs with descended testes.56 The resulting phenotype with fibroblast cultures suggested that the androgen receptor can vary from complete (severe) to incomplete (mild). and an XY karyotype. 198 Gonadal Development and Disorders of Sexual Differentiation 6 Figure 6. Male pseudohermaphroditism due to a failure of target organ Breeding of dogs with PMDS should be discouraged. It has been sug- PMDS dogs with endometritis can be treated successfully by gested that in the absence of dihydrotestosterone the labios- hysterectomy (fig. (3) partial or complete absence of androgen receptor ation although they can easily be found by ultrasonography activity. 6. but complete testicular fe- cul-de-sac caudal vagina. but the genital duct and /or external genitalia type with testes bilateral to the vulva and no uterus.17: Longitudinal ultrasonogram from the ventral abdominal wall of a male basset Persistent Müllerian ducts in a male basset hound as seen at laparotomy.16: Figure 6.56 Indeed.82. hydrotestosterone by 5a-reductase. Under the influence of AMH the minization in the dog has not yet been reported. while severe gene mutations cause complete population (fig. in some patients with PMDS the internal hormone (LH) or its receptor. no Müllerian duct also result in male pseudohermaphroditism. Abdominal radiography and retrograde contrast radiography pending on the primary defect. defects in LH mal male external genitalia. The physical result ranges from am- bivalent appearance to phenotypic male – but sterile – dogs. but not as yet in the dog. or (4) defective conversion of testosterone to di- (fig.16). fingers of the surgeon). was nonfunctional. duction. cause of abnormalities of the epididymis or testis. (2) defects in androgen pro- female genitalia cannot be detected by radiographic examin. lerian duct (d) is visualized. The testicular feminization was incom- . Dorsal to the bladder (a) bladder is retracted caudally to reveal the uterus and uterine horns (between the and craniodorsal to the prostate (b) and cranial urethra (c). Most also require orchidectomy be. in Since they have bilateral testes and secrete normal amounts of rare cases defective androgen-dependent masculinization can testosterone and anti-Müllerian hormone. crotal folds fail to fuse and the urogenital sinus fails to close. nor. This varying phenotype can may reveal female internal genitalia in dogs with a male ap. Studies are incompletely masculinized. As both response to androgens is referred to as testicular femini- parents of affected animals are carriers. 6. 14 and 21. Nickel.) .18: Schematic representation of familial relations in basset hounds with persistent Müllerian duct syndrome (PMDS).F. 7 include even more affected littermates. supporting an autosomal recessive mode of inheritance: (Courtesy of Dr. Mating of assumed male carriers nos. R. 26 and 27 with related females resulted in affected offspring such as nos. Abnormal sexual differentiation 199 6 Figure 6. Offspring of affected male no. Biol Reprod 1991. stones in the canine sex determination pathway. HUGHES IA. for an epididymis and partially developed ductus defer. VIVIAN N. HARVEY MJ.259: 15. MANGANARO TF. London: Academic Press 1981. XX / XY chromosome chimaerism in an intersex dog.66:1655–1658. Sexual differ- entiation: Early hormone synthesis and action.145:404–405.90:93–95.75: the genital system. bryo. MALOUF N. Vet Rec 2004. KUIPER H.70:383–389. termination pathway. 1980. PERCHELLET JP. MACLAUGHLIN DT. PRÉPIN J. Genetics.22:9–17.100:18–38. Differentiation of the genital tract: Stimulators and in- 91–101. ZHANG YH. Mechanisms of sex dif- ferentiation in animals and man.29:1–41. SINSHEIMER JS. gene for SRY-negative XX Sex Reversal in the American Cocker Spaniel Model.123–136. Disrupted sex differentiation and feminization of genetic and histologic examination of four tortoiseshell cats. Edwards. 831–838. ROGERSON P. HUANG BL. MEYERS-WALLEN NV.142:340. thought to be a case of complete testicular feminization. sue (chapter 12. 6. 397–402. 7. Bergsma D. 8. 16. LONG SE. line siblings. Sf1 and Mis expression: Molecular mile. Dtsch man and domestic animals. HANNEMA SE. 9. Nature 1991. VAN WORMER RH. Without karyotyping. Intersexuality in the dog. KURODA T. MUNRO CD. 2. XX / XY Chimerism in a tricolored male cat.45:626–633. http://bakerinstitute. 165–203. Horm Res 2007. DORMAN KS. JOST A. GOODFELLOW P. NICHOLAS FW. 18. In: Austin.5. 17. HEWICKER-TRAUTWEIN M. Studies on sex differentiation in mammals. Genes essential for 13. MORENO-MILLAN M. eds. KIRKNESS E. hibitors. no uterus. DISTL O. minization the breeder should be informed of the X-recessive like structure. Environ Res 2006. HARE WC.84 a complete clitoridectomy can be performed. Inherited disorders in sexual develop- ment.68:338–343. VIGIER B. VILAIN E. 2006. Disorders in sexual development in the dog and cat.edu/faculty/page. PUJAR S. Theriogenology 2007. MEYERS-WALLEN VN.cornell. Vet Rec 1979. Vet Rec 1998. SCHIMMER BP. The development of the vagina in the human. and no Müllerian duct derivates. 14.105:230–232. O’RAHILLY R. 34:171–178. Am J Hum Genet 2001.154:637. KOOPMAN P. Can Vet J 1976. eds. 38. two abdominal testes at the caudal poles of the kidneys. KUIPER H. Migration of gonocytes in the mammalian gonad and their differentiation. PARKER KL. The chromosome complement was 38.XY chromosome chimaerism in three fe- The critical period for Müllerian duct regression in the dog em. an enlarged clitoris protruding from a vulva. MORAN C. BASRUR PK. If necessary. In: 26. and SOX9: Evolutionary stratification of sex-de. Cytogenetics 1967.85 inheritance of the trait in humans. Cell Mol Life Sci 1999. Ann Med 2002. 200 Gonadal Development and Disorders of Sexual Differentiation plete.XX /39. HOEFNAGEL D. RG.67:142–151. MCCABE ER. GUBBAY J. ditism) in a dachshund dog. KOTHAPALLI KS. PATEL M. MEYERS-WALLEN VN. Pri- mate DAX1. 6 References 1.XY and the cat was Resection of an os clitoris stops vulvar irritation. SCHEDL A. Morphogenesis and malformation of seshell cats: mosaicism due to gene instability? J Hered 1984. Biol Reprod 5.php?id=207. 23. gonadal development. PETERS H. GILLIES CB. chimerism or phroditism in cats due to testicular feminization. OCANA-QUERO JM. PARKER KL. Genes essential for early events in 21. New York: Alan Liss 1977. 24.110:457–461. JOSSO N. SRY. genomics. 17:7–15. GRIFFIN JE AND GEORGE FW.55: development. WILSON JD. Fertile male tortoi- Blandau RJ. 4. GR. LOVELL-BADGE R. but drogen-dependent masculinization. LYLE SK. DISTL O. In dogs and cats with a female phenotype the finding of ele- ens were present as Wolffian duct derivates. Regulation of Wolffian duct early events in gonadal development. 10. 12. .68:275–280. Phenotypic intersex (female pseudohermaphro- 2005. Philos Trans R Soc Lond B Biol Sci 1970. BENIRSCHKE K. 3. In all cases of testicular fe- blind scrotum. 20.1).96:452–454. Vet Rec 1999. One cat had mosaicism cannot be distinguished from a disorder of an- a vulva and clitoris of normal size and shape. Recent Prog Horm Res 1973.351:117–121. GENERO ER. CONCANNON PW. Male development of chromosomally female mice transgenic for Sry. Orchidectomy The other case consisted of a Himalayan cat with testes in a may be necessary in some cases. XX / XY chromosome chimaerism in a biology of sex determination in small animals. DONAHOE PK.6:228–241. WEAVER AD. ARNOLD AP. Cyto- 11. SCHIMMER BP. Tierärztl Wochenschr 2003. J Hered 1999.82 vated plasma testosterone concentrations after stimulation with hCG or GnRH can prove the presence of testicular tis- There have been two reported cases of male pseudoherma. Mol Reprod Dev MCDONALD M. MEYERS-WALLEN VN. MEYERS-WALLEN VN. Theriogenology Border terrier.vet. 25. J Hered 2005. and molecular 19. Exclusion of Lhx9 as a candidate 22. LONG SE. GOLINSKI P. J Vet Intern BERESZYNKI A. Israel J Vet Med 55. Male tortoiseshell cats in 44. NORBY DE. XX sex reversal in the American Cocker Spaniel dog: Phenotypic expression and in- 39. SMITH FW JR. GOLDSCHMIDT B. PATTERSON DF. Theriogenology 1985. an- euploids.1397: 38. GÜNZEL-APEL AR.9:33–35. vice (www. WATERS DJ. International Veterinary Information Ser- Dtsch Tierärztl Wschr 1983. X trisomy in an infertile bitch: cytogenetic.169: the XXY Klinefelter’s syndrome in man: tortoiseshell and calico 116–117. polyploids.80:43–47. New York. calico (T-C) cats. opment in dogs and cats. Hum Genet 1988. WEBER AF. BUOEN LC. ROGGE UW. first case of X-chromosomal monosomy in the dog. MADL JE. HUNTINGTON A. RANDOLPH JF. and chimerics. bringer in Holstein. DRÖGE- MÜLLER C. male cats. POULAT F. PROCIUK U.X0) in a Burmese cat with gonadal dygenesis. PIENKOWSKA A. Cryptorchidism associated with 78. OEHLERT ML. SCHÄRER V.org). DAZA MA. BENEVIDES FILHO IM.200:1104–1106. Current Veterinary Therapy. Prolonged proestrus in 46. J Vet In.org /article/56_2_4. ECQ.XY/79. . X tri- (77. Dreifarbiger Kater. SOUZA LM.Suppl 57:435–438. Ithaca. GOODFELLOW PN.181:798–801.64:272–278. Sry- 43.X0 chromosome complement in a kitten. J Am Vet Med Assoc 1982. SZYMAS J. MEYERS-WALLEN VN. BEYER D.htm). SELDEN JR. anatomic and histologic studies. Res Vet Sci 1981. STRÖM B. J Reprod Fert 1989. Reproductive dis- Assoc 1992. mination in mammals.37: 394–401. AXNER E. WEBER AF.X0–78.30. Philadelphia: WB Saunders 1986. DAMBACH D. WEGNER W. Sry-negative XX Sex Reversal in a family of Norwegian Elkhounds. 37.org /article/58_4_7. Premature gonadal failure in female dogs and procal translocation. 499–500. New York: 52. Persistent Müllerian duct syndrome in minia- ture Schnauzers. JOHNSTON SD. Disorders of sexual 2001. LÖFSTEDT RM. KÖNIG H. J Reprod Fertil 2001. J Am Vet Med Assoc 1983. Infertility related to X-trisomy in a Labrador Retriever bitch. Theriogenology.3:90–95. CARVALHO heritance. Canine gonadal dysgenesis syndrome: a case of mosai. 30. DA. Hodenhy- poplasie (Fehlen von Spermiogonien) und linksseitige Nebenhode. GUS- a bitch with X-chromosomal monosomy (77:XO). 54. DESCLOZEAUX M. BOIZET-BONHOURE B. ed. X-chromosomal monosomy 47. GODYNICKE S. somy in an Airedale bitch with ovarian dysplasia and primary anes- tern Med 1989. JEZYK PF. 50. WALLGREN M. trus. X-chromosome monosomy (37.isrvma. Cytogenet Cell Genet 1974. Hered 1973. DE SANTA BARBARA P. RW. JOHNSTON SD. BUOEN LC. PATTERSON DF. 49. KÜPPER U. VET 1991. PIEN- 6-month-old Dobermann pinscher with ambiguous genitalia as a KOWSKA A. Disorders of Sexual Differentiation.13:448–453. MELNICZEK JR. KUIPER H.21:627–631. LONG SE. 51. PADILLA JA.182:986–989. HASKINS ME. LINDHOFF S. 45. MADL JE. Philadelphia: WB Saunders 1989:1261–1269. 56. Med 1989. BENIRSCHE K.XX). DYBDAHL THOMSEN P. BUOEN LC. USA 2001. BUNCK C. GOMES HF. cats. GOLDSCHMIDT B.XXY mosaicism in dog. LEAMAN T.272–280.X0) in a Doberman Pinscher with gonadal dysgenesis. GIGER U. FO. A male to female sex-reversed dog with a reci- 35. JOHNSTON SD. SRY and sex deter- Academic Press 1976:303–337. THULINE HC. Israel J Vet Med 2006. In: Morrow. MEYERS-WALLEN NV. development in dogs and cats. HENTHORN PS. PATTERSON DF. MARSHALL LS. PATTERSON DF. BYSKOV AG. J Am Vet Med TAVSSON I. WEBER AF.80:23–30. Dtsch Tierärztl Wschr 1978. J Small Anim Pract 1980. WEBER AF. SMITH genesis.htm). CONCANNON PW. MOURA VLS. J Hered 2000. orders in 10 domestic male cats. TURCZUK-BIERLA I. ed. SCHELLING C. Vet Rec 1999 144:9–12. FLORES JM. BENIRSCHKE K.56 (http://www. cats: an examination of testicular histology and chromosome com- plement. PATTERSON DF. GIGER U.6: 57. JAY P. Fertility in two cats with X-chromosome mosaicism and unilateral ovarian dys- 34. A 37. FINDLEY D. An animal model for negative XX sex reversal in a Jack Russell Terrier. LOVELL-BADGE R. Characterization of two Sp1 binding sites of the human sex de- termining SRY promotor. PATTERSON DF. Animal models of sex chromosome mosaics.3:245. DAVID M. CENTERWALL WR. BEREPUBO NA.567–564. MEYERS-WALLEN VN. J. SIMPSON J. SOUZA LM. Am J Vet Res 1975. LINDBLAD K. References 201 27.90:341–384. In: Kirk. LINDE-FORSBERG C.ivis. ROWLAND R. Current Therapy in SOULLIER S. 33. Male tortoiseshell the United Kingdom.36:1275–1280. Zum Phänomen steriler Schildpattkater. development in the dog. 28. JOHNSTON SD.13:564–569.isrvma. 6 31. SWITONSKI M. SWITONSKI M. MAYENCO-AGUIRRE AM. BUOEN LC. JOHNSTON SD.24:597. GRUFFYD-JONES R. EL-JAICK KB. A 48.C. Charly – ein Glücks- cism (77. 41. Vol X. Male tortoiseshell and Med 1999.27:71–92. Disorders of sexual 53. BERTA P. HEWICKER-TRAUTWEIN M. J Small Anim Pract 1996. CENTERWALL WR. PAULINO FO. Inherited abnormalities of sexual devel- naplasie bei einem dreifarbigen Kater vom 39/ XXY-Karyotyp. Vet Rec 1999. MEYERS-WALLEN NV. Biochim Biophys Acta 1998. 58 (http://www. J Reprod Fert 1987. Annu Rev Genet 1993. 247–252. Suppl 39:65–72. 29. HEGREBERG GA. TSCHUDI P. DISTL O. LONG SE. 2nd ed. 58. 32. 36. HAUSER B.145:582–584. JACKOWIAK H. 40. Vet J 2005. J Vet Intern 42. BASSE A. MEYERS-WALLEN VN. ARNOLD S.91:149–150. An XO-cat. Biol Reprod 1969. Can Vet J 1976. 67.98:437–445. KENNEY RM. MEYERS-WALLEN VN. Vet Rec 2004. PARK RD. KOO GC. Female pseudohermaphroditism in three sib- ling greyhounds. Methyl testosterone-induced female pseudohermaphroditism 81.40:1093–1105. Intersexuality in the dog. Exclusion of candidate genes for canine Wschr 1972. KUIPER H. KIRKNESS E. MOORHEAD PH. DUNN HO. morpho- logische und zytogenetische Befunde bei einem Pudel mit Pseudo- 64. GOEDEGEBUURE SA. DE ROOIJ DG. Tijdschr 6 63. Exclusion of PISRT1 as a candidate locus for canine SRY-negative XX sex reversal. WAGNER F. NARO TF. Anim Genet 2004. 60. HARTIG F. Anim Genet 2003. WALLEN VN. Assoc 1989. DONAHOE PK. RIJSSELAERE T.17:7–15. NATALE LJ. Tijdschr Diergeneesk 1975. Berl Münch Tierärztl MEYERS-WALLEN VN. KIRKNESS EF. LEE HB. J Hered 2005. hermaphroditism: Evidence in the dog.96:759–763. J Hered 2005. NICKEL RF. WENTINK GH. 71. VIDAL VP. Müllerian Inhibiting Substance is present in testes of dogs with persistent Müllerian duct syndrome. SCHEDL A. Lack of SOX9 gene polymorphism in sex reversal TERSON DF. CARLSON ED. J Small Anim Pract 73.201:644–646. Male pseudohermaphroditism in a cat. Persistent Müllerian duct syndrome in the Bassethound. WILSON JD.37:1015–1022. KVELLESTAD A. PUJAR S. MEYERS-WALLEN VN. Veterinani Medicana 2007. Congenital adrenal hyperplasia secondary to 1997. PETER AT. J Am Vet Med Assoc 2004. CHO YG. Current Therapy dog.35:466–467. MARKVELDER D. KOTHAPALLI K.38:21–24. PATTERSON DF. CHO SJ.117:31S. SRY negative). DE ROOSTER H. GREVEL V. KUIPER H. NIEMAND S. VAN DER GAAG I. 78. MANGA- IS.1:41–48. dometriale Zysten bei einem Zwergschnautzer mit persistierenden Müllerschen Gängen.90:93–95. HASKINS ME. AALFS RH. DRÖGEMÜLLER C. PATTERSON DF. 84. Müllerian Inhibiting Substance in sex-reversed 75. CHABOISSIER MC. 68.Suppl 47:441–452. BREEUWSMA AJ. MEYERS- WALLEN VN. SHANE BS. 70. ALAM MR. DZIMIRA S. 557–564. VAN WORMER R. LEE JI. HOFFMANN R.41:22–26. HANSEL W.155:400–401. SOX9 induces testis development in XX transgenic mice. OLSON PN. Science 1978.96:797–802. J Reprod Fertil 1993. Tijdschr Diergeneesk 1973.28:216–217. SEIM HB. DONAHOE PK. anomalies in dogs and cats. MANGANARO TF. Phenotypic feminiz- ation in a genetic male dog caused by nonfunctional androgen re- 69. Nat STEIGER K. present in testes of dogs with persistent Müllerian duct syndrome. MEYERS- Diergeneesk 1992. Müllerian Inhibiting Substance is ports. KIM 74. Sertoli-Zell-Tumor und glanduläre en- Genet 2001. SCHMERLBACH K. PATTERSON DF.41:881–888. 85. Per- 66. THORESEN SI. 79. PATTERSON DF. JL. SWITONSKI M. NARO TF.195:631–634. NOWACKA J. Philadelphia: WB Saunders.34:467–469. OKKENS AC. ism in six female littermates after administration of synthetic an- drogens to a pregnant bitch. In: Morrow. Exclusion of WT1 as a candidate gene for canine SRY-negative XX sex reversal. True Hermaphrodit. VAN SLUIJS FJ. GRIFFIN JE. ed. 1986. Tierärztl Prax 2005. Theriogenology 1993. Genetics of sexual differentiation and dogs. POLOS I. MEYERS-WALLEN VN. ASEM EK. 61.33:280–286. DONAHOE PK. in Theriogenology. BIEWENGA WJ.225:238–241. FISHER S. LINDBLAD K. Genetic basis of XX male syndrome and XX true dogs (78. 65. VERCAUTEREN G. GOLDSCHMIDT MH. PUJAR S. 62. 2nd ed. 76. UENO S. hermaphroditismus masculinus internus. J Am Vet Med SAUNDERS J.41:881–888. ment. WACHTEL SS.52:74–78. Three cases of intersexuality in the development in the dog. GRANDY JL. Reprod Dom Anim 2006. HARE WC. MEYERS-WALLEN VN. HASKINS ME. sistent Mullerian duct syndrome causes male pseudohermaphro- ditism in a mixbred dog. Anabolics are a hazard in some cases. NIZANSKI W. VISEK WJ. SCHÖNE J. SRY-negative XX sex reversal. DA. Disorders of sexual TEUNISSEN GH. J Am Vet Med Assoc 1989. KIRKNESS EF. 82. MEYERS-WALLEN VN. MANGA- in dogs. 80. WENSING CJ. KIEFER I. MEYERS-WALLEN VN. 11beta-hydroxylase deficiency in a domestic cat. J Hered 1999. Klinische. UBBINK G. DISTL O.XX. Biol Reprod 1987.100:391–392. 83. . FREAHMAN Biol Reprod 1989. KOTHAPALLI KS. KLIMOWICZ S. PATTERSON DF. BREDAL WP. PAT. 202 Gonadal Development and Disorders of Sexual Differentiation 59.194:1747–1749. 77. Male pseudohermaphroditism in dogs: three case re. KOTHAPALLI KS. GÖRTZ K. UENO S. TAE HJ. Biol Reprod 1989. 72. SELDEN JR. KIM NS. Testicular feminization in a cat. KNIGHTON EL. MEYERS-WALLEN VN. Inherited disorders in sexual develop- ceptors.12:224–227. (Modified from Evans and Christensen. with opened ovarian bursa.1: Dorsal view of the genitalia of the bitch. and those of the cat partially. the ovarian bursa (fig. The bursa by suspensory ligaments to the middle and ventral thirds of contains the uterine tubes and is usually opaque in the dog 7 Figure 7.1). 7. 1993. Schaefers-Okkens Hans S. They are attached by the broad the dog are enclosed completely. (Modi- fied from Evans and Christensen. 1993. The ovaries are connected to the cranial ends of the uterine horns The ovaries lie caudal to the kidneys. The ovaries of or fourth lumbar vertebra. 203 7 Ovaries Auke C.2: Lateral aspect of the left ovary.2). 7. Kooistra 7.1 Introduction the last one or two ribs (dog) or to the diaphragm (cat). partially opened on the midline.)1 . at the level of the third by the proper ligaments of the ovary (fig. ligaments to the dorsolateral wall of the abdominal cavity and in a peritoneal pouch.)1 Figure 7. shrinkage begins in response to reduced estradiol-dependent water retention. estrus.2.2 Follicular phase As tertiary follicles develop in the ovaries they produce estra- diol-17b. Superficial cells 7. These cyclic changes are . dominate as the follicular phase progresses (fig. leading either to a plateau interval or a sharp increase just before the beginning of the preovulatory luteinizing hormone (LH) surge. and parturition vaginal smear increases and the percentage of parabasal and small intermediate cells decreases (fig. 7. oscopic examination because the ovary is hidden in the ovar- fundibula are open lateral to the ovaries to collect the ova ian bursa and because the follicles remain below the ovarian following ovulation. How- and parturition in the dog ever. and have a months. At the end of the follicular phase. 7.2 Estrous cycle. the decline in estradiol-17b and the rise in progesterone con- terval may be regular or variable in individual bitches. 7. 7.3).1. mainly within the bursa but a portion generally protrudes through the slit-like opening of the bursa. with peak concentrations of approximately 300–350 pmol/l about due to its fat content. which lasts about three the vaginal mucosal folds are swollen. such as hyperemia and edema of the vulva and bloody vaginal discharge. 204 Ovaries 7.3: Schematic representation of the estrous cycle and anestrus in the dog. The interestrous in.6). with a range of three to 17 days. anestrus.1. the uterine horns. anestrus. the phase of preovulatory luteinization and ovulation. follicles develop during the follicular phase and become vis- ible at the surface of the ovary due to the considerable in. In the dog. phase (fig. Proes- trus is defined as the period from onset of sanguineous vaginal discharge and vulvar swelling until the first willingness to accept mating.. It has an average duration of about 70 days if we assume that it ends when plasma progesterone concentration declines for the first time to 쏝 3 nmol/l.4). Figure 7. The surface of the ovary is covered by 1–2 days before the preovulatory LH surge (fig. 7 In addition to this behavior-oriented classification. The average duration of proestrus is nine days. it is not a reliable indicator of the preovu- In the healthy bitch the onset of puberty occurs at six to latory LH surge or of ovulation. 7. The discharge usually persists and may remain sanguineous or turn straw-colored.3). Tertiary LH surge.1 Estrous cycle The stages of the canine estrous cycle are proestrus. and the luteal phase (fig.7). the fimbriated extremities lie surface until just prior to ovulation. plasma estradiol-17b concentration decreases to basal values Germ cells growing inward from the cortex give rise to fol.5). 7.2 Then the germinal epithelium of the cortex and is free of serosa. During estrus the bitch accepts mating and the vulva begins to shrink and soften. and thickening of the vaginal wall. Follicle development is not readily apparent during lapar- crease in the amount of follicular fluid they contain.1 Estrous cycle. although vaginal cytology gives an indication of the stage of the estrous cycle. the es- trous cycle can be classified according to ovarian function. centrations in plasma. pregnancy.8). 7. The percentage of superficial cells in the pregnancy. The external signs of proestrus. The hormonal changes are also associated with lengthening and hyperemia of 7. i. Each estrous cycle. enlargement of the cervix.2. during with a range of four to twelve months. very pale. many of which degenerate and become atretic. and metestrus (diestrus) (fig.2. Metestrus (diestrus) begins when the bitch no longer accepts mating. as the follicular phase. are related to the high estradiol-17b concentration (fig. The in. Vaginoscopy will reveal that 18 months of age. with a range of three to 21 days. is followed by an anestrus of variable duration. The smoothly rounded (balloon-like) surface during the follicular mean interval between estrous cycles is about seven months.e. 7. Estrus has an average duration of nine days. of approximately 35 pmol/l about 80 h after the preovulatory licles. The plasma estradiol-17b concentration increases gradually during the early follicular phase. (C) Plasma concentrations of LH and estradiol from 100 h before until 100 h after the preovulatory LH surge in a beagle bitch with a preovulatory surge in plasma estradiol coinciding with the start of the pre- ovulatory LH surge. ovulation.. in 6 bitches. Estrous cycle. and progesterone before and after the preovulatory LH surge (at time = 0).4: (A) Mean plasma concentrations of LH. anestrus. and the fertilization phase. pregnancy.. 2006. estradiol.e. Note the bifurcated preovulatory LH surge. (Modified from De Gier et al. i. Note the decrease in plasma FSH in the early follicular phase. (B) Plasma FSH concentration in two beagle bitches during the follicular phase (until 100 h before the pre- ovulatory LH surge).)2 . and parturition 205 7 Figure 7. FSH. during the follicular phase. at ovu- intermediate (i) cells. (May-Grünwald Giemsa stain. x200). Figure 7. . showing primarily Vaginal cytology in the bitch during the second half of the follicular phase. 206 Ovaries A B 7 Figure 7.8: Vaginoscopic view in the bitch at the onset of the follicular phase. The smear shows superficial cells (s) and leukocytes (l). lation. (May-Grünwald Giemsa stain. x200).5: The vulva of a Beagle bitch during anestrus (A) and proestrus /estrus (B). Figure 7. and erythrocytes (e). erythrocytes (e).6: Figure 7. some superficial (s) and parabasal (p) cells. and at the onset of the luteal phase.7: Vaginal cytology in the bitch at the onset of the follicular phase. Note the swollen. pale mucosal folds with a smoothly rounded surface (balloons) and the bloody secretion between the folds. anestrus. with frequent increases of short duration. In the latter the polar body are not completed until at least 48 h after ovula- vaginal wall is extremely folded. Plasma FSH concentration is lower be- fore the surge than after (fig.2 There is rapid and extensive luteinization during the preovu- latory LH surge. days before fertilization can occur. The LH surge is frequently bifurcated (fig.2. During the second part of the follicular phase plasma progesterone concentration can increase slightly. and cer. and parturition 207 A Figure 7. Ruptured follicles have several character- C istics of rapidly developing corpora lutea (fig.1. A recent study showed that . 7. 7. The mean plasma LH concentrations before and after the surge do not differ. 7.2 The preovulatory FSH surge begins con- comitantly or a few hours prior to the preovulatory LH surge.9A–C).10). 7. Note the very short cervical canal. probably as a result of par- tial luteinization of granulosa cells. pregnancy. In the dog most ova are released in an immature state as primary oo- Figure 7. The first meiotic division and the extrusion of the first vix of a bitch (A) during anestrus and (B) during proestrus /estrus. Plasma LH concentration is low during the follicular phase. and is not bifurcated. similar to the concentration in late anestrus.9: Schematic illustration of a sagittal section through the vestibule.4B). Estrous cycle.2. vagina.4A). (C) Close-up view of the cervix and cranial vagina tion. most marked in the dorsal median fold and precede those of the midvaginal mucosa (fig. 7. cytes. 7. Total maturation after ovulation requires two to three during anestrus. The bursa which normally encloses the ovary has been removed.3 The plasma con- centration of follicle-stimulating hormone (FSH) is relatively high at the beginning of the follicular phase. but declines to low levels dur- ing the progression of the follicular phase (fig.10: 7 Ovary of the bitch at the time of ovulation.2 Plasma B progesterone concentration fluctuates at low levels.3 Preovulatory luteinization and ovulation The average duration of the preovulatory LH surge is 36 h.4C) and coincides with a rising plasma progesterone concentration. 10 This is most likely the re- tal kinetics.2. In GH. coming from on uterine epithelium. 7. This reaches associated with the intracellular presence of immunoreactive a plateau from about day 10 to day 30 after the LH surge.3. insulin resistance may Thereafter experimentally induced inhibition of prolactin se.. be a safeguard against hypoglycemia. while insulin is secreted as a luteotropic factor in the second half of the luteal phase. It is not prostaglandin luteal phase may also cause some insulin resistance.11). except for a slight increase in tology of the vaginal mucosa changes from chiefly superficial the second half of the luteal phase. mucosa starts about midway through the follicular phase and These hormonal changes may promote the physiological pro- continues through the phase of preovulatory luteinization and liferation and differentiation of mammary gland tissue during ovulation. progression of the luteal phase (figs. but in of the luteal phase induce elevated plasma GH concentrations some bitches it begins days before the LH surge and others and the decline in the progesterone concentration during the not until days thereafter or never. 7. there being greater basal GH . which has led to the assumption that prolactin acts of a low carbohydrate meal (a prey). whereby many longitudinal folds can be observed the luteal phase in the bitch. the shrinkage of pseudopregnant bitches (see chapter 2.20 FSH.10–12 The mean plasma LH concentration scarcely ing the initial part of the luteal phase. the mucosa thins and part of the luteal phase than in the second half of the luteal profiles become round.1.7 long periods between catches of prey. during the first breed or age on ovulation rate. ent uterine epithelial changes occur. For an F2a from the endometrium. and developmen.11 In overtly At the time of the maturation of the oocytes. 36–48 h later.14 Plasma GH concentration is higher in the first sition period from estrus to metestrus. The most peculiar aspect in the canine species is sult of partial suppression of pituitary GH release by proges- oocyte meiotic maturation. and LH are characterized by a fluctuating baseline with occasional distinct elevations. In progestagen-treated Thus estrus behavior is observed in the bitch during the dogs the hyperplastic changes in the uterine epithelium are period of increasing progesterone concentration.16 whereas prolactin promotes final mammary differentiation.15 Plasma progesterone concentration is around 6–13 nmol/l The pattern of secretion of progesterone thus influences the at the time of the LH surge and 15–25 nmol/l at the time pattern of secretion of both GH and prolactin in the bitch.8. 7.4 There was no significant influence of high plasma progesterone concentration. lobu- 7. canine mammary gland secretions and particularly in colos- trum. The start of estrus behavior is High plasma progesterone concentrations during the first half usually synchronous with the preovulatory LH surge. progesterone-depend- remainder of estrus and the onset of metestrus (diestrus). as in the cow and ewe.e.6 During the first half of the luteal phase the canine resistance during the first half of pregnancy.14).5) and in pregnant the vaginal mucosa continues and increasing numbers of bitches the rise in plasma prolactin concentration is much sharp-edged summit profiles appear in the vagina. 7. animal such as the dog. Shrinkage of the vaginal second half of the luteal phase increases prolactin release.18 Progesterone-induced GH production may also have nonpregnant bitches it then declines slowly to a basal level of metabolic effects. and IGF- binding proteins.17 Plasma estradiol-17b concentrations are significantly higher throughout the luteal phase than at four to nine days after the Progesterone-induced GH production may also have an effect LH surge. maturation. Progestagen-induced GH excess leads to 3 nmol/l for the first time about 75 days after the onset of the insulin resistance. Growth hormone. 208 Ovaries fertilization usually occurs 90 h or more after ovulation in secretion and less GH secreted in pulses during stages having a metaphase II oocytes.4 Luteal phase loalveolar development. What initiates regression of the corpus elevated plasma GH concentrations during the first half of the luteum in the bitch remains unknown. This is an indication that the fertile period is over.5 The concentration of progesterone.2. there may ectomy does not influence the length of the luteal phase in have been evolutionary advantages in this temporary insulin the bitch. changes during the luteal phase. evolving from predators.19 It could serve to main- cretion causes a sharp decline in progesterone secretion tain blood glucose concentration immediately after the intake (fig.. with insulin-like growth factor (IGF)-I.12).12.12).9 in response to other food components such as amino acids. In the tran- greater. The mean plasma prolactin cells to chiefly intermediate and parabasal cells and leukocytes concentration increases slightly but significantly during the (fig. high GH concentrations have been demonstrated in erties in the bitch.12). in concert 7 (fig. increases in the peripheral blood during the whether or not the bitch is pregnant.11 of ovulation. There are no strong indications that LH has luteotropic prop. The transition from estrus to metestrus (diestrus) occurs dur- tion. part of the luteal phase (fig 2. through which GH may promote gastric and intestinal The secretion patterns of prolactin. In this period the cy- changes during the luteal phase. Especially during corpus luteum functions independent of pituitary support.13). while fertilization follows the terone-induced GH production in the mammary gland (see same pattern as in other mammals.e. initiates mammary proliferation. Finally. indicating pulsatile secre. i.15). In the beginning of metestrus there is phase and anestrus (fig 2. for hyster.13). development in the newborn. IGF-II. growth hormone (GH).4 also chapter 2.13. During each luteal phase. 7. i. 7.15 The exposure to progesterone-induced luteal phase (fig.10 Pulsatile secretion of GH also a visible patchwork of red and white areas (fig.2. 7.1). regardless of the corpora lutea. 1990. and parturition 209 Figure 7. This rounded and there is a patchwork of red and white smear shows intermediate cells (i) and leucocytes (l). The profiles are to ten days after the preovulatory LH surge. (Modified from Okkens et al. orally) from day 20–24 after the onset of the luteal phase until the end of tration reached 16 nmol/l. (A) The mucosal shrinkage has resulted in longitudinal folds. and prolactin in three dogs dur.. Plasma progesterone concentration was 22 nmol/l.11: Vaginoscopic view at the time of ovulation.15: Vaginal cytology during metestrus.. twice day after the onset of the follicular phase on which plasma progesterone concen. 7 Figure 7. The data have been synchronized to day 1. and LH of four dogs ing the follicular and luteal phases. Estrous cycle. (B) Close-up showing shrinkage of the longitudinal A B folds of the dorsal median fold in the cranial vagina. Mean plasma concentrations of progesterone. daily. anestrus. . the day after the onset of the follicular phase on which plasma progesterone concentration reached 16 nmol/l.12: Figure 7. pregnancy.13: Mean plasma concentrations of LH. (Modified from Okkens et al. progesterone. prolactin.14: Figure 7. which begins six Vaginoscopic view during metestrus.) 8 the luteal phase (bar).) 8 Figure 7. areas. The data have been synchronized to day 1. the treated with the dopamine agonist bromocriptine (20 µg/kg body weight. 1990. Variation in mean interestrous intervals may be breed cabergoline. ing of plasma prolactin concentration (fig. shortens anestrus and is associated with a lower- related and there may also be differences among strains with. an increase in the circulating plasma FSH concentration is a dence that factors that decrease opioidergic activity promote critical event in the initiation of ovarian folliculogenesis. it does interval.25.24 and there is increased LH pulsatility (fig.27.2.32 Finally.26 There is some evi. when the influence of progesterone on the endometrium is no longer evident. administration of bromocrip- tine in a dose too low to decrease plasma prolactin concen- The endocrine changes that lead to termination of anes. (fig. or when sporadic elevations.31 Also.3. and thus to the start of a new estrous cycle.e. This further supports the notion that in the bitch shortly before the onset of proestrus. or low and does not begin to rise until late anestrus. i.33 (fig. Adminis- the year and there appears to be little. indicating that it is not the decrease bitch in estrus may cause the onset of proestrus to be ad. 7.3.16). 1999.. although low dosage metergoline decreases prolac- Other environmental factors can also affect the interestrous tin release via a serotonin-antagonistic pathway. tration nevertheless induces a premature new follicular phase trus. there is an increase in hy- . The estrous cycle can begin at any time throughout initiation of a new follicular phase in the bitch. and late an- estrus.16).18). The increase in basal plasma prolactin concentration is low during anestrus and does not FSH concentration which occurs during the progression change during the transition from anestrus to the next follicu- of anestrus is critical in the initiation of folliculogenesis lar phase. a new follicular phase. are not com.21 The progression from early to late anestrus is also characterized by a greater number and greater amplitude Bromocriptine-induced shortening of anestrus is associated of gonadotropin-releasing hormone (GnRH) pulses. 7. placing an anestrous bitch in close proximity to a not shorten anestrus.30 estrous cycle.25 Finally. the transition from the luteal Apart from changes in the hypothalamic-pituitary-ovarian phase to anestrus is gradual and varies considerably among axis. during the course of anestrus in the bitch.29. in plasma prolactin concentration but another dopamine- vanced by several weeks.17). bitches housed together agonistic influence that is responsible for the transition to often have synchronous cycles..12 LH release and the termination of anestrus. the mean interval is quently. tration of dopamine-2 agonists. to define the end of the luteal phase. * Significantly different from early anestrus. under physiological conditions plasma pletely understood in the bitch. there is involvement of dopaminergic influences in the bitches. 7. plasma estradiol concentration is usually plasma progesterone concentration falls below 3 nmol/l.3.1. with a prompt rise in basal plasma FSH concentration with- dition. which may be influenced by the photoperiod. 210 Ovaries Figure 7. mid-.)3 7 7.22 In ad.5 Anestrus pothalamic mRNA encoding for the estrogen receptor and in The time of onset of anestrus depends on the criterion used the expression of the gene encoding for P450 aromatase. However.28 Although there are development subsides after two to three months.12 similar to what occurs during normal late anestrus to late anestrus23. by dopamine agonists is the result of suppression of prolactin The basenji and the Tibetan mastiff both have a single annual secretion. Progres- sion of anestrus is associated with a significant rise in plasma FSH concentration but no significant change in plasma LH concentration.16: Mean (± SEM) basal plasma concentrations of FSH and LH in six beagle bitches during early. if any. Moreover. as prolactin may inhibit gonadotropin release. In the collie. it has been suggested that the shortening of anestrus 36 weeks and in the German shepherd dog it is 20–22 weeks. when mammary which catalyzes estrogen biosynthesis. for example. 7. (Modified from Kooistra et al. such as bromocriptine and fluence. seasonal in. there is increased pituitary sensitivity to GnRH and out a concomitant increase in basal plasma LH concen- increased ovarian responsiveness to gonadotropins from early tration. In any case. Conse- in breeds. 3 days (n = 290). The variation in the length of ges- 184) with a variation of 24 days (54–77). In a beagle four to seven days. (Modified from Okkens et al. with a ous breeds the mean gestational period was 62. within was calculated as the interval from the preovulatory LH surge an individual breed the number of pups had no influence on to parturition. The luteal phase and especially anestrus are considerably short- ened. pregnancy. and 50 (n = 8) µg/kg body weight twice daily starting 28 days after ovulation and con- tinuing until the next ovulation. The gestational period was 61. the difference in mean plasma prolactin concen- tration before and during treatment was not significant but the interestrous inter- val was significantly shorter than that of the control bitches. of eight pups. This study indicates that breed is a calculated in bitches of six breeds (n = 113) that had been major determinant of the length of gestation in the bitch and mated at a fixed time after ovulation.18: Mean (±SEM) interestrous interval in control bitches and in bitches receiving the dopamine agonist bromocriptine in oral doses of 5 (n = 60). There were one to 15 pups per litter. which strongly correlates with the preovula- The length of gestation varies greatly in dogs.1. 1985.36 mating was based on the rapid increase in plasma progesterone . * Indicates significant difference.0 days (n = variation of 8 days (58–65). or even less when litters of one pup were colony the mean gestational period was 65. 20 (n = 6).2. Estrous cycle. In the bitches receiving 5 µg/kg twice daily.17: Plasma concentrations of progesterone and prolactin in a bitch treated with the dopamine agonist bromo- criptine (bar).. In the bitches receiv- ing 20 or 50 µg/kg twice daily.4 days.35 The variation was. In dogs of vari. from ovulation in the first estrous cycle to the onset of the next follicular phase. plasma prolactin concentration was significantly lower during treatment than before treatment.6 Pregnancy and parturition concentration. with a range of tation and litter size were negatively correlated. However.. with a median with a variation of 16 days (57–72). In another study the length of gestation was the length of gestation. excluded. how. 2003. reduced to three days (64–66) (n = 54) when gestation with litter size for litters of 13 or fewer pups. tory LH surge.)29 7 Figure 7. The length of gestation correlated negatively ever. anestrus.34 The length of ges.) 32 7. tation within any one of the six breeds was low. (Modified from Beijerink et al. and parturition 211 Figure 7.36 The optimal time for that this is coupled to breed-related differences in litter size. The mean plasma cortisol concentration increases signifi- cantly prior to parturition. Nevertheless. which circulates in elevated concentrations after three to four weeks of pregnancy.. until it de- clines to a plateau at 16–48 nmol/l. and inhibits uterine motility. 7. 7. plasma progesterone concen.19). (Modified from Van Der Weyden et al.21). such as bromocriptine Birth (B) = period between birth of the first and the last pups.21). tration prior to parturition. prolactin is a luteotropic factor. During 7 pregnancy. After par- turition.) 37 and cabergoline. progesterone concentration in plasma fluctuates in a manner similar to that during the estrous cycle.14. In the bitch the duration of pregnancy is equal to or some- what shorter than the luteal phase.14.14-dihydro- 15-keto prostaglandin F2a (PGFM). Although progesterone is secreted by the corpora lutea. promotes placental integrity.37 During prepartum luteolysis and parturition.14. The prepartum increase in plasma cortisol concentration in the bitch is probably re- lated to the physical and emotional stress caused by enhanced uterine activity and labor pains (fig. transient surge in tration. tin secretion by dopamine agonists. several injections of it must be given to induce parturition and even after induction a nor- mal course of parturition is not certain. 7. Dur- Figure 7.19: ing the rapid decrease in circulating progesterone concen- Mean values for uterine activity (burst frequency/h). During pregnancy the plasma hormone profiles are very similar to those described for the luteal phase of the estrous cycle.40 Plasma LH and FSH concentrations decrease between late gestation and the 30 h period prior to parturition.39 Just as it is in the estrous EMG activity for various periods around spontaneous parturition in five dogs. Progeste- rone promotes endometrial gland growth. Ovariectomy during pregnancy re- sults in either resorption of the fetuses or abortion. and the hormonal changes during the last days of pregnancy and during parturition. then falls rapidly to 3–6 nmol/l just before parturition. and the relative distribution (%) of the duration of individual bursts of prolactin secretion (fig.38 PGF2a is important for pre- partum luteolysis. a fairly stable metabolite of prostaglandin F2a (PGF2a) originating from the fetal-pla- cental unit. The decrease in progesterone concen- tration is essential for the onset of parturition and is negatively correlated with a progressive qualitative change in the pattern of uterine activity (fig. Dif. plasma LH and FSH concentrations are lower than in the late gestational period. Suppression of prolac- ferences between columns with a similar superscript are significant (P 쏝 0. the plasma concentration of 13.14 No data are available on fetal and placental cortisol secretion in dogs. is high (fig. stimulates uterine secretions.001). 1989.39 Plasma prolactin concentration rises during pregnancy. with the exception of relaxin.14 . the plasma progesterone concentration is not overtly influenced by the number of corpora lutea. there is a large. It is maintained at this level for one to two weeks. causes abortion in the second half of preg- nancy. 7. 212 Ovaries Progesterone is the hormone responsible for the maintenance of pregnancy in the dog. cycle.20). Different superscripts A.C and 1..5 kg.. Estrous cycle. for puberty does not lation.21: Mean serum concentrations of progesterone. Cats kept in a common household can become nonseasonal breeders as a result of night-time Puberty occurs at between four and 18 months of age in the illumination. king. Although considered to be induced ovulators. 1978. the day after parturition (0–24 h after expulsion of the last pup). vaginal stimu- cal condition is also an important factor.2 denote significant differences.)39 7. before parturition (30–0 h before expulsion of the first pup).2 Estrous cycle. and the 2nd and 3rd days after parturition (24–72 h after ex- pulsion of the last pup). Copulation. pregnancy. and parturition 213 7 Figure 7.B. pregnancy. Pu. Queens are induced ovulators. (B) Mean (± SEM) plasma progesterone (red bars) and PGFM concentrations (blue bars) in six bitches during late gestation (days 54–58 of pregnancy). ovulation can also be induced by external stimuli such as stro- haired breeds.)14 Figure 7. It often occurs when the hours of daylight are increasing. Queens can go through several periods of estrus per season and parturition in the cat (seasonally polyestrous). cortisol.2. and prolactin in the period around parturition and lac- tation in a group of six beagle bitches.20: (A) Plasma concentrations of progesterone and prostaglandin F2a metabolite (PGFM) at 12 h (P4) and 6 h (PGFM) intervals around the time of expulsion of the first pup (t = 0) in a three-year-old beagle bitch. Physi. logues induce ovulation within 24–48 h.41 It is likely that berty may occur earlier in short-haired breeds than in long. (Modified from Concannon et al. and administration of gonadotropin or GnRH ana- usually occur before body weight reaches about 2.42 . as many as 60 % of unmated female domestic cats ovulate without known external provocation. queen and its onset is influenced by the season of the year. 2008. (Modified from Baan et al. anestrus. anestrus. Estrus.2.. four copulations within 26–81 min (green line). the phase in which mating is allowed. Proestrus is char- acterized by rubbing the head and neck against objects but not permitting breeding by the male. Figure 7. postestrus. or 8–12 copulations during 4 h (blue line).)43 7. 214 Ovaries 7 Figure 7. pseudopregnancy.43 The external genitalia are slightly swollen and some clear secretion appears. All copulations were on the third day of estrus. (Modified from Verhage et al.23: Mean serum LH concentration in cats confirmed to have ovulated following one copulation (red line). estrus. There is a distinct increase in anuclear cells and a slight increase in partially cornified superficial cells.. and polyestrus in the cat. rhythmic stamping of the hind legs. Intermediate cells decrease during the follicular phase and parabasal cells are absent in the second half of the follicular phase.)44 . lasts seven to nine days. The ab- sence of cellular debris in the vaginal smear is the earliest sign of follicular activity. It is observed in only a minority of the estrous cycles and lasts for about one to two days. and restlessness. Estrus behavior includes crouching with the forequarters pressed to the ground and the pelvis elevated. 7. plasma estradiol concentration rises to 184–257 nmol/l and then decreases within five to seven days after copulation (fig. and metestrus (diestrus).1 Estrous cycle and anestrus The stages of the estrous cycle of the queen include proestrus. 1980. Estrus occurs during maximal follicular activity and estradiol secretion. (Modified from Concannon et al.22: Plasma estradiol and progesterone concentrations during pregnancy. 1976.22). and in cats which did not ovulate following a single copulation (black interrupted line). frequent vocalizing.2. Estrous cycle. Plasma progesterone concentration is at its basal level during the postestrus period.5). trus begins. Ovulation is followed by pregnancy or a luteal phase photoperiod changes and are highest during periods of dark- without pregnancy (called »pseudopregnancy«). 7. Thereafter plasma progesterone con- period of refractoriness to this copulation-induced LH re.24: 7 (A) The ovary of a queen six days after mating. particularly at the end of this phase. The duration of estrus ap- pears to be similar in queens regardless of whether there is co. In the coital contact. Anestrus is a period without cycle activity.45 Folliculogenesis and estradiol secretion are nancy in the queen does not give rise to signs and symptoms stimulated during days with 14 h of light. Plasma estradiol itus with ovulation. there can be follicle growth (and regression) which causes ings is. ness (fig. 7. x475).46 Estrus can be in- In both pregnancy and pseudopregnancy. and returns to the basal gesterone concentrations in pseudopregnancy and pregnancy level within 24 h. or no and progesterone concentrations are at baseline levels. with luteal tissue called corpora rubra because of its red color. pregnancy.44 The increase in LH release due to multiple mat. The interestrous interval for a pseudopregnant occur following a single mating. trous cycle frequency of two per month. Plasma pro- after copulation. LH release begins within minutes approximately 60 days in the pregnant queen. melatonin. which af- Ovulation usually occurs 24–48 h after copulation and the fects the hypothalamic-pituitary-ovarian axis. (H&E stain. It consists primarily of large luteal cells and blood vessels (bv). November. after which the next es.2. not indefinite and the LH response declines elevations in plasma estradiol concentration. If breeding is permitted. During the progeste- and more prolonged when multiple matings are permitted rone-dominated phase. coital contact without ovulation.22). continuous exposure to light does not ap- . 7. December) in average duration of eight to ten days. duced with as little as 12 h of light if a social stimulus such as one concentration begins to rise 24–48 h after ovulation. (fig. In the early follicular phase there may be a are similar until day 21. The luteal three weeks after an increase to 12 h of light. An estrus in which the queen has not been in. northern hemisphere this phase occurs during late autumn duced to ovulate is followed by a postestrus period with an and the onset of winter (October. however. centration is lower in pseudopregnancy than in pregnancy lease. peaks within 2–4 h. the presence of a tomcat or a queen in estrus is introduced companied by the development of luteal tissue. but it can be delayed for up to nin and prolactin concentrations change congruently with 90 h. but it subsequently develops into yellow rapidly after a change from 14 h to 8 h of light (fig. ac. A rise in plasma LH concentration does not always (fig. The progesterone-dominated phase though gonadotropin secretion may be decreased during a lasts about 38 days in the pseudopregnant queen and short light period. after a certain number of matings. Plasma melato- occurrence of the LH peak. Pseudopreg. anestrus. Photoperiods influence the reproductive processes via the pineal gland and its principal hormone. Al- corpora lutea (fig. 7. (B) Microscopic section of a corpus luteum of a queen 21 days after mating.23). but the LH peak is higher queen is approximately seven weeks. 7. leading to an es- and is thus not comparable to that in the bitch (chapter 2. plasma progester.24). queens exposed to natural daylight.47 Estrous activ- tissue is initially red and therefore sometimes referred to ity ceases immediately and estradiol concentration decreases as corpora rubra.25). and parturition 215 A B Figure 7.26). 25: Figure 7.. middle panel et al.)46 Figure 7. (Modified from Leyva et al. 1983.27: The effects of three different photoperiods on mean plasma concentrations of me.)45 . The purple horizontal bars indicate periods of sexual receptivity. 216 Ovaries 7 Figure 7. (Modified from Banks cate the timing of each lighting regimen.26: Plasma estradiol concentration in two cats during a photoperiod regimen of 14 h of light. 1989.. (Modified from Leyva et al. lower panel: 24 h of light. Day 0 is the day of copulation.. Horizontal bars indi. then 8 h of light. 1984.) 49 14 h of light and 10 h of darkness. upper panel 8 h of light and 16 h of darkness. measured at 2 h intervals. Mean (± SEM) plasma concentrations of prolactin and progesterone in eight latonin and prolactin in four cats. queens during gestation. and then 14 h of light again. progesterone secretion The combined use of cabergoline and prostaglandins has also decreases and abortion may follow.54 The narrow margin between a lethal dose (LD50) and a thera- It is not yet clear why there is a difference between pseudo. and bone marrow month with exposure to 24 h of light.46 gestation (chapter 7. fer. Estradiol secretion dur. tility may be lower than normal.8.1). The use of many of the abortifacients is accom- progesterone or secretes it in amounts insufficient to maintain panied by unwanted and sometimes severe side effects. produced throughout the entire pharmacological agents that suppress prolactin secretion (dur- pregnancy by the corpora lutea. different in failure of implantation and hence embryonic death. unwanted pregnancy in dogs can be terminated by In the cat. then slowly declines during Repeated administration of prostaglandin F2a or its analogues 7 the second half of pregnancy (fig.2 Pregnancy and parturition sequently. Aglepristone has a binding affinity for the progesterone receptor that is probably three times greater than that of the native hormone. 7. resulting may also interact with the glucocorticoid receptor. (three. pyometra. pregnancy. During the second part of the luteal phase.50 antiprogestins having different binding affinities for the pro- However.3 Medical pregnancy weight or 10 mg/kg body weight administered twice with a termination 24 h interval is six days. This may cause a Maintenance of pregnancy in the bitch depends on ovarian depletion of the tertiary follicle population. of which practice. Excretion is essentially via the feces. This prolongs the transport time in the 24 days. depending on the dose (fig. suppression. the action of progesterone. Antiprogestins revers- to 21 weeks. Around 60 % of the administered dose is ex- avoided early in gestation by administering relatively large creted within the first 10 days and a total of around 80 % in doses of estrogens. The mean resi- dence time for a single administration of 20 mg/kg body 7. reaches a pla. Little is known about fertility during this estrus. Medical pregnancy termination 217 pear to be optimal. 7.51 although using low doses of estradiol benzoate ing estrus under exposure to 24 h of light appears to be ap.49 If prolactin secretion is suppressed by treatment and the day of pregnancy on which administration is begun. while the number of large antral follicles doubles about 45 days after the onset of continuous light. stone. thereby preventing en- but if it occurs during lactation. have a chemical structure related to that of progeste- rone. i. such as prolactin.53 Con- 7. they are gen- increase in the pseudopregnant queen. The placenta either does not secrete progesterone.2. which is not uncommon. but they carry a p-(dimethylamino) phenyl group at the The first estrus after parturition can be expected within one 11b-position of the steroidal skeleton. and the need for repeated administration are import- pora lutea..52 light. hyperpnea. Antiprogestins oviduct and tightens the utero-tubular junction. and aglepri- could be arrested development. ataxia). and increases again just before delivery cacy of the dopamine agonists differ. and pregnant and pregnant animals in the functional activity of cor.27). attention has been given to agents that prevent and subsequent development of an ovum when a fetus is al. after which a secretion of progesterone by the corpus luteum throughout long interval is necessary for tertiary follicle restoration. the use of estrogens can result in side effects such as gesterone and glucocorticoid receptors. Plasma progesterone concentration increases con- tinuously through days 25–30. such been proved. progesterone receptor anta- ready present in the uterus (superfetation) has. progesterone. however. Fertilization tioned drugs. never gonists. is probably responsible for ing midgestation) or interfere with the synthesis or action of maintaining pregnancy.2. peutic dose.2. luteotropic factors from the pituitary. pressing pituitary secretion of prolactin. Reports on the effi- teau at about day 50. Pregnancy involves pregnancy-specific secretion of ant factors limiting the use of prostaglandins in veterinary luteotropic hormones of placental or pituitary origin. which may be the cause erally effective at lower doses than with single administration of the early regression of the corpora lutea. registered for use in humans. with the dopamine agonist cabergoline. ibly bind to the progesterone receptor. .e. Cycle frequency decreases to one per cystic endometrial hyperplasia. which limits its biological activity.48 during midterm pregnancy in the bitch results in luteolysis. cause luteolysis by sup- pregnant queen begins to increase around day 35.55 When used in combination. Progesterone receptor blockers (antiprogestins). and there are fewer side effects. five and seven days after mating) decreases the inci- proximately twice that observed under exposure to 14 h of dence of these adverse effects. Fertilization of oocytes by spermatozoa of different males Because of the undesirable side effects of the above men- (superfecundation) is common in domestic cats. diarrhea. This rather long mean residence time is due to both slow absorption from the injection site and For many decades unwanted pregnancy in dogs has been slow excretion. Prolactin secretion in the better tolerated than bromocriptine. dogenous progesterone from occupying its binding site.27). which is prolactin appears to be important. Prolactin secretion does not been reported. are essential for maintenance of the corpus luteum. Dopamine agonists such as cabergoline. The explanation for fetuses of different ages as mifepristone. side effects (vomiting. there should be careful control mature luteolysis is probably caused by increased PGF2a secre.57. in the dog. Because not all bitches and queens abort completely after one vels in two to four days (fig.28).57.57 leading to a sig. dicated that pregnancy was terminated by abortion and not by fetal resorption. Aglepristone is also useful for pregnancy termination in the queen. aglepri- stone can be used for abortion until day 45 of pregnancy. There remains the question whether it is advisable to treat un- nography. In these cases only anestrus is shortened. several examinations are necessary for possible blocker. the main metabolite of PGF2a.. symptoms of pseudopregnancy. In addition. treated unnecessarily.62 The advised treatment for pregnancy termi- cantly during aglepristone treatment and pregnancy is ter. When administered in nificantly shorter luteal phase than in control dogs. Aglepristone was effective in terminating pregnancy in 66 of 69 dogs in which pregnancy had been confirmed by ultraso. for the development of endometritis. if the drug is administered after day 40 of gestation.59 tion is not complete. to confirm the expected abortion. which mimics a sudden decline in progesterone incomplete abortion or ongoing pregnancy. from the day of ovulation (Day 1) to the end of the luteal phase. the second half of pregnancy. have sia of mammary gland tissue indicate that there is a risk for been reported after pregnancy termination by the progeste. 2000. probably due to incomplete abortion. examination by palpation and ultrasonography prolactin concentration is probably due to occupation of the after one week is necessary.58. A similar increase in plasma prolactin con. According to the instructions of the manufacturer. A seven days after administration of 10 mg aglepristone per kg good reason to treat only after pregnancy confirmation is the body weight on two consecutive days between 27 and 31 days fact that after a misalliance less than 40 % of bitches become following mating. Mucoid vaginal discharge is the only Plasma concentrations of prolactin and progesterone in a four-year-old beagle gynecologic sign if aglepristone is administered around day 28 7 bitch. if not properly guided. abortion in the second half of pregnancy may cause serious centration is observed after ovariectomy in the luteal phase. around day 26. obstetrical problems. because of the risk less than 3 nmol/l within eight to 34 days. (Modified from Galac et al. However. On Days 30 and 31 (arrows). Day 45 has probably been chosen because thereafter expul- sion is a premature parturition rather than an abortion.56 In another study.57 This increase in plasma treatment. oxytocin should be given and its effect monitored. the bitch was treated with aglepristone in a subcutaneous dose of pregnancy. plasma progesterone declines to aglepristone in the first half of pregnancy. concentration. After repeated administration of central progesterone receptors by the progesterone receptor aglepristone. In line with this supposition.57 Only a small amount of mucoid vaginal pregnant61 and thus early treatment will result in 60 % being discharge was observed and ultrasonographic examination in. although its efficacy in the queen seems to be less than Plasma progesterone concentration does not change signifi. no other symptoms nor signs of parturition are of 10 mg/kg body weight. increases in circulating cats treated with aglepristone for fibroadenomatous hyperpla- concentrations of PGFM. endometritis. Observations of pregnant tion. 7. not the luteal phase. have been reported in some of the dogs treated with aglepristone in midgestation. This pre.)57 observed during this stage of gestation.58 After aglepristone two consecutive days. due to shortening of both the luteal phase and anestrus. 218 Ovaries Consistent with the substantial increase in plasma prolactin concentration. nation in queens is 15 mg aglepristone per kg body weight on minated despite a high concentration. Shortening of the interestrous interval. including moderate anorexia and lethargy. Plasma prolactin concentration increases within 24 h after aglepristone treatment in midgestation and returns to basal le. signs of parturition such as uterine contractions and straining may be observed.60 It can be concluded that aglepristone is suitable for pregnancy Figure 7.58 The interes- trous interval is also shortened when aglepristone is adminis- tered either to bitches in early gestation or to nonpregnant bitches in the first half of the luteal phase. It is probably better not to administer treatment in midgestation. is commonly observed after aglepristone treatment in midgestation. .63 If abor- rone receptor blocker mifepristone. all pregnancies (n = 6) con.28: termination in the dog. intentionally mated bitches just after mating or when preg- firmed by ultrasonography were terminated within four to nancy has been diagnosed unequivocally. not proceed a standard obstetric protocol was employed.4 Induction of parturition 7. In a study of has not occurred within 25–30 days from the onset of proes- this the course of parturition. Persistent estrus 219 B Figure 7. This usually occurs every 2 h until expulsion of the last pup. estrous cycle and older dogs. are still present. Continuous or was administered on day 58 of pregnancy.2 days) was significantly shorter than in those that whelped incomplete ovariectomy. Ovarian cysts and ovarian tumors can cause persistent estrus rone concentration was still elevated. 7. ization (fig. progesterone.5 days). In addition. had no significant influence on growth rates. the intervals between pups. the vaginal six control bitches. the number stillborn.5 Persistent estrus The progesterone receptor blocker aglepristone is an effective The bitch is considered to have a persistent estrus if ovulation drug for induction of parturition in the bitch. after which ovulation occurs and corpora lutea Pup survival and mean birth weights also did not differ sig. followed after 24 h by admin. and growth rates trus. In young dogs.08 mg/kg is not uncommon and is probably the result of a failure of fol- body weight) of or by oxytocin (0. persistent estrus istration of either the PGF2a analogue alfaprostol (0. such as sanguineous discharge were recorded in six bitches that received aglepristone and in and estrus behavior. If parturition did persistent estrus can also occur in the queen.2 ± 0. (H&E stain). while estrus symptoms.64 Aglepristone (30 mg/kg body weight) smear contains a majority of superficial cells. Follicles normally undergo preovulatory turition did not differ significantly between the two groups. Ovarian cysts and symptoms of persistent in the bitches in which parturition was induced (59. During 7 these estrus periods the measured plasma progesterone concentration did not reach levels normally observed at the time of ovulation. the latter depending on the degree of lutein- and the number of clinical interventions needed during par.65 In the latter study. are formed. Note the luteinized cells bordering the luteinized follicular cyst. The length of gestation in dogs and cats. at which time plasma progeste. which persistent estrus is commonly associated with cysts.5 ± estrus are known to occur in bitches that have undergone 0. however. The duration of the expul.29: (A) Follicular cyst (fc) and luteinized follicular cysts (lfc) in a four-year-old bitch with shortened interestrous intervals and persistent estrus symptoms. the without the formation of cysts.15 IU per kg body weight) liculogenesis and subsequent ovulation. (B) Close-up.29). showing the wall of the follicular cyst (fc) and the wall of a luteinized A follicular cyst (lfc). luteinization.66 . There is probably a difference in the pathogenesis of persist- Parturition has also been induced by aglepristone at a lower ent estrus between young dogs during their first and second dose (15 mg/kg body weight). as opposed to older dogs in bitches whelped within 27 to 38 h after treatment was started. pup survival. Luteinized follicular cysts. fail to ovu- nificantly between the two groups and aglepristone treatment late. Ex- pulsion of the first pup occurred between 32 and 56 h after Pathogenesis treatment with aglepristone. licular cysts may synthesize and secrete estrogens and sion phase. 7. Cystic follicles and luteinized fol- spontaneously (62. If lu- teinization of cystic follicles or further luteinization of lutein- ized cysts takes place. Ultra- sonography is very valuable in diagnosing ovarian cysts and cystic tumors (fig. although the size and consistency of these tumors vary considerably. vaginal cornification. This functional tumor is usually a noscopy reveals that the swelling of the vaginal mucosal folds granulosa cell tumor. and a normal follicular phase and ovulation tration of low.05 mg/kg problem in older dogs is often recurrent. turely regressing follicles. Rarely. such as gonadorelin or tration in the cyst fluid was 1195 pmol/l. Differential diagnosis A split heat is a heat that stops before ovulation and starts again after an interval of days to weeks. In contrast. are the other import. which fre- quently originate from sex cord stroma. estrus will stop. As mentioned above. but are sometimes observed in young charge changes from red to brown and the vaginal smear con- bitches or in bitches with ovarian tissue left in situ as a result tains intermediate cells. but plasma estradiol concentration is not consist- .66 appropriate mating period. and the plasma concentrations of progesterone and estradiol. 7. Abdominal palpation can be helpful in ruling out a tumor. the problem persists estrus can be stopped by oral adminis- zation follows. Computed tomography provides better spatial resolution than ultrasonography. supposedly because of defective he.1 mg/kg body weight. Split heat is observed fairly often in both young and older bitches and especially in certain breeds. A split heat may be difficult to distinguish from persistent estrus if the interval is 7 Figure 7. respectively. second week: 0. If Young dogs generally respond well to treatment and luteini.30). estrogens administered to terminate an un. as the German shepherd dog. Ovarian follicular body weight). 7. Treatment is usually not necessary but close cause of persistent estrus. Ovulation usually occurs if proes- sibly by inducing ovarian cysts. Granulosa cell tumor of a nine-year-old Belgian shepherd dog that had estrus be. plasma progesterone concentration will increase. but this does not always resolve the problem. vaginoscopic findings. and is easier to perform and to interpret (fig. The plasma concentrations of progesterone and estra- diol-17b were 7 nmol/l and 270 pmol/l.1 ml/kg body weight). buserelin (repeated subcutaneous doses of 0. doses of megestrol acetate (first can be expected during their next cycle.31). pos.30: very short or unobserved. The estradiol-17b concen- Cysts can be treated by giving GnRH.6 Split heat Functional. is diminishing. the week: 0. 220 Ovaries ently elevated. hormone-producing. Therapy havior for four months. estrus behavior. They may arise from mature or atretic follicles and their occurrence may increase with age. and the vaginal smear will con- tain mainly intermediate and parabasal cells and leukocytes. ovarian tumors. parabasal cells. Diagnosis The diagnosis is based on the persistence of sanguineous dis- charge. Vagi- of incomplete ovariectomy. monitoring of the estrous cycle is essential to determine the patic metabolism of reproductive steroid hormones. When interpreting ultrasonographic findings it is important to realize that in the dog the morpho- logy of cysts may mimic that of vesicular follicles and antra in young developing corpora lutea. 7. 7. It is probably caused by prema- wanted pregnancy occasionally cause persistent estrus. once daily. liver disease is the trus returns.32). a split heat is a heat which stops before ant cause of persistent estrus (fig. The vaginal dis- older dogs and cats. A history of incomplete ovariectomy or hor- mone therapy can contribute to the diagnosis. They occur mainly in ovulation and starts again after days or weeks. Ovarian tumors should be removed. cysts producing estrogens are common in queens. such Furthermore. and leukocytes. Plasma progesterone concentration is lower than 16 nmol/l. 7. Diagnosis A general physical and gynecological examination71 should be performed. ultrasonography revealed liv. secreted by the corpora lutea.3). ageing and the interestrous interval increases after eight years livered. If 쏜 3 nmol/l.11). . 7. tebra (L3) of a four-year-old collie with persistent estrus.2. which is just above the threshold sult of a decreased circulating level of gonadotropic hor- necessary to maintain a vital pregnancy. During medroxyprogesterone acetate treatment the scribed in a bitch which had estrous cycles with very short lu- plasma concentration of endogenous progesterone decreased teal phases and short interestrous intervals.70 The duration and further.8 Prolonged anestrus Progesterone. If a bitch has been in estrus and its in- rately by radioimmunoassay because the commercial ELISA terestrous interval is now more than twelve months or twice kits are not reliable in the critical range of 3–16 nmol/l.67 Because of the potential side effects of progestagens. in close contact with the ventral extremity of the spleen (S). in order to prevent abortion due to progesterone defi. Prolonged anestrus 221 Figure 7. such as progestagens or glucocorticoids.69 On the other hand. Originating from the left ovary there is a large.5-year-old Bernese mountain dog was reported to ated with prolonged or abbreviated proestrus or mild estrus have had two previous pregnancies ending in abortion around symptoms. Fur. this anestrus is considered to be thermore. of age. A major cause of pri- lead to infertility. also has been reported to cause prolonged day 58. A 2. its usual interestrous interval. it appears to be rare.68 Lymphocytic oophoritis. oophoritis has also been de- ciency. bitches should not be of a silent estrus or the owner’s failure to detect estrus. On day 42.7 Hypoluteoidism 7. An apparent prolonged anestrus can also be the result such as CEH-pyometra (chapter 7. hypothyroidism may also be associ- terone.32: 7 Longitudinal ultrasonogram of the abdomen of the bitch of fig. Oral treatment with mones. in spontaneous hypercortisolism anestrus is probably the re- creased to 8. pothyroidism. For the diagnosis mary anestrus is true hermaphroditism or pseudohermaphro- plasma progesterone concentration must be measured accu. Prolonged anestrus may also be induced by drugs day 50 of pregnancy. Although hypoluteoidism can is considered to have primary anestrus.30. One of the reasons for prolonged anestrus is hy- abortion is not detected by the radioimmunoassay for proges. However. ditism (chapter 6. In the latter case and ing fetuses but plasma progesterone concentration had de. treated with progestagens after ovulation unless primary hypoluteoidism has been proved. cystic.31: Figure 7. after which one or more of the following tests may be useful: 쎱 Measurement of the plasma progesterone concentration. and four living and one dead pup were de. space-occupying lesion (arrow). most likely an immune- medroxyprogesterone acetate was started and continued until mediated disorder. On day 59 a cesarean section was performed because frequency of estrous cycles become more irregular with of dystocia. revealing Contrast-enhanced CT image of the abdomen at the level of the third lumbar ver- small and large cysts in the tumor.3 nmol/l. it is essential that any progestagen used to prevent prolonged. anestrus. is necessary for A bitch which has not been in estrus by 18–24 months of age maintenance of pregnancy. the bitch was probably in estrus and either the owner did not notice it or the bitch had a silent estrus. dopamine agonists. administered dopamine agonist and the period in the estrous typically female dogs. The abnormalities may include the cycle or anestrus in which treatment is started. such as bromocriptine and cabergoline. and vier des Flandres.32 The result of 쎱 Determination of the karyotype. followed by a GnRH analogue Medical prevention of estrus can be accomplished with sev- on the first day of induced estrus.3. The insufficient response to porcine LH in bitches in early High FSH and LH values indicate gonadal absence (apla. FSH. Early-age gonadectomy is associated with an increased Induction of a follicular phase can be achieved by several incidence of cystitis.2). has certain advantages. such as the risk of anesthesia and surgery. ovulation in 16. 쎱 Measurement of plasma concentrations of LH and FSH. 7.25. 222 Ovaries 쎱 Measurement of plasma concentrations of thyroxine and proestrus occurred but not estrus had all been treated in early TSH. Abnormalities in sexual treatment with dopamine agonists depends on the dose of the differentiation may present as primary anestrus in pheno.41 In a study in which GnRH was ad- ministered in pulses of 15–500 ng/kg body weight every In the cat ovariectomy is the treatment of choice. It does not 90 min for seven to nine days to 36 anestrous bitches. If 7. Weimaraner. Hypothyroidism is treated with l-thyroxine (chapter 3. of the induced estrus. equine Chorionic Gonadotropin. country. thyroid scintigraphy and /or a TSH-stimu. tration that is observed after LH treatment suggests that an in- lation test may be performed (chapter 3. and Rottweiler appear to be es- their efficacy of inducing estrus as well as the resulting fertility pecially at risk for developing urinary incontinence.80 A fertile estrus could also be induced by administering a timed-release GnRH agonist. . When bromo- 7 presence of abnormal complements of sex chromosomes criptine was started during the luteal phase.73 and mammary tumors in the cat are quite often malignant. estrus may be induced (chapter 7. Progestagens are the most important among them trus was induced by porcine LH in all of 16 bitches. not all of which can be used in every also be terminated by administering LH. There are also possibile side effects. however. trus (see also chapter 8.9).1).78 Urinary incontinence occurs rionic Gonadotropin. primarily for short-term pre- twelve came into estrus and seven ovulated.5 years of age.1): This test can Shortening of anestrus and thus stimulation of folliculogenesis confirm male pseudohermaphroditism or true herma. including the use of synthetic estrogens. estrus can be detected by cytologi- cal examinations at regular intervals and close visual examin. in an oral dose of as well as sex chromosome complements that do not 20 mg/kg twice daily. of which but androgens can also be used.9 Estrus induction such as urinary incontinence or unwanted changes in the hair coat.1). tine treatment appears to be normal. ment of pyometra and progesterone-induced GH excess (chapter 2. tumorigenic and pregnancy in 12 bitches.32 When it was 쎱 Laparoscopy or laparotomy. treatment is formed before or after the first luteal phase but in any case not possible. and mainly in dogs of large breeds. the next proestrus appeared after a mean interval of 쎱 Abdominal ultrasonography usually does not reveal the about 45 days. endogenous pro- ment resulted in proestrus in 26. Follicular aromatase in rats and diagnosis. mined by measuring progesterone. Those in which vention. several disadvantages. It also prevents the develop- found.2. Although not essential for tors in this stage of anestrus. GnRH greater if the intervention is carried out prior to the first es- agonists. it is of interest that an elevated LH.2.74 Anestrus in the bitch can eral types of drugs. can be further stimulated with GnRH. If no specific cause for the prolonged anestrus is before about 2. estrus in 20. Ovariectomy ation of the vulva. can also be induced by administration of dopamine agonists phroditism in a phenotypically female dog.72 regulation control by FSH. crease in follicular steroidogenesis is a primary effect of LH. In most cases of true It considerably lowers the risk for mammary cancer if per- hermaphroditism or pseudohermaphroditism. the mean interestrous interval was match the animal’s phenotype (chapter 6.75 The rapid increase of plasma estradiol concen- still suspected. Estrus can be prevented medically or surgically.1).78 The risk of urinary incontinence is methods. There are. Bou- human Menopausal Gonadotropin). In one study proes. anestrus may be due to lack of FSH or follicular FSH recep- sia.18). Efficacy was dose-dependent. giant schnauzer.3. exogenous gonadotropins (LH. These methods vary widely in sheepdog. treat. ovariectomy) or failure. The boxer.79. as in the bitch.10 Estrus prevention the animal has silent heats. It is effective after a single procedure. Furthermore.5. Treatment Treatment depends on the cause of the prolonged anestrus. Old English opiate antagonists (naloxone). human Cho. but not of most other species studied appears to be primarily under up- FSH. 100 days after ovu- and collect tissue for histological examination. 7. The optimal mating period can be deter.4. Irish setter.29. Doberman. to examine the genital tract started in the same dose during anestrus. and the irrever- sibility of the procedure. lead to urinary incontinence.69 shortened from 216 to 96 days (fig.76 쎱 A GnRH-stimulation test with measurement of plasma testosterone concentrations (chapter 12. If the results are inconclusive and hypothyroidism is anestrus. gesterone and progestagens are.2).77 The fertility of estrus initiated by bromocrip- cause of prolonged anestrus. lation. 88 In dogs. In addition. The side productive function for one year. the In the usual household the queen is not affected by photo- early stimulatory effect of GnRH analogues. prevented re. it is not tered during anestrus. The mechanism of the contraceptive action with a cotton probe) or by treatment with a gonadotropic of progestagens is still unclear. However.A. suitable for Another option is to reduce estrus frequency in the queen by use in clinical practice. and weight gain. should the queen could be induced in the other three after 1. to 30 mg/kg for a dog of 3 kg. The gestation will be pro- medroxyprogesterone acetate (MPA) treatment did not affect longed and a caesarian section may be needed. including clitoral hypertrophy. which causes es. dog and queens may develop urine spraying behavior. vaginal discharge. Estrus recurs after two to nine months. androgens may cause defects in 21 days. Estrus prevention 223 Androgens probably inhibit pituitary gonadotropin release. probably has a stronger progestagenic effect than MPA.S. If ad. but during MPA treatment LH GH caused by progestagen administration can be treated pulses coincided with small and sometimes insignificant FSH successfully by the progesterone-receptor blocker agle- pulses (fig. Side effects associated with the use of progestagens for estrus duce the increased circulating LH concentration in ovariec.4. nor was the hypersecretion of LH and FSH ministered subcutaneously at the onset of the follicular that occurs in ovariectomized bitches suppressed. an.87. the oral medication The age at puberty of the treated bitches was 25. liver twelve months. mibolerone.15 The hypersecretion of coincide with an FSH pulse. period influences and may cycle throughout the year. GnRH agonist implants.3 months). In most bitches the first estrus after bitches prior to the first estrus. gestrol acetate did not suppress basal gonadotropin secretion 쎱 Prolonged pregnancy. owners clinical use.86 The results of this study also suggest that pristone. is also anabolic. in the dog are proligestone and MPA.85 쎱 Diabetes mellitus. period of time also prevent estrus by down-regulation of GnRH receptors on pituitary gonadotropes.2–14. however.83 In another study. This occurs if progestagens are ad- during anestrus. The induced pseudopreg- dence that contraceptive progestagens inhibit gonadotropin nancy delays the recurrence of estrus. LH pulses litus is largely due to GH excess. MPA can also be administered orally. but there are indications of changes in the pulsatile se.82 unexpectedly be found to be pregnant.3 months. long as estrus prevention is wanted or for a maximum of ministered to a pregnant dog. androgens the advised dose of megestrol acetate. high contraceptive doses of me.89 there may be a direct negative effect of medroxyprogesterone 쎱 Increased risk of neoplastic transformation of mammary acetate on follicle development in the ovary. this is usually caused by the glu- Pulsatile FSH and LH release is maintained during MPA treat. release.81 In one study. In addition.33). therefore lies in its minimal influence on the endometrium. In some species there is evi. (18–31) months. diabetes mel- cretion pattern of the gonadotropins. In cats. applied who can detect the symptoms that precede estrus can admin- before puberty (mean age: 4.33). and for medroxyprogesterone Thickening of the myometrium may occur but only when acetate the single subcutaneous injection dose is 2 mg/kg excessive doses are used. ister these drugs only when these symptoms occur. Androgens may also have side injection of proligestone can be expected within nine to effects. They should be adminis- bitches treated with this drug appears to be good. make them less suitable for 2 mg megestrol acetate once weekly. inducing ovulation. ment. except for an increase two months after the 쎱 Hypersecretion of mammary GH (chapter 2.34). is 7 turition behavior. daily (10 mg for large dogs during the first five days) for as drogens can induce development of mammary tumors. cocorticoid effects inherent in progestagens. about one month before the expected recommended in the U. Furthermore. Androgens are contraindicated three years.2). after injection of MPA it may be up to two to dysfunction. Although subsequent fertility in (with a maximum dose of 60 mg). One orally adminis. In general. a progestagen which may cause an increase in aggressiveness and a change in mic.84 Chronic phase and the bitch is mated.86 tissue. hormone or GnRH during estrus. It has taneous injection dose recommended by the manufacturer for no progestational or estrogenic activity and its advantage proligestone ranges from 10 mg/kg for a dog of about 60 kg. 7.11). This can be accomplished by mechanical stimulation of the vagina (touching the vestibulum /vagina Progestagens. Alternatively. This ranges from hyperplasia to adenomas and . Following removal of the effects of oral administration appear to be less serious than implant estrus occurred naturally in seven of ten bitches and those accompanying injections.2. FSH secretion. In the U. high doses of medroxyprogesterone acetate administered to beagle bitches for several months did not re. The progestagens most frequently used for estrus prevention thus preventing follicular development.S. 7.A. have not yet been marketed.9 ± 0. 5 mg once in bitches with a liver or kidney disease. and did not affect LH secretion (fig. Long-acting GnRH antagonists. ter 7. apart from glucocorticoid effects. or 2 mg/kg for eight days starting at the onset of proestrus. This trus if they are administered in anestrus and sometimes also if can be prevented by oral administration of 5 mg MPA or administered in the luteal phase. Considering the results which are obtained with lower doses GnRH agonists administered at high doses over a long of MPA. this recommended dose seems quite high. the urogenital tract of female puppies. The single subcu- tered synthetic androgen.5 ± 5 can be stopped and parturition allowed to occur normally. for use in breeding bitches or in follicular phase (fig. start of treatment. 7. However. prevention: tomized bitches nor did it lower LH concentration in intact 쎱 Development of cystic endometrial hyperplasia (chap- bitches. Bitches may begin to urinate like a male 0.5 mg/kg orally once daily for 32 days starting in anestrus. 33: Six-hour plasma profiles of FSH and LH in a three-year-old beagle bitch before and three.)86 .. 224 Ovaries 7 Figure 7. six. 2008. nine and twelve months after the start of treatment with medroxy- progesterone acetate (10 mg/kg. * Significant pulses of both FSH and LH. ^ Significant LH pulse without significant increase in FSH. every four weeks). (Modified after Beijerink et al. 7. with the exception of »prolonged pregnancy«. The latter disorder can be treated effectively with the progesterone receptor blocker aglepristone.63 The occurrence of these side effects. is largely dependent upon total pro- gestagen exposure. malignant tumors. However.35). A ten-month-old queen with fibroadenomatous hyperplasia of the mammary glands. the hyperplasia itself may also give rise to problems. Estrus prevention 225 7 Figure 7. . The progestagen-induced neoplastic transformation of mammary tissue starts with proliferation of undifferentiated terminal ductal structures.35: with proligestone. leading to a very large fibroadeno- matous hyperplasia (fig. In young queens exogenous progestagens (and also endogenous progeste- rone!) may cause extensive proliferation of mammary duct epithelium and stroma. With the advised dosage regimens the ex- posure may be higher with MPA and megestrol acetate than Figure 7.90 This proliferation increases the sus- ceptibility of the mammary tissue to malignant trans- formation. the latter being a rather weak progestagen. Following her first estrus she had been treated with 2 mg megestrol acetate once weekly for three weeks.34: Optimal period for progestagen treatment for estrus prevention in the bitch. especially in the queen. so-called terminal end buds. i. which is often the case under progeste- rone influence. but it does not usually lead to permanent renal 7.. x40). but rare in cats. In CEH without infection there are no inflammatory cells. while in- fection results in neutrophils and plasma cells. which have completed several luteal phases. especially after adminis- tration of progestagens. (H&E stain. This may be the result of blood loss in the uterus. strated in dogs with pyometra. A CEH-associated alterations of the uterine glandular epithe- lium first occur close to the uterine lumen (fig. Although endogenous progesterone and but the inflammatory process can also lead to decreased ery- exogenous progestagens may induce both development of thropoiesis. The (B) Multicystic proliferation in the bitch due to cystic endometrial hyperplasia with enlarged uterus may cause abdominal distention. Clinical manifestations Bitches and queens with uncomplicated CEH do not exhibit signs of systemic disease. It is therefore a common disorder in decreased ability to concentrate urine.42 which may be due to the fact that queens do not always require coital con- tact to induce ovulation (chapter 7. It is uria and polydipsia are common in dogs with CEH-endo- not the result of »retained« corpora lutea. The bacterial infection may cause deposition of immune complexes in the glomerular capillary walls.37). dometritis. CEH is usually diffuse.36: (A) Cystic endometrial hyperplasia in an eight-year-old bitch. In this uterus is filled with aggregates of bulging cysts arising from the endometrium. Massive quantities of pus may be found in the lumen of the Figure 7. Queens with CEH-endometritis often have corpora lutea without a history of mating. metritis.91 In addition. The lumen of the uterus. CEH and hypersecretion of GH in mammary tissue.2. mucometra develops (fig. The systemic disease is usually B milder when the cervix is open than when it is closed. which is mainly composed of epithelial open cervix vaginal discharge ranges from yellow to choc- tissue with scant connective tissue. the latter does not seem to play a role in the pathogenesis of CEH. Vomiting associated with the uremia may be an aggra- Pathogenesis and pathology vating factor. a de- consequence of repeated endogenous progesterone influence crease in renal sensitivity to vasopressin has been demon- during successive luteal phases or as a consequence of exo. This probably means that several ovulations have occurred unnoticed and conse- quently the animal has been repeatedly under progesterone in- fluence.e. 7 If the cervix is closed. If the endometrial hyperplasia is accompanied by inflammation the condition is The bacterial infection and more specifically E.18 .11 Cystic endometrial hyperplasia. With an papillary overgrowth of the endometrium. CEH can develop either as a may cause loss of medullary hypertonicity.92 These changes may lead to a genous progestagens. 7. be observed.36). depending on the presence or absence of blood. situation the animal is lethargic and may be anorectic. GH has been demonstrated by immunohistochemistry in the Anemia is present in about 40 % of bitches with CEH-en- hyperplastic glandular epithelial cells of the uterus of proges. of the uterus of the bitch and the queen. 7. olate or red. This may cause proteinuria. CEH-endometritis has also been observed in ovariec- tomized queens that have been treated with progestagens. especially if the cervix is closed (pyometra). One must also be alert to the possibility of Cystic endometrial hyperplasia (CEH) is a common disorder peritonitis due to a perforated uterus. tagen-treated dogs. failure. If in- fection is also present the signs and symptoms are often de- pendent upon cervical patency. but it can be limited to only parts of the uterus. Infertility due to failure of implan- tation or to fetal resorption can. The associated poly- older bitches. but note that accessory glands can also be present in the myometrium (adenomyosis) or even in the serosa (endometriosis). due to hypovol- emia.2). coli antigens called CEH-endometritis. however. The elevated plasma urea and creatinine concen- endometritis trations are generally prerenal in origin. 226 Ovaries In the queen CEH is mainly a disease of older animals but oc- casionally it occurs at an early age. 3. and has an irregularly Lateral radiograph of the abdomen of a seven-year-old mixbred dog with pyo. owner wishes to breed it. 7. In cases of CEH without dometritis. thickened wall with small cysts. or vaginitis.38) or.37: 7 (A) Mucometra with a thin uterine wall in a seven-year-old Bouvier des Flandres. treated for several years with high doses of progestagens. to the relevant chapters. selected by means of bac- . vaginal tumors causing dis- estrous cycle or under influence of exogenous progestagens. It occurs during the luteal phase of the also be associated with pregnancy. fluid-filled uterus causes displacement of other viscera. The uterus Figure 7. Medical treatment should include administration for at least two weeks of an antibacterial agent. Ovariohysterectomy is the treatment of choice for CEH-en- ably. ultrasonography (fig. Rou. 7.38: is slightly dilated. can be observed during vaginoscopy. medical therapy can be started. Inspissated mucus (M) causes amorphous echogenicity in the dependent part of the uterine horns. and hyperproteinemia. ane- mia. and sporadically other bacteria.39). coli. fluid-filled. Diagnosis Differential diagnosis CEH-endometritis is usually a disease of the middle-aged or Several of the signs and symptoms of CEH-endometritis can elderly bitch or queen. sonography.4. The enlarged uterus can be Treatment palpated or visualized by radiography (fig. (B) Transverse ultrasonogram of the abdomen of the same bitch. Culture of the discharge hyperthyroidism. and hypercortisolism. Figure 7. The dilated. prefer. For other causes of polyuria /polydipsia In cases of endometritis with an open cervix the discharge such as progestagen-induced GH excess. charge. Cystic endometrial hyperplasia-endometritis 227 A B Figure 7. tine laboratory examinations often reveal neutrophilia. If the affected bitch or queen is young and the accumulation of fluid. metra. diabetes mellitus. including chapter 2. The uterus is severely dilated (delineated by interrupted line) and filled with fluid (F). visualization is only possible by ultra. the reader is referred usually reveals E.3.39: Ultrasonogram of the abdomen of a seven-year-old bitch with cystic endometrial hyperplasia. 2. later conceive and deliver normal litters. and salt dinoprost tromethamine in a dose of 100–150 µg/kg progesterone. and evacuation of the uterine contents can be expected. ataxia. 12. such (see also previous sections). due to breeding management lessness. 5. U = urethral orifice. cervix dilatation. Walking the dog during this time diminishes the side effects. but it can be as few a fairly good prognosis. and 15. such as canine brucellosis or herpesvirus infection. This section will therefore focus on fer- Prognosis tility disorders related to breeding management problems. 7. CEH-endometritis may recur with the septa (fig. rest.1. Uterine contractions.94 PGF2a causes premature regression of the cor- pora lutea if it is administered repeatedly in the second half of the luteal phase. such as strictures and the onset of therapy. fectious diseases. (3) cystic endometrial hyperplasia. 2. There is a risk of uterine perforation during this estrous cycle. aglepristone. or as clopros- tenol in a subcutaneous dose of 1 µg/kg on days 3. Fertility disorders may be related to (1) abnormalities of the quently. Fertility problems may arise during any stage of Treatment in the queen is as described for the bitch. within the uterus. in a dose of 10 mg/kg body weight on days 1. As mentioned in chapter 7. The prognosis after medical treatment alone is often uncer- tain. The onset of after medical treatment is much better than in dogs. but occasionally it is as early as two to three days before or as . bitch and can be solved if a proper breeding program is intro- duced (chapter 14. may in- clude salivation. body weight twice or thrice daily for four days. good breeding management. such as split heat. persistent estrus. 228 Ovaries Figure 7. diarrhea.40). 8. as does a lower dose administered more fre. vomiting. but probably improved since a progesterone receptor Knowledge of reproductive physiology is indispensable for blocker in combination with PGF2a can be used. Many of the observed fertility as 100 mg ampicillin in 5 ml water. and hypolu- medical therapy and the risk is greater if the cervix is closed at teoidism. it is sometimes possible to pass a tomcat catheter through missed conception. They may result in a failure to mate. LH. teriological culture and an antibiogram. Additional adminis- tration of the progesterone receptor blocker aglepristone.41: treatment.93 The combination of antibiotics. observed mainly at the onset of PGF2a therapy. (2) anatomical abnormalities. or premature termination of pregnancy the cervix in order to deposit a water-soluble antibiotic. as opposed to that for medical treat. the reproductive cycle. and PGF2a may further improve the results of Figure 7. and 15 improves the outcome. or (4) in- next estrous cycle. Side ef. 8 10. hyperpnea. a tion. The length of estrus is usually ment of severe CEH in the elderly bitch. In cats the prognosis nine days but may range from three to 21 days. as three to as many as 17 days. many cats estrus is usually synchronous with the preovulatory LH surge. In addi. Endometri. and pupillary dilatation within minutes after problems administration.40: Vaginal septum between the vestibule and the 7 vagina in a bitch. 7. tis in the bitch after a mismating treatment with estrogens has the length of proestrus is usually nine days. Estrus problems are the result of inappropriate management of the generally follows soon after completion of the treatment. Prostaglandins may be administered as the PGF2a The optimal time of mating related to plasma concentrations of estradiol.12 Fertility disorders in the bitch fects. observed during anestrus.3). Moreover. with normal fertility and 81 of 104 (78 %) of those with sub- ment of plasma progesterone and vaginoscopy. thereby ex- breeding a bitch on a standard day in the cycle will usually ceeding 16 nmol/l. By determining the optimal time for therefore of the utmost importance. 7.42: Plasma concentrations of LH and progesterone during the periovulatory period (LH surge at time = 0) in two bitches: Lower panel: six-year-old beagle. Also note the bifurcated LH surges. pregnancy was achieved in 105 of 112 (94 %) bitches optimal time for mating. plasma progesterone concentration remains stable for three days. The primary methods are measure. some tration increases slightly at the time of the preovulatory LH bitches never exhibit estrus behavior. Determination of the ovulation period is requires at least 7 h. The concen- . Hence it is clear that surge and then rapidly at the onset of ovulation.)2 late as four to five days after the LH surge. The ovulation period can be defined satisfactorily by thrice- weekly measurements of plasma progesterone. Several methods have mating using a rapid radioimmunoassay for plasma progeste- been described to determine the ovulation period and the rone. 2006.. (Modified from De Gier et al.95 In the latter group only 23 % of previous matings had been successful. optimal fertility. but some bitches will still be bred too early ration of the oocytes and capacitation of the sperm. after the initial increase.41) and is based on the time needed for matu- give better results. The latter and others too late. Fertility disorders in the bitch due to breeding management problems 229 7 Figure 7. The optimal time for mating begins 24 h give poor results. Breeding according to estrus behavior will later (fig. plasma progesterone concentration in- creases markedly within 24 h. Upper panel: five-year- old beagle. DJAJADININGRAT-LAANEN 7. J Reprod Fertil trous cycle and anestrus in beagle bitches. Secretion of growth hormone and prolactin during progression of the luteal phase in healthy dogs: 5. ing the luteal phase and mid-anoestrus in beagle bitches. SCHOE. During the noassays for determination of the plasma LH concentration transition from estrus to metestrus the percentage of round are not yet available. progressing proestrus-estrus. DIELEMAN SJ. However.2. KOOISTRA HS. The urogenital system.97 7 and are therefore secondary changes. but because both pre-ovulatory follicles and post- mating the ovulation period. KOOISTRA HS. CONCANNON PW. an able. inexperience. VERSTEGEN JP. KOOISTRA HS. lifespan of the corpus luteum in the cyclic dog. 1346–1359. THOU. BEVERS MM. Vaginoscopy can also be used to attempt to determine preferably twice a day. progesterone. OKKENS AC. or the owner (inexperi- ence). REYNAUD K. J Reprod Fertil ing hormone. the corpus luteum in the cyclc dog. OKKENS AC. OKKENS AC. BEVERS MM. ONCLIN K. With due regard for possible hereditary consequences. CHEBROUT M. but in-hospital ELISA LH kits are avail. POPP- SNIJDERS C. Theriogenology 2002. WILLEMSE AH. but dog. In: 6. some bitches will refuse method for estimating the ovulation period than measuring the dog or other mating problems may arise.7:169–173. Reproduction 2005.1).167–172. VIARIS DE LESEGNO C. 3. WILLEMSE AH. are especially prone to mating problems. Theriogenology 2006. Hence the use of vaginal cytology is not suit- the preovulatory LH surge. prolactin and alpha. . CHRISTENSEN GC. however. progesterone and prolactin during pregnancy.57:1957–1972. Concurrent pulsatile secretion of luteinizing hormone lated changes in canine luteal regulation: in vivo effects of LH on and follicle-stimulating hormone during different phases of the es. BEVERS MM. vaginal abnormalities). EVANS HE.42). MARSELOO N. There are. FONTBONNE A. Biol Reprod 1999. Pulsatile secretion pattern of growth hormone dur- MIRE S. Influence of hypophysectomy on the plasma concentrations of luteinizing hormone. DIELEMAN SJ. KOOISTRA HS. Vet Quart 1990. Some breeds. estradiol-17b. WILLEMSE AH. OKKENS AC. RIJNBERK A. J Reprod TANT-MAILLARD S. More importantly. 7. ONCLIN K. Mol Cell Endocrinol 2002. Vaginal cytology is very useful in diagnosing early proestrus. and early embryonic development in the bitch. Interpretation of the changes is also subjective. DIELEMAN SJ. ral problems. 230 Ovaries Determining the preovulatory LH surge would also be suit. However. or metestrus (chapter 7. For the experienced veterinarian it is a such as English and French bulldogs and the Newfoundland useful tool for monitoring the stages of the estrous cycle. 1986. more frequent blood sampling would be early metestrus smear can easily be confused with an early required than for progesterone because of the risk of missing proestrus smear. OKKENS AC. a review. References 1. ovulatory corpora lutea have cavities. follicle-stimulat.197. 9.2.118:417–424. The cause of mating advice based on vaginoscopy should include the the mating problem can be related to the dog (abnormal anat- recommendation to mate at least twice. Evidence for prolactin as the main luteotrophic factor in the cyclic dog. 4. BEVERS MM.119:217–222. VAN HAAFTEN B. the time able for determining the appropriate period for mating the between the preovulatory LH surge and the rapid rise in bitch. with an interval of omy. DIELEMAN SJ. Rapid radioimmu. Vet Quart 1985. Comparisons of es. no reliable changes in the smear indica- able for estimating the time of ovulation. OKKENS AC. LH and FSH patterns in pregnant and non-pregnant beagle bitches. Temporal relations between AAME. Evans HE. 65–71. Vaginoscopy is thus a less reliable In spite of correctly timed breeding. behavioral problems). ovulatory. 11. DIELEMAN SJ. In vivo meiotic resumption. This method appears to be less practi- the ovulation period (chapter 7. DE GIER J. The mucosal changes cal than detection of ovulation via determination of the are. Philadelphia: Evidence for the non-involvement of the uterus in the lifespan of WB Saunders 1993:531–540.130:193–201.1). mination. however.65: 8. MOL JA.96. 10. fertilization Fertil 2000. DEN HERTOG E. ed. Miller’s Anatomy of the dog. 2.12:193–201. the bitch (behavio- 48 h. LUBBERINK SC. tradiol.77:187–192. cells increases rapidly and leukocytes reappear. CHAS. plasma progesterone. Hence plasma Also ultrasonography can be used for ovulation deter- progesterone concentration is the preferred variable for esti. tive of the preovulatory LH surge or of ovulation. artificial insemination can be used.60: 2000. MURPHY B. and early luteal phase in the bitch. examination must be performed by experienced persons with excellent equipment. a response to hormone-controlled alterations plasma progesterone concentration. Time-re- MAKER J. 3rd ed. OKKENS AC. VERSTEGEN JP. plasma progesterone concentration (indicating ovulation and formation of corpora lutea) varies (fig. melanocyte-stimulating hormone during the follicular. KAUR S. 16. MOL JA. KUMAGAI D. TEUNISSEN JM. Concentrations of reproductive hormones in canine serum throughout late anestrus. 28. 34. NETT TM. Neurosci Letters 2002. Suppl 51:393–344. Am J Vet Res 1983. J Reprod Fertil 1994. Suppl 51:295–301.69:399–407. BEIJERINK NJ. J Reprod Fertil 1997. OKKENS AC. 22. FSH secretion pat. Pro. Biol Reprod 21. SCHOE. 35. 24.67:215–225. Domest Anim Endocrinol 2007. BOWEN RA. SELMAN PJ.101:221–225. BHATTI SFM. VERSTEGEN JP. COLAGIURI S. SAWADA T. MATSUYAMA S. VAN SLUIJS FJ. TORII 2002:57–64. MILLER JC. INABA T. MORI J. size and breed on the duration of gestation in dogs. Strengholt. The. riogenology 2003.207:1–4.117:387–393. DIELEMAN SJ. Enhancement of es- like growth factor I and glucose homeostasis. OOS- TERLAKEN-DIJKSTERHUIS MA. WILLEMSE AH. Theriogenol- ogy 1999. De geboorte bij de hond en zijn wilde verwanten. Increasing gonadotropin-releasing hormone release by perifused hypothalamus form early to late anestrus in the beagle bitch. SUTHERLAND RL. trogen receptor gene expression in the beagle bitch. DIELEMAN SJ.210:96–106. TAKA- SNIJDERS C. References 231 12. OKKENS AC. STRA HS. OKKENS AC. J Reprod SUGIURA K. TSHA. VAN OSCH W. NAAKTGEBOREN C. MOL JA. Naarden. HAZE. controls mammary gland development via direct and indirect Shortening of the interoestrous interval and the lifespan of the cor- mechanisms. SAWADA T. In- MAKER J. POPP. SAWADA T. ONCLIN K. the bitch. Biology of gonadotrophin secretion in adult ghan hounds and the effect of metergoline. The carnivore connection: dietary bitches. Suppl 51:55–58. 23. TAKAMOR Y. TORII R. BEHRENDT MD. Neur. Prolactin dis- MALA M. MOL JA. J Reprod Fertil 1997. SCHOENMAKERS I. VAN NECK JW. OKKENS AC. MOL JA. TAKANO H. TAVERNE MAM. J Reprod Fertil 2001. Hormonal changes does not affect the pattern of pulsatile secretion of follicle-stimulat- in spontaneous and aglepristone-induced parturition in dogs. insulin. VAN HAAFTEN B. KOOISTRA HS. DIELEMAN SJ. proestrus and estrus. KAWATE N. TORII R. carbohydrate in the evolution of NIDDM. KOOISTRA HS. DIELEMAN SJ. 36. centration in mammary secretions and plasma of the periparturient bitch and in plasma of the neonate. Suppl 51: 33.44:1819–1821. lin-like growth factor (IGF) and IGF-binding proteins in the nor. KOOI. Suppl 47:3–27.37: 1280–1286. WEIJDEN GC. pression in the mediobasal hypothalamus during anestrus in the beagle bitch. BEVERS MM. Dev Biol 1999. R. VAN DEN INGH TSGAM. pus luteum of the cyclic dog by bromocriptine treatment.333:107–110. J Reprod Fertil 2001. J Reprod Fertil 1997. KOOISTRA HS. 1982. SELMAN PJ. Low doses of bromocriptine shorten the interoestrous interval 20. DIELEMAN SJ. 27:1196–1206. and prepubertal female dogs.33:294–312.60:1379–1386. KOOISTRA HS. BEIJERINK NJ. OKKENS 14. DIELEMAN SJ. INABA T. NONAMI M.7:173–176. KIN. Canine osci Letters 1996. 363–367. BEVERS MM. BRISKEN C. orders. WUINTERO CH. WEINBERG RA. TAMADA H.131:413–421. TORII R. Fertil Steril 1997. OKKENS AC. KOOISTRA HS. VAN DEN Increasing sensitivity of the pituitary to GnRH from early to late BROM WE. WILLEMSE AH. TANI H. TAVERNE MAM. OKKENS AC. Serotonin-antagonist-induced lowering of prolactin secretion DAHL H. .128:181–188. J Reprod Fertil 1993. DIELEMAN SJ. TANI H. I. INABA T. gestation length: Variation related to time of mating and fertile life of sperm. Suppl 57:193–197. Reproduction riogenology 2008. MATSUYAMA S. KAWATA N. SAWADA T. KOOISTRA HS. DUCATELLE R. AC. Vet Quart 1985. YAZIGI RA. Dopamine agonistic effects as opposed to prolactin concentrations in plasma as the influencing factor on the duration of anoestrus in 19. terns during pregnant and nonpregnant luteal periods and 24 h se- cretion patterns in male and female dogs. LAUWERS F. DE GIER J. 30. 2004. TANI H. 26. WISSLER R. SALAMEH WA. DIELEMAN SJ. VAN HAAFTEN B.227: 7 149–152. RUTTEMAN GR. RIJNBERK A. RAO NA. Diabetologia 1994. MORJ Y. insu. OKKENS AC. KELLY PA. WHALEY S. DIELEMAN SJ. LEIN D. TANI H. KOOISTRA HS. Influence of litter anoestrus in the beagle bitch. 13. CHAVARRIA TE. 18. gestin treatment in the dog. RIJNBERK A. VAN DE BROM WE. BEVERS MM. CONCANNON P. BEVERS MM. CORYN M. 32. Plasma concentrations of prolactin in overtly pseudopregnant Af. Neurosci Letters 1997. OLSON PN. Prolactin 29. OLSON JD. HATOYA S. Bromocriptine-induced premature oestrus is associated creased LH pulse frequency and estrogen secretion associated with with changes in the pulsatile secretion pattern of follicle-stimulating termination of anestrus followed by enhancement of uterine es- hormone in beagle bitches J Reprod Fertil 1999. BEVERS MM. 25. TAMADA H. BAAN M. BINART N. OKKENS AC. Eur J Endocrinol 1994. VAN HAM LM. Role for progestins-induced mammary-derived growth hormone in the pathogenesis of cystic endometrial hyperplasia in 31. in the bitch without lowering plasma prolactin concentration. OKKENS AC. Enhancement of aromatase gene ex- Fertil 1997. ing hormone and luteinizing hormone in the bitch. TAMADA H. The- WINKEL HAW. Seventh revised edition.52:593–607. 15. KOOISTRA HS. The role of progestins. Growth hormone con. BEVERS MM. VAN DER Suppl 57:15–21. Effects on growth hormone. INABA T. NAMURA T. SPRANG EP. TAMADA H. OKKENS AC. 27. DUCHA- TEAU L. MATSUYAMA S. CONCANNON PW. trogen receptor gene expression in the mediobasal hypothalamus during anestrus in the beagle bitch. the Netherlands. mal and neoplastic mammary gland of the bitch: a review. 17. 71–77. J Vet Intern Med 2002.202: 1855–1858. using low dose oestradiol benzoate. OKKENS AC. CONCANNON PW. OKKENS AC. BUTLER WR. of mid-term pregnancy in the dog with oral RU 486. pregnancy in bitches following unwanted mating: a clinical trial pects of pregnancy and parturition in dogs. NYLAND TG. BEVERS MM. GALAC S. Induction of parturition in the abortifacient in a bitch. DIELEMAN SJ. ONCLIN K. DELAHAUT P. MADEJ A. gesterone. Effects of aglepristone.43:813–822. 64. BERGMAN JGHE. administered during the early luteal phase in non-pregnant nipulation on ovarian activity and melatonin and prolactin secretion bitches. Termination of mid-gestation pregnancy in bitches with aglepristone. MARTAL J. SILVA LD. FRANK DA.33:331–336. 48. Prevention of WURTH Y. Luteo. J Small Anim ferent photoperiods on plasma concentrations of melatonin. BERTHELOT X. GALAC S. LEFAY MP. VERHAGE HG. Suppl 39:125–133. Introduction of oestrus in cat by photoperiodic ma. TAINTURIER D. Physiological as. 60. 50. 61. STABENFELDT G. 54. a dopamine agonist. KOOISTRA HS. TAVERNE MAM. TAVERNE MAM. KINDAHL H. prostenol or alphaprostol. J Am Vet Med Assoc 1993. STABENFELDT GH. VAN OORD HA. . Biol Reprod with aglepristone. PAAPE SR. tion in dogs: effects of cabergoline. VERSTEGEN JP. RONSIN P. HUSTED PW.TOUZEAU N. Plasma levels rone receptor antagonist. prolac. Pract 1992. 49. 65. tagonist. BANKS DH. group-housed cats based on serum and faecal concentrations of progesterone. ONCLIN K. VERSTEGEN JP. either clo- agonist. KNIGHT PJ. Hormonal variation 44. DAELS P. bitch with the progesterone-receptor blocker aglepristone. BRUYAS JF. J Reprod Fertil 1993. trophic action of prolactin in dogs and the effects of a dopamine in combination with a synthetic analogue of PGF2alpha. Theriogenology 1995. DONNAY I. JÖCHLE W. Termination 45. Theriogenology 2007. KOOISTRA HS. Suppl 57:237–242. P. RIOU M. FIENI F. The effect of dif. ONCLIN K. WEHREND A. BRUYAS JF. 59. tin and cortisol in the domestic cat. ECTORS F.62:494–500. LEYVA H. TAINTURIER D. Parturition and lactation in the bitch: serum pro.28:923–932. 47. 55.63:1958–1972. monly used to terminate canine pregnancy. 62. 52. Prostaglandins HAMILTON JM. Effect of light ma. FELDMAN EC. KOOISTRA HS. SILIART B. DAVIDSON AP. Fertil 1997. SILIART B. VAN DER WEYDEN GC. Lab Anim 1993. cortisol and prolactin. riogenology 2006. Efficacy and toxicity of estrogens com. Theriogenology 2000. Incidence of spontaneous ovulation in young. In vivo investigation of luteal func- CURRIE WB. BEVERS MM. DIELEMAN SJ. NELSON RW. KUTZLER MA.115: 1729–1736. ONCLIN K.53:941–950. FIENI F. preg- nancy and pseudo-pregnancy. BRENNER RM. J Reprod Fertil 2001. BAAN M. Treatment of fibroadenomatous hyperplasia in cats cat: I Pseudopregnancy. J Reprod Fertil 1989. VERSTEGEN JP. placenta and prolactin secretion. J Am Vet Med Assoc BRUYAS JF. Mestranol as an DIELEMAN SJ. Estrus induction and synchronization in canids 56. SILVA LDM.14-dihydro-15-keto. Reflex LH release in after early or mid-pregnancy termination in bitches with agle- estrous cats following single and multiple copulations. CONCANNON PW. CONCANNON chienne: l’aglepristone. cabergoline. LAMOND DR. Suppl 43:403–409. SILVA LDM. 232 Ovaries 37. KOOISTRA HS. GÖRLINGER S. Suppl 47:165–173. ANDERSEN AC. WHEELER SL. MICHEL FJ. SUTTON DJ. GEORGIEV P.84: Domest Anim Endocrinol 1997. OKKENS AC. The- riogenology 2005. and felids. Theriogenology 2004.68:354–374. a progesterone receptor an- 46. 239–243. cabergoline.14:25–38.14:579–585. BEHRENDT MC. The- lutea. LEYVA H. BOWEN RA. CONCANNON PW. J Reprod 57.27:278–280. GEARY MR. Biol Reprod 1976. TAINTURIER D.16:710–713. HANSEL W. NEWTON L. hypothermia and abortion in beagle bitches. LINDE-FORSBERG C. pregnancy and lactation. RACHAIL M. Rec Med Vet 1996. 1983. GUNDERMUTH DF. J Reprod Fertil 2001. Suppl 51:177–184. ADDIEGO L. Prolactin in the OKKENS AC. DE GIER J. DIELEMAN SJ. with a progesterone antagonist aglepristone (RU534) to induce par- turition in bitches.186:783–788. 51. Suppl 51: Suppl 39:211–224. 63.23:111–117. 1980.172:359–367. MUNRO C. VERSTEGEN JP. J Reprod Fertil 1993. Theriogenology 1975. BUTINAR J. Mid-gestation pregnancy termi- rone during pregnancy in the cat: studies on the roles of corpora nation by the progesterone antagonist aglepristone in queens.65:1401–1406. Etude clinique d’une anti-hormone pour provoquer l’àvortement chez la 42.Suppl 57:243–248. LEIN D. CESTNIK V. Termination of un- 40. and prolac- prostaglandin F-2a in maternal plasma during prepartum luteolysis tin on progesterone secretion during mid-pregnancy and -diestrus. Prostaglandin F2a induce lu- 39. MARNET PG. BEAMER NB. BERNARD F. 1977. Biol Reprod 1978. 7 41. of estradiol and progesterone in the cat during poly-estrus.13:533–542. HANSEL W. Endocrinology 1984. J Reprod Fertil 1997. Comparison of two protocols 1985. Regulation of progeste.19:1113–1118. MARTAL J. Elevated concentrations of 13. NETT TM. teolysis. a progeste- 43. HOGSON B.4:1–9. WOUTERS- BALMAN P. VAN DE BROEK A. STABENFELDT GH. J Reprod Fertil 1988. FIÉNI F. in the domestic cat. 38. 53. Prostaglandin induction of abortion in pregnant nipulations and social stimuli. ISAMAN L. bitches after misalliance. MICHEL C. OLSON PN. and parturition in dogs (Canis familiaris). J Reprod Fertil 1989. Biol Reprod pristone (RU534). BADINAND F. 58. MADLEY T. VOORHOUT G. MARNET PG. wanted pregnancy in dogs with the dopamine agonist. CONCANNON PW. 64:213–219. NAKAGAWA A. BHATTI SFM. GALAC S.116:73–80. Theriogenology 2006. 2e ed.125 (Suppl 1):27–31. J Vet Med 2003. luteinizing hormone and follicle-stimulating hormone secretion in female dogs. and gonadal endocrine function in dogs. Oophoritis in a dog with abnormal corpus luteum function. CONCAN- NON PW. Vet Rec 1991. insulin. Progestagens and mammary gland develop- bil E. 1997. SCHAEFERS-OKKENS AC. HOUPT KA. 85. MIDDLETON DJ. OKKENS AC.50:375–379. Am J Vet Res 1985. J Reprod Fertil 1989. TAMADA H. NICKEL RF. glucose. THOMPSON FN. CATERSON ID. cats. Canad J Vet Res 1987. In: Textbook of Veterin. 75. KIMBALL M. WILLEMSE AH. 78. Suppression of cortisol responses to exogenous adrenocortico- trophic hormone. Philadelphia U. BOSTEDT H. WATSON ADJ. BEIJERINK NJ. DUCHATEAU L. SILVA L. DIELEMAN SJ. eds. given short-term therapies of prednisolone and megestrol acetate.A. Treatment of growth hormone 1997. 3rd edition. and the occurence of side effects attributable to 74. genology 2007. BEIJERINK NJ. 72. Am J Vet Res 2004. J Am Vet Med Assoc LARSEN NH. 77. SAWADA T. OKKENS AC. J Am Vet Med Assoc 1965. KOOISTRA HS. GONDA M. Rijnberk A. GOODPASTURE JC. Treatment with a sub- cutaneous GnRH agonist containing controlled release device re- 68.. SPAIN CV. DIELEMAN SJ. WEHREND A.39:175–187. CONCANNON P. SANDERS NETT TM. BOWEN RA. 76. SJ Ettinger. Neill JD. induction of oestrus and fertile ovulations in response to pulsatile administration of GnRH to anoestrous dogs. RIVIÈRE-GODET E.66: NELL JF. CONCANNON P. RUBION S. 84. OKKENS AC. ment: Differentiation versus carcinogenesis. OKKENS AC. VERSTEGEN J. TORII R. JOHNSTON SD. Acta Endocrinol 1991. MIS. Induction of oestrus and ovulation in dogs by treatment with PMSG and bromocriptine. LM. In: The Physiology of Reproduction. MORI J. WB Saunders pregnancy termination in dogs. Acta Endocrinol 1987. versibly prevents puberty in bitches. VAN HAM cycles in dogs by administration of purified pig LH. of fertile estrus in bitches using a sustained-release formulation of a GnRH agonist (leuprolide acetate). KOOISTRA HS. INABA T. MUN. 421–425. Theriogenology 2006. in cats during therapy with megestrol acetate M. Pathogenesis of renal damage and polydipsia in dogs Suppl 39:330–331. VANDERLIP S. CHAKRABORTY PK.111:35–40. HOWE CJ. J Reprod Fertil 87. 82. BHATTI SFM.125 (Suppl 1):32–37. DUCHATEAU L. Ef- 70. with pyometra. MCCANN JP.49: 88. ONCLIN K. Follicular steroido- genesis and its control. BEVERS MM. Acta Endocrinol 1991. to osmotic stimulation and effects of desmopressin on urinary con- centrating capacity in dogs with pyometra. KINZIGER M. RUSSO J. LASLEY B. Long-term risks and 92. eds. ations of bitches after conservative treatment of pyometra with the DORP W. ARMSTRONG DT. luteinizing 69. Theriogenology 1998. Glucose intolerance in cats 975–982. J. Theriogenology 73. Follow-up examin- 80. OHMURA glucocorticoid excess.66:797–803. HEIENE R. J Reprod Fertil 1989. VAN VONDEREN IK. KOOI- STRA HS. Clinical approach to infertility in bitches with hormone. 2008. Adenohypophyseal function in bitches treated with medroxy- progesterone acetate.65: 79. 7 71. Vasopressin secretion in response 2004. Growth hormone. RUTTEN F. 91. VAN HAAFTEN fects of contraceptive doses of the progestagen megestrol acetate on B. Therio. Ter- mination of obligate anoestrus and induction of fertile ovarian 89. 81. RUTTEMAN GR. Saunders/Elsevier. KEMPPAINEN RJ. 93. BHATTI SFM. Endocrinol 1983. TRASCH K. KOOISTRA HS. KOOISTRA HS. CONCANNON PW. KOOISTRA HS. BUIJTELS JJCWM.46:2623–2625. DRIANCOURT MA. GORE-LANGTON RE.32:63–78. RUSSO IH. References 233 66.51:60–65. BEIJERINK NJ. DESMOULINS PO. OLSON PN. VAN HAAFTEN B. HUSTED PW.67:1039–1045. In: Medical History and Physical Examination in Com. 67. Van Sluijs FJ. Effects of prednisone on thyroid 1651–1654. SCARLETT JM. WATSON ADJ. VAN HAM LM.Vet Clin North Am. Theriogenology 2005. Persistent estrus in the bitch. MOL JA. ed. Progestagens and mammary tumours in dogs and 404–408. Steroid receptors in mammary tumours of the cat.224:380–386. Induction and prednisolone. Acta antigestagen aglepristone. 2009. Domest Anim Endocrinol 2007. Female reproduc- tive tract. MINKE J. Small Anim Pract 1991. DUCHATEAU L. OKKENS AC. MOL JA.128:333–334. 1994. GÖRLINGER S. 83.S. Oxford: MOL JA. SALAVERT F. OKKENS AC. SIGOGNAULT A. COLON J. HANSEN B. Company. Basal and GnRH-induced secretion of 86. FLOCHLAY- Hypoluteoidism in a bitch.108–117. LORENZ MD. KOOISTRA HS. FSH and LH in anestrous versus ovariectomized bitches. J Reprod Fertil 1993. DIELEMAN SJ. Kno- 90. MOE L. MIDDLETON DJ. OKKENS AC.70:179–85. J Reprod Fertil LML. VICKERY BH.Suppl 51:41–54. excess in dogs with the progesterone receptor antagonist agle- pristone. ALTSZULER N. TANI H. Use of potent LHRH analogues for chronic contraception and ary Internal Medicine.147:736–745. VAN DE GAAG I. New York: Raven Press. LH release. Pulsatile plasma profiles of FSH and LH before and during me- droxyprogesterone acetate treatment in the bitch. MCRAE GI. Endocrinol 1991. and diabetes in beagle bitches treated with medroxypro- primary anestrus. HAMPSHIRE J.96: 293–302. MISDORP W. benefits of early-age gonadectomy in dogs. BLANKENSTEIN MA. VAN HAM LM. DIELEMAN SJ.21: gesterone acetate. 1989:1793–1796. panion Animals. MOLMEN GS. Suppl 47:519–521..125 (Suppl 1):7–12. ÅSHEIM Å. . WRIGLEY RH. cortisol. HAYER P. VAN HAAFTEN B. CASTEX G. 234 Ovaries 94. VERSTEGEN JP. OKKENS AC. and the early luteal phase in the bitch. HOPPEN HO. ONCLIN K. DIELEMAN SJ. GÜNZEL-APEL AR. 96. laparo- and cloprostenol to treat open cervix pyometra in the bitch. Vet Rec 1989. A study of two protocols combining aglepristone ian changes around ovulation in bitches by ultrasonography. RODRÍGUEZ R. GOBELLO C. ovulation concentration. Vet Radiol Ultrasound 1996. scopy and hormonal assays. J Reprod Fertil 1993.60:901–908. 7 . SILVA LDM. AH. The. WILLEMSE 97. Timing the mating of dogs on the basis of blood progesterone Ultrasonographic monitoring of follicular development.37: riogenology 2003. 95. LÜSSEN D. Assessment of ovar- CORRADA Y. KLIMA L. Suppl 47:93–100. 313–320.125:524–526. sp = spermatogonia. which is Sertoli cells. For are transformed into spermatozoa.1: Cross section of a seminiferous tubule in the dog. Lc = Leydig cells. van Sluijs 8. togenesis. bv = blood vessel ([A] schematic. (2) the insure proper conditions for germ cell development in the meiotic phase. which line the seminiferous tubules. their long axis directed caudodorsally. while peptide hormones (including the gonado- the seminiferous tubules. (Courtesy of Dr. Seminiferous tubules are the site of membranes of adjacent Sertoli cells form specialized junc- spermatogenesis. They are composed of supporting cells and sperma.1 Introduction testes. spt = spermatids. In the basal region of the seminiferous epithelium the plasma togenic cells (fig.1 tropins) are generally excluded. Halsema. drawing by H. while others are almost completely excluded. 8. They border of the testis and consists of a head. K. in which spermatids aneously.) . Sertoli cell barrier. or secreted into the tubular lumina are retained there by the togenesis nor a change in tubular diameter in healthy canine barrier and probably do not function as endocrine factors A B Figure 8. Peptide hormones produced With increasing age there is neither deterioration in sperma. Androgens and the ductus deferens. x475). where spermatogonia develop into tional complexes which constitute the structural basis of the spermatozoa. in which spermatocytes develop. the spermatozoa are released into the lumen of entry rates.. Sc = Sertoli cells. In the cat the testes are located closer to androgen receptors are essential for maintenance of sperma- the anus and their long axis is directed caudoventrally. in which undifferentiated spermatogonia previously known as the blood-testis barrier. and tail. pt = peritubular cells. aged dogs often have testicular tumors which affect spermatogenesis and are often not clinically detectable. is probably to undergo rapid cell multiplication by mitotic divisions. [B] PAS-hematoxylin stain. have an im- relatively large in dogs. The express androgen receptors and receptors for follicle-stimulat- head arises from the testis cranially and is the thickest part. is attached along the dorsolateral portant supportive function during spermatogenesis. whereas males are still fertile without the influence of FSH.2 In the dog the testes lie obliquely within the scrotum. The primary function of this barrier. spc = spermatocytes. This occurs in three distinct phases: (1) the pro.e. spz = spermatozoa. example. body. 235 8 Testes Jeffrey de Gier Frederik J. of the germ cells via the synthesis and secretion of molecules tached to the caudal end of the testis and is continuous with which act upon the surrounding germ cells. i. Teerds.J. The epididymis. However. testosterone and glucose appear to have accelerated matogenesis.1). and (3) the tubules. Some molecules enter the tubules nearly instant- differentiation phase or spermiogenesis. 3 8 Tubules with seminiferous epithelium make up about 80 % of the testis. liferation phase. After completion of sper. a process referred to as spermiation. ing hormone (FSH) and are thought to regulate development The body or middle part is slightly smaller and the tail is at. 2: Schematic illustration of the conversion of testosterone to dihydrotestosterone and estradiol. The conversion is protein. . Sertoli cells also produce androgen-binding which has a higher affinity for the receptor.3. lymph. outside the testis. 4. and anti- the mitochondria to pregnenolone. prostate.3: 씰 Endocrine control of testicular function. disulphide-linked sub- dig cells. many effects are exerted after its conversion to dihydrotestosterone. 8. Spermatogenesis is controlled by FSH. with feedback from inhibin. They are the main constituent of the endocrine peripheral contribution to total estradiol production appears portion of the testis and produce the androgens that drive the to be large (of the order of 75–80 %) as compared to the tes- spermatogenic process. units termed a and either bA or bB. activin. Like other steroid hor. Testosterone is converted to dihydrotestosterone in several target tissues. which are stimulated by luteinizing hormone (LH). 236 Testes Figure 8. shares a sequence homology with members of the transform- mones it is produced from cholesterol. The b subunit of inhibin The primary androgen is testosterone. which is required to maintain the high concen. 8 Figure 8.4 testes. and bone. catalyzed by 5a-reductase and aromatase. trations of testosterone in the tubular compartment needed which is not present in the tubular compartment of the for spermatogenesis.1.3 The Leydig cells.4 ticular contribution. Pregnenolone is further Müllerian hormone (AMH).4 Testosterone can also be converted to estradiol by the aromatizing enzyme system that is present in mammalian Between the seminiferous tubules lie groups of interstitial or testes as well as in adipose tissue. Apart from direct interaction of testosterone with the androgen receptor. Blood is quantitatively the most important effluent system because the flow rate is 20 times that of lymph or tubular fluid. effected by an NADPH-dependent 5a-reductase (fig. and tubular fluid. Androgen secretion is regulated by LH. which is converted in ing growth factor b family such as TGFb. 8. with feedback from testosterone (T2). respectively.2). It consists of two dissimilar. 8.3). Testicular steroids are secreted into blood.1 Hormone synthesis and secretion Another hormone secreted by the testis is inhibin. (fig.3). a glyco- The main hormones secreted by the testes are androgens and protein hormone produced primarily by the Sertoli cells estrogens. Androgens are produced by the interstitial or Ley. metabolized outside the mitochondria to several other ste- roids via various pathways (see also fig. Male hypogonadism refers to all forms of endocrine and secretory hypofunction of the testes. An- drogen secretion is regulated by LH and spermatogenesis is The ultimate form of primary hypogonadism is that resulting controlled by FSH and locally produced androgens (fig. Primary hypogonadism – to low values for prolonged periods of time (fig. androgens mainly act as paracrine agonists. The behavior of most sexually intact Diurnal rhythmicity has been described. gonadism.4: Plasma concentrations of LH and testosterone in a dog after administration on day 0 of an implant that slowly releases the GnRH agonist deslorelin. 8. low concentrations of gonadotropins due to a pituitary lated by the frequency of GnRH pulses from the hypothala. internalization.2 Regulation of testis function In rare cases it may be due to a chromosomal defect. The same holds true for corticosteroids. These causes plasma LH gonadotropic hypogonadism. such as endo.12 The high plasma androgen concentration sup- directly the process of spermatogenesis. endogenous and exogenous corticosteroids reduce the plasma Together with other locally produced factors.8 presses pituitary gonadotropin secretion and consequently testicular testosterone secretion.XXY karyotype (chapter 6. Because the testosterone concentration in testicular tissue is normally much higher (25–100×) than in plasma. from castration.10 the morning and peak levels in the afternoon (LH) or evening (testosterone). trauma. tumor. Isolated gonadotropin deficiency has not yet been de- mus. as a consequence of synthesis and secretion of LH and FSH are differentially regu.2 Hypogonadism tosterone concentration will become too low to stimulate tes- ticular function.7 inhibit gonadotropin secretion. Antiandrogens such as cyproterone back control by testosterone.11 Administration of supraphysiological genous opioids and proteins produced by the peritubular cells doses of androgens also results in hypogonadotropic hypo- (P-Mod-S). scribed in dogs or cats. LH concentration. In addition. pituitary FSH acetate may act as progestagens and their therapeutic use may secretion is inhibited specifically by inhibin. as testosterone is vital for plasma concentrations of gonadotropins – may result from spermatogenesis. LH pulses household. they regulate Sertoli cell function and thereby in.15 .6 FSH is also secreted in a pulsatile fashion.9 Testicular function is controlled by the gonadotropins. coupling after sustained exposure to the GnRH analogue. the urban or rural location of the frequency of approximately 4. Both Within the testis.2.3). such as in 8 male tricolor cats with a 39.13–15 This opposite effect is due to GnRH- many diseases. although its prevalence varies markedly from country to country. 8. GnRH-agonists. 8. and testosterone concentrations to first rise and then decline gonadotropic hypogonadism.1). de- LH is secreted by the hypophysis in a pulsatile pattern with a pending on cultural factors. Pituitary LH and FSH secretion are under negative feed. and testicular torsion. Two forms pogonadism in dogs is the use of implants of slow-release of hypogonadism are recognized: (1) primary or hyper.4. result- atrophy of the testes in the presence of normal or increased ing in temporary loss of fertility. with lowest levels in male cats makes them undesirable as pets. The term hypogenital. and (2) secondary or hypo. Hypogonadism 237 Figure 8.5 castrated than male dogs. with reversible secondary hy- pogonadism.4). such as orchitis of either infectious (Brucella receptor down-regulation. the LH-dependent testicular tes- 8. and the species: male cats are more likely to be are usually followed by a testosterone pulse within 60 min.5 pulses every 6 h. such as deslorelin. and signal un- canis) or autoimmune etiology. A more recently introduced iatrogenic cause of secondary hy- ism is used for underdeveloped external genitalia. but Secondary hypogonadism occurs rarely. It is very common in dogs and cats.1. Gonadectomy leads to a slightly increased occurrence ectomy.27.25. The consequences of increased appetite. of injuries of the anterior cruciate ligament. it concentration. characteristics. 238 Testes Figure 8. Regardless of gender. i.e. although roaming as well as aggressive behavior toward other males. tropin concentrations also affect the biology of collagen and have been reported to be associated with prepubertal gonad.7 and table 9.28 Decreased plasma an- Gonadectomy is often carried out before the cat reaches pu.10.29 but not to the extent that it leads to clinically delays that closure and leads to significant. intake. 8.. leptin. The A B typical barbs on the penis of the intact male are absent in the castrated male. there is a larger proportion of collagen in gonadectomized dogs than in intact dogs. neutered males.4 and 11. most completely by treatment with estradiol.10). spontaneous femoral capital physeal Sex steroid deprivation and persistently high plasma gonado- fractures. hypogenitalism.30 It also alters the weight. Affected tomcats do not have a typical feline masculine appearance and the prepuce In male dogs gonadectomy does not result in hyperprolac- and penis remain underdeveloped.27 Gonadectomy does not gen- affects male behavior. but LH concentrations are high because of the ab- that are typical of male felidae (fig.5: Penis of an intact (A) and castrated (B) tomcat.19–22 The vast majority of the affected cats were over. 8 Clinical manifestations With time the main changes after gonadectomy seem to be Testis atrophy is characterized by small and soft testes. and body fat mass can be prevented al- ing GnRH agonists also induces transient testicular atrophy. and prolactin.16 slight differences have been found between gonadectomized and intact dogs in some test results. Hypogonadism also sence of androgen feedback.5).23. which is con- which can be used clinically to assess the duration of action of sistent with studies in rodents demonstrating the importance an implant.26 If testis atrophy occurs at an early age the androgen defi. but in contrast to female dogs (chapter 7. in cats leading to in- atrophy does not affect the epididymis. body weight. with histological signs of necrosis of the epiphysis. . drogen concentration following gonadectomy in dogs is ac- berty and initially leads to no serious physical or behavioral companied by loss of bone volume and increased plasma PTH problems. muscle. The penis lacks the barbs tinemia.2. which is relatively creased body weight and increased plasma concentrations of large and firm in comparison with the adjacent testis. lessening the tendency to marking and erally affect thyroid or adrenocortical function.17 When performed prior to physeal closure. lengthening of long bones (see also chapter 9. The possible clinical consequences of overweight are covered ciency may result in underdevelopment of secondary sexual in chapters 5.24 The increase in food ondary reversible hypogonadism induced by implants releas.18 In cats. male dogs rarely develop neutering-induced urinary incontinence.2). proportion of collagen and muscle fibers along the lower uri- nary tract. although not noticeable problems. readily visible. insulin. Sec. IGF-I.31 The resulting decrease in tissue elasticity has an adverse effect on the collecting phase of micturition and on bladder contrac- tion. of gonadal estrogen in increasing the satiating potency of cholecystokinin released in response to ingested lipid. The incidence of cryptorchidism in the cat has been re- Prognosis ported to vary from 1. transmission of the defect is probably due to Their size can be measured with calipers (fig. Maltese. The reported incidence in dogs varies from 1. Normal testicular descent can be divided into three phases: ease (chapter 2. been investigated in long-term studies.35 A retrospective study36 has usually been elected by the owner and requires no treat. 8. Yorkshire terrier.5 × 1.2.7 % to 3.3 Cryptorchidism Hypogonadism (including the result of castration) should be differentiated from cryptorchidism.34 depending on the population studied.5) indicates secretion of androgens by testicular Leydig to 9.6) or esti.7). 8 Differential diagnosis 8. The prognosis in second- ary hypogonadism depends on the course of the primary dis. replacement can be given lifelong.8 %.5 × 2 cm in toy breeds to 3 × 3 × 5 cm in mal allele. This requires large numbers of puppies and makes the condition difficult to Treatment eliminate from a canine population. the genotype of the carrier fe- imately 1 cm. can only be detected in males. Cryptorchidism has been The most frequent cause of hypogonadism is castration. In tomcats the presence of barbs on the penis scrotum. . Diagnosis Although a single autosomal recessive allele has been cited as a The consistency of the testes is determined by palpation. excluding the epididymis.37.35 Cryptorchidism occurs more often in test (chapter 12. In the dog the homozygous for the defect and their removal from the breed- dimensions of the testes depend on the body mass. 8.7 %. probable cause. androgen replacement therapy may be given. is esti- mated by comparison with the ellipsoids.2 % (fig. Because cryptorchidism is a sex-limited trait that large breeds. Pekingese.7: Calipers for measuring testicular size.1). Cryptorchid dogs are considered to be mated with Prader’s orchidometer (fig. The miniature dachshund. Chihuahua. This found in at least 68 canine breeds. requested. and Shetland sheep- dog. more than one gene. Cairn terrier. The volume of the testis.5. miniature schnauzer. purebred than in crossbred dogs and bilateral cryptorchid dogs are reported to be more inbred than unilateral cryptorchids. English bulldog. Pomeranian. The presence of an endocrinologically functional testis congenital disease and is considered to be a sex-limited can be demonstrated unequivocally by a GnRH-stimulation inherited trait in dogs. treatment of obese orchiectomized cats with estradiol has not boxer.33.38 Persian cats were Primary hypogonadism is usually incurable but testosterone overrepresented in both studies. whose size is marked in ml. of 2912 dogs identified 14 breeds with a significantly in- ment.32 They ing line generally causes a decrease in frequency of the abnor- range from 1. 8. miniature poodle. In the cat the testes have a diameter of approx.6: Figure 8.6). Old English sheepdog. It is a cells. Ectopic testes are difficult Cryptorchidism is a developmental defect in which there to detect by palpation in obese animals and in abdominal is failure of complete descent of one or both testes into the cryptorchids. male can only be assessed by progeny testing. Cryptorchidism 239 Figure 8. In the rare cases in which treatment of hypogonadism is creased risk: toy poodle. Prader’s orchidometer. 4 = external oblique abdominal muscle.8). 2 = gubernaculum. Abnormal location of opening of the inguinal canal. 1 = testis. The final re- to the inguinal canal. This the cauda epididymis and testis through the abdominal wall. 3 = vagi- nal process. is the inguinoscrotal migration that moves the testis into the and (3) inguinoscrotal migration of the testis. At the same time. 7 = cremaster muscle. of the testis from its original position just caudal to the kidney enchymal cord that extends from the caudal pole of the testis to the vicinity of the internal inguinal opening. 8.9). 1980. During the process of descent. (Modified from Wensing. 5 = internal oblique abdominal muscle.8: Schematic representation of the normal descent of the testis (A 씮 D). 6 = perito- neum. The en. and the testis fails pulls the testis and epididymis distally through the abdomen to leave its original position caudal to the kidney. the suspensory ligament between the cranial pole of the testis and extra-abdominal part of the gubernaculum does not expand the abdominal wall close to the diaphragm regresses. from a subcu. moving bernaculum regresses and pulls the testis further caudally. In these cases there is a partial migration controlled by the gubernaculum testis (fig. been observed. the cranial the gubernaculum can take three forms (fig. This is a mes. This results . 8. the sult in such cases is either permanent low abdominal crypt- gubernaculum increases in size just distal to the external orchidism or delayed testicular descent. specifically retention near toward the inguinal area and then through the inguinal canal.39 The process of descent is with low frequency. beyond the inguinal canal but. followed by slight testis relocation to the future in. the neck of the developing bladder as the abdominal cavity These steps constitute abdominal translocation and transin- enlarges. First. the gu- guinal ring.)104 (1) abdominal testis translocation. thrusts back into the largement or outgrowth of the gubernaculum exerts traction abdominal cavity (reversed outgrowth). The traction norm- upon the intra-abdominal part of the gubernaculum and this ally developed by the outgrowth is absent. (2) transinguinal migration of the testis. scrotum. 240 Testes 8 Figure 8. 8 = external spermatic fascia. instead. guinal migration. but substantial underdevelopment does occur tion in the bottom of the scrotum. After completion of the outgrowth. Complete absence of the outgrowth reaction has not taneous location outside the inguinal canal to the final posi. (Modified from Wensing. 8. (A) Reversed outgrowth of the gubernaculum. (B) Outgrowth of the gubernaculum partly in the abdomen.44 In hu- ficult to predict. deficient domen. requiring less than two to four days. Secondly. Insl3 testes. gested.47 Cats with unilateral crypt- is the longest phase of testicular descent. and sex ratio in the litter have been documented. Plasma concentrations of testosterone and estradiol in dogs ation of the cranial suspensory ligament and the expansion of with unilateral inguinal or abdominal cryptorchidism do not the gubernaculum. orchidism. deficient production /action of anti- of the internal inguinal opening will then occur. Transit through the inguinal canal is rapid. and deficient action of Insl3.43.39 In most species abdominal translocation differ from those in normal dogs. Thirdly. mans cryptorchidism is associated with impaired germ cell chidism is the most likely result.9: Schematic representation of three forms of abnormal descent of the testis. Cryptorchidism 241 Figure 8. in which But in most cases the etiology is unknown. which acts as a are considered to be infertile.45 However. chidism are generally regarded as being potentially fertile. the outgrowth Several possible etiologies for cryptorchidism have been sug- occurs partly in the inguinal canal and partly within the ab. 1980.46 structure. Dogs with bilateral cryptorchidism stimulates production or release of CGRP. the behavioral characteristic of intact males. litter size. but low abdominal or inguinal cryptor. outgrowth reaction is partly outside the abdomen. in which the scrotal testis has been removed. Testosterone testes from the scrotum. such as abnormal testicular differentiation. (C) Outgrowth of the guber- naculum partly outside the abdomen. descending The most striking abnormality is the absence of one or both down with the developing gubernaculum.38 nal translocation. but in the dog ingui.40–42 Testoste. the Müllerian hormone (AMH). and altered plasma concentrations of gonado- tropins and inhibin. Directional guidance for inguinoscrotal testis mi- gration is provided by calcitonin gene-related peptide Clinical manifestations (CGRP) released from the genitofemoral nerve. it is not clear whether these abnormalities stimulates growth of the gubernaculum to form an anchoring are a cause or a consequence of cryptorchidism. reach the internal inguinal opening. produced by the fetal Leydig cells.39 There is an increased risk of neoplasia in cryptorchid testes and some types of testicular neoplasms may cause femini- zation and blood dyscrasias (chapter 8.35 rone and AMH are not obligatory for the thinning and elong. but naculum to grow toward the source of CGRP. albeit that in dogs case descent will progress further and the testis may even predisposing factors such as familial occurrence. which has led to the suggestion that there Abdominal translocation of testes is dependent on insulin-like may be primary developmental disorders in cryptorchid peptide 3 (Insl3). have noscrotal migration requires a similar interval as the abdomi. Dogs with unilateral cryptor- chemoattractant and induces the developing tip of the guber.8. development. their fertility is probably lower than that of normal dogs.) 104 8 in high abdominal cryptorchidism. The final outcome is dif. Only slight displacement of the testis in the direction androgen production. The numbers refer to the same structures as in fig. .4). Detailed data have been pub- monorchism. of the prostate gland may provide evidence for the presence or Testosterone has been tried as a therapy for cryptorchidism absence of circulating testosterone. in which no testicular tissue is present. cryptorchidism may be Cryptorchid testes may be present in the abdomen. ence of barbs on the penis (fig. position of the testes reliably because of their small size during the first weeks of life.51–53 The scientific basis for make inguinal testes extremely difficult to palpate. lished only for beagle and mongrel puppies. In dogs rectal palpation success can only be expected in inguinal cryptorchidism. Those in the inguinal area can sometimes be dogs. In addition.10: (A) Contrast-enhanced transverse CT image of the abdomen of a five-year-old male miniature schnauzer with persistent Müllerian duct syndrome (PMDS). Diagnostic imaging of the with little or no success. Based on these findings. basal ty. arrow) can be identified. Abdominal testes can. However. since there is no evidence that testicular descent is controlled by gonadotropins. testicular descent has been inguinal ring. a fluid-filled uterus (UB. P = pampiniform plexus. Surgical removal of the with one or two cryptorchid testes (chapter 12. presented with 8 unilateral cryptorchidism and signs of feminization. puppies should Diagnosis be examined at six to twelve weeks of age. Differential diagnosis There is disagreement in the literature about the time of tes- Unilateral cryptorchidism should be differentiated from ticular descent in dogs and cats. it is generally considered to be unethical be- and GnRH-stimulated plasma testosterone concentrations cause it conceals a congenital abnormality and promotes may distinguish between animals without testes and those spread of the defect in the population. 8. 242 Testes A B Figure 8. As the Bilateral cryptorchidism in cats can be suspected by the pres.50 Thus periodic reexaminations should be performed palpated. at the diagnosed tentatively.5. retained testis or castration are frequently advised because this eliminates the risk of developing testicular neoplasms and pre- . It contained a Sertoli cell tumor.1). If the testes have Cryptorchidism is diagnosed by inspection and palpation. showing an intra-abdominal neoplastic testis (T).55 However. or in the inguinal canal.54.53 Surgical placement of the retained inguinal region and the abdomen by ultrasonography or com. ve testicular function and may even result in normal fertili- tis. In addition. Monor. testis in the scrotum (orchidopexy) has been shown to impro- puted tomography (fig. Cats have large inguinal fat pads which anecdotically to be effective.5). inguinal canal is usually closed in abdominal cryptorchids. uterine body) and uterine horns (UH.48 In these dogs chism has been described in two cats. 8. Li = ligament. (B) The neoplastic cryptorchid testis (T) was in close proximity to the uterine horn (UH). but in young animals it is difficult to determine the until six months of age. this form of treatment is not clear. the cremaster muscle may Treatment hold immature testes in the inguinal canal or retract them Human chorionic gonadotropin (hCG) and gonadotropin- from the scrotum when the animal is exposed to stress during releasing hormone (GnRH) have been tried and reported physical examination.10) often reveals a cryptorchid tes.38 the testes reached their final position in the scrotum at 35 and 40 days postpartum.49. If palpation and diagnostic imaging are inconclusive. reported to be complete as late as six months of age in some not be palpated. not descended by eight weeks of age. Testicular neoplasia 243 vents spread of the defect within the population. Although there is a higher risk of developing Sertoli cell tumor and seminoma in cryptorchid testes than in scrotal testes, the risk of fatal complications such as pancytopenia or metastasis is still very low. A decision analysis has shown that the risk of tumor-related mortality and morbidity is of the same order of magnitude as the risk of mortality and morbidity due to an- esthesiological or surgical complications.56 Based on these findings there is no persuasive reason to advise castration of cryptorchid dogs. 8.4 Testicular neoplasia Testicular tumors are relatively common in dogs. Their esti- mated incidence is 67.8 per 100000 male dogs,57 representing 5–15 % of all neoplasms in this species.58 There are three major types of testicular neoplasms in the dog: Sertoli cell tumor, seminoma, and Leydig cell tumor, and they occur 8 with approximately equal frequency. Cryptorchidism is an important risk factor for testicular neoplasms. In cryptorchid dogs, the incidence of Sertoli cell tumor is 23 times higher and that of seminoma 16 times higher than in dogs with scro- tal testes. The incidence of Leydig cell tumors is similar in cryptorchid and scrotal testes.36,58–61 Other tumors (gonado- Figure 8.11: blastoma, rete testis mucinous adenocarcinoma, leiomyoma Plasma concentration of estradiol in five control male dogs (blue) and five with of the tunica vaginalis, schwannoma, and undifferentiated Sertoli cell tumor (beige) at various times after IV administration of 0.5 µg busere- sarcoma /carcinoma) have been described in individual lin per kg body weight. dogs,62–65 but these are exceptional cases. Bilateral tumors and the occurrence of more than one type of tumor in a single dog or even in a single testis are not uncommon.66–69 Using antibodies against the LH receptor and 3b-HSD to identify Leydig cells and against vimentin to identify Sertoli cells, 13 of 86 canine testicular tumors were found to contain tumor cells of more than one type.70 Testicular neoplasms are report- sias.77–82 Feminization and blood dyscrasias have been at- ed rarely in cats. None were present in 1,567 feline tumors tributed to increased secretion of estrogens by the tumor, (from both sexes), but single case reports have included Ser- but this has been investigated in only a small number of toli cell tumors,71,72 Leydig cell tumors, and other types such dogs.80,83,84 In one study the plasma concentration of estra- as teratoma73 and androblastoma74. Mixed tumors have also diol was elevated in three of ten dogs.80 In another study the been described in cats.72,74 A striking finding in cats is the difference in plasma estradiol concentration between tumor relatively large number of tumors in ectopic testicular tis- bearing and healthy control dogs was not significant,83 but sue.75,76 The common practice of castrating male cats at an determinations with a different estradiol radioimmunoassay early age may contribute to the low incidence of testis tumors revealed elevated plasma concentrations of estradiol before in this species. and after stimulation with the GnRH-analogue busereline in five dogs with feminizing testicular tumors compared with Tumor size, hormone secretion, and the incidence of metas- five healthy control dogs (fig. 8.11). These findings indicate tasis vary with the histological type. Sertoli cell tumors and that feminization in dogs with testicular tumors is probably seminomas may become quite large, especially in cryptor- caused by increased secretion of estrogens by the tumor. It chid testes. Leydig cell tumors are the smallest and may be was also found that Sertoli cell tumors secrete increased an incidental finding at necropsy. Approximately 8–39 % of amounts of bioactive inhibin,83 but the significance of this the Sertoli tumors in dogs are associated with femini- finding is unclear at present. zation.34,69,77 Feminization has also been reported in a dog with a seminoma and in a limited number of dogs with Ley- Clinical manifestations dig cell tumors, but these are exceptional cases and may re- Testicular tumors cause noticeable testicular enlargement. In present undetected mixed tumors. Feminization in dogs cryptorchid dogs this may result in a palpable abdominal mass. with testicular tumor may be associated with blood dyscra- Dogs with testicular neoplasia may have bilaterally symmetri- 244 Testes A B 8 Figure 8.12: A ten-year-old dachshund with pendulous prepuce and bilaterally symmetrical alopecia (A). These signs were C caused by a mixed Sertoli cell tumor /seminoma in an ectopic testis in the inguinal area (B, C) and were resolved after removal of the tumor. Note the small contralateral scrotal testis (B). cal alopecia (fig. 8.12), atrophy and pigmentation of the skin, may also be caused by other conditions, such as idiopathic or and signs of feminization such as gynecomastia (fig. 8.13), a immune-mediated thrombocytopenia, myeloproliferative dis- pendulous prepuce (fig. 8.12), atrophy of the prepuce, and orders, and aplastic anemia. Symptoms and signs of abdominal atrophy of the contralateral testis, and they may be attractive testicular torsion are nonspecific and other causes of »acute to other male dogs. There may be blood dyscrasias varying abdomen« must be considered as possible differential diag- from thrombocytopenia to pancytopenia. In severe cases this noses. may lead to hemorrhagic diathesis and anemia (fig. 8.14). Diagnosis Occasionally dogs with an intra-abdominal testis tumor are Testicular neoplasia in dogs and cats is diagnosed by the find- presented as an emergency, due to testicular torsion.85,86 ing of a palpable mass in a scrotal or ectopic testis. The con- Anorexia and lethargy may be accompanied by swelling of the sistency is usually firm and these tumors are rarely found scrotal and inguinal areas and a stiff gait. Physical examination painful by palpation. In dogs with testicular enlargement due reveals a painful abdominal mass. It should be added that non- to orchitis or testicular torsion the swelling is mostly soft and neoplastic abdominal testes may also undergo torsion.87 Scro- painful. In cryptorchid dogs, testicular tumors may not be no- tal testicular torsion is very rare in dogs.88 ticed unless skin disorders or signs of feminization develop. Cytological examination of a fine-needle aspiration biopsy Differential diagnosis may reveal the type of testicular neoplasm (fig. 8.15). Ultra- Testicular enlargement by tumor should be differentiated sonography of scrotal testes may be used to detect small neo- from orchitis and testicular torsion. The skin disorders may plasms in the testis that otherwise may be missed by palpation. mimic other endocrine diseases such as hypothyroidism (chapter 3.3), hypercortisolism (chapter 4.3), and possibly growth hormone deficiency (chapter 2.2.2). Blood dyscrasias Testicular neoplasia 245 Figure 8.13: Figure 8.14: Gynecomastia in a seven-year-old Bouvier with a Sertoli cell tumor in an abdomi- Petechia on the penis of a dog with thrombocytopenia, which can occur as a result nal testis. of estrogen-induced bone marrow depression. 8 A B Figure 8.15: Fine-needle aspiration biopsies of canine testes. (A) Sertoli cell tumor. There is a uniform population of pleomorphic cells. Note the marked variability in nuclear size. The nuclei are generally round to oval and have a finely-clumped chromatin pattern with prominent and occasional multiple nu- cleoli. There are variable degrees of cytoplasmic vacuolization. (B) Seminoma. Note the marked variations in cell and nuclear size. Nuclei have coarsely-clumped chromatin and usually contain a single, large, irregularly- shaped nucleolus. There is often a high mitotic index. Cytoplasm is lightly baso- philic and granular. (C) Leydig cell tumor. There is a uniform population of cells with abundant cyto- plasm and numerous small cytoplasmic vacuoles containing cholesterol C (May-Grünwald Giemsa stain, x1000). 246 Testes This technique may also help in the search for the presence of neous hypercorticolism did not differ from that in healthy an ectopic testis tumor (see also chapter 8.3). dogs, but the response to suprapituitary stimulation tended to be lower than in healthy dogs.92 Treatment Testicular tumors are treated by orchidectomy. Removal of Clinical manifestations the tumor is usually simple, but blood transfusions may be Male infertility ranges from complete absence of libido to the necessary in patients with severe blood dyscrasias. If both inability to sire offspring in spite of normal mating. Depend- testes are tumorous, both should be removed. In cases of uni- ing on the cause there may be other signs that are characteris- lateral testis tumor the contralateral scrotal testis, which may tic of the underlying condition. be atrophic due to suppression of GnRH secretion by feed- back of the autonomously hypersecreting tumor, can be left Diagnosis in place. An ectopic contralateral testis is best removed be- Diagnosis of male infertility is based on a Breeding Soundness cause of the high incidence of Sertoli cell tumors in nonscro- Evaluation (BSE), which consists of a medical and reproduc- tal testes. tive history, a complete physical examination, semen collec- tion for semen analysis, testing for Brucella canis, and ultra- Prognosis sound examination of the testes, epididymes, and prostate. The prognosis after surgical removal of the affected testis de- Endocrine testing of the hypothalamic-pituitary-gonadal pends on the type of tumor but is usually good. Associated axis by a GnRH-stimulation test may be necessary (chap- skin disorders and signs of feminization are reversible, but ter 12.5.1). Particular attention should be paid to endocrine 8 more severe forms of blood dyscrasia are not amenable to diseases such as hypothyroidism and hypercortisolism. Tes- treatment and can result in fatal complications. Metastases are ticular biopsy is performed only if the results of all less invas- uncommon but may occur with all types of testicular tumors. ive methods are inconclusive. The reported incidence is 1–10 % for Sertoli cell tumors, 3 % for seminomas, and 2–3 % for Leydig cell tumors.34,59–61,67 Possible results of semen analysis include oligozoospermia (쏝 200 million sperms in the entire ejaculate, providing that the ejaculate was collected in a representative way); tera- tozoospermia (쏝 70 % of sperm cells with normal morphol- 8.5 Male infertility ogy); asthenozoospermia (쏝 50 % progressively forward motility); leukozoospermia (쏜 2000 white blood cells per µl Infertility in the male dog or cat may be congenital (thus no in the ejaculate); azoospermia (no sperm observed in the offspring) or acquired (may have sired offspring). Possible ejaculate); and hemozoospermia (blood seen grossly or in cy- causes of congenital infertility include an abnormal hypotha- tological smears). More than one abnormality may be present lamic-pituitary-gonadal axis, chromosomal and /or sexual in a single sample (fig. 8.16). differentiation abnormalities (see chapter 6), segmental apla- sia of the ducts, cryptorchidism (chapter 8.3), and defects in Testicular biopsy is indicated in dogs which are persistently spermatogenesis. Acquired fertility disorders may be caused azoospermic or severely oligospermic. A wedge biopsy is pre- by testicular hyperthermia due to inflammation or environ- ferred over a percutaneous needle biopsy because specimens mental factors, testicular neoplasia (chapter 8.4), infections of obtained with needle biopsies contain insufficient tubules in the reproductive tract, endocrine disorders, exposure to circular cross section to allow detailed histomorphometric toxins, medication, or may be idiopathic. Idiopathic infertil- analysis of spermatogenesis.93 Testicular biopsy is not entirely ity is the most common form in men (~ 50 %) and it is as- harmless and should be undertaken with care. However, if sumed that a large proportion of these have a genetic origin.89 superficial avascular areas are biopsied the method can be A similar high incidence of idiopathic infertility is suspected considered safe.94 Antisperm antibodies induced by Trucut in the dog. Endocrine disorders associated with infertility testicular biopsies were found to be transient and nonpredic- are hypothyroidism and hypercortisolism. Hypothyroidism tive of changes in the total number of morphologically nor- caused by lymphocytic thyroiditis was shown to be related in mal motile sperm cells.95 incidence to lymphocytic orchitis and reduced fertility in a colony of beagles.90 However, hypothyroidism induced by 131I Leukozoospermia indicates prostatitis (with or without be- did not change reproductive function in male dogs.91 nign prostatic hyperplasia), orchitis, epididymitis, and /or uri- Exogenous glucocorticoid excess in dogs was found to exert nary tract disease. Orchitis and epididymitis are diagnosed by negative feedback on the secretion of LH by the pituitary, re- ultrasonography and fine needle aspiration biopsy. The latter sulting in decreased secretion of testosterone by the Leydig method should be used with care. Epididymal aspiration may cells.11 Basal plasma LH concentration in dogs with sponta- cause hematoma, fibrosis, or sperm granuloma, which could result in obstruction.96 Diagnosis of infection of the repro- ductive organs requires bacteriological culture of the ejacu- late. Mycoplasma and E. coli are the infective organisms cul- tured most frequently.97 Male infertility 247 Teratozoospermia may be caused by insufficient testosterone production, hyperthermia, reproductive tract infection, or genetic or familial disorders. It is often observed in combi- nation with leukozoospermia and infection. Asthenozoo- spermia may be caused by ciliary dyskinesia, antisperm anti- bodies, benign prostatic hyperplasia, reproductive tract in- fection, or improper collection or handling of the sample. Oligozoospermia may be caused by toxins, medication (sex steroids, anabolic steroids, glucocorticoids, ketoconazole, ci- metidine, and chemotherapeutic agents), reproductive tract infection or obstruction, and benign prostatic hyperplasia. It may also be due to incomplete ejaculation. Azoospermia may be the result of a congenital defect or epi- didymal blockage. As in oligozoospermia it can be due to in- complete ejaculation. When it is suspected, semen should be Figure 8.16: collected several times under different circumstances to en- Differential interference contrast photograph (x300) of semen from a healthy dog with 85 % of normal spermatozoa. Abnormalities include detached head (dh), sure that a full ejaculate is obtained. Collection should sperm tail without head (st), cytoplasmic droplet (cd), and folded tail (ft). (Cour- be made at least three times at two month intervals before more invasive diagnostic procedures are attempted. Alkaline tesy of Prof. Dr. B. Colenbrander.) 8 phosphatase (AP), which is secreted by the epididymis, can be measured in the seminal plasma of the first and second frac- tions of the ejaculate of oligozoospermic or azoospermic dogs. This may help to differentiate between complete and incomplete ejaculation, for in complete ejaculation AP is Treatment of infertility of male dogs with GnRH agonists, 쏜 5000 IU/l98,99 while values 쏝 5000 IU/l in several ejacu- dopamine agonists, and neutriceuticals such as glycosamino- lates indicate ductal blockage rather than incomplete ejacu- glycans and antioxidants, have not been well evaluated and lation. In such cases fine needle aspirates can be obtained from should therefore be used with caution and only after a thor- the epididymes, but with the risk of causing sperm granuloma ough diagnostic work-up.101,102 and induction of antisperm antibodies. A search for chromo- somal abnormalities should be started in dogs with a lifelong Owners of treated animals should be informed that the sper- history of hypoplastic testes and no sperm. matic cycle in the dog requires approximately 62 days plus an additional 15 days for sperm transport through the epididy- Treatment mis, during which time the sperm cells mature. Response to Treatment of male infertility depends on the underlying treatment may require several cycles of spermatogenesis and cause. Infections of the reproductive tract are treated with thus several months may be needed for regeneration and im- long-term (four to six weeks) appropriate antibiotic therapy. provement. In all cases in which male infertility is likely to be Antibiotics that penetrate and maintain therapeutic levels a hereditary disorder, treatment should not be offered and the in the male reproductive tract are trimethoprim-sulfa and dog should be withdrawn from breeding. fluorinated quinolones. Acute orchitis and /or epididymitis require rapid diagnosis and treatment. Unilateral orchidec- Prognosis tomy is successful in preserving a normal spermogram from Leukozoospermia due to infection of the reproductive tract the remaining testis in more than 75 % of the cases. Aggres- has a guarded prognosis because there is considerable risk of sive antibiotic therapy may also be successful, but sperm epididymal blockage by scar tissue. Teratozoospermia has a granulomas often form, leading to epididymal blockage. guarded prognosis, but exceptionally well-planned matings Blockage of the reproductive tract can be treated surgically, may be successful. Abnormal sperm morphology in men is but the chance of success is small. sometimes correlated with a high incidence of chromosomal abnormalities of the affected sperm, which may lead to aneu- If the results of a GnRH-stimulation test reveal a high plasma ploidy in embryos resulting from in vitro fertilization or in- level of estradiol-17b and relatively low testosterone, there tracytoplasmic sperm injection.103 There has been no re- may be hyperfunction of the aromatizing enzyme system and ported correlation of teratozoospermia with birth defects in treatment with aromatase inhibitors can be considered. These puppies after normal matings. Asthenozoospermia has a drugs inhibit the enzymatic transformation of testosterone to guarded prognosis, but in some cases sperm motility can be estradiol-17b and as a result plasma estradiol decreases and improved considerably by extending the semen with an ex- plasma testosterone increases.100 In several selected clinical tender. Oligozoospermia and azoospermia generally have a cases this therapy has improved semen quality in dogs.100 poor prognosis, but semen quality may improve if there are underlying causes that can be treated successfully. 248 Testes References 1. SENGER PL. Spermatogenesis. In: Senger PL, ed. Pathways to 16. NEILSON JC, ECKSTEIN RA, HART BL. Effects of castration pregnancy and parturition, second revised ed., Pullman USA, Cur- on problem behaviors in male dogs with reference to age and du- rent Conceptions Inc.; 2003:214–239. ration of behavior. J Am Vet Med Assoc 1997;211:180–182. 2. PETERS MAJ, DE ROOIJ DG, TEERDS KJ, VAN DER GAAG 17. HOWE LM, SLATER MR, BOOTHE HW, HOBSON HP, I, VAN SLUIJS FJ. Spermatogenesis and testicular tumours in FOSSUM TW, SPANN AC, WILKIE WS. Long-term outcome of ageing dogs. J Reprod Fertil 2000;120:443–452. gonadectomy performed at an early age or traditional age in cats. J Am Vet Med Assoc 2000;217:1661–1665. 3. HOLDCRAFT RW, BRAUN RE. Hormonal regulation of sper- matogenesis. Int J Androl 2004;27:335–342. 18. ROOT MV, JOHNSTON SD, OLSON PN. The effect of pre- puberal and postpuberal gonadectomy on radial physeal closure in male and female domestic cats. Vet Radiol Ultrasound 1997; 4. DOHLE GR, SMIT M, WEBER RF. Androgens and male fertility. 38:42–47. World J Urol 2003;21:341–345. 19. QUEEN J, BENNETT D, CARMICHAEL N, GIBSON A, LI C, 5. GÜNZEL-APEL AR, HILLE P, HOPPEN HO. Spontaneous and PAYNE-JOHNSON E, KELLY DF. Femoral neck metaphyseal os- GnRH-induced pulsatile LH and testosterone release in pubertal, teopathy in the cat. Vet Rec 1998;142:150–162. adult and aging male beagles. Theriogenology 1994;41:737–745. 20. CRAIG LE. Physeal dysplasia with slipped capital femoral epiphysis 8 6. KNOL B, DIELEMAN S, BEVERS M, VAN DEN BROM W. Diurnal and seasonal variations in plasma levels of luteinizing hor- in 13 cats. Vet Pathol 2001;38:92–97. mone and testosterone in the male dog. In: 12th Int. Congress on 21. McNICHOLAS JR WT, WILKENS BE, BLEVINS WE, Animal Reproduction; The Hague; 1992:1788–1790. SNYDER PW, McCABE GP, APPLEWHITE AA, LAVERTY PH, BREUR GJ. Spontaneous femoral capital physeal fractures in 7. O’CONNOR AE, DE KRETSER DM. Inhibins in normal male adult cats: 26 cases (1996–2001). J Am Vet Med Assoc 2002;221: physiology. Semin Reprod Med 2004;22:177–185. 1731–1736. 8. VERHOEVEN G. Local control systems within the testis. In: De 22. FISCHER HR, NORTON J, KOBLUK CN, REED AL, Kretser D, ed. Clinical Endocrinology and Metabolism. Londen, ROOKS RL, BOROSTYANKOI F. Surgical reduction and stabil- Blackwell; 1992:313–333. ization for repair of femoral capital physeal fractures in cats: 13 cases (1998–2002). J Am Vet Med Assoc 2004;224:1478–1482. 9. KÖNIG H, SCHÄRER V, KÜPFER U, TSCHUDI P. Hodenhy- 23. KANCHUK ML, BACKUS RC, CALVERT CC, MORRIS JG, poplasie (Fehlen von Spermiogonien) und linksseitige Nebenho- ROGERS QR. Neutering induces changes in food intake, body denhypoplasie bei einem dreifarbigen Kater vom 39/ XXY-Karyo- weight, plasma insulin and leptin concentrations in normal and typ. Dtsch Tierärtzl Wschr 1983;90:341–343. lipoprotein lipase-deficient male cats. J Nutr 2002;132: 1730S–1732S. 10. ROOT KUSTRITZ MV. Determining the optimal age for gonadectomy of dogs and cats. J Am Vet Med Assoc 2007;231: 24. MARTIN LJM, SILIART B, DUMON HJW, NGUYEN P. Spon- 1665–1675. taneous hormonal variations in male cats following gonadectomy. J Feline Med Surg 2006;8:309–314. 11. KEMPPAINEN RJ, THOMPSON FN, LORENZ MD, MUN- NELL JF, CHAKRABORTY PK. Effects of prednisone on thyroid 25. CAVE NJ, BACKUS RC, MARKS SL, KLASING KC. Oestra- and gonadal endocrine function in dogs. J Endocrinol 1983;96: diol, but not genistein, inhibits the rise in food intake following 293–302. gonadectomy in cats, but genistein is associated with an increase in lean body mass. J Anim Physiol Anim Nutr 2007;91:400–410. 12. World Health Organization. Contraceptive efficacy of testosterone- induced azoospermia in normal men. World Health Organization 26. ASARIAN L, GEARY N. Estradiol enhances cholecystokinin-de- Task Force on methods for the regulation of male fertility. Lancet pendent lipid-induced satiation and activates estrogen receptor- 1990;336:955–959. a-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 2007;148:5656–5666. 13. INABA T, UMEHARA T, MORI J, TORII R, TAMADA H, 27. GÜNZEL-APEL AR, SEEFELDT A, ESCHRICHT FM, SAWADA T. Reversible suppression of pituitary-testicular function URHAUSEN C, KRAMER S, MISCHKE R, HOPPEN HO, by a sustained-release formulation of a GnRH agonist (leuprolide BEYERBACH M, KOIVISTO M, DIELEMAN SJ. Effects of acetate) in dogs. Theriogenology 1996;46:671–677. gonadectomy on prolactin and LH secretion and the pituitary-thy- roid axis in male dogs. Theriogenology 2009;71:746–753. 14. TRIGG TE, WRIGHT PJ, ARMOUR AF, WILLIAMSON PE, JUNAIDI A, MARTIN GB, DOYLE AG, WALSH J. Use of a 28. FRANK LA, ROHRBACH BW, BAILEY EM, WEST JR, GnRH analogue implant to produce reversible long-term suppres- OLIVER JW. Steroid hormone concentration profiles in healthy sion of reproductive function in male and female domestic dogs. intact and neutered dogs before and after cosyntropin adminis- J Reprod Fertil 2001; Suppl 57:255–261. tration. Domest Anim Endocrinol 2003;24:43–57. 15. KUTZLER M, WOOD A. Non-surgical methods of contracep- 29. FUKUDA S, IIDA H. Effects of orchidectomy on bone metabolism tion and sterilization. Theriogenology 2006;66:514–525. in beagle dogs. J Vet Med Sci 2000;62:69–73. References 249 30. SLAUTERBECK JR, PANKRATZ K, XU KT, BOZEMAN SC, 46. SUOMI A-M, MAIN KM, KALEVA M, SCHMIDT IM, CHEL- HARDY DM. Canine ovariohysterectomy and orchiectomy in- LAKOOTY M, VIRTANEN HE, BOISEN KA, DAMGAARD creases the prevalence of ACL injury. Clin Orthop Rel Res IN, MAU KAI C, SKAKKEBAEK NE, TOPPARI J. Hormonal 2004;429:301–305. changes in 3-month-old cryptorchid boys. J Clin Endocrinol Metab 2006;91:953–958. 31. PONGLOWHAPAN S, CHURCH DB, KHALID M. Differences in the proportion of collagen and muscle in the canine lower uri- 47. MATTHEEUWS D, COMHAIRE FH. Concentrations of oestra- nary tract with regard to gonadal status and gender. Theriogenology diol and testosterone in peripheral and spermatic venous blood of 2008;70:1516–1524. dogs with unilateral cryptorchidism. Domest Anim Endocrinol 1989;6:203–209. 32. WOODALL PF, JOHNSTONE IP. Dimensions and allometry of testes, epididymides and spermatozoa in the domestic dog (Canis 48. BAUMANS V, DIJKSTRA G, WENSING CJ. Testicular descent familiaris). J Reprod Fertil 1988;82:603–609. in the dog. Anat Histol Embryol 1981;10:97–110. 33. KAWAKAMI E, TSUTSUI T, YAMADA Y, YAMAUCHI M. 49. COX VS, WALLACE LJ, JESSEN CR. An anatomic and genetic Cryptorchidism in the dog: occurrence of cryptorchidism and study of canine cryptorchidism. Teratology 1978;18:233–240. semen quality in the cryptorchid dog. Nippon Juigaku Zasshi 1984;46:303–308. 50. DUNN M, FOSTER W, GODDARD K. Cryptorchidism in dogs: A clinical survey. J Am Anim Hosp Assoc 1968;4:180–182. 34. REIF JS, BRODEY RS. The relationship between cryptorchidism and canine testicular neoplasia. J Am Vet Med Assoc 1969;155: 51. BURKE T. Anatomical abnormalities. In: Burke T, ed. Small Ani- 2005–2010. mal Reproduction and Infertility. Philadelphia: Lea & Febiger; 1986:227–244. 8 35. ROMAGNOLI SE. Canine cryptorchidism. Vet Clin North Am Small Anim Pract 1991;21:533–544. 52. FELDMAN E, NELSON R. Disorders of the canine male repro- ductive tract. In: Feldman E, Nelson R, eds. Canine and Feline En- 36. HAYES HM, JR., WILSON GP, PENDERGRASS TW, COX docrinology and Reproduction. Philadelphia: WB Saunders Co; VS. Canine cryptorchidism and subsequent testicular neoplasia: 1987:481–524. case-control study with epidemiologic update. Teratology 1985;32: 51–56. 53. RHOADES JD, FOLEY CW. Cryptorchidism and intersexuality. Vet Clin North Am 1977;7:789–794. 37. MILLIS DL, HAUPTMAN JG, JOHNSON CA. Cryptorchidism and monorchism in cats: 25 cases (1980–1989). J Am Vet Med 54. KAWAKAMI E, TSUTSUI T, YAMADA Y, OGASA A, YAMAU- Assoc 1992;200:1128–1130. CHI M. Spermatogenic function in cryptorchid dogs after orchiop- exy. Nippon Juigaku Zasshi 1988;50:227–235. 38. RICHARDSON E, MULLEN H. Cryptorchidism in cats. Comp Contin Ed Vet Pract Small Anim Pract 1993;15:1342–1369. 55. KAWAKAMI E, TSUTSUI T, YAMADA Y, OGASA A, YAMAU- CHI M. Spermatogenic function and fertility in unilateral cryptor- 39. AMANN RP, VEERAMACHANENI DN. Cryptorchidism in chid dogs after orchiopexy and contralateral castration. Nippon Jui- common eutherian mammals. Reproduction 2007;133:541–561. gaku Zasshi 1988;50:754–762. 40. HUTSON JM, WATTS LM, FARMER PJ. Congenital unde- 56. PETERS MAJ, VAN SLUIJS FJ. Decision analysis tree for deciding scended testes in neonatal pigs and the effect of exogenous calcito- whether to remove an undescended testis from a young dog. Vet nin gene-related peptide. J Urol 1998;159:1025–1028. Rec 2002;150:408–411. 41. HUTSON JM, HASTHORPE S. Testicular descent and cryptor- 57. THEILEN G, MADEWELL B. Tumors of the urogenital tract. In: chidism: the state of the art in 2004. J Pediatr Surg 2005;40: Theilen G, ed. Veterinary Cancer Medicine. Philadelphia: Lea & 297–302. Febiger; 1979:375–381. 42. NG SL, BIDARKAR SS, SOURIAL M, FARMER PJ, DONATH 58. DORN CR, TAYLOR DO, SCHNEIDER R, HIBBARD HH, S, HUTSON JM. Gubernacular cell division in different rodent KLAUBER MR. Survey of animal neoplasms in Alameda and models of cryptorchidism supports indirect androgenic action via Contra Costa Counties, California. II. Cancer morbidity in dogs the genitofemoral nerve. J Pediatr Surg 2005;40:434–441. and cats from Alameda County. J Natl Cancer Inst 1968;40: 307–318. 43. DOLF G, GAILLARD C, SCHELLING C, HOFER A, LEIGHTON E. Cryptorchidism and sex ratio are associated in dogs 59. NIELSEN S, LEIN D. Tumours of the testis. Bull WHO and pigs. J Anim Sci 2008;86:2480–2485. 1974;50:71–78. 44. GUBBELS EJ, SCHOLTEN J, JANSS L, ROTHUIZEN J. Rela- 60. PRANGE H, KATENKAMP D, BAUMANN G, FALK-JUNGE tionship of cryptorchidism with sex ratios and litter sizes in 12 dogs G, KOSMEHL H. Pathology of testicular tumors in dogs. 1. Epi- breeds. Anim Reprod Sci 2009;133:187–195. demiology and comparative epidemiological aspects. Arch Exp Veterinarmed 1986;40:555–565. 45. VIRTANEN HE, CORTES D, RAJPERT-DE MEYTS E, RITZÉN EM, NORDENSKJÖLD A, SKAKKEBAEK NE, 61. NIETO J, PIZARRO M, FONTAINE J. Testicular neoplasms in TOPPARI J. Developement and descent of the testis in relation to dogs. Epidemiological and pathological aspects. Recueil Med Vet cryptorchidism. Acta Paediatr 2007;96:622–627. 1989;165:149–153. 23: Pract Vet Small Anim Pract 1993. SHINOZAKI M. VAN DER GAAG I. anterior pituitary function of dogs with pituitary-dependent hyper- adrenocorticism. J Am 85.78:1070–1072. DEDERICHS D. Tumors of the testes. DE JONG FH. GORMAN SC.53:1355–1363. Bone-marrow damage due to estrogen in dogs with testicular neoplasms.65:228–231. tive function in adult male dogs. 67. Vet Med Small Anim Clin 1983. Kirk R. ROSEN DK. KAMIMURA Y.20:229–231.18: 84.47:763–766. 3 cryptorchid dog. neoplasms in domestic mammals. J Vet Med A Physiol Pathol Clin Med 2004. . RADI ZA. YAGER JA. 95. WILSON GP. YOUNG ACB. Bone marrow hypoplasia in a feminized dog with a DC. Sex cord stromal tumor of the cat: so-called androblastoma with Sertoli-Leydig cell 92. Leiomyoma of the tunica vaginalis in a 80.41:75–78. J Endocrinol 1997. Teratoma in a feline unilateral cryptorchid testis. LIU SK. HEYWOOD R. FOWLER DJ. JR. Blood dyscrasias associated with testicular tumours dog. in the dog. HITTMAIR KM. YASUDA N. MILLER MA. EBERT JW. KOCIBA GJ. Reproduction 88. dominal testicular torsion in a cryptorchid dog. KASBOHM C. Effect of repeated testicular biopsy on cats: a report of 17 cases. Vet Radiol Ultrasound 2004. Vet Pathol examination of the male dog. Vet T.20: 219–228. ATTIA KA. 64. STEEN- 65. WILSON GP. SARLI G.3:225–229. VICENTE WR.4:531–544. Extratesticular interstitial and Sertoli cell tumors in previously neutered dogs and 94. GIACHINI C. 87. 1992. J Am Vet Med Assoc 1993. Two cases of intrascrotal torsion of a normal 2001. HOFMANN W. BLOUIN 78. J Am Vet Med Assoc 1981. 2nd. Int J Cancer 1976. FOOTE RH. Vet Pathol 1980. Vet Pathol 2004.53:125–133. 8 68. Semin Vet Med Surg (Small Anim) 2007. SJ. A canine testicular tumor BERGEN J. TIDWELL AS.121:287–296. ROTHWELL TL. testicle. ARBITER D. Arch Androl 2007. 63.13: 104–110.51:124–126. Probl Vet Med Assoc 1981. Vet Pathol 1986. Rete testis mucinous 81. CHASTAIN C. FOSTER RA. 66. 83. HOSGOOD G. MIYOSHI N. Survey with follow-up of 67 dogs with testicular sertoli cell tumours. JAMES RW. MOL JA. ed. PATNAIK AK. 1977:1054–1058. XU FN. JOHNSTON SD. EDWARDS DF. Tes- ticular neoplasms and concomitant clinical changes in the dog. 72. Bone mar- row hypoplasia in eight dogs with Sertoli cell tumor. Inhibin. CARPENTER JL. Schwannoma in the testis of a dog. 77. Sertoli cell tumour in a 89. 1988.18:201–207.202: 93. J Endocrinol 1990. 82. 250 Testes 62. Basics for a complete reproductive cell tumor and Sertoli cell tumor in the testis of a cat. J Vet Intern Med 1999.45:58–61. WEAVER AD. VAN SLUIJS FJ. ROOT MV. REIFINGER M. Vet Pathol 1981.163:1364–1368. MORRIS B. SCHWARTZ A. Intraabdominal tor- 69. ZAKI AA. TEERDS KJ. Alterations in pattern. COMHAIRE F. BEVERS MM. lar biopsy or epididymal aspiration in dogs. BEVERS MM. Cornell Vet 1975. Eur J Comp Anim Pract 2007. Fatal bone marrow depression as a result of Sertoli cell adenocarcinoma in a dog. MOSTACHIO GQ. Intra-ab- Vet Med Assoc 1973.18: 740–744. Can Vet J 2006. BEST SJ. J Am Vet Med 96. SHERDING RG. MOTHEO TF. HAYES HM. SCHEELE D. 91. LIPOWITZ AJ. Serial percutaneous 1865–1866. 1994.149:408–412. Current Veterinary Therapy VI. DIELEMAN resembling gonadoblastoma. DIETRICH MA.17:41–44.178:494–496.178:497–501. Statistical studies of the occurrence of testicular sion of a neoplastic testicle and prostatic cyst in a cryptorchid dog. Functional ectopic interstitial cell tumor in a castrated male cat. HARTNETT SE. gonadotrophins and sex steroids in dogs with Sertoli cell tumours. RAMOS-VARA JA. J Small Anim Pract 1979. Philadelphia: Saunders Co. J Androl 1997. RIJNBERK A. HINES ME.17:508–513. 71. 73. BENAZZI C. MATTHEEUWS D. TURK MA. EILTS BE. Effect of 131I-induced hypothyroidism on indices of reproduc- Pathol 2001. TURK JR. Interstitial 90. KING R. PACCAMONTI DL.38:729–730. TONIOLLO GH. MORGAN R. 79. testis function and semen quality in dogs. KLAIJ IA.44:394–397. J Am Anim Hosp Assoc 1982. PAPADIMITRIOU JM.113:105–107. CAR- DILLI DJ. PENDERGRASS TW. cat.9:41–45. APPARICIO M. Comp Cont Educ TON DJ. HOROHOV DW. GRADNER G. WALLACE MS. MULLANEY SHIMIZU T. Genetic risk factors in male infertility. MILLER DL. beta-hydroxysteroid dehydrogenase and vimentin to characterize different types of testicular tumour in dogs. BRUNETTI B. Vet Rec 1983. Theriogenology 2000. 76. MIDDLE. VAN SLUIJS FJ. Feminizing testicular tumor. GALLINA AM.15:197–201.. DOXSEE AL.18:970–975. 3RD. testicular biopsy in the Beagle dog. Anti-sperm antibodies and seminal characteristics after testicu- Sertoli cell tumor. TIMMERMAN MA. JOHNSON C. 86. 74. MEIJ BP. tumor (in a dog). Use of antibodies against LH receptor. HECHT S. DEROOIJ diagnosis: intra-abdominal torsion of a non-neoplastic testicle in a DG. GROOTENHUIS AJ. SAAR C. HUNT WL. NACHREINER R.154:505–512 75.127:235–242. OLIVIER NB. Infertility in the male dog. Canine testicular tu- mors: epidemiologic features of 410 dogs. Zentralbl Veterinarmed A Schweiz Arch Tierheilkd 2007. KRAUSZ C. 629–631.35:63–72. In: 482–487. PETERS MAJ. J Small Anim Pract 1979. Ultrasound 70. Tierarztl Prax 1975. 68:322–328. HESS M. AZIZ N. 8 .62:165–178. Current Therapy in Theriogenol- spermic dogs and one azoospermic dog with high plasma estra. Theriogenology 2006. Developmental anomalies. Treatment and Prevention of Reproductive Dis- diol–17beta concentrations. STORNELLI A. eases in Animals. BASCHARD H. TSUTSUI T. Sperm chromosomal abnormalities are linked to sperm morphologic deformities. WENSING CJG. 100.79:212–215. ogy: Diagnosis. Collection of tissue and culture samples 101. KAWAKAMI E. Therioge. Changes in plasma testosterone levels and semen quality after 3 injections of a GnRH analogue in 3 dogs with spermato- 99. Philadelphia. 2003.67:1249–1252. including cryptor- of a capsule containing an aromatase inhibitor in four oligozoo. LEWIS-JONES I.38:1–4. ARAUZ M. SUI T. Theriogenology 2004. ed. chidism. 1980:583–589. In: Morrow DA. DE LA SOTA genic dysfunction. Improve- ment in spermatogenic function after subcutaneous implantation 104. The- 567–574. References 251 97. Unilateral and bilateral vasectomy in the dog: alkaline phos- phatase as an indicator of tubular patency. HORI T. WB Saunders Co. Fertil Steril 2003. HORI T. DOUGLAS A. HOWARD P. KAWAKAMI E. ROOT KUSTRITZ MV. TSUT- nology 2007. 102. Common causes of male dog infertility. Reprod Domest Anim 103.66: ceutical agents used to enhance semen quality in the dog. 98. riogenology 2006. HIRANO T. Documented and anecdotal effects of certain pharma- from the canine reproductive tract. MEMON MA. RL. J Vet Med Sci 2005. HIRANO T. SESHADRI S. MASAOKA Y.66:613–617. This page intentionally left blank . it tends to raise coagulation. kidney. more cally significant ionically active fraction.5 months a tration in the extracellular fluid will tend to increase. Hazewinkel Hans S.55 % Ca (LowD).3 % Ca (ExcessP) or 0. . the gut.1). and blood When calcium is absorbed from the intestine. Independent of hormonal bound to plasma proteins (mostly albumin).3 % Ca (ExcessD) or 0. Due to direct regulation. the calcium concen- and 12. sential structural component of the skeleton and contributes to many important physiological functions.1 % calcium and skeleton.2: Plasma calcium concentrations (with median values) are given for adult dogs and Three organs are especially involved in calcium homeostasis: intestine. Tryfonidou Herman A. Kooistra 9. young poodles2 fed 1.5 months a cium concentration in the extracellular fluid. young Great Danes1 fed 1. muscle contraction. and young Great Danes fed 1. When cal- concentration of calcium remains constant despite the vari. young dogs (all younger than six months) receiving food containing 1. mongrel dogs on standard will be filtered in the glomeruli. (fig. Calcium homeostasis is maintained by direct mech- Figure 9. 9. Three organs are es- pecially involved in maintenance of the calcium homeostasis: Calcium is the most abundant mineral in mammals. 9. In healthy states the total labile pool into the circulation and less is lost via the kidneys plasma calcium concentration varies within narrow limits and (fig. such as nerve Direct regulation conduction.1 Introduction anisms and by calciotropic hormones. from the soluble phase into the circulation. In addition. which contributes to the normalization of the cal- food only without vitamin D (Hypo D).5 months more calcium will be stored in the labile phase of the skeleton and more calcium a diet with 3.1: Figure 9. It is an es. cium concentration decreases. 253 9 Calciotropic Hormones Marianna A.2). the median plasma calcium concentrations vary within narrow limits. diet containing 100 mg vitamin D/kg diet (Hyper D). It is essential that the calcium is filtered by the glomeruli and excreted.5 mg vitamin D/kg diet (Normal). and the skeleton.3 Despite 6–10x difference in daily calcium or vitamin D intake. more calcium enters from the ations in its intake and excretion.33 % Ca (LowP). About half of the circulating calcium is loosely the plasma calcium concentration. In both situations endogenous fecal excretion does 9 is fairly constant even under extreme dietary variations not seem to be much influenced.W. diet with 3. enzyme activity. Ten percent is control some calcium is deposited in bone and less is dissolved bound to other ions and the remainder comprises the biologi. When calcium is absorbed from the intestine. the kidney. (A) In adult dogs a calcium intake of 100 mg per kg body weight per day covers all losses. (B) In young dogs calcium metabolism is characterized by high calcium turnover in the skeleton and more efficient absorption. the requirements in absolute amounts de- pend on the size and growth rate of the dog. in addition they activate osteoclasia and osteoid and cartilage mineralization. . Figure 9.4: Influences of calciotropic hormones on calcium metabolism. CT decreases osteoclastic activity and thus increases bone mineralization. 254 Calciotropic Hormones A B 9 Figure 9. and may vary from 50–350 mg/kg body weight. PTH increases osteoclasia and calcium reabsorption in the renal tubules.3: The relative calcium fluxes in adult and young growing dogs. Vitamin D metabolites increase active calcium absorption in the intestine and renal reabsorption. 1.04 0. over. (NRC 2006) tation.1.1). 9. the parathyroid glands arise from the third and fourth endodermal pharyngeal pouches.1 0.0 55 IU skeleton (fig. The cytoplasm of active chief cells has a higher density due to the abundance of Table 9.8 taining plasma calcium concentration in the normal range.5: The location of the parathyroid glands.8 0.3B). Hormonal control 80 IU Liver 27. Syn. k. k.14 n.03 0.1. Minimal 100 0.0 0.20 4 IU Rumen 23.4 In conditions in which calcium homeostasis is for growth under stress (such as rapid growth. or pregnancy and lactation) calcium metabolism is * = grams per 100 g product with dietary energy density of 4000 kcal ME/kg regulated by the calciotropic hormones: parathyroid hor.02 0. growth presents a formidable challenge for main.or under supplemen. Two smaller parathyroids are usually located be- neath the thyroid capsule. and if this gene is mutated the parathyroid glands fail to form. 9.02 0. The expression of this gene is restricted to the chief cells. a low calcium intake may be Catfish 20.18 20 IU sufficient to replace the losses in urine and feces (fig. It has clear or slightly eosinophilic cytoplasm. The caudal or »internal« parathyroids are subcapsular and usually embedded in thyroid tissue.20 n. such as carnivores may eat when bones are not Egg 25 0. However.1 0. migration with the descent of the thymus may give rise to ectopic parathyroid tissue. the calcium content of animal foodstuff is too low to variations in plasma calcium concentration. The cranial or »external« parathyroids are Dry matter* Calcium* Phosphorus* Vitamin D+ loosely attached to the thyroid capsule.3 0. Poultry 30.2 PTH synthesis and secretion The major cell of the parathyroids is the chief cell. accounting for their final location at the cranial pole of the thyroid (fig. depending on the amounts of intracellular fat and glycogen (fig.01 0. They develop from the third bran- chial pouches in association with the thymus. fulfill the recommendations. . + = IU per 100 g product (1 IU vitamin D = 0. Horse meat 25.2 1. n.11 0.3A). Introduction 255 9. and calcitonin (CT) (fig.4).18 4 IU Heart 24. vitamin D.36 There is an efficient hormonally controlled system that helps to retain calcium in animals living in a calcium-deficient en. 9.1.5 The parathyroid glands generally consist of four small oval disks with a diameter of 1–4 mm. This is especially so in young dogs of allowance large breeds. = not known thesis and release of these hormones are mainly triggered by Absolutely and relative to phosphorus.025 µg) mone (PTH).1 Parathyroid hormone 9. vironment and eating food with a low calcium content by-products (table 9.1 Development of the parathyroid glands Developmentally. requirement since large amounts of calcium are transferred to the growing Recommended 100 1. 9.01 0. The two largest parathy- roids arise from the fourth branchial pouches and remain al- most stationary during embryonic development. Studies in mice have demonstrated that the transcription factor encoded by Gcm-2 is a key regulator of parathyroid gland development. In adult animals. embedded at various depths near the caudal thyroid pole. 9. k.5). 9 9.5 0.15 100 IU part of the meal.1: Analysis of foodstuffs for carnivores Figure 9.1.6). especially when radioimmunoassay are used that recognize only the car.f.8 In situations of hypocalcemia. i. Circulating C-PTH fragments may also be derived from peripheral (largely renal and hepatic) breakdown of the intact hormone. this occurs even in the presence of PTH and /or 1. C-PTH fragments may cause PTH resistance in renal failure patients (see also chapter 9. single chain polypeptide synthesized by proteolytic cleavage of a preprohormone (chapter 1. released by OBL and from the bone during resorption.e.8 Clinically. osteoblasts (OBL). Other adaptive mechanisms of the parathyroid cell to sustained hy- pocalcemia are increased PTH gene expression and proli- feration of chief cells. 256 Calciotropic Hormones Figure 9. whereas their renal excretion is decreased. In the absence of a stimulus for PTH release. PTH and calcitriol (1. Also note that there is a nonsuppressible element to PTH secretion even at very high calcium concentrations.25(OH)2D. This may result in high immunoreactive PTH concentrations not related to the concentrations of bioactive PTH. Histological section of the parathyroid gland of a dog with renal secondary hyper. CaS for PTH indicates the Ca2+ setpoint for PTH secretion. Figure 9. note the large pale (= active) chief cells (H&E. have chemotactic and mitogenic actions on bone cells.).6. as in hypercal- cemia. How- ever. the extracellular ionized calcium concentration suppressing the plasma PTH parathyroidism.5).6: tration and PTH secretion. boxy-terminal parts of PTH. Since C-PTH fragments do not bind to the receptor of PTH. . PTH is an 84 amino acid. The full biologic activity of the intact hormone resides within the amino-terminal 1–34 fragment.2). x600). Biologically active factors (b. concentration to 50 % of its maximum.3.7: Inverse sigmoidal relationship between the extracellular ionized calcium concen- Figure 9.25(OH)2D) change the shape of the OBL.2. they have long been considered to be biologically inactive.a. The amino acid se- quences of canine and feline PTH are highly homologous with the sequence of this peptide in other mammalian species. allowing osteoclasts to resorb bone. recent findings suggest that C-PTH fragments may exert effects opposite to those of PTH(1–34).7 The intact 1–84 molecule is the major circulating form. and the major product released is intact bioactive PTH(1–84). 9 organelles and membrane-bound secretion granules as well as to the loss of glycogen and lipid. separate bone from nonresorbing osteoclasts. degra- dation of PTH within the parathyroid cell is minimal. there is increased degradation of intact PTH causing the release of carboxy-terminal fragments (C-PTH). CT prevents bone resorption by promoting the retraction of the brush border of the osteoclasts.8: Bone lining cells.. 9. PTH secretion is regulated at bone.9 In addition to the ionized calcium PTH cause catabolic actions: osteoblasts shrink and change concentration. there may actually be cium concentration to rise.1.5'-adenosine mono. When in patients with hypoalbuminemia a »normal« and retention of calcium by the kidneys causes the plasma cal- plasma calcium concentration is found. In the kidney. directly to the maintenance of normocalcemia by stimulating fluences the protein binding of calcium. 9 9.1. etal growth. tration in dogs decreases during the first months of life cium is measured.3 Regulation of PTH secretion phosphate (cAMP) and possibly other second messengers (see The ionized fraction of blood calcium is the most important also fig. ized. since it is the main calcium-binding pro. . Thereby. 9. The phosphatemic effect of PTH and calcitriol tends to blunt the hypercalcemic effect of 9. Thereby osteoclast produc- tion and activation is blocked resulting in inhibition of bone resorption. In addition. Acid-base status also in. cruited and activated by local biologically active factors (figs. In normal physiological bone remodeling the osteoblast plays a central role. The production of RANKL is under the influence of the calciotropic hormones PTH and calcitriol. their shape. The mol. bone matrix.7). 9. the PTH / plexes. de- concentration may be less for slow than for fast reductions in pending on the mode of secretion.8. which in turn enhances intestinal and acidosis increases the ionized calcium concentration. calcitriol (1. phate.1. Intermittent low doses ecular mechanism underlying ionized calcium-regulated of PTH cause anabolic actions in bone. osteoblasts produce osteoprotegerin (OPG) that acts as a decoy receptor and blocks the RANKL binding to RANK. i. Therefore one should be aware of factors (fig. the combination of calcium mobilization from bone tein. calcium and phosphate absorption and calcium reabsorption and mobilization from bone. Introduction 257 Figure 9. a metabolite of vita.4) in cells of the main target organs.1. 1. High concentrations of calcium concentration. PTH enhances reabsorption of calcium a setpoint that maintains the concentration of plasma ionized from the glomerular filtrate and increases excretion of phos- calcium within narrow limits.4 PTH action PTH owing to the formation of calcium phosphate com- Binding of PTH to a plasma membrane receptor. PTH causes the release of calcium and tration on PTH secretion occur within minutes.10) and thereby parallels bone cell activity during skel- that may influence the fraction of plasma calcium that is ion. The ef- (fig. with an increase in PTH secretion involves activation of a cell surface calcium. In this context it should be mentioned that tration. Osteoclasts are re- PTH secretion. Of these. When plasma PTH levels are persistently increased. causes a rise in cyclic 3'..9) originating from osteoblasts and resolved from The effects of changes in plasma ionized calcium concen. Left: The ligand of the receptor activator of nuclear factor -kb (RANKL) is produced by osteoblasts and stroma cells and binds to the receptor RANK pres- ent on osteoclasts. Overall. alkalosis decreases the formation of calcitriol. 9. Thereby bone resorption is stimu- lated.9: Osteoclast differentiation and activation. Concentrations below the set.e.25-(OH)2D.The PTH response to similar reductions in calcium fects of PTH on bone can be either catabolic or anabolic. phosphate into the extracellular fluid. PTH. and collagen synthesis. Right: On the contrary. the number of osteoblasts. the alkaline phosphatase concen- sensing receptor. but this is counteracted by the phosphaturic action of PTHrP receptor. cal. kidney and determinant of PTH secretion. the circulating albumin concentration is of greatest relevance. allowing osteoclasts to come into contact with min D) and phosphate have significant roles in regulating bone-matrix surface and to resorb bone. The plasma PTH concen- often total (= bound and ionized). point stimulate and those above it inhibit hormone secretion PTH also stimulates the renal production of calcitriol. rather than ionized. PTH contributes in- elevated levels of ionized calcium. Figure 9. Amphibians. dogs in the kidney into 24.)11 in the skin (fig. (Modified from How et al. CT. as they are solely dependent on dietary resources to meet their vitamin D3 requirement. prolonged radiation. bound to vitamin D-binding proteins (DBP) and transported to the liver for its first tiles.. Other isomers including lumisterol and tachysterol can be formed under that is naturally occurring in plants and cholecalciferol (vita. rep.25-(OH)2D and the biologically most active metabolite.10 dehydro- cholesterol (7 DHC) is photosynthesized under the influence of sunlight (UV-B) 9.1. followed by a second hydroxylation in the skin under the influence of UV light. vitamin D is an es- sential vitamin for dogs and cats. When synthesized or absorbed with the food. respectively. omnivores.and 1a-hydroxylase. and cats are not capable of synthesizing sufficient vitamin D3 1994. vitamin D is min D3) that is synthesized by vertebrates.1 Vitamin D sources and synthesis into provitamin D3.11 but not the dog and cat.25-(OH)2D.10: Plasma concentrations (mean ± SEM) of immunoreactive PTH. birds.11). . followed by a temperature-dependent isomerization into vita- There are two forms of vitamin D: ergocalciferol (vitamin D2) min D3. are significantly negatively correlated with age.11: 9. and 1. and herbivores synthesize vitamin D3 hydroxylation by 25-hydroxylase into 25-OHD. 1. However. but not 1.2.25-(OH)2D by 24.12 Thus.2 Vitamin D In the skin (beige area) of most mammals.25-(OH)2D in growing Great Danes from six to 26 weeks of age. 258 Calciotropic Hormones 9 Figure 9.10 This is due to low levels of 7-dehy- drocholesterol (7-DHC) in the skin11 caused by high degra- dation of 7-DHC by a reductase. 9.1. Both PTH and CT. g. 9. (Modified from Hazewinkel and Tryfoni- dou.25-(OH)2D = calcitriol). whereas calcitriol uct in the catabolic pathway of vitamin D with no biological circulates in levels of pmol/l. the bioactivation of vitamin D is the formation of 1. 25-OHD and (fig.2.12: General diagram of vitamin D metabolism and catabol- ism describing the regulation of the major vitamin D metabolites. 24. Introduction 259 9 Figure 9.2 Vitamin D metabolism biologic activity mainly in bone.14 The enzymes responsible Vitamin D must be metabolically activated before it can pro. most important. The second.3 Regulation of vitamin D metabolites to calcium homeostasis. the biologi- cally active vitamin D metabolite in target organs related 9. The .25-(OH)2D production and metabolism /catabolism. respectively.11).25-(OH)2D is now considered to have the vitamin D status (e. another The plasma level of all vitamin D metabolites is a function of metabolite is produced in the kidney.1.25-(OH)2D in the duce its known physiological actions in target organs. deficiency or intoxication). This metabolite was first considered to be a prod.13. 9.e.. However.25-(OH)2D and 24.)102 9.12).1. i.25-(OH)2D circulate in levels of nmol/l. Plasma levels of 25-OHD reflect action. In addition to calcitriol. step in 24-hydroxylase distributed in various tissues (fig. 2002. 24.. 24. for the production of 1.25-dihy- droxycholecalciferol (1. D is hydroxylated by 25-hydroxylase in the liver to 25-hydro.2. Vitamin kidney are 1a-hydroxylase and 24-hydroxylase. The catabolism of both vitamin D metabolites is mediated by xyvitamin D (25-OHD). In young large breed dogs plasma pense of hydroxylation into 24.12). The vitamin D content of the food was the Plasma levels of the vitamin D metabolites differ between same for both groups. and ATP-ase are stimulated and thereby cellular absorption. in keeping with the high demands in the rapidly-growing skeleton of these dogs with juvenile gigantism. For example. 1993.25(OH)2D synthesis at the ex. resulting in tight regulation of the plasma 1.13: Plasma concentrations of the vitamin D metabolites and of PTH in poodles with thereby regulates its own biological activity. and expulsion of calcium.14: Intestinal calcium absorption is the sum of passive and active absorption. calci- tonin decreases calcitriol formation but stimulates 24-hy- droxylation. and calcitonin.25-(OH)2D con- centration (fig. Calcitriol also regulates its own catabolism by induction of 24-hydroxylase activity at the level of the target organs and Figure 9. reflected in no differences in 25-OHD concentrations in the small and large breed dogs raised on the same balanced diet plasma of both groups. with sufficient vitamin D. Renal synthesis of calcitriol is directly responsive to plasma concentrations of calcium. 260 Calciotropic Hormones Figure 9. 9. transport. phosphate. The catabolism of calcitriol is recipro- cally related to the synthesis of calcitriol. 9. respectively).16 . whereas PTH has the opposite effects (fig.15. nutritional hyperparathyroidism (NHP) compared with normally fed dogs (NC) (0.13).05) that the catabolism of calcitriol is lower in large breed dogs than in small breed dogs.05 % and 1. Transcellular active 9 absorption is influenced by 1. PTH.1 % Ca. This can be explained by the fact (* p 쏝 0. In NHP. calcitriol concentrations (앐 300 pmol/l) are two times higher ship between the synthesis of these metabolites (Modified from Nap. PTH increases 1.25(OH)2D. plasma levels of calcitriol are a function of production and catabolism and are under hormonal and mineral influences. This illustrates the reciprocal relation. Passive paracellular calcium absorption occurs under the influence of the concentration gradient between the intestinal lumen and the interstitium.)2 than in small breed dogs. In the intestinal cell synthesis of alkaline phosphatase (AP).25-(OH)2D. calcium binding protein (CaBP). .17 tion from the chief cells.1). vation of a calcium-sensing receptor on the cell surface of the nomic actions of calcitriol have an uncertain role. although independent of calcium absorption. 9. parafollicular position (fig. These are a and (2) a permissive role for PTH action on osteoblasts. neural crest bilaterally to the fourth pharyngeal pouches and cium. the same receptor that leads to decreased PTH secre- lated that they modulate the genomic actions of calcitriol.3 Calcitonin Calcitriol exerts its genomic effects through the nuclear vita- min D receptor in the three main target organs: bone. The amino acid sequence of canine .3. and only differing in seven amino acids (*) from bovine CT. calcitriol stimulates the uptake.1 CT synthesis and action Both synthesis and secretion of CT are stimulated by calcium In addition to its genomic effects. respectively (chapter 3.15).15: (A) canine calcitonin (CT) consists of 32 amino acids with a disulfide bridge between the cysteines at positions 1 and 7.4 The mol- that are too rapid (within minutes) to involve changes in gene ecular mechanism underlying the stimulatory action of a high expression. calcitriol also has effects infusion as well as by calcium ingestion (fig.1. 9. 3.14 The effects of the developing neck. and sodium. (CT) in two distinct cell types. mostly in a the proximal small intestine.2. i. phosphate.19 (B) Effects of the infusion of 1 mg calcium per kg body weight on plasma ionized calcium and CT concentrations of a healthy dog. phosphate absorption is promoted similarly. transport. The majority of the nonge. and the feedback control of its become localized in the thyroid gland.e. The C (1) an increase in the number of osteoclasts and their activity. pair of transient embryonic structures derived from the fourth 24. and extrusion of calcium (fig. These effects take ten to 14 days to be ex. The C cell precursors migrate from the calcitriol on the kidney include increased reabsorption of cal. Introduction 261 9 A B Figure 9.14). cells originate from the ultimobranchial bodies. 9.1). nongenomic pathways. In the mucosal cells of the C cells are scattered in the interfollicular space. C cells. The main effects of calcitriol on bone include the parafollicular or C cells.25-(OH)2D mainly stimulates bone formation without a pharyngeal pouch and located symmetrically on the sides of concomitant increase in bone resorption.4 Vitamin D action 9. The thyroid glands produce thyroid hormones and calcitonin and intestine. it is specu.18 Within the thyroids own synthesis (closed feedback loop). These effects are me. ionized calcium concentration on CT secretion involves acti- diated by a membrane receptor. the thyroid follicular cells and pressed. kidney. In the distal part of the small intestine.1.1. 9.13. By labeling diphosphonates with 99mtechnetium.1. 9. woven) bone which organizes itself into highly or. The clinical relevance mineralization of bone. ing.9). where they shape the metabolism funnel. 262 Calciotropic Hormones calcitonin (cCT) has been elucidated (fig.. the plasma calcium concentration is prevented from ization. allowing for the proportional growth chemical concentration and composition of this interstitial of the epiphyses. the physeal growth explaining the communication between osteocytes and os- plates (fig. and the number of osteoclasts is only a fraction of the number etal growth. Growth in length of the through this network which will mechanically activate osteo- long bones is limited to those places in which cartilage re. osteoblast and osteo- chemical processes of direct formation of crystalline HA and clast activity is coupled (fig.18).21 Osteoblasts covering bone surface. 9. electrical potentials can change the ends of the long bone. i.e. the kidney in the dog.12). and the teum. electrical induction and as a result new bone will be formed ganic material. physico. Electrical potentials can originate from loading of bone growth occurs via the process of endochondral ossification crystals (HA) by the piezoelectric effect or can be applied by (fig. an increase in pres- In adulthood. caniculi network as the structure that mediates mechanosens- tive (i. calcium. Since most cellular activity occurs during skel. This proportional growth and longitudinal fluid.16). most derangements of skeletal integrity are ob. forms primi. of osteoblasts. aqueous biological environment. an in- rophosphate. by gastrin).10). but influences the hypothalamic satiety center and influences 1. about one quarter of bone is organic material sure on porous bone will cause fluid flow by compression or by (of which 90 % is collagen) and about three quarters is inor. where they adapt the medulla to hemopoetic Functionally the skeleton can be considered as two organs: and mechanical demands (fig.4 Calciotropic hormones and bone are mainly found in metaphyseal areas.8) and 9. 9. In addition to the hor- growth of HA crystals play a role in tissue mineralization. The latter is initially a poorly crystallized cal. naling pathways of osteoclast differentiation and activation is cium phosphate and blocking the formation and growth of the receptor activator of nuclear factor -kb (RANK) pathway HA crystals.19. For regulatory process of bone formation. There consequences for skeletal integrity. 9.16). mains during the adolescent life.24 In addition. They are used as a coating of causing osteoclasts to retract their brush border and to de. two phosphate molecules linked through an creasing number of substances is being recognized that oxygen molecule.17..25 Thus. and with phosphate-oxygen replaced by a phosphate-carbon binding) have the same binding and mineralization inhibiting During calcium ingestion. inhibits calcium phosphate crystallization influences bone metabolism. be considered as the mechanosensory cells of bone. 9. CT has no direct effects on the intestine or ization (figs. This is a hormone-independent cium phosphate and later crystalline hydroxyapatite (HA). Each has its own regulatory mechanism with The osteocyte is the most abundant cell type of bone. boring osteocytes and surface osteoblasts by cytoplasmic ex- tensions running through caniculi.4). for CT in the dog. Loading of the bone may cause a flow of interstitial fluid ganized lamellar bone (fig. In physiological states including growth.15) and this has local Ca2+ and PO43– concentration to a point where HA pre- allowed the development of a homologous radioimmunoassay cipitation begins. in- rising (and therefore the PTH concentration does not fall) creased radionuclide accumulation can be found at skeletal and thus calcium is routed to the bone and not lost via the sites with increased (physiological or pathological) mineral- kidneys (fig.16). lar structures. normalizing the pressure. 9.8). mineralization and they are used as a marker of tissue mineral- quence.20 The circulating concentrations of CT decrease during the first three months of life in the dog Diphosphonates (not normally present in biological systems (fig. the so-called bone lining cells. involving the same cellu. surrounding the cartilaginous template. In addition to this cellular regulation of mineralization. cytes as well as ensure transport of cell signaling molecules. produced by osteoblasts.e.g. as well as on the inner surface of the diaphysis at the 9 endosteal side. 9. 9.19. 9.23 special medical equipment to stimulate fracture healing or endosseous new bone formation. mone-independent regulation of bone remodeling. (1) a supporting and protecting framework and (2) a reservoir of minerals. One of the most important sig- in soft tissues and body fluids by binding to the surface of cal. Enzymatic degradation of pyrophosphate by al. implants such as heart valve replacements to prevent their crease lysosomal enzyme secretion (fig. 9. The role of osteocytes can Growth in width of the long bones starts when the perios. As a conse. are extruded from osteoblasts into the extracellular matrix. 9. 9. 9. the plasma CT concentration is properties as pyrophosphates and are completely stabile in an raised directly (by calcium) and indirectly (e. Py.8).26 kaline phosphatase. 9. (fig. can raise the .and phosphate-rich vesicles of this regulatory mechanism is illustrated in fig. are approximately ten times as many osteocytes as osteoblasts.22. 9. The osteoclasts are able to resorb mineralized bone at their brush border with the aid of acid phosphatase (fig.16). The osteocytes communicate with neigh- served in dogs and cats during early life..25-(OH)2D synthesis (fig. separate multinucleated osteoclasts from bone matrix. The cartilage also extends to the epiphyseal teoblasts. Multinucleated chondroclasts remove the remnants of mineralized carti- months.5-year-old Labrador retriever with lameness of the right front leg for four ization. (6) epiphyseal cartilage. (2) diaphysis. causing death of chondrocytes in their lacunae. in comparison with the left side. typical of enostosis. they move away from their nutrient vessel. This is in- dicative for a fragmented coronoid process. revealing increased bone cell activity in the me- dullary cavity (arrows) of the left and right ulna. (4) secondary ossification center (epiphy- sis). Figure 9. using diphos- al. (3) periosteum. . (Modified from Nap et base of the medial coronoid (arrow).)22 phonates labeled with 99mTc04–.. The intercellular substance mineralizes and consequently seals off the chondrocytes from nutrition. introducing osteoblasts which Figure 9. 1994.18: Bone scintigraphy scans. During longitudinal growth 9 (앖) periosteal bone formation (+) and bone resorption (–) in the medulla and at metaphyseal sides.5-year-old Labrador re- triever with shifting lameness and bone pain without fever. The radiograph of the right elbow revealed only minor sclerosis at the lage to complete the process of endochondral ossification.16: (A) Schematic representation of the proximal end of a long bone with (1) medul- lary cavity. using diphosphonates la- beled with 99mTc04–. (B) The inset shows the process of endochondral ossification: chondrocytes are orientated in rows and while dividing and enlarging. Introduction 263 Figure 9. of a 1. (5) physeal growth plate. The bone scintigraphy scans.17: cover the mineralized cartilage with osteoid that will be bone after its mineral- A 2. Metaphyseal vessels grow into the empty lacunae. clearly demonstrated increased bone cell activity in the area of the right medial coronoid. maintain the bone’s characteristic form as part of the remodel- ing process. It may be a transient or a permanent with clinical manifestations of tetany. Thus for the time being for these species the definition of the disease may be Clinical manifestations confined to deficient secretion of PTH.g.3 mmol/l may not be associated hyperparathyroidism. The radiograph after plate removal six months later (C) revealed disuse osteoporosis. primary hypopara.. which has an in. in cases of spontaneous PTH deficiency. In this spontaneous disease the few histological studies available have Hypoparathyroidism is the state of deficient PTH secretion or revealed parathyroid atrophy. 264 Calciotropic Hormones 9 A B C Figure 9. In contrast.29 have not been observed in dogs and cats. i.e. The latter may be the result of the release of biologi. theoretically a primary form and a secondary is rare. but so far these abnormalities mune mediated cause of the atrophy. hibitory influence on PTH release (chapter 9. suggesting an im- (pseudohypoparathyroidism). For example.1). the decreased concentration of extracellular ionized calcium. The rate of decrease in the plasma calcium concentration is an important determinant in the development of neuromuscular Pathogenesis manifestations.1. fixation with a bone plate was performed. in which a plasma lowing surgical treatment of hyperthyroidism or primary calcium concentration of 1. osteoporosis due to lack of external forces.e. Following corrective osteotomy (B). Secondary hypoparathyroidism is currence appears to be highest in young adults (one to four encountered in situations of hypercalcemia. because of the causative hypercalcemia.. values are still higher (e. hormone deficiency. signs of hypocalcemic tetany From a pathogenetic point of view there are two main causes may occur in dogs after bilateral thyroidectomy when calcium of primary PTH deficiency: (1) neck surgery and (2) idio. As with other endo. which neutralized the forces acting on the bone. . the hypofunction will The presenting signs and symptoms are directly attributable to not become manifest as such. The disease may occur at almost any age but the oc- form can be distinguished.28. i. thyroidism has serious clinical consequences.. no parathyroid tissue may action.8 mmol/l) than might be found pathic disease. In both the dog and the cat spontaneous hypoparathyroidism crine glands.2 Hypoparathyroidism This section will concentrate on the second form.27 In addition lymphocytic cally ineffective hormone or target cell resistance to PTH infiltrations have been found in some cases.19: The clinical relevance of the hormone-independent processes of bone remodeling is demonstrated with a radiograph of the tibia of a ten-month-old dachshund with severe varus deformity and thickening of the concave cortex (A).4). 1. be found on surgical exploration. The former type is especially encountered fol. years of age). However. depending on the viability of the tissue left in situ at the time of surgery (see also chapter 3. 9. but usually associated symptoms and signs cholecalciferol may be difficult to administer to small animals point to the underlying disease so that there is little chance of because of the small volumes required from the available confusion. 9.32 cutis and skin necrosis. Diagnosis rear limb cramping. propriately low plasma PTH concentration while there is hy- sory excitability. An inap- which can be interpreted as paresthesias due to increased sen. and III) of a two-year-old female German shepherd dog with primary hypoparathyroidism (calibration: 1 cm = 1 mV. The increased muscle tone may lead to hyper. Dilution of the calcium gluconate The mechanism is still obscure.20). puerperal tetany. The cardiac manifestations of hypocalcemia may in. Stokhof). epi. On the other used is sensitive enough to measure plasma PTH in healthy hand. and hypoalbuminemia may also dihydrotachysterol.A.30 The onset of these neuromuscular signs is often roidism is virtually certain if hypocalcemia and hyperphos- during exercise.30 medication can be started.31 In ad.1). 0. once tetany occurs there may be an alarm reaction giv. ethylene glycol (antifreeze) have a more rapid onset of action but a shorter half-life than poisoning.38 Differential diagnosis Oral maintenance therapy comprises supplementation with a Although not completely identical. (5–10 min) intravenous injection of calcium in a dose of thermia. by measurement of the plasma PTH concentration.2. In the ECG prolongation of the as calcium gluconate. (Courtesy of Drs. have been validated for use in dogs and cats. the calcium gluconate can be administered subcuta- sion may be seen (fig. provided that the assay dition there may be lethargy and anorexia. (B) During administration of calcium these ECG changes disappeared. paper speed 25 mm/s). the diagnosis of hypoparathy- convulsions.J. requires slow fasciculations. preparations. Several dogs and cats with pri. J. or dihydrotachysterol. or stress. and In the absence of renal failure. Calcitriol and 1a-hydroxycholecalciferol renal failure. at the time of this recording total plasma calcium had only increased to 1. 1a-hydroxychole- lepsy. amin D may be administered as calcitriol.9 % NaCl) every 6 h until oral mary hypoparathyroidism have bilateral lenticular cataract. and the T waves were deep and wide. known from the disease in humans. and muscle Emergency treatment of hypocalcemic tetany.0 mmol/l) the recordings were disturbed by muscle twitching. Hypoparathyroidism 265 A B Figure 9.5–1.3). but these cataracts are not at. The latter two vitamin D may also give rise to muscle twitching (chapter 4. (A) On admission (total plasma calcium 1. animals. calcitriol and 1a-hydroxy- be considered. Vit- features may be observed in hypoglycemia (chapter 5. in principle conditions such as PTH-independent. generalized muscle spasms. In addition. 9 Neuromuscular signs may include focal muscle twitching. as these injections may lead to calcinosis calcium-phosphate product. but rather to the (local) istrations is advised.20: ECG recordings (leads I. excitement. trolled. Occasionally severe hyperkalemia calciferol. II. As to compounds require 25-hydroxylation in the liver. similar neuromuscular vitamin D compound and calcium lactate or carbonate. stiff gait. In some cases intense phatemia are found. van Nes and A. neously (1:4 diluted with 0. and possibly tetanus.33–36 Examination often reveals a somewhat anxious and panting Treatment animal that may have a stiff gait.35 mmol/l. The diagnosis may be further supported facial rubbing and licking and biting of the legs may be seen. .37. which is the cause of hypocalcemia. muscle rigidity. Once the signs of hypocalcemia are con- QT interval and T wave changes such as peaking and inver.0 mmol Ca2+/kg body weight (= 20–40 mg Ca2+/kg) clude a weak femoral pulse. acute pancreatitis. Commercially available assays for intact human PTH ing rise to restlessness and panting. pocalcemia confirms the diagnosis. solution and caution in giving repeated subcutaneous admin- tributed to the hypocalcemia per se. This caused the plasma calci- Pathogenesis um concentration to gradually rise until it was within the reference range (zone). 9.5 g calcium lactate twice daily.43 In addition. most commonly by an adenoma of the chief cells.3. pansion. it may be expected that pri- omit supplementation with calcium.39.46 Keeshonds are overrepresented in case series of tration the prognosis is excellent. but in man monoclonality has been demonstrated in some cases of primary parathyroid gland hyperplasia. Secondary hyperparathyroidism is an adaptive increase in PTH secretion.41 Very rarely the is disease caused by a parathyroid carcinoma. 9. i. With proper guidance the life expectancy is not different from that of a healthy dog. 9. normal or atrophied. the increased PTH secretion is the re- sult of chronic decreases in the concentration of ionized cal- cium in plasma.) by an adenoma of more than one gland or by one or more minimally enlarged glands with multiple hyperplastic nodules. further the distinction between hyperplasia and neoplasia. 266 Calciotropic Hormones be measured daily and when less critical. Several conditions may lead to these events. hypocalcemia. but in dogs and cats there are only two in which secondary hyperparathyroidism produces clinically significant manifes- tations: chronic renal failure (chapter 9.e. suggesting that there is no functional difference between the percalcemia (fig. nodular hyperplasia have characteristics of intrinsic auto- After about two to three weeks dihydrotachysterol reaches its nomy.42 Differentiation of parathyroid adenoma from primary hyper- Dihydrotachysterol is given initially in a dose of 20–30 µg/kg plasia is troublesome.3 Hyperparathyroidism Hyperparathyroidism can be primary or secondary.44 It firmed by measurements of plasma calcium. Clinical manifestations Primary hyperparathyroidism is an uncommon disease of Prognosis older dogs (욷 6 years) and there is no pronounced sex predi- With adequate monitoring of the plasma calcium concen. The PTH excess may also be caused van Nes.39. In the latter.45. J. weekly. the calcium supply via mary hyperplasia would be characterized by polyclonal ex- commercially manufactured foods will be sufficient.2) and calcium defi- 9 ciency during growth (chapter 9.3. indicating that multinodular hyperpla- istration of dihydrotachysterol there is no immediate risk of sia is a multiple form of parathyroid adenoma. The dog did very well for common cause of primary hyperparathyroidism in both many years on twice daily 100 µg dihydrotachysterol and twice daily 1 g calcium the dog and cat. 9. suppression of the remaining parathyroid cells. two to four fol- low-up examinations per year are usually sufficient.22) is the most When hypercalcemia developed the doses were lowered.. Primary hyperparathyroidism is the state of autonomous hypersecre- tion of PTH. Once the dog or cat is stable on maintenance therapy.J. Initially the calcium should canine primary hyperparathyroidism and in this breed the dis- . adenoma at the other.3). lection. unrelated to intrinsic disease of the para- thyroids.3. In the long run it is often possible to two abnormalities. With discontinuation of the admin.21).21: 9. blurring Hypercalcemia may be suggested by polyuria and when con. supplementation may therefore be argued that there is a continuum of mor- should be stopped to minimize the risk of renal insufficiency phological structures with focal hyperplasia at one end and due to nephrocalcinosis. maximal effect and the dose has to be lowered to prevent hy. Figure 9. as the effect of the drug continues for several days. (Courtesy of Dr.1 Primary hyperparathyroidism The dog described in the legend of fig. A small solitary parathyroid adenoma (fig.40 At surgery the other glands may appear lactate as a supplement to a balanced commercial dog food. Both parathyroid adenoma and multiple body weight.20 was treated initially with 500 µg dihy- drotachysterol and 2. together with calcium lactate (25–100 mg/kg). In cats it is sometimes possible to pal- weakness. This.23).2).46–48 In cats the dis. The presence of hypercalcemia is established when three possibly with a predilection for females and Siamese cats. Because of the small size of the parathyroid lesions. less of a diagnostic problem because of the changes associated with the primary disease. Hyperparathyroidism 267 Figure 9.50 develops insidiously in an from lymph node(s) and /or bone marrow (see also chap- otherwise healthy dog. the approach should be to may be no symptoms or signs and the disease is discovered be. Especially in cats the manifes. Moderate hypercalcemia with no obvious identifiable cause is seen regularly in cats. probably resulting from procedures include careful inspection of the perianal region.2. exclude hypercalcemia of malignancy. vomiting. Nevertheless. and weight loss due to primary hyperparathyroidism. palpation of enlarged thyroid glands. and cytological examination of aspirates the kidney collecting ducts. which is more com- cause hypercalcemia is found by a routine laboratory examin. Roughly three categories or stages of propriate signs. unless the disease is complicated by an- urolithiasis and secondary urinary tract infection. and primary hypoadrenocorticism (chapter 4.or hypophosphatemia and the ap- vere systemic illness. The hypercalcemia is frequently associated with usually unremarkable. combination with normo.49 measurements of total and ionized plasma calcium concen- tration reveal values exceeding the reference range. the third and thus far most common form the disease period may be rather short and the animals are presented with poly.45 other disorder such as renal failure. Note the parathyroid adenoma originat. rarely palpable in dogs. and elevated levels of alkaline phosphatase) are (fig. .4). Differential diagnosis The main problem in the differential diagnosis of primary hy- Figure 9. they are uria /polydipsia (dogs!) and lethargy. Other causes of hypercalcemia hyperparathyroidism. hypophos- egory are usually characterized by weakness and lethargy phatemia.1) pose thyroid gland. acute renal fail- ing from the parathyroid tissue at the cranial pole (top) of the ure.22: perparathyroidism is distinguishing it from other conditions 9 Surgical specimen following unilateral thyroparathyroidectomy associated with hypercalcemia and specifically hypercalcemia in a nine-year-old male Malinese shepherd dog with primary of malignancy (chapter 9.5. In the second form polyuria. 9. order follows an autosomal dominant mode of inheritance with possibly age-dependent penetrance. in The disease may be asymptomatic or there may be mild or se. in cats polyuria is less common.40 Radiography and rou- orexia and malaise. tine laboratory data (other than hypercalcemia. such as hypervitaminosis D (chapter 9. pate enlarged parathyroid glands in a manner similar to the tations may be rather nonspecific and can be confined to an. mon than hypercalcemia of parathyroid origin.41 In ter 9. When presented.51 Longhaired cats seem to be predis- posed and diet history may reveal that acidifying diets have been fed. This idiopathic hypercalcemia in cats may be associ- ated with calcium oxalate urolithiasis. dehydration. In the mildest form there perparathyroidism. Diagnosis ease is even less frequent and occurs in the same age range. and weight loss.40. cases in the third cat. decreased vasopressin-regulated expression of aquaporin-2 in thoracic radiography. may give rise to the suspicion of primary hy- presentation can be distinguished.23: A nine-year-old male Malinese shepherd dog with emaciation.4). anorexia. The exclusion ation. there is a rapid decline in the circu- calcium concentration on PTH release.56 The In order to prevent signs of hypocalcemia. however. tration (fig.. When an adenoma is not identified im- roid causes of hypercalcemia may rely on measurement of the mediately. are still suppressed from the long-term hypercalcemia. volume expansion. and 45 of 49 percutaneous ultra. tion of the remaining parathyroid tissue. i. 9. together with the elevated bone turnover and thus high calcium accretion (»bone hunger«) may lead to postoperative Dogs with hypercortisolism may have elevated plasma PTH hypocalcemia. perioperative measures to reduce the hypercalcemia confirms the diagnosis of primary hyperparathyroidism. ceptor on the surface of the chief cells and thereby decrease graphy using 99mtechnetium-sestamibi has been proven useful PTH secretion may hold promises for the medical treatment in identifying parathyroid tumors. intravenous therapy with isotonic sa- 9 curring in approximately 70 % of dogs with primary hyper. as this is now a sults of another retrospective study indicated. One hypercalcemia for a median of more than 500 days.52–54 Parathy. However. dogs with primary so that there is sufficient stimulus for restoration of the func- hyperparathyroidism have also been treated using per. this carefully for the presence of nodular hyperplasia. sestamibi scintigraphy has a poor sensitivity and specificity when used in hypercalcemic dogs for the detection of mor. oc. Especially in critically hypercalcemic of renal failure (see chapter 9. that more serious risk than in primary hyperparathyroidism. Once the cal ablation (injection of ethanol)58 or radiofrequency heat plasma calcium concentration is stable. of primary hyperparathyroidism in the near future. when the plasma calcium concentration declines to the lower lostane treatment.55 decline.e. vita- ultrasound-guided ethanol ablation had limited effect. But a should be directed at increasing urinary calcium excretion by plasma PTH concentration within the reference range.2) should be started tisolism have been reported to reduce significantly with tri.2).. Surgical removal of a parathyroid adenoma results in a rapid phological changes of the parathyroid glands.e.1.60 The re. fibrosis can make future surgery or ablation difficult. vitamin D and calcium (see chapter 9. min D can be attempted gradually by first giving it every thyroidectomies. This parathyroidism is complicated by renal failure. i. Macroscopi- is best performed with the two-site type of assay that measures cally suspected glands are removed. min D induces not only hypercalcemia but also a tendency to ing ultrasound-guided ethanol or heat ablation of a parathy.2). 9. administration of elevated plasma PTH concentrations in dogs with hypercor. usually within 48 h.3. A serious diagnostic lating PTH concentration.45 also confirms the diagnosis. A retrospective study indicated that 45 of 48 para. an elevated PTH level cases. while the unaffected parathyroids problem may arise when it is suspected that primary hyper. and post-ablation periglandular routinely seen on ultrasonographic examination.24). parathyroidism. 99mtechnetium. It may be necessary cutaneous ultrasonographically guided techniques of chemi. line. leaving at least one para- intact PTH and is unaffected by renal function. all four parathyroid glands should be inspected plasma PTH concentration. the sound-guided heat ablation treatments resulted in control of calcium supplementation can also be lowered gradually.57 limit of the reference range. If signs of tetany have already oc- curred. ministrations. should be careful not to induce hypercalcemia.60 Leakage of the ethanol or ex- tension of thermal necrosis into the surrounding tissues may cause damage to structures such as the recurrent laryngeal nerve. to continue this substitution for several weeks. calcium gluconate can be given intravenously and /or Treatment subcutaneously (see chapter 9. withdrawal of the vita- ablation59. times to ablate all abnormal tissue and the operator needs to go through a learning curve.61 The efficacy of percutaneous ethanol injection for or hypoechoic compared with surrounding thyroid paren. hyperphosphatemia. in calcium and phosphate metabolism in these dogs. but due to their small size parathyroid glands are not not approach that of surgery. When the hypocalcemia does not recur. as in hypercal- cemia of nonparathyroid origin PTH concentrations should Following surgical removal of the parathyroid mass(es) or after be low as a result of the inhibitory effect of the high plasma ethanol or heat ablation. As discussed in chapter 9. Therefore plasma calcium concentration concentrations.62 Cal- roid glands exceeding 4 mm in diameter are highly suspicious cimimetic compounds that stimulate the calcium-sensing re- for parathyroid pathology. The aim is to maintain the Surgical resection of abnormal parathyroid tissue has long plasma concentration in the lower part of the normal range. In human medicine the sonographically guided per- cutaneous injection of ethanol is considered an alternative to . However. which may be associated with abnormalities should be monitored carefully after the treatment (fig.46 Dur. treatment of primary hyperparathyroidism in humans does chyma. which combination much more easily roid tumor it is often necessary to redirect the needle several leads to nephrocalcinosis than hypercalcemia per se. In humans. 268 Calciotropic Hormones The parathyroid glands may be visualized by ultrasonographic surgery in patients who are not suited for surgical interven- examination as round or oval structures that are anechoic tion. been the treatment of choice.24). parathyroid scinti. in plasma calcium concen- tration and a rise (if lowered) in plasma phosphate concen- Definite differentiation between parathyroid and nonparathy. 13 of 18 percutaneous ultrasound-guided other day and then increasing the number of days between ad- ethanol ablation procedures. In the absence thyroid gland in situ. 2 Renal secondary trophy of all parathyroid glands. which causes precipitation of calcium in soft tissues.1 the increase in biologi- Several factors are involved in the pathogenesis of secondary cally inactive C-PTH fragments may cause PTH resistance in hyperparathyroidism in animals with chronic renal failure renal failure patients. Prognosis precipitate calcium in soft tissues and also seem to decrease When the source of the PTH excess can be removed or the release of calcium from bone. and (2) decreased pro- concentration ranged from 15–22 ng/l. The initial stimulus appears to be chronic reduc- tion in circulating ionized calcium because of renal retention of phosphate. in the intestinal absorption of calcium. The renal insufficiency con- hyperparathyroidism tributes to the increase in PTH levels because it is associated with a decreased rate of removal of the hormone from the cir- Pathogenesis culation. The main stimuli are (1) renal retention of phos- (arrow) of a solitary parathyroid adenoma measuring 7 × 5 × 4 mm.25: Plasma calcium and phosphate concentrations in a seven-year-old castrated fe. which stimulates PTH secretion and results in hyper- 9. 9.3.25). Hyperparathyroidism 269 9 Figure 9. and apparently had not yet caused suppression of the nonaffected parathyroid tissue to the extent that postsurgical hypocalcemia developed. As discussed in chapter 9.24: Figure 9. The concerted actions of these factors lead to hypocal- cemia. In this dog the disease was rather mild duction of 1. A further contributing factor to the hypocalcemia is the relative skeletal resistance to PTH.8 (fig. the prognosis is excellent. decreased destroyed successfully and the posttreatment period can be production of 1.63 In addition.25-(OH)2D in the kidney causes a reduction overcome adequately. Principal factors involved in the pathogenesis of secondary hyperparathyroidism male Airedale terrier with primary hyperparathyroidism before and after removal due to chronic renal insufficiency. and of short duration (polyuria lasting three to four weeks). Plasma PTH phate.25-(OH)2D. High plasma concentrations of phosphate may . 26: Demineralization of all bones of the skull and mandible of a dog with advanced secondary renal hyperparathyroidism. The laboratory findings are usually dominated by the abnor- malities associated with the renal insufficiency. Due to subperiosteal bone resorption the contours of the bone are hardly visible. The skel. creatinine. for which the term »rubber jaw« is used.65 The most important step in the preven- secondary hyperparathyroidism may develop. proach may be extended by supplementation with calcium As a result of the accelerated bone resorption the mandibles and vitamin D sterols (chapter 9. Restriction of dietary proteins has similar to those of hypoparathyroidism may occur. PO. such as When renal insufficiency develops before maturation of the 22-oxacalcitriol. PTH secretion increases and gradually causes the skeletal changes indicated above.27: A five-year-old cat with chronic renal insufficiency. The teeth have maintained a normal density. In not affected and the changes are most prominent in the skull cases in which there is a tendency to hypocalcemia this ap- with loss of teeth and hypoostotic osteodystrophy (fig. and depression.66 The phosphate etal changes range from mild to severe forms of fibrous restriction may be reinforced by administering aluminum- osteodystrophy.5–5. low daily doses of calcitriol (2. causing an increased contrast between teeth and bone. q 24 h) can The jaws may fail to close properly (fig. have been experimentally proved to be ef- skeleton the repair by proliferation of connective tissue may fective in decreasing plasma PTH concentrations without exceed the rate of bone resorption.68 Their clinical application needs in bone volume.27). vomiting. Despite the often low normal plasma calcium concentrations. facial swelling (fig. control renal hyperparathyroidism67 but may induce hypercal- cemia on the long term. In older dogs the volume of bone is usually containing antacids that prevent phosphate absorption. 9 Figure 9. The associated secondary renal hyperparathyroidism (plasma PTH = 882 ng/l) had caused severe bone demineral- ization with a so-called »rubber jaw« and the inability to close the mouth. poly. 9. polydipsia. Although not tion and treatment of renal osteodystrophy is the restriction common. This results in an increase causing hypercalcemia. Supplementation with may become pliable. 9. not been proved to have a beneficial effect. 9. In longstanding cases signs of and quality of life. This hyperostotic osteodystrophy results in further evaluation. symptoms of neuromuscular irritability and tetany of dietary phosphorus. but in some cases these features may be centration below a »toxic« level in order to improve survival mild or only intermittent. Clinical manifestations The animal may be presented with the classic signs of renal Treatment insufficiency. The aim of the treatment is to reduce the plasma PTH con- uria. Analogues of calcitriol. such as ele- vated plasma concentrations of urea.2). such as anorexia.26). .0 ng/kg. and phos- phate. 270 Calciotropic Hormones Figure 9.64.28). especially of the larger breeds.69 In growing dogs. In this young dog the secondary renal hyperparathyroidism caused hyperostotic osteo- dystrophy.29).28: 9 A seven-month-old male Great Dane with renal insufficiency. Clinical manifestations phates in newly-formed osteoid and cartilage. 9. plasma level of alkaline phosphatase will be increased. tone. Depending on the growth velocity of the animal (and . Plasma and urinary concentrations of phosphate will decrease. There may be fractures eventually will lead to an augmentation of the intestinal ab. As ex- mented intestinal phosphate absorption and increased bone plained earlier. coat. The upon palpation.3 Nutritional secondary thereby its calcium requirement) and the severity of the cal- cium deficiency. 9. the tubular maximum for the diagnosis (fig. Lifting of the upper lip (B) revealed that the facial swelling was due to increased volume of the maxilla.1). 9. the increased bone resorption will cause hyperparathyroidism clinical problems within one to three months. causing compres- plasma will tend to decrease.4). and a disproportionally enlarged abdomen due to the and 1. phosphate may be elevated. PTH production and secretion increase.3. and cats a substantial amount of calcium is laid down as calcium phos. leading to On presentation. The animal will be reluctant to walk due to (fig. 9. Due to high bone turn-over. If insufficient Cancellous bone in the epiphyseal and metaphyseal areas may calcium is available in the food. Osteoclasts at the endosteal side of long bones Since in carnivores nutritional secondary hyperparathyroid.25-(OH)2D synthesis. will remove cortical bone to such an extent that the cortex ism (NSH) is especially seen in animals fed an unbalanced will bend under the influence of body weight and muscle food mainly based on meat or meat by-products (table 9.29). whereas the latter effect requires a few days but bone pain and pathological fractures. the calcium concentration in become so thin that spiculae will collapse. causing folding (greenstick) fractures and deformed this entity is also known as the all meat syndrome. Concomitantly and tively regulated and its measurement does not contribute to due to the hyperparathyroidism. due to compression fractures of vertebrae (fig. plasma calcium concentration is very effec- resorption with liberation of phosphate. the patient will be alert and have a good hair increases in calcium reabsorption in the kidney. tration.1). initiating hyperparathyroidism.14). causing hyperphosphaturia and pre. the venting further elevation of the plasma phosphate concen. skeletal protuberances. which led to facial swelling (A). Hyperparathyroidism 271 B A Figure 9. sion fractures. 9. and bones may be painful sorption efficiency of calcium and phosphate (fig. In NSH. osteoclasia. 9. In severe cases there may be paresis posterior circulating phosphate concentration will increase due to aug. and abnormal alignment of bones. The former two effects result in a fact that the growth of the skeleton lags behind that of the soft rapid normalization of the plasma calcium concentration tissues (fig. Compression fractures of vertebrae can. focused on dietary com. and radiographs of the affected sites. whereas PTHrP mainly acts in an be prescribed during this period.e. Later it became ap- bolic disorders such as osteogenesis imperfecta. since the bone analogous to that of proopiomelanocortin (fig.13).29). 9. thin cortices and wide medullae of the long bones. but (fig. have a bad prognosis. and com- pression fractures of vertebrae (arrows). and growth plates of normal width bordered by a well-mineralized metaphysis (fig. especially the vertebrae. Extra calcium tions mainly in an endocrine manner to regulate extracellular as calcium carbonate (50 mg Ca/kg body weight per day) can calcium concentration. by loosening of teeth due to alveolar resorption. 9. mon ancestral gene and represent two members of a small odontal diseases should be taken into account. PTH func- improve skeletal mineralization in three weeks.4). and food with a normal cal. 1. functions. 9. gene family. and logical and developmental responses.5.13). 9.25-(OH)2D concentrations will be elevated logical fractures. but shares 70 % sequence homology with Treatment PTH in the N-terminal region. The most char. 9. In adult dogs. In adult animals the calcium requirement is lower than in thus its effects on intestines and bone cells.2 % on a dry matter basis). three months of age and fed chicken meat almost exclusively. additional administration of vitamin D is contrain- calcium deficiency may cause problems that become manifest dicated. pathological fractures of both femurs. ment is begun soon enough. The PTH / PTHrP receptor is expressed in cium content (i. Prognosis Diagnosis The prognosis depends on the severity and the extent of patho- PTH and 1. as well as inborn meta.3.29: (A) Kitten.70 Peptides containing the first 34 amino acids of mited to good nursing to prevent additional damage to the both PTH and PTHrP bind with equal affinity to PTH / skeleton. constipation may not remain a pathological fractures. not necessarily. PTHrP is larger than PTH (139–177 versus 84 amino acids). in that it will break just proximal to the splint. PTHrP receptor. Bone biopsies reveal mineralized osteoid with massive osteoclasia. but these measurements are not readily available.29).7) and hypovitaminosis D identified as the protein responsible for humoral hypercalce- (chapter 9. disturbances. Narrowing of the pelvis may cause recurring position. nor by osteosynthesis. was in good general condition but unable to stand. Since the endogenous autocrine or paracrine manner to modulate a range of physio- 1.4). in which treat- acteristic features are thin cortices. bending of protuberances (including problem (fig. is processed into a series of peptides with potentially different because of the weakened nature of the bones. constipation although in less severe cases. 272 Calciotropic Hormones A B Figure 9. (B) The radiograph revealed the disproportionally enlarged abdomen. very prolonged dietary (fig. mia of malignancy (see also chapter 10.25-(OH)2D concentration in the plasma (fig. Healed greenstick frac- The most practical way to make a diagnosis is the combi. tures and bent long bones will not always cause locomotion nation of a carefully taken history.2) and par. is highly increased 9 young growing animals.4 Hypercalcemia of malignancy Differential diagnosis Parathyroid hormone-related protein (PTHrP) was initially Hypervitaminosis A (chapter 9. The posttranslational pro- In the severe stage of NSH the pathological fractures of the cessing of PTHrP is extremely complex and appears to be long bones can neither be treated by splinting. 4. Nevertheless.1) should be considered. calcaneus and ischiatic tuberosity). parent that PTH and PTHrP genes have arisen from a com- renal secondary hyperparathyroidism (chapter 9.. Therapy is li.69 This will many tissues and its transcription is tissue specific. a wide medullary cavity. 9.1).71 PTHrP is synthesized . with a marked a receptor (RANK) on their surface. Other mech- Perineum of a twelve-year-old female cocker spaniel with a anisms of humoral hypercalcemia of malignancy include large adenocarcinoma of the apocrine glands of the anal sac tumor production of various substances that stimulate bone region. increased plasma PTHrP concen. synthesis of PTHrP may be part of this pattern. 9. early reports the dogs were almost exclusively female. it was already speculated in the 1940s that in man certain tumors might produce a substance similar to PTH and this condition was called pseudohyperparathyroid- ism.74. There is some contra- increasing RANKL expression and decreasing the production dictory information regarding gender predisposition.80 overrepresentation of boxers. Malignant tissues often revert to a fetal pattern of gene expression. the endogenous RANKL in.92–94 It has been suggested that this lymphoma the plasma PTHrP concentration by itself may not change could be a reflection of an increased frequency and ear- be high enough to cause hypercalcemia and thus other fac. Hypercalcemia of malignancy 273 at one time or another during fetal life in virtually every tis- sue. lier age of neutering in recent years. Although awareness of the physiological roles of PTHrP is of recent origin. Clinical manifestations ceptor activator of nuclear factor-kappa b ligand (RANKL).88 Multiple myeloma is associated with hyper- malignancies that produce substances that act locally in the calcemia in 15–20 % of cases. gistically or additively.30: 9 tion of PTHrP. as well as in malignant melanoma78 and multiple myleoma.9). a Hypercalcemia of malignancy is diagnosed in 57–67 % of hy- newly discovered member of the tumor necrosis factor super.73 In addi- tion.86 Only occasionally they are so large at the time of presentation that there are problems with defecation (fig. This swelling has an in- cases involving the mandible with radiographic evidence of tact overlying skin that is usually not attached to the tumor.79.. In the of osteoprotegerin (OPG). the condition was found to be associated with adeno- carcinomas originating from apocrine glands of the anal sac region in dogs.72. with the histo- most hypercalcemic dogs with adenocarcinomas derived from pathology being an important inclusion criterion.88 Most canine malignant lymph- omas that are associated with hypercalcemia belong to the Local osteolysis may be expected especially in hematological T-cell subclass. malignancy-associated hypercalcemia may arise through: (1) local osteolysis due to bone metastasis.92 The patient groups seem tors.84 In dogs with malignant tribution was about equal. 86 In 10–40 % of dogs with capable of stimulating the activity of osteoclasts by binding to malignant lymphoma there is hypercalcemia. to differ also with regard to the prevalence of hypercalcemia.35 In squamous cell carcino.e.75 Hypercalcemia of malignancy associated with elevated circulating PTHrP concentrations has also been described in cases of malignancies originating from the mam- mary gland76 and the ovary77. ported in about half of the dogs diagnosed with anal sac gland trations have been found to be associated mainly with malig. Dogs with adenocarcinoma of apocrine glands of nant lymphoma and carcinomas.91 In hibitor.81 Tumor- derived PTHrP activates osteoclasts systemically through the Adenocarcinomas of apocrine glands of the anal sac region RANK / RANKL /osteoprotegerin triad (fig.30). hypercalcemia of malignancy was most often detected in because of a swelling in the perineum.83.82 The plasma PTHrP concentrations are elevated in more recent reports on retrospective studies. humoral hypercalcemia of malignancy was first described in malignant lymphoma in the 1970s. the anal sac may be presented for the signs of hypercalcemia or mas. When a . (2) secre- Figure 9. the sex dis- apocrine glands of the anal sac.83. In dogs and cats. which is only 30 % of hypercalcemic cats. neoplasia is diagnosed in family and a critical regulator in bone metabolism. resorption. bone lysis.90. An important humoral pathway for hypercalcemia of malignancy involves the production of soluble forms of re. and (3) production of calcitriol. which caused hypercalcemia. carcinoma. may interact syner.89 bone marrow to mobilize calcium and phosphate. 9. i.74.87 In contrast. 83–85 In the early case series almost all dogs were hypercalcemic. percalcemic dogs.79 Pathogenesis In principle. including cytokines (notably interleukin-1) and growth factors such as transforming growth factor beta (TGF-b). whereas in the recent retrospective studies hypercalcemia is re- In hypercalcemic cats. such as the production of calcitriol. by occur mainly in older (욷 9 years) dogs. This decrease in circulating calcium concentration There are two case reports on anal sac adenocarcinoma in the is associated with a decrease in plasma PTHrP concen- cat.1.2) has been developed for dogs with anal often. but hypercalcemia was not a feature. liver. abdominal ultraso- ney). A The cross-section of the surgical specimen illustrates the intimate relationship between the anal sac 9 and the tumor (B). As mentioned above..84 hypophosphatemia. polydipsia. an increase in the plasma PTHrP concen- sac is mostly due to an excess of PTHrP. and lethargy in dogs. Signs of lower urinary tract disease abolish hypercalcemia if there are no metastases or there are have been observed in about 25 % of hypercalcemic cats. However. oma can be secured. weight loss. As a consequence hypophosphatemia is found less (see also chapter 3. the malignancy-induced hypercalcemia also causes Treatment anorexia and malaise. anorexia.3. In keeping with the concept that In cases in which nonparathyroid malignancy is suspected but the hypercalcemia associated with adenocarcinoma of the anal cannot be proved. procedures such as thoracic radiography. in metastases that have lost the capacity to produce PTHrP some cases associated with calcium oxalate urolithiasis.31: Perineum of a nine-year-old female German pointer with an adenocarcinoma of the apocrine glands of the right anal sac region. there may already be metastasis to regional lymph nodes (in. lung. it appears to enter into the mass (fig. 274 Calciotropic Hormones B Figure 9. which may be the reason that malignant lymphoma in a sac gland carcinoma. A modified clinical stage scheme.31). laboratory examin.83 In dogs with anal sac gland carcinoma various che- The differential diagnosis of hypercalcemia has been discussed motherapeutic agents have been used. tration may indicate whether the hypercalcemia is caused by ation often reveals the combination of hypercalcemia and an underlying malignancy.96. not result in significantly longer median survival time. and /or cytological examination of aspirates from lymph nodes or bone marrow the diagnosis malignant lymph- As in primary hyperparathyroidism.97 tration.94 In cats. kid. The tumors are The cause of the hypercalcemia may be apparent because invariably malignant95 and by the time of the first examination there is malignant lymphoma or an anal sac tumor. based on the TNM system calcemia.86 (fig. This scheme permits categorization that high frequency is associated with nephrocalcinosis and renal is useful in decisions on treatment and communication on insufficiency. lignancy gives rise to polyuria.32). the hypercalcemia of ma. prognosis. probe is introduced into the orifice of the corresponding anal Diagnosis sac. In one study this did briefly in chapter 9. 9.4. in malignant lymph- oma most probably also other factors contribute to the hyper. but the polyuria and polydipsia are less Surgical removal of an adenocarcinoma of the anal sac may pronounced than in dogs. 9. it may happen that hypercalcemia is found and that only with ternal iliac/ lumbar) or to distant sites (e. A probe has been introduced into the natural orifice of the anal sac (A).83 Chemotherapy for malignant lymphoma may also decrease both calcium and PTHrP concentrations in Differential diagnosis plasma. nography.92 In .g. Due Dogs and cats are dependent on the dietary vitamin D con. and in- sufficient renal reabsorption of calcium and phosphate. This may be related to the fact that D deficiency may develop. there are often metastases to regional lymph nodes. making it inaccessible to the os- . this drug should not be given until rehydration is complete. because it may further reduce glomerular filtration rate and thereby re- duce the filtered load of calcium.102. however. Hypercalcemia. Removal of an anal sac tumor led to normal calcium and sis. 9.5 Vitamin D-related disorders This in turn stimulates the parathyroid glands to hypersecrete PTH. The first goal of fluid therapy is to restore normal hydration.5. the plasma calcium concentration tends to decrease.99. which have a much less fa. Vitamin D-related disorders 275 another study there were some indications that platinum chemotherapy (cisplatin and carboplatin) may have some anti- tumor activity. but may be mentioned by the owner because it is a classic bone disease.100 phosphate concentrations.32: sodium per kg body weight rapidly decreases circulating total Plasma calcium and phosphate concentrations in a twelve-year-old female long- and ionized calcium concentrations without evident toxico.. 9.3. Biphosphonates may also be safe and effective in the treatment of dogs and cats with hypercalcemia associated with increased bone resorp- tion. Glucocorticoids are primarily used to reduce bone resorption from malignant lymphomas. insufficient calcitriol is negative predictor for survival.e. low osteoclastic activity. while the plasma calcium concentration is moni- tored. This leads to insufficient calcium and phosphate ab- sorption from the intestine. and commercial pet foods contain suf.93 Successful treatment of hypercalcemia of malignancy may result in transient hypoparathyroidism and hypocalcemia. relevant disturbances in bone metabolism. Medical treatment for hy. resection of these iliac/ lumbar lymph nodes may have a positive effect on prognosis. Only when extremely deficient chemotherapy is worse than in dogs with malignant lymph. Furosemide may be added to the infusion so that it is administered at a rate of 1 mg/kg/h. 9 percalcemia may include glucocorticoid therapy (see also chapter 4.101 mals (rickets) occurs rarely. home-made diets ized. This section will However. However. The mineralized bone is therefore sealed off eventually containing animal fat. Intravenous administration of 1–2 mg pamidronate di. as the hypo- volemia decreases glomerular filtration and thus calcium clearance. Therefore volume ex- pansion with fluid therapy is an important supportive measure before treatment can be started that will result in elimination of the cause(s) of the increased bone resorption. haired German pointer. diets are fed (i.9 % NaCl (10–15 % of body weight) is administered intravenously over a period of ~ 6 h. by nonmineralized osteoid. Prognosis In dogs with malignant lymphoma that is associated with hypercalcemia. and then especially in pups or hypercalcemia is especially encountered among lymphomas kittens which have not had the chance to store enough vita- of the T-cell immunophenotype. plasma calcium concen- tration may reach critically high values. Figure 9. therefore focus on rickets. to hypovitaminosis D. thereby increasing calcium reabsorption and osteo- 9. is a When there is a low vitamin D intake.103 Prey. As a result. In adult dogs and In the absence of metastases the prognosis after surgical cats hypovitaminosis D (osteomalacia) does not cause clinically removal of an adenocarcinoma of the anal sac is excellent.6). For this purpose 0. min D in their body fat.69 Hypovitaminosis D in young ani- vorable prognosis than the B-cell lymphomas.98 Especially if there is dehydration.1 Hypovitaminosis D clastic activity (fig. only lean meat or only vegetables) vitamin oma and normocalcemia. the prognosis for response and survival with ficient vitamin D (table 9. Thereafter the rate of administration is gradually reduced to 2 ml/kg/h.4) and decreasing the renal tubular maximum for phosphate (causing hypophosphatemia). newly formed osteoid is not mineral- tent to fulfill their requirement.1).94 formed. The plasma calcium ing poorly-mineralized trabeculae and an extremely wide concentration is low to normal (fig. The legs are bent and the metaphyseal areas of long disturbing growth in length. A biopsy of the greater tubercle. However. Figure 9. 9. (B) The radiograph of the radius and ulna revealed thin cortices. The povitaminosis D (fig. as well as pronounced palpable areas near the growth plates of all ribs.33). will reveal osteoid seams cover- bones and ribs are enlarged (fig. wide medullary cavities.1). phate concentration is low in plasma (쏝 1 mmol/l) and high in urine (쏜 20 mmol/l). 276 Calciotropic Hormones A 9 Figure 9. 9.33). 9. tration of vitamin D metabolites and the radiological appear- . depending on the On radiographic examination the cortex of the long bones is mineral content of the food. 9.33: (A) Young mixbred dog with clearly noticeable bulging metaphyseal areas of the distal radius and ulna. the well-mineralized cortex differs considerably from what is seen in hypovitaminosis D (see for com- parison fig. animal is reluctant to walk and palpation of the bones causes to obtain cancellous bone and growth plate cartilage without pain.33). 9. teoclasts for resorption and remodeling. 9. and its are very low and the concentration of calcitriol is low to nor- body conformation may be disproportional due to the fact mal. whereas the phos.33).16).34: Radiograph of a four-month-old boxer with hyper- trophic osteodystrophy. A pathognomonic radiolu- cent area (arrow) parallels the growth plates and is separated from it by a thin mineralized area. its coat may be in poor condition. typical for hypovitaminosis D. Diagnosis Clinical manifestations The plasma concentrations of 25-OHD and 24. This entity can be confused with or be complicated by nutri- tional secondary hyperparathyroidism. The radiological abnormalities are quite typical for hy- that growth of bones lags behind that of the soft tissues. growth plate.25-(OH)2D The animal is alert. The newly-formed The growth plates are extremely wide for the chronological cartilage will not mineralize and this prevents completion of age of the animal (fig. the cascade of events in endochondral ossification (fig. the latter due to the concomitant Differential diagnosis hyperparathyroidism. the plasma concen- thin and may be folded or there may be pathological fractures. and increased width of the growth plates B with a mushroom appearance. In addi- tion. Hypervitaminosis D usually results from excessive supple.108–110 to such an extent that corrective orthopedic surgery can be Vitamin D intoxication leads to increased formation of performed if necessary. 25-OHD.25-(OH)2D by activated macrophages in the granu. but with disturb- of 1. with focal disorders of endochondral ossification characterized by arrest of chondrocyte apoptosis. with necrosis in the most severe cases (B). poparathyroidism. in- 9. Vitamin D-related disorders 277 B C 9 Figure 9. and increased calcium and phosphate reab- Prognosis sorption in the kidneys.2 Hypervitaminosis D and vitamin D cluding vessel walls and heart valves. 9. retarded A formation of primary spongiosa.35). min D in the treatment of hypoparathyroidism or from in- mineralization of cortices. These disturbances result in valgus deformation due to radius curvus syndrome (A).5. Hypercalcemia combined with elevated plasma latter. 9.35: Dogs raised on diet supplemented with 100 times more vitamin D than the recommended requirements de- velop severe disturbances of endochondral ossification without clinical signs of vitamin D intoxication. and callus will occur toxication with cholecalciferol-containing rodenticides.69 Within four weeks. The resulting hypercalcemia as well The prognosis for mineralization of bone and cartilage is as the direct feedback effect of vitamin D on the activity of good. hypertrophic osteodystrophy (fig.105 Granulomatous characterized by normocalcemia. normophosphatemia. The elevated plasma concentrations of calcium and phosphate lead to increased urinary excretion of both elements. tous lymphadenitis106 and in dogs with granulomas due to an- giostrongylosis. Eventually calcification of soft tissues will occur. as soon as possible. which increases the tubular maximum for phosphate. as well as kidney tubules intoxication with renal failure as a consequence.25-(OH)2D has been reported in a dog with granuloma- disorders such as chondrodysplasia104 have to be considered. In contrast to vitamin D intoxication. Growing dogs raised on a balanced diet have regular growth plates (C). The growth plates are irregular.107 Treatment The dog or cat must be fed a normal food. growth plates. hypervitaminosis D is mentation of vitamin D in the diet. ance of growth plates will be different.34) and congenital 24. containing 400 IE Vitamin D intoxication may result from overdosage of vita- vitamin D per kg. but functional recovery depends on the severity of the the chief cells in the parathyroid glands (fig. ances of endochondral ossification (fig. 9. With regard to the lomas. and protrusion of the growing cartilage in the metaphyseal area. and disease in humans is also associated with increased production no clinical signs of soft tissue calcification. augmented calcium and phosphate absorption from the intestine.12) causes hy- skeletal abnormalities.111 In hyper- . 3. However.108 If complicated by renal insufficiency. and ano.4). since the release of the vitamin D stores in lage maturation is characterized by thickened cartilage and is body fat may take several weeks. In creased osteoclastic activity and hypermineralization of the cases with severe hypercalcemia (쏜 4. ness.6 Calcitonin-related dominated by one or more of the signs of hypercalcemia.1 Nutritional secondary vestigations will reveal that calcium and phosphate concen.8). For the differen.108 However. 9. nal calcium absorption. mental settings and in several disease processes in dogs and ness of 24-hydroxylase. The disturbed carti- least one month.. 9. the plasma CT concentration is disease (chapter 9. the prognosis is guarded. In addition. not the main cause of hypercalcemia in hypervitaminosis D. disorders rexia. and the special diet should be continued for at and prevent blood vessels from invading.100. 9. added to the mineral content of the bone (fig. mineralization as well as signs of osteochondrosis may be clasts has been recommended. maintenance of calcium homeostasis and only minimal In milder cases. weakness.116 Persistent hypercalcitoninism causes de- should be given to minimize intestinal calcium absorption. with finding of elevated concentrations of calcium and phosphate severe consequences for skeletal development. the use of heterologous calcitonin may cause clinical features.111. Mild volume expansion together with furosemide the chondrocytes do not mature. Especially hypercalcemia of malignancy (chapter 9.22. Routine laboratory in.4.0 mmol/l). lead to disturbed endochondral ossification. by gastrin).115 in plasma and urine. osteoclasia is observed in the same patient in varying gradations.1. If there is renal damage. The treatment with glucocorticoids. resulting in may ensue. and anorexia. hypercalcitoninism trations in plasma and urine are elevated. tial diagnosis of hypercalcemia. a diet without calcium young dogs. The imbalance of the calciotropic hormones and weakness. 108 known as osteochondrosis. Es- 9 (except when calcitriol has been administered and is the cause pecially young dogs of large breeds are often given extra of intoxication). general skeleton.113. The use of substances that inhibit bone resorption. consequence. treatment can be successful. there may be vomiting and other signs of azotemia. In mild cases glucocorticoids can be prescribed to reduce intestinal absorption and increase renal Chronic high intake of calcium causes C-cell hyperplasia in excretion of calcium. The circulating con- centration of PTH is low and that of 25-OHD is high.108 microscopic changes in endochondral ossification.112 Commercially available dry dog food may exceed by four to 13 times the recommended Prognosis requirements of vitamin D. such as polydipsia /polyuria. raised directly (by calcium) and indirectly (e. separately. such as the biphosphonates widely used for the treatment of . and the effective. In this situation centration.3. the reader is referred to causing osteoclasts to retract their brush border (fig. Supplementation of balanced commercial foods and the use whereas the plasma calcitriol concentration is low to normal of home-made unbalanced diets are common errors. does not mineralize. Studies in giant and miniature dogs have revealed that in large-breed dogs overfeeding of a Diagnosis balanced diet or supplementing an otherwise balanced diet The diagnosis can be made on the basis of the history and the with calcium or vitamin D causes hypercalcitoninism. ready to be used at a later stage or increasing renal calcium excretion and by decreasing intesti.3 Clinical manifestations The symptoms and signs of vitamin D intoxication may be 9.6. high calcitonin levels. fluid therapy should be given. 278 Calciotropic Hormones vitaminosis D effective counterbalance is provided by low osteoporosis in humans.114 levels than in controls. mineral and vitamin mixtures. As a chapter 9. and the chondrocytes continue to live furosemide. the plasma calcium concentration is prevented from rising (and therefore the PTH concentration does not Treatment fall) and thus calcium is not lost via the kidneys but routed The aim of the treatment is to minimize nephrocalcinosis by primarily to the bone. dehydration. in some cases one of these disturbances may dominate the In addition.g. since the (direct or indirect) effect of calcium on chondrocytes may dehydration contributes to the increased plasma calcium con. It has been shown that a tenfold Neuromuscular disturbances and encephalopathy due to rapid increased vitamin D intake during growth is sufficiently development of severe hypercalcemia may occur and death counterregulated by the calciotropic hormones. has given promising results in experi- plasma PTH levels. resulting in lower plasma calcitriol cats. the intercellular substance will promote calciuria.2) should be ruled out.4) and hyperphosphatemia due to primary renal During calcium ingestion.117 Treatment of the hypercalcemia with injections of calcitonin The consequences of decreased osteoclasia with hyper- in order to reduce calcium release from the bone by osteo. Therefore each entity will be discussed antibody formation and contribute to the feeling of ill. 1 Cervical spondylomyelopathy Retarded skeletal remodeling of the spinal canal at the cranial 9. In milder cases mental orthopedic disorders. and positive Diagnosis crossed extensor reflexes of the pelvic limbs.1. both in the medullary cavity on organized fibrous The clinical findings include uncoordinated gait in young tissue and subperiosteally due to the elevation of the perios- dogs (approximately six months of age) of a giant breed (e. and sixth cervical vertebrae and mye. a delay in remodeling of the nutri- give rise to ataxia (uncoordinated gait).120.119 Great Dane). ununited anconeal process) can give identical clinical signs. thereby being one of tional foramen in the diaphyses of all long bones is present.36: Myelogram of the cervical region of a six-month-old Great Dane with an uncoordinated gait. which may lead to cer. ing lameness of varying severity. Later there is extra bone Diagnosis formation.. fifth. teum by the edema (fig. inflammatory (infectious) meningitis.. severe lameness of lography will reveal impingement on the spinal cord at these one or more legs.1. clinical improvement. but the prognosis in more severe cases with multiple compressions is guarded.17.1. which in. The radiograph re- veals impingement of the spinal cord at the cranial ori- fices of the 5th and 6th cervical vertebrae (arrows). with pain in response to extension of the neck. Cervical disc pro. the long bones. Surgical decompression is indicated in 9 duces decreased osteoclastic skeletal remodeling (fig. and avoidance Chronic excessive calcium intake (with or without a constant of microtrauma caused by pulling on the collar may lead to ratio to phosphorus) causes hypercalcitoninism.1 Decreased osteoclasia correction of the diet. and bones may reveal medullary new bone formation (fig. glucocorticoid therapy. 118 Especially foramina. conservative treatment. 9. Calcitonin-related disorders 279 Figure 9.6. typi- cal of the canine wobbler syndrome. 9. which do not widen in proportion to soft tissue growth. 9.2 Enostosis vertebral orifice may cause irreversible damage to the spinal In dogs with enostosis (also known as canine panosteitis and cord. pain reaction upon hyperextension of the neck. traumatic or congenital abnormalities should be considered in In the more severe cases there may be noticeable subperito- young dogs with these neurological signs. neal new bone.36).1. 9. Other causes of lameness of one or more legs trusion and the vertebral instability as seen in older dogs (ap.6.g. and positive crossed extensor reflexes of the rear limbs. proximately six years of age) of large breeds (e.18) and other imaging techniques may help to The spinal cord may be so seriously damaged that the lesion is make the diagnosis and differentiate it from other develop- irreversible and any treatment unsuccessful.37).1. edema occurs in the medullary cavity and be- neath the sensitive periosteum.6. Consequently. Routine laboratory investigations are incon- clusive. 9. hyperactivity of the reflexes of the pelvic limbs. the causes of the so-called canine wobbler syndrome. 9. Radiographs of Dogs of larger breeds not over two years of age develop shift- the cervical vertebrae may reveal narrowing of the cranial ori. may cause noticeable hindrance to both Prognosis nervous structures and blood vessels. In mild cases improvement will follow after four weeks of vical spondylomyelopathy and enostosis.121 Physical examination fices of the fourth.g. young dogs with progressive signs. Doberman) fragmented coronoid process. 9. can occur solely or together with enostosis and may confuse the results of the physical examination. Bone scintigraphy Treatment (figs.37). In the subacute phase (at least three weeks after the Differential diagnosis start of the initial signs) radiographic examination of long Discospondylitis. respectively. . in these young dogs (including osteochondritis dissecans. and a painful reaction to deep palpation of locations (fig 9. may reveal an elevated body temperature.4). This occurs especially in the cervical region and may eosinophilic panosteitis). microtrauma can cause fissure lines and eventually nonsteroidal anti-inflammatory drugs or with low doses of separation of diseased cartilage. suffering from enostosis with shifting lameness. It can be present Treatment temporarily in dogs of large breeds without becoming clini- The treatment should be directed at augmentation of osteo. 9. vitamin D. 280 Calciotropic Hormones A Figure 9. influences the growth in length of the radius.116. causing the there have been no studies proving that this will have a benefi. it also meat (Table 9.1. occur in the growth plate of the distal ulna (which accounts for 90 % of the growth in length of the ulna). Prior to that age these symptoms may recur re. 9.16) but especially at may be included in the list of differential diagnoses of shifting sites and times of high growth velocity.1 Radius curvus syndrome This abnormal development of the front legs can develop in Prognosis dogs with an age of four to six months and especially in dogs The prognosis for enostosis is good in the long term. radius curvus syndrome (fig.2 Osteochondrosis Disturbances of skeletal mineralization including nutritional Osteochondrosis is a disturbance of endochondral ossifica- secondary hyperparathyroidism. such as causes a decrease in the growth in length of the ulna.6. When present in joint carti- cial effect. Differential diagnosis 9.122 In particular. since of large breeds.1.123 When present to such an extent that it clastic activity by providing foods low in calcium. called osteochondritis dissecans.111 but not with excess protein.1). with or of two years. resulting in 9 edema beneath the sensitive periosteum and the medullary cavity. raised on excessive amounts of food or raised periods of severe and shifting lameness disappear after the age on lesser amounts of food but with excess calcium. These confluent dense areas are first present near the nutritional foramina (arrow) of the long B bones.3. Although this might theoretically be logical. cally significant.6.124 with or without excess peatedly.2. provided that joint cartilage damage has been excluded. A relative delay in remodeling of the nutritional foramen causes impingement of the nutrient arteries. 9.115. nine months of age. pain upon palpation of the long bones.125 . glucocorticoids. without excess phosphate. In periods of pain. (B) German shepherd dog. painful conditions such as tion.38). it can lameness with elevated temperature. and even infectious diseases present during the growth period (fig. the dog can be treated with lage. It can be localized at any site where growing cartilage is hypertrophic osteodystrophy. and radiopaque areas due to new bone formation in the medullary cavity.37: (A) Schematic representation of the pathophysiologic mechan- ism of enostosis. The cortex receives its blood supply from the periosteal arteries (outer 1/3) and medullary vessels (inner 2/3). 9.123 When the valgus deformity is severe.38) and an abnormal alignment of both the carpus and the elbow Treatment joint. eight months of age. together with a curva. ture of the radius and a thickened concave cortex (fig. (C) The radius may push the humerus proximally against the anconeal process. and carpal abnormalities. Due to elbow incongruity. Diagnosis growth plates of the distal radius or ulna may cause early clo- There will be bilateral valgus deformity with cranial bowing sure of the affected (part of the) growth plate and conse- of the radius. the anconeal process can be Restriction in food and calcium intake alone can lead to nor- loosened in its growth plate (fig. Traumatic injury to the . valgus deformity. mostly this affects only one front at the distal growth plate of the ulna. causing an ununited anconeal process.122 malization of the endochondral ossification. 9.119 with a retained cartilage cone (arrow) in the distal ulnar meta- physis (B). the Alaskan malamute104) are physically similar in the front Additional corrective surgery will be needed in these cases. detachment of the an- (such as the basset hound) or as in inherited disorders (as in coneal process. which breaks off in its growth plate.69. conservative treatment will not Differential diagnosis normalize the stance nor will it prevent secondary effects. Radiographs will demonstrate a cartilage cone quently valgus deformation. Dogs with chondrodysplasia as prescribed in breed standards such as incongruity of the elbow joint.38: (A) Deerhound. but also short in the rear legs. leg and no cartilage cone is present. Calcitonin-related disorders 281 C A 9 B Figure 9. with bilateral valgus deformation due to radius curvus syndrome. 126 legs.38). . Of all environmental factors cal. 9.. Large the inflammation of subchondral bone and joint capsule cartilage flaps can be removed and lesions curetted to induce causes pain.127 Joints are overfilled ondary arthrotic changes. whereas lesions in tation may be present. and arthro. and the joint affected. Re- moval of the flap was followed by curettage of the cartilage defect. (B) Based on the concomitant clinical manifestations. 9. Their influences on bone or cartilage cells are summarized as follows. early healing (fig.7 Miscellaneous Clinical and radiological investigation will help to make the diagnosis.2 Osteochondritis dissecans Treatment Osteochondritis dissecans (OCD) designates osteochondrosis In mild cases no treatment may be needed or nonsteroidal in joint cartilage whereby thickened cartilage is detached and anti-inflammatory drugs can be given when needed. drosis) in other joints can be prevented from detachment by The genotype of the dog also plays an important role in the decreasing overload (by reducing body weight and by rest) in occurrence of this disorder. or even a mineralized cartilage flap (fig. 9.127 lage. of medium-sized or large breeds. the proximal shoulder can heal completely.e. order to diminish microtrauma of the unmineralized carti- cium intake is the most important. Arthrography.2. being approxi. stifle.e. 128 bone can be seen. Diagnosis 9.117 It can occur in a variety of joints (i. Prognosis mately half a year of age and often rapidly growing. Thickened cartilage (i.39). There is an indentation of the contour of the subchondral bone at the caudal aspect of the humeral head (arrow).1. other hormones scopy may precede arthrotomy.39: (A) Radiograph of shoulder joint of a seven-month-old Bouvier de Flandres with lameness of both front legs and pain reaction on hyperflexion of the shoulder joint. arthrotomy was performed and revealed osteochondritis dissecans with a cartilage flap. are lame The prognosis depends on the severity of the lesion.6. . and crepi. the sec- or have a stiff gait in one or more legs. and nutritional factors may play a significant role in bone metabolism. The lesion in and painful upon hyperextension or hyperflexion. osteochon- elbow. shoulder. indicating osteo- chondrosis. 282 Calciotropic Hormones A B 9 Figure 9. computed tomography. and tibiotarsal joint) and is very often bilateral. In addition to the calciotropic hormones.39). The dogs. With radiographs or other imaging the talus may continue to interfere with joint stability and techniques an indentation of the contour of the subchondral cause severe arthrosis. 3.16). Early gonadectomy leads to enuchism: later physeal closure and taller stature. Controls 10 41.2: dogs133 acting with the local GH-IGF-I axis. Microradiograph of transverse section of the rib of a dog with hypercortisolism. 9.6 ± 1. their effect on bone is generalized osteoclasia. (Courtesy of Department of Pathology.6 ± 0.6 ± 1.) either endogenous or exogenous glucocorticoids only rarely leads to pathological fractures in mature dogs and cats. Since glucocorticoids in- crease PTH release and decrease calcium absorption from the Figure 9.23.14) Thyroid hormone influences proliferation and maturation of the growth plate chondrocytes. re. 9. resulting in decreased longitudinal growth.132 This may lead to stunted growth in height when given for a pro- longed period to immature animals. Table 9. 3. Free University.9) at eight weeks of age: (A) healthy and (B) congenitally hypothyroid.23.1 weeks 18. chronic excess of (arrow). Osteoporosis characterized by widened Haversian canals as compared to normal sulting in osteoporosis (fig. Berlin.23. However.40: Radiographs of two littermate tomcats (see also fig. Testosterone causes an increase in bone growth. revealing retarded skeletal growth and development.23. Growth hormone (GH) promotes the differentiation and 9 (via IGF-I) the proliferation of the chondrocytes of the growth plates (fig.129 Estrogens exert their effect directly Table 9.0 cm Cessation of ovarian function also causes bone loss in dogs.130 Thyroid hormone deficiency in young dogs (fig. whereas es- trogens accelerate skeletal maturation and thereby cause pre- mature closure of the growth plate. by interacting locally with the GH- IGF-I pathway and the effects of thyroid hormone.7 cm Osteoporosis is a major problem in anestrogenic women.2).9 cm 7 weeks 14 59. Castration of immature Age at Number Physeal closure of Length male dogs and cats results in greater height at the shoulder gonadectomy of dogs distal radius-ulna of radius (table 9. 3.8) and cats leads to retardation of growth and matu- ration of the skeleton (figs.129 Deficiency of GH at a young age causes proportional dwarfism (fig. 9.10.4 ± 3.41: intestine. Miscellaneous 283 B A Figure 9. 2.131 Glucocorticoids are known to impair chondrogenesis di- rectly and indirectly. as well as indirectly by inter.134 but mostly not to the extent that it leads to clinical problems.40). 7 months 8 54.6 ± 1.2 weeks 16.2: Effects of prepubertal gonadectomy on skeletal growth in through the estrogen receptor.2 weeks 17.133 whereas exogenous gonadal steroids may stunt growth after an initial growth spurt.8 ± 0. and probably part of these effects is mediated by modulating local GH and /or IGF-I actions.41). . preparturient hypocalcemia has also been re- High doses of vitamin A inhibit chondrogenesis in growth ported. factor. 284 Calciotropic Hormones A Figure 9. causing ankylosis.139 plates and inhibit collagen synthesis by osteoblasts in both dogs and cats. and osteoclastic activity..42). In a very severely hy- formation without osteolysis. i. bination of a heavily lactating animal with signs of increased prove with appropriate analgesia and feeding a low vitamin neuromuscular excitability.42: Hypervitaminosis A in a three-year-old cat.135 Vitamin A is pocalcemia may occur in bitches and less often in queens. restless ani- Hypervitaminosis A in cats is characterized by new bone mal with tachycardia and hyperthermia. As in hypocalcemia of primary hypoparathy- . 9.e. weakness and paresis. panting. This causes by atony. two to three weeks postpartum. The radiographs revealed new bone formation without B bone loss on the vertebrae (A) and around the elbow joint (B). Little is known about the pathogenesis. than in dogs. Retinoic acid in. and ataxia to tetany with tonic/clonic convulsions and opis- thotonus. lameness. but lular growth and differentiation. without laboratory confirmation. 9. The diagnosis is usually made by the recognition of the com- nosis. Laboratory examination will re- A-containing food for several weeks. the cat will im. since At the peak of lactation. In cats. hy- cats lack carotenase in their intestinal mucosa.136 Vitamin A is important for insufficient calcium supply during nursing may be a causative normal osteoblastic. Cats require retinol (as present in a variety of foodstuffs). and stiffness (fig. chronic Once the plasma calcium concentration has reached a critical vitamin A intoxication is more likely to be diagnosed in cats level. treatment is begun without delay.140 pain. The vitamin A con- centration in plasma or in a liver biopsy (since the liver is the Diagnosis major organ in vitamin A storage) can support the diag. 9 Vitamin A (or retinol) is formed in the gut of dogs by the re. pocalcemic (and hypomagnesemic) lactating bitch the typical tion of ligaments.8 Puerperal tetany versible reduction of retinaldehyde originating from carotene. In this dog the clinical manifestations were dominated bodies and ankylosis of vertebrae and larger joints. Treatment The condition may be fatal if left untreated. Puerperal tetany occurs mainly in bitches of small breeds with teracts via nuclear receptors with the genome to regulate cel. Examination usually reveals an anxious. Since cats are not able to form retinyl esters in Clinical manifestations order to excrete the excess of this fat-soluble vitamin. the signs may proceed rapidly from restlessness. chondroblastic. which was fed almost exclusively cat food and raw liver and was referred because of lameness of both front legs and an inability to groom itself. muscles. Consequently. large litters.137.138 Although ankylosis is irreversible. veal hypocalcemia and usually also hypophosphatemia. and joint capsules. starting at the points of inser. oxidized in its target cells to retinoic acid. which causes muscle tremors and rigidity were not part of the clinical fea- narrowing of the intervertebral foramina in the vertebral tures. Nutritional influences on growth and skeletal develop. Endocr Rev 2004. docrine mechanisms. J Endocrinol 2001.132: body size in the dog is associated with transient GH excess at a 2644–2650. J Anim Sci 2003.35: Curr Opin Nephrol Hypertens 2005. 9. HOW KL. GRONE A. 2007:233–258. BROSSARD JH. AQUILERA-TEJERO E. STEINMEYER CL. Hormonal regulation of calcium homeostasis in 5. FELSENFELD AJ. Gen Comp Endocrinol 1994. NORMAN A. D’AMOUR P. ROSOL TJ. 21. References 285 roidism. Cloning and sequence analysis of the complementary DNA for and molecular mechanisms. Calcium metabolism: an overview of its hormonal regulation STERHUIS MA. VAN DEN BEMD GJ. KWANT MM. Front Horm Res 1987.96:12–18. GRAHAM A. young age. Nutrition. major regulator for the expression of renal 25. SHINKI T. TRYFONIDOU MA. 8. PELLING D. metabolism. 1568–1580.9 % NaCl).25-Dihydroxyvitamin D3: A case study of Transcaltachia. 4. HAZEWINKEL HAW. HAZEWINKEL HA. GOEDEGEBUURE 12. HAZEWINKEL HAW. Moderate cholecalciferol supplementation 15. Proc Natl Acad Sci dietics in the dog and cat. well-balanced diet.2) during the remainder of the lactation dose is given subcutaneously (1:4 diluted with 0.129:903–908. VASTEN- and interrelation with skeletal integrity. CHEW DJ. mone. SUDA T. Am J Vet Res 2002. Dietary vitamin D 22. ed. 24. GOEDEGE. NAP RC. 19. Inadequate photosynthesis of vita. BEVERS MM. GUEZ M. When sufficiently mature. HAZE- WINKEL HAW. There is no need to give extra calcium in excess of the normal requirements during pregnancy. Thesis. 1993. FAVIER RP. there are usually no recurrences. canine parathyroid hormone-related protein and parathyroid hor. A molecular hormone fragments: role in parathyroid hormone physiopathology. Thyroid development and its disorders: genetics TJ. WOLFSWINKEL J. If not. skeletal development in young growing dogs.160:241–243. Ineffective vitamin D synthesis in cats is reversed by SA. VAN DEN BROM WE. KOHN CW. an inhibitor of 7-dehydrocholestrol-delta7-reductase. MCCAULEY LK.66:363–374.63:194–197. California: Academic Press. CAPEN CC. TRYFONIDOU MA. nancy and lactation care should be given to supply the dam tational calcium loss. DEAN DD.14:330–336. Gene 1995.55:1724–1733. 1994.25-dihydroxyvitamin D3 and bone GJCM. SCHOENMAKERS I. Growth and skeletal develop- dependence of cat and dog due to inadequate cutaneous synthesis of ment in the dog in relation to nutrition. a review. MOL JA. MOL JA. 13. OOSTERLAKEN-DIJKSTERHUIS MA. MOL JA. HAZEWINKEL HAW. NAP RC. Glorieux FH. Utrecht University. ment in the dog. 7. DI LR. For the next preg- Puppies or kittens should be removed to reduce the lac. 14. DeLUCA HF. The signs of tetany usually disappear within a With a nutritionally balanced diet and oral calcium supple- few minutes. HOW KL.81: Proc Natl Acad Sci USA 2004.16:50–59. HAZEWINKEL 16. CAPEN CC. BIRKENHÄGER-FRENKEL DH. 10. calcium gluconate is injected intravenously (see Prognosis chapter 9. Pike JW. J Nutr Influence of different calcium intakes on calciotropic hormones and 1999. Kidney Int 1999. BURG M. San Diego. Vet Quart vitamin D. UENO Y. 11. Sequences of the cDNAs encoding 1(alpha). 9 3. Biological po- and a hypocalcemic clamp on parathyroid hormone secretion: a tency and radioimmunoassay of canine calcitonin. England: Waltham. J Nutr 2002. SYLVIA VL. The origin of the parathyroid gland. Steroids 2001.101:17716–17719.1990:66–68.96:8253–8258. malnutrition and D3–1a-hydroxylase gene in normocalcemic rats. 189–195. Rapid biological responses mediated by DEWILLE JW. Regul Pept 1991. ESTEPA JC. Vitamin D. HACKENG WHL.17:221–232.25-(OH)2D3 regulates cartilage and bone via autocrine and en- 2. POLS HA. Carboxyl-terminal parathyroid Elucidation of the sequence of canine (pro)-calcitonin. In: Edney ATB. VAN LEEUWEN JP. RIJNBERK A. DE FM. VAN DEN BEMD BUURMAN CJ. HAZEWINKEL HAW.21:147–153. 24. and in line with experiences in other species it may even be contraindicated.2). OKABE M. ALMADEN Y. the puppies with a complete. KOOISTRA HS. In Feldman D. HOLL MS. DeLUCA HF. HAZEWINKEL HAW. ARNOLD IC. VOORHOUT G. SCHWARTZ Z. 20.25:722–746.17:333–344. USA 1999. MOL JA. 17. Vet Q 1999. 24 h and in the meantime fed a milk substitute. BOYAN BD. dogs during growth at different rates. RODRI. Large depresses intestinal calcium absorption in dogs. VOORHOUT G. BOSCH R. TORIBIO RE.170:479–484. Effect of rate of calcium reduction SNIJDELAAR M.hydroxyvitamin min D in dogs. VAN LEEUWEN JPTM. MORRIS JG. biological and protein chemical approach. ROSOL 18. OOSTERLAKEN-DIJK- HAW. eds. SCHOENMAKERS I. HAZEWINKEL HAW. VAN DEN BROM WE. References 1. Domest Anim study in dogs. MOL JA. VAN DEN BROM WE. In order to prevent rapid recurrence a similar mentation (chapter 9. VOORHOUT G. . VAN DRIEL M. Endocrinol 1999. period. STEVENHAGEN JJ. Additional feeding of or kittens can be weaned. they can be returned after the litter as early as possible may also help to prevent tetany. feline preproparathyroid hormone. Steroids 2001 66:375–380. MOL JA. 6. NAP RC. Calcitonin is a BUURE SA. EARM JH. MIDKIFF AM. JAMES KM. J Feline Med Surg 2006. J Oral Implantol 42.37:370–373. BRUYETTE DS. En. J Vet Int Med 1988. Vet Radiol Ultrasound 1997. Vet J 2007. 46. familial isolated hyperparathyroidism do not account for hyperpara- thyroid function testing. LACEY DL.191: 54. Osteocyte 41. 2005. J Am Vet Med Assoc 1993. J Med 1991. 33. NYLAND TG.8:340–344. Electrical stimulation of bone and its implications for endosseous dental implantation. parathyroid glands. NELSON RW. and the calciferols. 1990. J Vet Intern Med 2007. Human-parathormone 48. J Am Vet Med Assoc 1987. NILSSON O. PARY BW. 35. In: Wilson JD. CANTOR T. J Am 157–165. GOLDSTEIN RE.5:47–51. BOND KA. GOOSSENS MM. DEVRIES SE.2:7–14.37:364–369. GUPTILL L. HAVIV YS. Vet Quart 1997. RANDOLPH JF. NELSON RW. SAFADI R. LINDBLAD-TOH K. FLANDERS JA. Am J Vet Res 1989. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. Decreased aquapoin–2 ex- calcemia of malignancy.18:1101–1107. Foster DW. BARON J. Detection of 50.9: RODRÍGUEZ M. 24. Idiopathic hypercalcemia in cats. 51. TORRANCE AG. . 25.19:523–526. Osteoclast differenti- ation and activation. Primary hypoparathy. 26. parathyroid hormone-related protein in cats with humoral hyper- HAN JS.52:422–425. VITTONE V. RICHARD V. Vet Med Assoc 1991. ducts of polyuric hypercalcemic rats. Schweiz Arch Tierheilkd 2001. BROWN MF. PEETERS ME. 286 Calciotropic Hormones 23. Radioimmunoassay of parathyroid 49. thyroidism in Keeshond dogs. Saunders Co. Am J Vet Res 1991. CAPUCCHIO MT. Am J Nephrol 1999. DRAKE C. Horm Res 2005. J Am Vet Med Assoc 1990. CHRISTENSEN BM. GINN PE. Pri- docrine regulation of the growth plate. ATWATER DZ.38:462–466. GRAHAM PA.21:199–203. ESTEPA JC. CAVANA P. Ultrasonography of the thyroid and 2001. pression and apical plasma membrane delivery in kidney collecting 36. Dynamics of secre. treatment. SARFATI E. J Clin Invest 29. SPIEGEL AM. GEAR RN. WADE CM. Comp Pathol 2003. Vet Clin North Am Small Anim Pract 1998. ism in a dog.174:652–654. sample handling studies. Inheritance. FOX LE. FELDMAN EC. 47. 37. CAZOLLI DM. 52. PHILLIP M. LOPEZ I. RICHTER KP. BARTOLA SP. A rapidly progressive cataract STEIN O. VAN VONDEREN IK. treatment clinical and laboratory findings in dogs with primary hy- perparathyroidism: 210 cases (1987–2004). hyperparathyroidism in 29 dogs: diagnosis. Primary calcitonin. 2181–2193. RUOPP JL.and hypercalcaemia in the dog as determined by the »intact« and »whole« PTH assays. KLEIN-NULEND J. MARPLES D. Vet Clin Pathol 2002. POLLARD R. Curr Osteoporos Rep 2003. and para. 8th edition. RIJN- BERK A. 1992:1397–1476. Se- vere calcinosis cutis associated with treatment of hypoparathyroid. AURBACH GD. J Am Vet Med Assoc IRWIN PJ. FELDMAN EC. 38. NEIGER R. WISNER ER. Philadelphia: WB associated renal failure.129:61–69. BOYLE WJ. J Am Anim Hosp Assoc 2001. Primary hypoparathyroidism in the dog. NELSON RW. KENNEDY PC. High-resolution parathyroid so- nography.95:2047–2053.1:5–10.227:756–761. nohistochemistry in dogs with primary and secondary hyperpara- JOSEPH RJ. DRÜEKE TB.28: 973–978. J Small Anim Pract 2005. 40. REFSAL KR. NACHREINER R. Primary hypoparathyroidism in a cat complicated by suspect iatrogenic calcinosis cutis. BERGER B. Idiopathic hypoparathyroidism in five cats. RUSSELL NJ. FELDMAN EC. FRANKLIN RJ. FROKIAER J. RAMIREZ FM. J Am Anim Hosp Assoc 53. FELSENFELD AJ. FELDMAN EC.84:285–290. review. Nature 2003. MAN JS KOOISTRA HS. J Am Soc Nephrol 1998. DI- Nephrol Dial Transplant 2003.202:1132–1136. REUSCH C. eds. ARNOLD A. ZAMIR E. J Vet Int thyroidism: the question of adenoma and primary hyperplasia. SKELLY BJ.31:3–8. REIMERS TJ. WALLACE M. FELDMAN EC. 43. Ultrasonography of the parathyroid glands in dogs: a 350–356. KALLET AJ. NACHREINER RF. GAO P. 34. NYLAND TG. KOOISTRA HS. KNEPPER MA. HOAR B. DE LF. MARINO R. SIMONET WS. BURGER EH. Austr Vet J 2006. mode in a patient with autoimmune hypoparathyroidism and acute liver of inheritance. DEN HERTOG E. CENTER SA. SCHAER M.64: mary hyperparathyroidism in cats: Seven cases (1984–1989). STEINER M. Primary hyperparathyroidism in two cats. GOLD- 32. and candidate genes for primary hyperparathyroid- and renal failure. FELDMAN EC. PETERSON ME. URENA P.50:1123–1127. Pre- 9 30. VAN DER LINDE-SIP- hormone in cats.196:1285–1287. 31. WISNER ER. BILLER DS. FORBES S. LEON J. Wil. cases. ROBERTSON ID.423:337–342. RAMP WK. Mutations in genes causing human assay for use in dogs: Validation. HERRTAGE ME. roidism in a cat.. PROVENCHER BOLLIGER A. Primary hyperparathyroidism in dogs: 21 cases (1976–1986). NIJWEIDE PJ. CHEW DJ. Report of 15 cases and review of 13 previously reported 44. BRUM DE. Parathyroid hormone. ism in Keeshonden. FARCA AM. MARX SJ. 28. VAN DEN INGH TSOM. NIELSEN S. TIMOTHY SD. J Vet Intern Med 2000. tion and metabolism of PTH during hypo. 1995.14:619–626. Primary parathyroid gland hyperplasia in dogs: Six cases (1982– 1991). 39. and bone structure. Parathyroid hormone immu- 27.19:81–84.16:20–27. PENNINCK D. ROSOL TJ. AGUILERA-TEJERO E.143:55–62. GAZ RD. SKELLY BJ. Primary hypoparathyroidism in dogs: a retrospective study of 17 cases. outcome and liams Textbook of Endocrinology. Parathyroid carcinoma in a nephropathic Persian cat.199:1767–1771.46:10–16. 45. OWENS J. CAPEN CC. pedia of Canine Clinical Nutrition. TASHJIAN AH. CROWELL WA. mone and parathyroid hormone-related peptide. parathyroidism in dogs with chronic renal failure.41:461–469. ELSINGHORST THAM. MOTT J. 2005:789–795. J A peptide of diverse physiologic fucntions. Endocrinology 1992. YOROZU K. TAMURA H. 83. 72. ROSOL TJ.46:531–536. FELDMAN EC. 81. J Am Vet Med Assoc 2001. STEVENS JB. LAW JM. Lab Invest 67. GONZALEZ E. Retrospective evalu- ation of three treatment methods for primary hyperparathyroidism 75. HEGEDÜS L. EVANS H.v. 1993. Percutaneous ultrasonographically guided radio. CHEW DJ. 318–326.328:666–678. KAWATA S. J Am Anim Hosp Assoc 1975. SEGRE gression of induced chronic renal failure in cats. NELSON RW. LEVINE L. SANO T. The RANK / RANKL /OPG hyperparathyroidism. TEBB AJ. nutritional approach. JACKSON MW. NYLAND TG. Benefits of calcitriol B. Trends Endocr Metab Small Anim Pract 2005. Hypercalcemia in malignant and inflammatory dis- eases. HERRTAGE 70. J Small Anim Pract 2005. DOUGALL WC. 17 Suppl 10:46–52. POLLARD RE. RIJNBERK A. 348–383. 71. TEBB A. CHAISSON M. Endocrinol Metab Clin North Am 2002. HACK- FELDMAN EC.35:344–351. roidism in a cat. Pseudohyperparathyroidism in the 58. SCHAER M. TAKAHASHI F. ARTEAGE A. 56.103:1069–1075.46: tors. J Small Anim Pract 2000. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. with perirectal adenocarcinomas in elderly female dogs. COUTO CG. BAE BK. 26:1293–1330.218:1106–1110. WECKMANN MT. ELLIOTT J. Vet Clin North Am Small Anim Pract 1996.154:1087–1090. ROSOL TJ. GASCHEN FP. Pathogenesis Canine ovarian serous papillary adenocarcinoma with neoplastic and treatment of renal osteodystrophy. DEFTOS LJ. ROTSTEIN DS. eds. HAZEWINKEL HAW. Parathyroid hormone-related protein. UECHI M. 78. OSBORNE CA. Pseudohyperparathy- in dogs. Hypercalcemia and high parathyroid hormone-related peptide concentration in a dog with complex mammary carcinoma. 2005: Vet Radiol Ultrasound 2000. LONG CD. KIM CW. 80. NAGODE LA. 41:235–242. Review. LEQUIN RM. CHOI EW. CHEW DJ. HORI Y. FINCO DR. Biochem Biophys Res Commun 2005. on parathyroid hormone-related protein expression in the canine anal sac apocrine gland adenocarcinoma (CAC–8) nude mouse 61. Vet Clin North Am Small Anim Pract triad in cancer-induced bone disease. RAMSEY IK. 59:575–582. Percutaneous ultrasonographically guided chemical parathyroid ablation for treatment of primary hyperparathyroidism 73. VOELKEL EF.221:263–265. 2006. STEWART F.11:46–52. BLOMME EA. SLATOPOLSKY E. BARBER PJ.26:1293–1330. Pseudohyperparathyroidism associated frequency heat ablation for treatment of primary hyperparathyroid.43:70–77. Tijdschr ism in dogs. cal. 74. KOCIBA GJ. ultra- structural and histomorphometric investigations. 77. Parathyroid hormone (PTH)-related protein. Paris: Diffomedia. Double-phase pies and adult dogs. Protein and calorie effects on pro. KOEMAN JP. RAWLINGS JM. Diergeneesk 1978. Parathyroid hor- adrenocorticism: effects of trilostane on parathyroid hormone. HARRIS E. therapy and serum phosphorus control in dogs and cats with chronic renal failure.49:553–562. HUPPERT BJ. NAGODE LA. CW. KEENE BW. GENSURE RC. TAYLOR SM. Canine hyper. SHMON CL. Biochemical. J Am Vet Med Assoc 2002.36:376–378. Hyperparathyroidism in dogs with hyperadrenocorticism. Paraneoplastic syndrome. J Clin Ultrasound 2007. CHEW DJ. COOPER TL. Effects of i. 66. Dependence of humoral hypercalcemia of malignancy 9 in dogs. Hypercalcemia and high parathy- therapy and serum phosphorus control in dogs and cats with roid hormone-related protein concentration associated with malig- chronic renal failure. 63.215:217–221. GARDELLA TJ. GV. In Ettinger SJ. AYL RD. KARSTRUP S. PODELL M. Textbook of Veterinary Internal Medicine. 60.35:144–155. Blood Purif 2003. 57. Cancer Metastasis Rev 1996. LEE 1990. MATTE GG. In: Royal Canin Encyclo- parathyroid scintigraphy in dogs using technetium–99M-sestamibi. hyperparathyroidism. LEROY 64. CHEW DJ. MARTIN K. Nephrol Dial and 1. 68. Feldman EC. TESKE E. Missouri. and their recep- cium and phosphate concentrations. Am J Roentg 76.25:541–549. PRESSLER BM. OYAMADA T. Parathyroid sonography: Imaging Clin Pathol 2007.68:979–982. and intervention. Else- 65. HORNOF WJ. dog. ENG WHL. PTH. BROWN SA. STEINMEYER CL. DANIEL GB. HORNOF WJ. 21: hypercalcemia. MEUTEN DJ. PODELL M.162:125–135. GLENTHØJ A. BROWN CA. Nonsurgical treatment of primary hyperparathyroidism with sono- graphically guided percutaneous injection of ethanol. POLLARD R. KUBODERA N. PETERSON JL. DUDZIC EM. KANAKUBO K. NAGODE LA. CHOI US. model. RAMSEY IK. EVANS H. Both are essential to prevent or suppress toxic 82.131:1157–1164. Vet 62. READING CC. GOLDSTEIN RE. LONG CD. HOLM HH. FURUICHI T. NAGODE LA. MARKWELL PJ. vier Saunders. J Vet Med Sci 2006. HAMMER AS. WILKINSON 69. J Am Vet Med Assoc 1973.25-dihydroxyvitamin D in dogs with cancer-associated hy- Transplant 2002. and oral 1. Hypercalcemia in dogs with lymphosarcoma. J Am Vet Med Assoc 1999. KIM DY. 79. MATWICHUK CL. CAPEN CC. Vet Pathol 1998. . percalcemia. RASOR L. CAPEN CC.25-dihydroxy–22-oxavitamin D(3) on secondary hyper. LIU S. GRÖNE A. KI.31:141–158. J Am Anim Hosp Assoc 2007. 59. SLATOPOLSKY E. CHEW DJ. Am J Vet Res 1998. ROSOL TJ. JEE H. ME. Benefits of calcitriol 1983. Both are essential to prevent of suppress toxic nant melanoma in a dog. 537–542. JÜPPNER H. DE PAPP AE. SUNVOLD G. Osteoarticular affections in pup- AA. References 287 55. FELDMAN EC.4:181–187. J Small Anim Pract 2005. WILLIAMS LE. HOSTUTLER RA. VAN HEERDE P. J Am Vet Med 94.22:119–128. REINER RF.162:357–361. pathophysiology. NACHREINER R. Vet Clin Pathol tation of vitamin D. 107.60:1092–1097. McMANUS PM. J Am Vet Med Assoc 1973. FRENCH AF. MACEWEN EG. Clinical stage. REUSCH CE. BRA- 98. Hypercalcaemia associated with angiostrongylus vasorum in three dogs.28:565–585.16: the Alaskan Malamute. CHEW DJ.26:1417–1445. BREARLY MJ. CACERES A. HAZE- KOCIBA GJ. GLIATTO JM. MOL JA. MELLANBY RJ.78:690–692.46:334–338. FRESE KK. Am J Vet Res 2000. J Vet Intern Med 2002. cosis in dogs.46:79–84. Prognostic factors in canine non- hypercalcaemia. Veterinary Cooperative Oncology Group. KANEENE JB. TRYFONIDOU MA. DELUCA HF. LANA SE. GAMBLIN RM. mia. HAUSER B. Domest Anim Endocrinol 2003. HEN- Plasma concentrations of parathyroid hormone-related protein in DERSON D. 86. Clinical and pathologic features of chondrodysplasia (dwarfism) in son with human non-Hodgkin’s lymphoma.43:1008–1009. MEE AP. Serum levels of 25-hy. BRA. VADEN SL. 104. OOSTERLAKEN-DIJKSTERHUIS HERRTAGE ME. FRESE KK. NACHREINER R. HORN B. HAZEWINKEL HAW. KRUGER JM. KURZMAN I. GUNTHER R. KNAPP DW.159:833–838. droxycholecalciferol and 1. Vitamin D3 me- 2000. IRWIN PJ. FOOSHEE SK. Hodgkin’s lymphomas: a prospective study in 138 dogs. HERRTAGE ME. REFSAL 103. Am J Vet Res 1999. Hypercalcemia secondary to cholecalciferol rodenticide toxicosis in two dogs. DOBSON JD. Am J Physiol (Endocri- 97. J Vet Intern Med 2007.19:29–33. JL. 114. 88. VAN DEN BROM WE. 99.25-dihydrocholecalciferol in dogs with MOORE PF. 24-hydroxylase: potential key-regulator in hypervitaminosis D3 in growing dogs. Uses and effectiveness of pami- dogs with potential disorders of calcium metabolism. KRUGER JM. OOSTERLAKEN-DIJKSTERHUIS 95. PATNAIK AK. FITZGERALD SD. JOHNSON JL. FRANSON AM.34:341–352. 196:1265–1268. KRUGER JM.223:825–831. TESKE E. 110. RUTTEMAN GR. THAMM DH. GLICKMAN Toxicity of a vitamin D3 rodenticide to dogs.205:1722–1728. percalcaemia in two dogs caused by excessive dietary supplemen- Multiple myeloma in 16 cats: a retrospective study. J Am Vet Med Assoc 2004. tabolism in dogs. PARRY NMA. FITZGERALD SF. FORRESTER SD. therapy. O’RAHILLY S. Vet Rec dronate disodium for treatment of dogs and cats with hypercalce- 2006.4:205–207. 108. 105. 100. Use of pamidronate to reverse vitamin D3-induced toxi- toxicosis in dogs.27:349–355. NELSON RK. TRYFONIDOU MA. NACHREINER RF. Photosynthesis of KR Hypercalcemia and renal failure. 209–219. Anal sac adenocarci- 106. Siamese cat. MATTHIESEN DT.197:22–33. Mol Cell Endocrinol 2002. . 113. MELLOR P. FELICE LJ. 288 Calciotropic Hormones 84. CRAIG R. JAEGER JQ. vitamin D in the skin of dogs cats and rats. Vet Clin North Am Small Anim Pract Suppl 1:S29. MOL JA. nosis in canine anal sac gland carcinoma. 2006. Assoc 1990. Vet Quart 1994. RUMBEIHA WK. HALSALL D. Hypercalcaemia associated with granulomatous lymphadenitis and elevated 1. SAVARY KC. Use of pamidronate disodium to reduce cholecalciferol-induced Austr Vet J 2000.25 dihydroxyvitamin D concentration in a dog. Hypercalcemia associated with an adenocarcinoma WINKEL HAW. WOODGER N. DeNICOLA DB. J Small 92. J Am Anim Hosp Assoc 1991. MEE AP.14:184–189. and prog. OSBORNE CA. BENNETT PE. toxicosis in dogs. MARTIN LG. presentation and response to therapy. NACH- SELTON WE. MEUTEN DJ. successful treatment of hypercalcaemia of malignancy in a dog. 109. DODGE RK. MOORE AS. 9 90. J Feline Med Surg 2002. CONNOLLY DJ. 101. Canine malignant lymphoma: a review with compari. KANEENE JB. Hypercalcemia in cats: a retrospective study of 71 cases (1991–1997). SMART ME. HERRTAGE ME. Anal sac gland carcinoma in a cat. VILLIERS EJ. Vet Clin noma of the apocrine glands of the anal sac in dogs: 113 cases North Am Small Anim Pract 1998. CHEW DJ. Anim Pract 2005. RUMBEIHA WK. J Am Vet Med Assoc NW. J Vet Intern Med 2005. Vet Quart 1995. HAZEWINKEL HAW. 2005. MELLANBY RJ. CAPEN CC. ZOLTOWSKI C. SZYMKOWSKI M. Carci. 1996. Small Anim Pract 2006:47:207–212.21:274–280. TESKE E. dogs. 93.61:9–13. FOALE R. KLEIN S. Am J Vet Res 2000. GERBER B. HOLL MS. PRICE GS. FRIEND E. Vet Res Commun 2004. MELLANBY RJ. VAN DEN INGH TS. BONNEY P. (1985–1995). ROSS JT. 112. FITZGERALD SD. 96.16: 100–104. Etiology. Vet Pathol nology and Metabolism) 2003. VAN DEN BROM WE. BOAG AK. DIBARTOLA SP. Dietary 135-fold cholecalciferol supplemen- derived from the apocrine glands of the anal sac. Anal sac adenocarcinoma in a MA. Hypercalcemia and hypermagnesemia. KANEENE JB. J Am Vet Med Assoc 2003. MURPHY KF.24:265–285. HERRTAGE ME. TRYFONIDOU MA. 87. BUUR- MAN CJ. MA. Vet Pathol tation severely disturbs the endochondral ossification in growing 1981. BRASELTON WE. EVANS H. STEVENHAGEN JJ. Canine anal sac adenocarcinomas: Clinical 1988. Transient hypoparathyroidism following SELTON WE. Adenocarcinoma of the apocrine glands of the anal sac in dogs: A review of 32 cases. MELLANBY RJ. POLTON GA.17 diagnosis. BERRY JL. SUBDEN RE. RUMBEIHA WK. PENNOCK PW. KRUGER JM. BERRY noma in the dog: 14 cases.18:454–471.28:669–680.284:E505-E513. HOW KL. GOLDSCHMIDT MH. Hy- 89. J Vet Intern Med 102. SCAVELLI TD. VAN LEEUWEN JPTM. 85.61:9–13. and treatment. PATEL RT. COOPER BJ. J Small Anim Pract 1981. FLETCH SM.193:211–214. HAZEWINKEL HAW. McNEIL PE. 111. CHIAPU- Use of pamidronate disodium to reduce cholecalciferol-induced ZIO CL. J 91. J Bone Miner Res 1990. FASCETTI AJ. In- Medicine. 139. findings in young dogs chronically fed a diet containing excess cal- cium. ROBSON H. FITCH RB. BREUR GJ.132:1610S–1612S. Vet Rec Am J Vet Res 1992. HAZEWINKEL HAW. NAP RC. DEMKO J. 35:1111–1135. JEZYK PK. COX NR. YTREHUS B. GOODMAN SA. HAZEWINKEL HAW.66:606–630. ROUBIES N. SCHOENMAKERS I. In: Bojrab MJ. OLSSON SE. view of the literature. SHARP NJH. LAFOND E. SLATER MR.23:594–605. WIT JM. 38:467–477. J Neurobiol 2006. SHALET SM. and thyroid hor- mones during skeletal growth.39:299–302. GOEDEGEBUURE SA. J Nutr 1991. BRAWNER WR. MATHEWS U. Elsevier Saunders. BANETH G. Recent Advances in Canine and Feline Nutrition II. RAILA J.147:652–660. A radio. Vet Pathol 2007. 2000. eds. J Am Vet Med Assoc 1991. KARPERIEN M. J Am Anim Hosp Assoc 2002. Atlantoaxial conditions and growth plate. RAILA J. Philadelphia: Lea & biopsies. HAZEWINKEL HAW. 128. EKMAN S. Paresis and unusual elec- lengthening procedure using a circular external skeletal fixation trocardiographic signs in a severely hypomagnesaemic. BAKER HJ. physical.215:1127–1129. McKEE WM. THEYSE LF. Bone changes occurring early after cessation of ovarian function in 122. ed. Prog- nostic factors in treating antebrachial growth deformities with a 140. REINHARDT 137. Effects of diets with dif. HICKMAN MA. canine congenital hypothyroidism: skeletal changes with delayed treatment. FANTI P.44:429–448. eds. ercise as potential risk factors for osteochondritis dissecans in dogs. Thyroid hormone and the 118. Systemic and local regulation of the growth plate. VAN DER EERDEN BC. 1998:3–12. JOHNSON JA.121:S107-S113. 129. Diet and ex- ferent calcium and phosphorus contents on the skeletal develop. Vet Pathol 1986. caemic lactating bitch. hypocal- system in dogs.24: 117. Developmental orthopedic dis- 116.198: 121. FAUGERE MC. PATSIKAS MN. VCOT 1994. BONNETT BN. GOEDEGEBUURE SA. but it is not converted to vitamin A. Ultrasound 1994. 1993:777–796. BLOMHOFF R. Gonadectomy in immature dogs: effects on skeletal. J Nutr Dane pups. RE. developmental orthopedic diseases in dogs.52:137–147. Incidence of canine appendicular musculoskeletal disorders in 16 veterinary teaching 133. CARLSON CS. 119. AUSTIN CC.7:265–271. DONOGHUE S. eds. BLOMHOFF HK. SHILLE V. Vet Surg 2005. VOORHOUT G. Plasma transport and tissue distribution of beta-carotene. Ohio: Orange Frazer Press. VOORHOUT G. Preparturient hypocalcemia in four cats. Missouri. beagle dogs: a histomorphometric study employing sequential Disease Mechanisms in Small Animal Surgery. VOORHOUT G. J Small Anim Pract 1998. BLOOMBERG MS. . Serial orthopedic examinations of growing Great Dane pup. genesis of osteochondrosis. AUSTIN C.5:263–272. In: Ettinger SJ. AROCH I. WICHERT B. SCARLETT JM.7:363–368. 2005:563–566. FRIEDLER RM.53:2119–2124. Carey DP. HAZEWINKEL HAW. SCHWEIGERT FJ. In: Slatter D. Textbook of Veterinary Internal 132. metabolism and function. 130. Wilmington. vitamin A and retinol- 125. Growth and skeletal development in Great Dane pups fed different levels of protein intake. SAUNDERS HM.35:271–276. LEPINE AJ. SCRUGGS SL. SALMERI KR. 134. ATH. HAZEWINKEL HAW. hospitals from 1980 through 1989. HAZEWINKEL HAW. IGF-I. Pediatr Res 2002. RICHARDSON D. MCLAUGHLIN R. Textbook of Small Animal Surgery. ment and blood chemistry of growing Great Danes. BALLOCK RT. Smeak DD. Cats graphic study on the development of the antebrachium in Great absorb beta-carotene.32:171–177. VAN DEN binding protein in domestic cats. Hypervitaminosis A in the cat: a case report and re- pies fed three diets varying in calcium and phosphorus. Bloomberg MS. MALLUCHE HH. Feldman EC. COCKSHUTT J. BREUR GJ. The radiographic appearance of 1183–1192. Febiger. KIENZLE E.34:424–435. J Feline Med Surg 2005. References 289 115. POLIZOPOULOU ZS. LAUTEN SD. KAZAKOS G. hardt TA. glucocorticoids. SIEBLER T. RUMPH PF. Etiology and patho.130:849–856. ERB HN. NAP RC. VOORHOUT 127. Endocr Rev 2003. 135. Vet Radiol 1991. HATH. 126. Nutrition-related skeletal disorders. OHAD DG. 2003: 131. J Am Vet Med Assoc 1999. Wobbler Syndrome – Cervical Spondylopathy. 782–801. 138. WANG L. Morphological ease. COCK JT. 120. MONTGOMERY RD. CARLSON CS. 136. TA. Overview of retinoid 124. Vet Clin North Am Small Anim Pract 2005. Vet Radiol 2002.56–69. Breed susceptibility for 1193–1203. KINCAID SA. In: Rein. SCHWEIGERT FJ. WB Saunders Co. raised under standardized conditions. WILLIAMS GR. teractions between GH. VAN ’T KLOOSTER Integr Physiol 2001. Rev Endocr Metab Disord 2006. SHAO YY. 123. KADERLY G. and 9 behavioral development. Comp Biochem Physiol A Mol BROM WE. This page intentionally left blank . of which neuroendocrine cells with APUD characteristics are one constituent. gastric or hepatic tumors secreting incompletely processed in- crete hormones is not confined to endocrine glands. initially purified from porcine brain extracts and hence the crine glands of the anal sac region (chapter 9. in which DNES cells and local peptide. The best known action of ing cells that may exert autocrine and paracrine actions these peptides is that on the kidney. with a physiologically inactive 98-amino acid N-terminal Hormone excess syndromes caused by tumors in tissues that fragment of pro-ANP (NT-proANP). and hypoglycemia due to As discussed in chapter 1. These ectopic hormone syndromes are not truly ectopic. the term neuroendocrine was introduced.11). the cells of the DNES may be involved in excessive secretion under the Atrial natriuretic peptide (ANP) is a 28-amino acid peptide influence of exogenous or endogenous stimulation such as in secreted from the cardiac atria in response to stretching of the the case of progestin-induced GH excess (chapter 2.3 In addition to their important roles in physiology.2 Natriuretic peptides i.4.2).1 Introduction solism due to ACTH excess produced by a pancreatic neuro- endocrine tumor (chapter 4.1 A preeminent example of this system has been presented in chapter 2. They are released into the circulation in the recognition of the wide distribution of peptide-secret. In the sulin-like growth factors (chapter 5. Canine NT-proANP is do not normally secrete the hormone in significant amounts 87 per cent homologous with human NT-proANP. those producing gastroin. number of hormones and intrarenal paracrine factors. Examples are hypercalcemia NT-proANP fragments. It is secreted in equimolar amounts can also result from neoplastic transformation of DNES cells.2. 291 10 Tissue Hormones and Humoral Manifestations of Cancer Ad Rijnberk Hans S. where they promote the (fig. 10.1). Initially it was thought that stead.4). by stretching of the myocardium. and modulation of a containing neuronal cells and ganglia coordinate local neuro. In general.1 the capacity to synthesize and se. name.2 A common feature in these tional properties.2. tissue has not been described in dogs or cats and seems to be extremely rare in man. namics. although occurring in different anatomical sites. Kooistra 10.1) for vital processes such as epithelial growth. to some extent in dogs and cats but have not been discussed in It has therefore been proposed to de-emphasize embryologic detail in previous chapters and /or are known to be associated origin and instead to designate this widespread endocrine / with humoral manifestations of cancer. For example.4. last two decades it has become clear that body functions are also strongly influenced by diffuse hormonal secretion ema. paracrine /autocrine system as the »diffuse neuroendocrine system« or DNES. thereby endocrine regulatory functions.1. 2. characteristics the acronym APUD (amine precursor uptake steroid synthesis by neoplasms depends on their origin in ad- and decarboxylation) was coined for these cells. 10. This chapter concerns some peptides that have been studied testinal and pancreatic hormones are derived from endoderm.3. It atrium (figs..3). tubular sodium handling. which the neoplasm originated.2).2. cation of a property that is normally present in the cells from shared a common embryologic origin and common func. Because of some common biochemical syndromes is the elaboration of peptide hormones. and because renal or gonadal tissue. they are the consequence of tumor-induced amplifi- these cells.3. 10. In the excretion of sodium and water. hypercorti. 1. 10. Brain natriuretic peptide (BNP) was due to PTHrP secretion by a tumor originating from apo.e. 10 It is now known that not all of these cells originate from neu- ral crest or ectoderm. In- nating from many cellular sources. but it was subsequently found in much higher concen- . Complete synthesis of steroid (or thy- of the presumed common embryogenesis from the neural roid) hormones by tumors originating from nonendocrine crest. growth hormone (GH) producing cells in the mammary gland (fig. allowing have been termed »paraneoplastic endocrine syndromes« or measurements of NT-proANP in dogs with assays for human »ectopic hormonal syndromes«. These diuretic and natriuretic gut there is a functional convergence of tissue hormones and effects result from complex interactions with renal hemody- the nervous system.4). Natriuretic peptides (NP) are structurally related peptides that play an important role in the integrated control of volume Part of the relevance of these tissue hormones or the DNES is homeostasis (fig.1). opposing the actions of the renin-angiotensin system (chap- ter 4. 4 clinical assessment of heart disease. 1994. Recently assays laboratory than the active hormones. Canine NT-proBNP shares only 45 physiologically inactive fragments are also more stable in the per cent homology with human NT-proBNP. respectively. The half lives of both NT-proANP and NT-proBNP are lational modification similar to that for proANP.1: sion.3: Plasma ANP concentrations (mean ± SEM) in eleven dogs with pericardial effu- Figure 10.앗= decrease (Adapted from Stokhof et al. ProBNP undergoes posttrans. pericardial or atrial pressure but rather atrial stretch that causes ANP release. as influenced by pericardiocentesis (at time zero). The disulfide bond is essential for bio- logical activity. resulting in longer than those of ANP and BNP. These BNP and NT-proBNP. 292 Tissue Hormones and Humoral Manifestations of Cancer Figure 10.2: The amino acid sequence of canine ANP. make measurements of the pro-fragments more suitable for trations of NT-proBNP in dog plasma. 10 Figure 10. This illustrates that it is not Role of natriuretic peptides in volume homeostasis. Studies in dogs and cats . 앖= increase.. These characteristics have been introduced that enable measurements of concen.)5 trations in cardiac ventricles. 25 Nonneoplastic With progressive loss of renal parenchyma. It is primarily pro- duced in interstitial fibroblasts in the kidney. Erythropoietin 293 have revealed that measurements of plasma NT-proANP and NT-proBNP are useful adjuncts in diagnosing cardiac disease and in assessing the severity of the disease.22. mone induces Epo gene expression and directly promotes dif.23 Polycythemia has also been observed usually low (chapter 3.. such as in chronic renal disorders such as pyelonephritis have also been reported renal insufficiency.11 ment of the right caudal lobar pulmonary artery (arrow) caused by a thrombus. throcytosis has been suggested to be the result of circulatory centrations of Epo have been reported in the low normal disturbances in the kidney.4: sources account for less than 10 % of the production. such as a cecal leio- myosarcoma and a cervical schwannoma. tremors.26.24. bosis and hemorrhagic diathesis.17 Recombinant poxia without destruction of the cells responsible for Epo human Epo (rhEpo) has been used to treat this anemia. Glucocorticoids are important in promoting erythro. in dogs with tumors of nonrenal origin. In most of the reported cases cleated red blood cells. to cause secondary polycythemia. They include coping with hemorrhage or erythrolysis. such as in toms and signs can be related to hyperviscosity.28 between rhEpo and feline Epo (fEpo) or canine Epo (cEpo) to induce an immune response.14. circulating con. regenerative anemia secondary to renal failure without caus- enchyma.6–9 Renal function must be taken into account when interpreting elevated concentrations. due to progesterone-induced GH excess of mam. polycythemia. hematocrit values are solved the problems.21 ment in the hematocrit. in which the circulating concentration of .27 In these cases the ery- Indeed. in dogs with chronic renal failure. GH and IGF-I have been reported to rhEpo-treated dogs.4). In this syndrome most symp- poiesis directly in situations of hematological stress. a relative deficiency of Epo may develop. termed secondary polycythemia because it is mary origin (chapter 2.12 Chronic GH ad.e. despite mild to moderate anemia. The right ventricle is enlarged and there is marked enlarge- identical to feline and canine Epo. Human Epo is 85 % ent hypercortisolism and polycythemia.2. velop. sufficient to cause local tissue hy- range. Epo exhibits a high degree of twelve-year-old male beagle with pituitary-depend- sequence homology among mammals. but also local changes in renal blood flow caused by 10 renal cysts or tumors that compress the surrounding renal par. Other hormones may influence Epo secretion and ing the profound erythroid hypoplasia that may occur in thereby erythropoiesis. polycythemia vera. The use of rcEpo has been re. for cats and even with use of rfEpo red-cell aplasia may de- ministration to dogs causes a dose-related normochromic. fEpo was delivered via gene therapy. and seizures.3 Erythropoietin Erythropoietin (Epo) is a glycoprotein having a molecular mass of 34 kD and containing 165 amino acids.15 Thyroid hor.28 The release of Epo is regulated by classic feedback control. This includes not only systemic hypoxia. In production. Extrarenal Figure 10. In addition to these secondary forms of polycythemia there is ported to stimulate erythrocyte production in dogs with non. ataxia.2). These measure- ments are also helpful in distinguishing between animals with congestive heart failure and those with primary pulmonary disease.18 Apparently there is sufficient structural difference with pituitary-dependent hypercortisolism (fig. About 40 % of its mass is composed of carbohydrate.19 Unfortunately this does not hold true decrease Epo secretion from rat kidneys.13 This can explain why bitches that develop diabetes mellitus in the luteal phase of the estrous Increased production of Epo may lead to the syndrome of cycle.3. It is secreted in response to renal tissue hypoxia.10. disorientation. the underlying cause was a renal carcinoma and its removal re- such as in primary hypothyroidism.1). lethargy. The sludging of blood cells may result in throm- ferentiation and maturation of erythroid cells toward nu.16 In the absence of thyroid hormone.4. spontaneous hypercor- cell response. 10.3). episodic weakness. but in several treated animals the effect was tisolism may also be accompanied by elevated hematocrit short-lived because of the development of antibodies against values (table 4. i.20 This has also been reported to occur in cats in which normocytic. throid-stimulatory substance. for Transverse CT of the thorax at the level of T-7 in a which the liver is the main site.4 10. Consistent with the previously-mentioned effect both dogs and cats rhEpo induces a rapid and substantial red of glucocorticoids on erythropoiesis. whereas hyper- oxia decreases its production. may have low hematocrit secondary to excessive production of Epo or another ery- values. Polycythemia has been observed in a dog rhEpo. nonregenerative anemia leading to a 10 % decre. STREWLER GJ. BUNN HF. 7. increased thermogenesis in brown adipose tissue caused by plasias and tumors produce peptides causing hormonal syn. Lippincott Williams & Wilkins 2001: atrial natriuretic factor. In: 8. BOISSEL J-PR. SYME HM. . In: Kro. and T-regulatory lymphocytes a population of abnormally replicating erythroid progenitor that are involved in the development and progression of cells that fail to respond to inhibitory signals.34 The syn- tide secretion and diminished growth. sequence homology among mammals. Philadelphia. patients indirectly by promoting the expression of uncoupling ized with labeled ligands to receptors on the DNES cells. Principles and practice of endocrinology and lating amino terminal-pro-B-type natriuretic peptide concen- metabolism. CZELUSNIAK J. 5. J Am Vet Med Assoc 2008. fect of pericardiocentesis on circulating concentrations of atrial na.1. MARTIN M. a wide range of DNES hyper. and also by direct uncoupling of mitochondrial res- For example. Measurements of the particular 5'-triphosphate (ATP) synthesis.82:1507–1516. ed.21:238–242. CHU L.30–32 This cancer cachexia often results in Initial treatment consists of temporary alleviation by repeated marked weight loss and particularly loss of muscle mass. Principles and practice of endocrinology and guishing cardiac and noncardiac dyspnea in 48 dogs using plasma metabolism. Lippincott Williams & Wilkins 2001: tration in dogs with respiratory distress attributable to congestive 1622–1634. ESPINER EA. ATTREE S. lating natriuretic peptides in cats with heart disease. SOLTER PF. BOS- LITTLE C.232:1674–1679. In humans the systemic effects of pro-inflammatory or cause of this myeloproliferative disorder with character. A. 2. octreotide scintigraphy can visualize somatosta. GRUNINGER RH. SISSON DD. RUSH JE. J Vet Intern Med 2007. Med 2008. loidal and electrolyte solutions. OYAMA MA. The diffuse neuroendocrine system. BOSWOOD. cytokines such as interleukin-6 (IL-6) and tumor necrosis fac- istics of malignant transformation remains obscure. OVERDUIN LM. RIJNBERK A.33 tin-binding sites (see also chapter 5. Melmed S. OYAMA MA. LUIS FUENTES V. The enhanced protein degradation is me- diated by the ubiquitin-dependent proteolytic system. uncoupling of mitochondrial respiration from adenosine- dromes of an »ectopic« nature. nenberg HM. proteins.4 Humoral manifestations of cancer In addition to anorexia and protein loss.130:357–360. ROZANSKI EA. heart failure or primary pulmonary disease. Philadelphia. osteosarcomas in dogs in- crease resting energy expenditure and protein loss. FOX PR. There is experimental evi- hormone can be used as an aid in diagnosis and in following dence that TNF-a can stimulate heat production in cancer the result of treatment. tumors with somatostatin receptors may respond to a somatostatin analogue such as octreotide by decreased pep- Similar to neoplasms in humans. DECLUE AE. FINE DM. The mechanism cancer. RADEMAKER MT. Williams Clinical utility of serum N-terminal pro-B-type natriuretic peptide textbook of endocrinology. METCALF M. REINERO CR. TRACY TE. Ef. J Vet Intern J Small Anim Pract 2008. and 1605–1611. a hypermetabolic state also plays an important role in cancer cachexia. cardiac troponin-I. fever. MULCAHY LS. Humoral manifestations of malignancy. latter is due to increased degradation of myofibrillar protein. CONOLLY DJ. Erythropoietin structure-function relationships: high degree of neous pericardial effusion. Circu- triuretic peptides in the investigation of canine cardiac disease. Blood 1993.22).22:96–105. Both weight loss and loss of lean body mass are the well-known peptide hormones but may also include cy. endothelin. The diagnostic accuracy of different na.1 and fig. The phlebotomy and replacement of the removed volume by col. SOARES MAGALHAES RJ. and sometimes also decreased protein synthesis. triuretic hormone and arginine vasopressin in dogs with sponta.232:1496–1503. LOUREIRO J. B-type natriuretic factor. 9. 3. drome of cancer cachexia has been studied in canine and fe- line patients by measuring weight loss and changes in body The secretion of peptides by cancers is not confined to condition. dendritic cells.3.36 tokines. Polonsky KS. eds. tor-a (TNF-a) include fatigue. Tumor stroma contains inflammatory cells such as References 1. Eur J Endocrinol 1994. ed. There is As discussed in chapter 10.29 especially myosin heavy-chain. BECKER KL. which can be activated by cytokines such as TNF-a and IL-1. GOODMAN M. disease severity.49:26–32. more prevalent in cancer in cats than in dogs. and hyperalgesia. 5.35. J Am Vet Med Assoc 2008. depression. Larsen PR. Saunders/Elsevier 2008: concentration for identifying cardiac disease in dogs and assessing 1803–1820. STOKHOF AA. Evaluation of circu- Becker KL. LESSER M. JAMES RA. 6. SMITH P. piration. Fur- 10 thermore. anorexia. Philadelphia. STAFFORD-JOHNSON M.33 10. MOL JA. DUKES-MCEWAN J. PROŠEK R. The endocrine heart. WOOD A. Distin- In: Becker KL. 294 Tissue Hormones and Humoral Manifestations of Cancer erythropoietin is low and excessive erythropoiesis is caused by macrophages. Many of these tumors can be visual. 10. WEN D. 4. NYLÉN ES. Pharmacological and toxicological effects of 26. NISHIMURA R. MORRISSEY in a dog. SHIMADA A. SORENMO K. TRONCHE F.220:486–490. Secondary erythrocytosis associated with schwannoma 13. ELLIOTT S. BAEZ JL. Metabolic alteration in dogs with osterosarcoma. KATO Y. ALLEN DP. RANDOLPH JF.103:555–558. J Vet Intern Med 1992. MJ. MA Y. HOLDER D. MAZZAFERRO EM. ZHOU J. RANDOLPH JF. and clinical assess.49:363–366. VAN VONDEREN IK.35:802–807. 31. J Vet Intern 33.2:42–50. KELLENDONK C. HUBER J. TURNER AS. 30.184:199–207. MEYER HP. COWGILL LD. SATO K. Vet Quart 1993. Erythropoietins: 24. DISERENS D. FANNOCK IF. DI ROCCO F. CULBERTSON R. an adult with a systemic inflammatory syndrome. Human growth hormone and insulin- like growth factor-I inhibit erythropoietin secretion from the kid. Secondary polycythaemia associated with high REICHARDT HM. Expression of erythropoietin in cats treated with a condition and weight loss in dogs presented to a veterinary onco- recombinant adeno-associated viral vector. tients. Secondary erythrocytosis associated with high plasma 1573–1584. LAUR- failure. Toxicol with renal disease in the dog: two case reports and review of the lit- Pathol 1998.15:108–111. 23.31:29–33. HIKASA Y. MYERS JS. erythropoietin concentrations in a dog with cecal leiomyosarcoma.287–R600–R607. 28.13:2996–3002. GREYDANUS-VAN DER PUTTEN SWM. 14. PATRICK DH. LEBERBAUER C. PALLINI R. CAHILL KS. erature. 27.8:887–899. FRACASSI F. J Vet Intern Med 1997. J Feline Med Surg 2007. Mechan- Med 2004. PETER CP. EGRIE JC. ETTI L. PHAM E. Proinflammatory cytokines and sickness behavior: im- plications for depression and cancer-related symptoms. Pyrogenic cytokine interleukin–6 expression by a chordoid meningioma in 19. VELDHUIS KROEZE 15. MACDOUGALL IC.9:411–417. Am J Vet Res 2001. GESSI M. DIANA A. VAN ZWIETEN MJ. J Neurosurg Clinical efficacy and safety of recombinant canine erythropoietin in 2005. SHEHDULA D. Primary polycythemia in a dog with hypercortisol- BEUG H. Exper Hematol 2008.36: GOTA K. FERNANDES PJ. SHOFER FS. CHEN HY.18:81–91. STEIN TP. SERUGA B.26:185–200. YAMAUCHI A. Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1. OKADA T. LOBINGIER RT. SOHMIYA M. isms to explain wasting of muscle and fat in cancer cachexia. MEIJ BP. Nat Rev Cancer 2008. EJB. Anemia of chronic renal failure in dogs. STABINSKI LG. SCARLETT J. Blood 2005. JAMES KM. BERNSTEIN LJ. OHTA T. Am J Vet Res GK. Cont Nurs 18. 20. 34. MICHEL KE. KA- a common mechanism of action. Different steroids co-regulate long. 25. MOCHIZUKI M. Am J Vet Res 2005. Cy- Am J Physiol Regul Integr Comp Physiol 2004. HACKETT TB. term expansion versus terminal differentiation in primary human erythroid progenitors. 21. tokines and their relationship to the symptoms and outcome of cancer. FETTMAN 2004. FERNANDEZ E.1:293–298. SCARLETT JM. The plasma erythropoietin concentrations in a dog with a necrotising glucocorticoid receptor is required for stress erythropoiesis. 36.18:692–695. Gene pyelonephritis.66:1605–1608. Evaluation of body BJ. FANDREY phlebotomies. MACLEOD JN.24:109–114. UNFRIED G. J Vet Clin Sci 2009. NAGODE LA. J Vet Intern Med 2004. ZHANG H. J Am of weight loss and changes in body condition in feline cancer pa- Anim Hosp Assoc 1995. BRÜNE B. SLAPPENDEL RJ.66: logy service. A pros- 22. MATSUNAGA S. SORENMO K. LÓPEZ-SORIANO FJ. J Endocrinol 2005. . WESSELY O. SCHÜTZ G. CRAWFORD PC. 10 17. BAUER A. KESSLER M. FREITAG P. DOI K. STOKOL T.212:521–528. OGILVIE ment of recombinant feline erythropoietin. MURPHY CJ.105:85–94. WALKER MC. MORITA T. Curr Opin Support Palliat Care 2007. MEYER HP. WALTON J. STEINLEIN P. WINGFIELD WE. J Am Anim Hosp Assoc 1988. MACLEOD JN. MANDELL TC. 450–456. Polycythaemia vera in a dog treated by repeated 16. WATERS DJ. LAURIOLA L. dogs with anemia of chronic renal failure and dogs with recombi- nant human erythropoietin-induced red cell aplasia. DE BURLET G. BROWNE JK. J Small Anim Pract 2008. 12. neys of adult rats. MÜLLNER EW. J.11: 300–303. References 295 11. SASAKI N. Secondary polycythemia associated chronic porcine growth hormone administration in dogs. MAIRA G. Expression. BOULMÉ F. LEVY JK. BYRNE 35.6:264–270. bioactivity. LEVY JK. pective investigation on the prevalence and prognostic significance Concurrent renal adenocarcinoma and polycythemia in a dog.65:1355–1366. BUSQUETS S. KOOISTRA HS. J Vet Med Sci 2004. MICHEL KE. KRAUS JS. RE. PRUETERS JC. FREDE S. MILLER Forum 2008. SIMON GG. SHOFER FS. DENARO L. ARGILÉS JM. CROW SE. A. SAUNDERS KM. Dev 1999. Polyuria and polydipsia and disturbed vasopressin release in 2 dogs with secondary polycythemia. J Am Vet Med Assoc 1998. STOKOL T. KING LG. PRAHALADA S. BEUG H. MACLEOD JN. GIGER U. OZAKI K. 29. Use of recombinant human ery- thropoietin for management of anemia in dogs and cats with renal 32. NAKAYAMA H.62:1234–1239. J Am Vet Med Assoc 2002. ism. This page intentionally left blank . notably humans and rodents. often called the hunger hormone. dermatopathies.1).1 Introduction Obesity is a pandemic in humans and pet animals.9 Leptin is a hor. The excess energy leads to deposition of triglycerides in adipose tissue. Peptide YY (PYY) is thought to mediate the appetite-sup- mone synthesized primarily in differentiated adipocytes pressing effect of dirlotapide (Slentrol®.2. ghrelin been studied in dogs and cats. has been cloned and purified15 and has been shown to in- leptin. especially on the hypothalamus. Leptin has been found to be high in obese dogs10 and cats. No breed prevalence has been docu- mented in cats.8. which shown to increase when food is withheld and to decrease after senses external stimuli. ter 2. In dogs. in- cluding the Labrador retriever. Appetite is regu. The lated peptide. 11 dachshund. PYY = peptide YY.1 Appetite regulation tin-resistant state.4–7 As we increase our understanding of the physiology of dogs Figure 11. Unfortunately. including arthritis. cocker spaniel.1).2. Cholecystokinin. It decreases Understanding the regulation of appetite is an important part with weight loss. respiratory conditions.2 Pathophysiology energy expenditure.12. In healthy subjects. In cats. 11. which is secreted in the duodenum. (fig. The oversupply of high-energy diets to a pet population now frequently leading a very sedentary lifestyle is the most likely cause. 297 11 Obesity Margarethe Hoenig 11.14 In cats.1) and its appetite-stimulating effect is thought to lated by several hormones and gastrointestinal factors as well be mediated through neuropeptide Y and agouti gene-re- the central and autonomic nervous systems (fig. In dogs.11 which indicates that obesity is a lep- 11. Pfizer) and mitrata- . ing the factors involved in its pathophysiology and unraveling its causative role in co-morbidities. it increases several-fold the risk of developing diabetes mellitus. crease with fasting. 11. is an appetite suppressant in both dogs and cats.1–3 It is a risk factor for several diseases. neutering. cardiovascular disease. they include cholecystokinin. females are more prone to become obese. leptin acts centrally. we can expect to progress in defin. Gender.11 of understanding and treating obesity. is synthesized most of what is known about appetite regulation stems from primarily by the acid-producing cells in the stomach (chap- other species. very few original data are available from dog and cat studies and Ghrelin. and ghrelin.1: and cats and recognize obesity as a disease that should be Known regulators of appetite in dogs and cats. while in cats males are. inhibiting food intake and increasing 11. CCK = cholescytokinin. Few of the peripheral factors have feeding. and beagle. Cairn terrier.13 It is increased in obese dogs. An increased preva- lence of obesity has been found in certain breeds of dogs. Leptin is also highly correlated with fat mass and can be regarded as a marker of obesity. but there have been no published studies of ghrelin in obese cats. Obesity is now thought to occur in one-third to one-half of the dog and cat populations. urinary tract disease. recorded and monitored. and cancer. and age are risk factors for obesity in both dogs and cats. This most common nutritional disorder in cats and dogs occurs when energy input – food intake – is greater than energy output. plasma ghrelin concentration has been main central regulator of appetite is the hypothalamus. eventually amyloid deposition. com. FT4 has the strongest positive correlation with the which regulates lipoprotein lipase.32 Yet there is no evidence that pared with the obese cats having normal glucose tolerance. 11. obesity increases secretion of both insulin and of canine obesity. called amylin. fatty acids are not only de. when the endoplasmic reticulum is unable to process amylin ance was still normal in approximately 30 % of obese cats correctly. Janssen).17 A recent study revealed in humans.22 Similar data are not available for dogs. the insulin secretion pattern has al. sulin ratio when diabetes mellitus develops (chapter 5. although usually still within the normal range until been observed in obese dogs. This leads to the formation of toxic fibrils and with a similar degree of obesity. where fatty acids. betes mellitus and thus whether this ratio might be used as an sulin secretion and a decrease in insulin action. It is thought that this rise contributes to insulin resistance. Thyroid the liver but also by suppressing insulin-stimulated glucose hormones are involved in regulation of the resting (basal) transport through the insulin-sensitive glucose transporter metabolic rate. lipid. not only by increasing glucose output from Thyroid hormone changes are also seen in obesity. GLUT 4.. fatty acids in plasma. also all cases.29 Plasma total thyroxine when fasting blood glucose concentration is still maintained (TT4) and T3 concentrations were higher in obese than in within the normal range. It appears that insulin resistance precedes changes There are other hormonal changes in obese cats and dogs. i. indicator of the disease. and protein metabolism. lean dogs.23. glucose intolerance was related to the de. One of the main questions concerning the progression from lease. primarily due to a large increase in second-phase re. secretion of tumor necrosis factor a from large adipocytes. nonesterified posited in fat cells but are also shunted to muscle cells. this leads to amyloid formation in obese cats. which acts as a satiety signal. At a time volved in the low heat production.. It is the gree of obesity and was not seen until the dog exceeded its precursor of islet amyloid.17 The obese glucose-intoler. and proin- sulin levels in humans are related to atherosclerosis and car- diovascular disease. In dogs. and in cell differentiation. Persistent insulin resistance in cats eventually leads to a decrease in the total insulin secretory capacity and Compared with lean cats.28 Energy expenditure is lower in obese they are deposited. although still within the reference range.11. secretion of amylin follows the pattern of insulin secretion.2 Hormonal and metabolic changes obesity in cats26 but it is not known whether there is a change in the proinsulin:insulin ratio with the development of dia- The development of obesity leads to marked alterations in in. which is thought to be formed ideal body weight by approximately 70 %. there is hyperamylinemia. It has been proposed that this This suggests that proinsulin can be used as an indicator and change triggers PYY release. new agents used for the treatment In humans.2. obesity indices body fat.24 Proinsulin has been shown to be a marker for insulin resistance. The mechanism by obesity have not been studied in dogs.1). and lipolysis (chapter 3. with apoptosis of beta cells ant cats of that study had a significantly higher area under the that exceeds the rate of their regeneration. Changes in proinsulin secretion in crease in insulin resistance (fig. obese cats and dogs have low adiponectin concen- that each kg increase in weight led to approximately 30 % loss trations. GLUT 4 expression was decreased Free thyroxine (FT4) concentration and the FT4 fraction have when glycosylated hemoglobin values were still normal. are transcription factors involved in carbohydrate. In obese cats. which an increase in fat mass causes these changes is not understood.20 Probably because of increased development of the morbid obesity seen in clinical patients. obese cats have lower expression of overt diabetes mellitus. Its concentration is in insulin sensitivity is associated with increased lipolysis in inversely related to body mass and positively correlated with adipose tissue and a rise in the concentration of nonesterified insulin sensitivity.e. which and erratic. In cats. 298 Obesity pide (Yarvitan®. an in. at least in cats. At that time insulin secretion is low peroxisome proliferator-activated receptors (PPARs). girth. but it is not adequate to maintain glucose tolerance in concerns the role of islet amyloid polypeptide (IAPP).19 been shown to be significantly higher in obese cats than in 11 Changes in the subcellular distribution of GLUT 4 have also lean cats.31 In obese cats the curve of insulin concentration during the last 30 min of test. which suggests This suggests that abnormalities in insulin action rather than that neither obesity nor hyperamylinemia per se is sufficient in insulin secretion were already present in the cats when lean to cause amyloidosis in the presence of a normal beta cell and predisposed them to more severe changes when they be.8 PPARa is in- . came obese. ing and lower glucose clearance when they were lean.17 than in lean cats and increases with administration of triiodo- thyronine (T3). The beta cell response is adequate to maintain fasting compensated obesity to diabetes in both cats and humans levels. Dirlotapide and mitratapide inhibit micro. body mass index. proinsulin and there is a marked increase in the proinsulin:in- somal triglyceride transfer protein.1). mass.30 ready changed in obese cats and dogs compared with lean ani- mals.16 sensitive marker of beta cell dysfunction.e.2). cumulation in enterocytes. a hormone cosecreted with insulin. which leads to lipid ac.27 Adiponectin is secreted from adipose tissue and in insulin sensitivity and glucose effectiveness.25 Proinsulin secretion is also increased in 11. i.2. and leptin.18 The decrease modulates glucose and lipid metabolism. thermogenesis. suggesting that thyroid hormone is partly in- Obesity also leads to changes in insulin secretion.21 Glucose toler. As in insulin secretion. higher or not different from that in lean dogs and the high regulation of genes involved in fatty acid oxidation. abdominal fat deposition in cats is equally divided which have been associated with cardiovascular disease in hu.38 However. plasma cholesterol species. A nine-point body condition scoring sys- In obese dogs. drugs which increases insulin sensitivity in many dogs than in cats. which is thought to increase VLDL synthesis. in- Overproduction of VLDL in cats was associated with an in. There is an in. and diabetic cats are not prone to high blood in the change of insulin sensitivity in both species. suggest- entiation. lesterol.2: Known hormonal and metabolic changes in obese dogs and cats. fenofi. Atherogenesis and cor. pressure or such complications as hypertensive retinopathy or proteinuria.39 Overproduction of VLDL has also been associated diet.35–38 resistance. dogs and cats have although it has been shown that the PPARa agonist. obese humans. such as reduced hepatic insulin extraction. cats. The low density lipoprotein (HDL) fraction. Pathophysiology 299 Figure 11. lowers serum concentrations of triglyceride and choles. which represents cho.43 creased number of large and medium-sized VLDL particles. which argues against a primary role of visceral fat deposition betes mellitus. have been reported in obese dogs on a high fat diet. body composition. The type of fat deposition has received great attention in terations in lipid metabolism and lipoproteins. hypertension and atherosclerosis expressed in adipose tissue and is involved in adipocyte differ.33 It is activated by fatty acids and thiazolidine.35 obesity.11 In insulin-resistant obese dogs fed a high-fat diet.40. a change mostly due to an insulin and it leads to many of the metabolic abnormalities in increase in the very low density lipoprotein (VLDL) fraction. PPARg is highly creased. and perturbed lipid metabolism. plasma cholesterol has been found to be either tem is probably the most frequently used method in private . ab- with decreased expression of PPARa.38 However. decrease in HDL cholesterol is seen in long-term obesity in Information about PPAR expression in obese dogs is lacking. Diagnosis There are subjective as well as objective methods to assess There have been conflicting findings concerning cholesterol. ing that the dyslipidemia of obesity is more detrimental in diones.34 The low PPARg concentration seen is increased by increased HDL cholesterol. regardless of mans. Obesity is characterized in both dogs and cats by marked al. and the former remains high in spite of any decrease with terol. creased gluconeogenesis. volved in adipocyte mitochondrial biogenesis and the up. in contrast to humans.42 In newly obese cats. including cats. 11 expression suggests that fat cells of obese cats are less meta.37 A significant in obese cats supports the finding of marked insulin resistance. dominal subcutaneous fat increased more than visceral fat.44 onary artery disease are not features of feline obesity or dia. between subcutaneous and intra-abdominal. human medicine because visceral fat (the android type of fat crease in the plasma concentration of nonesterified fatty acids deposition) is thought to play a primary role in causing insulin (NEFAs).41 As in humans. much higher concentrations of HDL than LDL cholesterol brate. Visceral fat is resistant to the antilipolytic effects of Plasma triglycerides are increased. has been reported to be either increased or de- bolically active than those of lean cats. dogs enjoy other activities such as swimming. tein. cise by providing toys and by placing small amounts of food culated in cats according to the following formula: BMI = around the house rather than providing it in one dish.53 posits over the entire body. resulting in Obesity assessed by measuring the body circumference or satiety (chapter 11. Overfed cats are hepatic lipidosis. and there are fat de. because of the great variation in size of the general pet of fat by inhibition of microsomal triglyceride transfer pro- population. MRI can provide exact quantification of requirements. The veterinarian needs to monitor become available for dogs. This is accomplished through management of diet obesity is a disease and will have detrimental consequences for and lifestyle.11.50 Recently it was shown that a diet weight loss.47 BMI correlates well with Janssen Animal Health. chapter 8.1).16 Mitratapide measurements of body fat by dual energy x-ray absorptio.51 Because different fiber types and protein sources were an animal that is underfed and whose ribs are easily visible (1) used for all three diets in that study. solution is provided in bottles of three sizes to facilitate ad- metry (DEXA). shoulder to the tuber ischium. 9 if they cannot be palpated. depending on the amount of fat: 7 if the ribs are week has been reported to be safe.44 pide is resumed for an additional three weeks. It has also been cal. These drugs decrease intestinal absorption lations. Energy restriction ideal body condition is 5. Pfizer) was approved by the 11 the point of the elbow to the proximal boundary of the meta.46 It is voluntary food intake than a diet with either moderate pro- also difficult to score animals that have lost weight recently or tein / high fiber content or high protein /moderate fiber con- have long hair. Exercise is an important part of any program and high in fiber and high in protein led to greater reduction in will benefit both pet and owner.2 ml/kg. some require specialized equipment. . but only within well-defined popu. stances such as conjugated linoleic acid or carnitine needs to cause of heavy deposits of fat. a body condition score of 1–3 indicates tent. dirlotapide (Slentrol®. Scores of 6–9 indicate that a dog is overfed: 6 if the Owners of intact cats need to be aware that neutering de- ribs are difficult to palpate. it is not clear what effect or have minimal fat covering and are easily palpated (3).48 Girth and BMI measurements require ministration of the dose in the food according to the dog’s no specialized equipment.2). There is no similar drug for use in cats at present.49 and recently therapeutic intervention has also the pet if left untreated. There are also several computer programs that can covering. A 1–1. there creases energy requirements52 and increases appetite (see also is no observable waist or abdominal tuck.11. The diet should be high in protein. Many pet owners find it easier to increase energy expenditure There are also objective methods to judge obesity in dogs and in a dog than in a cat. and the abdominal tuck is help owners to design a weight-loss program for their pet. where height is the distance from the point of the shoulder through Recently. Indoor cats are Body mass index (BMI) is well known from human medicine.45. more limited in activity but owners can also encourage exer- where it is widely used to assess adiposity. especially in cats. The accumulation of lipids in enterocytes is thought to increase peptide YY concentrations in plasma. These if the ribs are easily palpated. In dogs. Treatment is given for three weeks and then in- of adiposity is possible with DEXA and magnetic resonance terrupted for two weeks to evaluate the dog’s nutritional imaging (MRI). others do not. which indicates a well-propor. and record indices of obesity at check-ups and provide which increases loss of fat mass and preserves lean body mass achievable milestones for the owner during the course of the in both dogs and cats. it is im- of treatment is to decrease energy input and increase energy portant for the veterinarian and the owner to recognize that output. 1–3 indicates an be examined in well-controlled studies. body weight (kg)/body length (m) × height (m). In cats. A score of 4 or 5 indicates an diets provide the necessary nutrients despite reduced caloric ideal body condition: the ribs are palpable and have some fat intake. 300 Obesity practice.01–0. Treatment Assuming that obesity is primary and not secondary to a Prognosis disease such as hypothyroidism or hypercortisolism. the aim In order for the treatment of obesity to be successful.5 % weight loss per scored 7–9. The dose of dirlotapide is titrated in- girth immediately caudal to the last rib correlates well with dividually within a range of 0. The can be ascribed to protein or to fiber. because dogs can be walked and many cats. The value of added sub- not easily palpated and 9 if they cannot be palpated at all be. pean Commission. but has the drawback of being subjective. should proceed slowly in order to avoid the development of tioned cat in which a waist is easily observed. The diet is adjusted accordingly and mitrata- specific adipose depots within the body. Federal Drug Administration in the United States for the carpal pad and length is the distance from the point of the treatment of obesity in dogs and mitratapide (Yarvitan®. Highly sophisticated assessment weight. Several commercial underfed animal: 1 if there is loss of muscle and fat mass and 3 weight-loss diets are available to dog and cat owners.2. evident. the waist is easily noted. Belgium) was approved by the Euro- other indices of obesity. Prevalence and risk factor for obesity in adult cats from private US veterinary practices. FERGUSON D. DETILLEUX J. PFÜTZNER AH. DIEZ M. age. A feline model of experimentally iliaris). Clin Lab 2004. KANGAWA K. Am J Epidemiol 1991. Assessment and mathematical modeling of glu- 4. J Am Vet Med Ass 1998. GLICKMAN LT. Domest Anim Endocrinol thyroxine proportionally to nonesterified fatty acid concentrations 2007. BHATTI SFM. VER- structure-activity characterization. LAR- KOH T. Eur J KL.32:93–105. HOENIG. HOENIG M. Domest Anim Endocrinol 2004. HENSON VIS SE.20:287–293.152:155–160. TSU- in dogs. 23. SWAI A. MORLEY JE. Domest 5. Fasting intact to different diets in lean and obese cats before and after weight loss. KIMURA K. diet. KATSUMI I. Insulin sensitivity. WALDRON M. and adipocytokine response PAHLER S. cose turnover and insulin sensitivity in lean and obese cats. Abnormal sub- cancer in pet dogs: a case-control study. HOENIG M. RAMAIYA ing and endocrine responses of plasma ghrelin in healthy dogs. SAITO M. NAGANOBU K. LEVINE AS. . MOHAMED-ALI V. J Appl Res Vet Med 2005. SIL. KUBO A. gender and breeds. DUCHATEAU L. PFÜTZNER A. HAM LML. VAN KOETSVELD PM.. CAFFALL Z. Body conformation. GOLDSCHMIDT 20. Vet Rec 1970.118:391–396. 7. Associations between body 17. FERGUSON DC. MONDOK A. DENVER AE. Bi- KLAUSNER JS. O’BRIEN T. MCKEE LJ. WEBER MM. KOOISTRA HS.41:31–37. HON. MARTINEZ J. JOHNSON K. KITAGAWA H.50:567–573. LEWIN MJ. Domest Anim Endocrinol 2008. FERGSUON DC. BARROS RP. Am J Pathol 2000. WALDRON M. Therap 2007. J. 14.79:169–175. KIRK CA. 1090–1099. HOENIG M.67:1557–1563. LIN XZ. References 301 References 1. BAEYENS D. Vet Biochem 2004. treated diabetic female dogs. MURAKAMI N. MU- RAKAMI N. FERGUSON 24.194:267–273. HARUKI S. Braz J Med Biol Res 2004. NAGI DK. SHIBATA H. M. dices of insulin sensitivity and myocellular lipid content by use of magnetic resonance spectroscopy in cats. and risk of breast MM.34:311–318 JOH T. KONRAD T. HOHBERG C. MASON E. HOENIG M. 2. SHIBATA H. JR. FORST T. HICKMAN MA. SMITH PM. NAKAHARA K. KAZUHIRO K. HOENIG M. KAIYA H. MATTHEEUWS D.30(Suppl 1):33–42. CAMPBELL SL. 1988. FERGUSON DC. LONG RC. and a Feline Proinsulin Enzyme-Linked ImmunoSorbent Assay (ELISA): A novel application to examine beta cell function in cats. KING VL. HON. FERGUSON condition and disease in cats. KOJIMA M. Obesity in the dog and cat. 22. LUND EM. 19. MACHADO UF. WILKINS C. Plasma leptin concentration in BIG M.37: 1095–1101. not GLUT 1 expression decreases early in the development of feline ary practices in the United Kingdom. for weight loss in obese dogs. J Am Vet Med Ass 1999. PFÜTZNER A. WALDRON M.214:1336–1341.20:1093–1100. ZAMPIERI RA. HALL G. 15. Vet Annu Anim Endocrinol 2006. 10. VAN DER LELY AJ. HOSODA H. TOMU H.133: cellular distribution of GLUT 4 protein in obese and insulin- 694–703. HOFLAND LJ.212: DC. BRANDAO J. Peptides 1984. LUND EM. SCARLETT JM. 16. Study of obesity in dogs visiting veterin. YUDKIN JS. 1973. Diabetes Care 2004. J Endocrinol 2007. KIRK CA. ASAKO O. DE CARVALHO PAPA P. Development of a Feline Proinsulin Immunoradiometric Assay 2006. KLAUSNER JS. SAITO M. BRENNAN CL.157:2143–2150. Res aspects for diagnosis and treatment of type 2 diabetes mellitus and Vet Sci 2002. KUNT T. KUNT T. Intact and total proinsulin: new dogs: Effects of body condition score. Purification and characterization of 28. DONOGHUE S. Assessment of the influence of fatty acids on in- 1725–1731. GOUBET S. KLEY S. obesity. YOKOYAMA M. Canine adiponectin: measurement of its serum /plasma concentration by ELISA and effects of obesity. 12. induced islet amyloidosis. VARGAS AM. MASAYUKI S. ARMSTRONG PJ. ISTASSE L. 11 9. A 13. Influencing the between-feed. DC. The re- Endocrinol 2005. GLUT 4 but 6. KOLAR LM. SATO M. DELOBEL A. GOSNELL BA.82:11–15. EDNEY AT. lationship of concentrations of insulin and proinsulin-like molecules with coronary heart disease prevalence and incidence. JEUSETTE IC. 25. in adult neutered female cats. 8. LÜBBEN G. a novel microsomal triglyceride dogs and cats examined at private veterinary practices in the United transfer protein inhibitor. THOMASETH K. TITTLE E. Am Anim Hosp Assoc 1984. CAFFALL Z.31:373–389. Effects of chronic obesity and weight loss on plasma ghrelin and leptin concentrations 27.1441:182–186. NAKAHARA K. Diabetes Care 1997.3:88–96. diabetes. Am J Vet Res 2004. SONNENSCHEIN EG. KANN PH. NODA S. BADO A. Effects of food intake and food withholding on 26. MCLARTY DG. MIYAZATO M. KANGAWA K. Obesity increases free feline ghrelin and its possible role. HOSOYA K. insulin resistance. 11.31:297–303. J Vet Pharm States. MOL JA. Health status and population characteristics of ologic activity of dirlotapide.27:682–687. VAN study of two ethnic groups.65: 3. Peptidergic regulation of feeding in the dog (Canis fam. WREN JA.26:291–301. Cholecystokinin suppresses food intake in cats: 21. ARMSTRONG PJ. Pharmacol Biochem Behav MEULEN A. THOMASETH K. RODRIGUEZ M. DOI K.5:675–679. OKAMOTO MH. SIEVERT CE. proinsulin is a highly specific predictor of insulin resistance in type 2 Am J Physiol Regul Integr Comp Physiol 2007. Res Vet Sci 2005. Am J Vet Res M. JORDAN K.292:R227-R234. Glucose tolerance and insulin response in obese dogs. FERGUSON DC. ISHIOKA K. fat distribution. Obesity in pet dogs. 18. ROTTIERS R. IDA T. Vet Rec 1986.86:612–616. ANDERSON RS. DU- BRASQUET M. FORST T. HOENIG plasma ghrelin concentrations in healthy dogs. tem for cats. ISTASSE L. ADER M. concentrations and energy requirements in male and female cats. metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. LE N-A. Philadelphia: WB obese dogs. GERMAN A. BIOURGE V. DE RICK A. STANTON CA. JEUSETTE I. BAILHACHE E. Saunders 2006.64: Glucose tolerance and insulin response in normal-weight and obese 1409–1413.21:1174–1180. Triiodothyronine 42. RITZEL. Amylin secretion mimics the defect in insulin secretion in obese cats. Replication increases ß-cell 44. FELDMAN EC. RAND JS. AJ.50:213–218. BOTTOMS GD. WEBER M. 32. IGF1.120:S3-S8. KABIR DE MAELE I. metabolic rate and glucose tolerance of do- 41. . AVRAMOGLU RK. A high-protein. KIM SP. KIM S. J Anim Nutr 2006. MARTIN L. DUCHATEAU L. HOENIG M. HEGSTAD RL. 35. CAFFALL Z. PPARs and the complex 46. Diabetes 2003. SERISIER S. DIEZ M. 2007. BASCIANO H. ROCCHINI differentially regulates key metabolic factors in lean and obese cats. BERMAN R. Feline Obesity.132 (Suppl. J Vet physiology of Metabolic Disease and Cardiovascular Risk. NGUYEN P. Dislipidemia in obese cats.62:131–136. SILIART B. Abdominal Obesity: Role in the Patho- obese dogs and in dogs undergoing a weight loss protocol. 30. GERMAN AJ. FERGUSON DC. B. 33. Diabetes 2003. HAMAR DW. Development and validation of a body condition 2002. Effects of neutering on hormonal 2006. GAYET C. JEUSETTE IC.34:229–237 dogs. WALDRON M. DIEZ M. HOLSON JC. A clinical tool. HSU I. FERGUSON DC. HOENIG M.63:634–639. 48. WANG YX. Insulin resistance and changes in plasma concen. 302 Obesity 29. BUTLER C. OUGUERRAM K. 38. Am J Vet Res 2002. 39. HOENIG M.52:2453–2460. score system for dogs. Am J Med 2003. HIMSEL CA. BRIAND F. Med. OUGUERRAM K.51:1357–1362.175–182 36. BARISH GD. Lipid and lipo- protein dysregulation in insulin resistant states. clearance and lipid metabolism in obese cats. MAGOT T. Feline Pract 1997.2): 1685S– Am J Vet Res 2003. HACKETT RM. SILIART 49. BANKS LL. LAFLAMME DP. Fenofibrate lowers lipid parameters in line Internal Medicine. DEVOIS C. HOENIG M. BAILHACHE E. NGUYEN P. BABU K. KREMPF M. Nature Medicine 2004. ROBERT A. In: Consultations in Fe- MAGOT T. MAO HZ.10:355–361. HOENIG M. 1687S. FERGUSON DC.52:559–564. FETTMAN MJ. LHOEST ET. RN. Development and validation of a body score sys- journey to obesity. Evaluation of thyroid function in M. JOHNSTON S. HOLDEN SL. BISSOT T. FERGUSON DC. BISSOT T. Clonidine prevents insulin resistance and hypertension in obese Dom Anim Endocrinol 2008. FERGUSON DC. ADELI K. Canine Pract 1997. CATALANO K. RICHEY J. ROCCHINI AP. Am J Vet Res 2003. 53.22:10–15. 31. MARKER P.21:1203–1208. 40. cats.52:1701–1708.136(7 Suppl):2037S–2040S. and NEFA in dogs during weight gain and obesity. KLEY S. J Anim Physiol Anim Nutr 2004. JORDAN E. Am J Vet Res 1990. LAFLAMME D.88:157–165. NGUYEN P. Metabolism 2003. NELSON RW. DAMINET S. SERVET E. HOENIG M. JEUSETTE I. J Vet Intern Med 2007. Am J Vet Res 200566:81–86. J Vet Intern Med 2007. high-fiber diet de- 290–299 signed for weight loss improves satiety in dogs. Influence of obesity on plasma lipid and lipoprotein concentrations in dogs.25:13–17. Clin Chim Acta 52. Dietary energy restriction and successful weight loss 11 tration of TNFalpha. Ef. Diabetes 45. J Nutr 2002. ISTASSE LP. 37. Effect of darglitazone on glucose 47. HOLSON J. Lipoproteins abnormalities in obese insulin-resistant dogs. WILKINS C. Domest Anim Endocrinol 2008.33:548–553. DUMON H. SILIART B. JOHNSON DE. Weight loss in obese dogs:evaluation of a high pro- fects of obesity on lipid profiles in neutered male and female cats. EVANS RM. ELLMERER M. Effects of neu- tering on body weight. SERGHERAERT R. VAN 43. mestic cats. Primacy of hepatic insulin resistance in the development of the sis. HOENIG M. Hypertension 1999. Res Vet Sci 1997. in obese client-owned dogs. 34. Ed: August JR. 50.51(S2):1711. CHIU J. 51. DIEZ MO.35: BIOURGE V. BERGMAN vulnerability to human islet amyloid polypeptide-induced apopto. VAN CITTERS GW.64:299–303.368:1–19. BIOURGE V. NGUYEN P. tein. 5th ed. low carbohydrate diet. Protocols and Algorithms . This page intentionally left blank . Basal cortisol was 48 ± 5 nmol/l and at the peak in 30–45 min the increment dogs with GH excess of mammary origin.1). Cortisol release from adrenocortical genital GH deficiency.1). can be used to stimulate endogenous GHRH release.3). 2–3 ml blood is col.1.0 ± 0. due to (1) damage by tumor or surgery. 1 µg oCRH/kg body Interpretation weight is injected intravenously.1. or (2) suppres. but there is also little or no response in some dogs with pituitary-dependent hypercortisolism.3 µg/l (mean ± SEM) and at 10–20 min after Interpretation GHRH administration plasma GH ranged from 5–28 µg/l.2 GHRH-stimulation test 12. 0. An in- tuitary-adrenocortical axis (chapter 4.3). . with a strong selective affinity 12.2. CRH test (chapter 12. At time zero. basal ACTH in control dogs was 4. ated GH levels. crease in plasma GH of 쏜 5 µg/l following intravenous ad- entiating between pituitary-dependent hypercortisolism and ministration of 2 µg ghrelin/kg body weight excludes con- adrenocortical tumor. so it Indication seems not reliable for differentiation. In healthy dogs the increase in GH tends to be Comment somewhat higher than after 1 µg GHRH/kg. probably via expression of vasopressin receptors associated with the neo- plastic transformation. 5. 305 12 Protocols for Function Tests Ad Rijnberk Hans S.7.3 ± 0. can be used in place of GHRH.1.1 Pituitary anterior lobe 12. congenital anomaly (pituitary dwarfism).3 The vasopressin analogue desmo- pressin (see also chapter 2. tumor.1. 30. Kooistra 12. as in the At –15.6 With a two-site immunoradiometric assay (IRMA).1 CRH-stimulation test Indication Suspicion of decreased secretory capacity of somatotroph Indication cells. In the peak occurring in 5–10 min. pituitary cystic lesions. other (para)sellar tumors. the cortisol-induced increase in endogenous somatostatin tone inhibits the GH response to hGHRH. Comment cortical tumors3 and caused no increase in ACTH in a dog An a2-agonist.4 xylazine (100 µg/kg body weight).5 Suspicion of multiple anterior pituitary hormone deficiencies due to pituitary tumor.3 Combined anterior pituitary to the V2 receptor.1. including tuitary function test (chapter 12. does not cause this release of cortisol from function test adrenocortical tumor.9. except for differ.2. mary gland.9 pmol/l (mean ± SEM) In dogs with congenital GH deficiency there is no significant and CRH caused an increment of 68 ± 14 pmol/l with increase in plasma GH concentration following GHRH. sion by exogenous or endogenous (adrenocortical tumor) glucocorticoid excess. pitu- itary surgery. lected in ice-chilled EDTA-coated tubes for measurements of ACTH and cortisol.3.8 In dogs with hypercortisolism. those erroneously thought to have acquired GH deficiency cantly from those in a CRH-stimulation test alone.1 The values in a combined anterior pi. 20. 10. Suspicion of decreased secretory capacity of corticotroph surgery) or (2) progestin-induced GH secretion by the mam- cells.11 tumors can be stimulated directly by vasopressin. or pituitary irradiation. GHRH adminis- tration results in almost no increase in the more or less elev- 12 was 380 ± 39 nmol/l. due to (1) a pituitary lesion (congenital anomaly.2 (chapter 2. and 45 min. Performance Blood samples are collected before and after intravenous ad- Performance ministration of 1 µg hGHRH/kg body weight. In healthy anestrous dogs basal plasma GH between pulses was 1.3) did not differ signifi.10 Also. either clonidine (10 µg/kg body weight) or with hypercortisolism due to ectopic ACTH secretion. ghrelin Vasopressin can be used in place of CRH to stimulate the pi.10 CRH caused virtually no release of endogenous ACTH or cortisol in dogs with autonomously hypersecreting adreno. 5 % of samples (n = 181). 2–4 µg of the va- .98. GH.15 Test strips are com- 12. However. If Uosm remains low and the (fig. is determined indirectly by measurements of Uosm.0048 + 2. in the follow. Only the LH response is lower in the combined measurements are repeated after desmopressin administration. four releasing hormones are injected via a pressin (DDAVP).e. Indication genic diabetes insipidus. resulting in marked variations in In this indirect test of vasopressin secretory capacity.32 × 10–5 Uosm. and primary polydipsia. 1000 mOsm/kg. water intake can vary Principle considerably over the day. but in 4.2 the polyuria and polydipsia and the increase in Uosm from low values to 쏜 1000 mOsm/kg.4 % the differ- ence was more than 500 mOsm/kg. P 쏝 0.2.001) and their linear regression is Usg = to be assayed in a one-step immunoassay based on a chemilu. The effect of endogenous vasopressin tested. approaches 5 % of initial the day and at 4 h intervals during the night for a period body weight. the standard deviation of the Usg values has been found to be 0. lections but Uosm is still 쏝 1000 mOsm/kg. nephrogenic dia- betes insipidus.g..028 Usg = miniscent reaction (e. To prevent the rapid proteolytic degradation of some of the Comment pituitary hormones. central diabetes insipidus is unlikely and there is either primary polydipsia or (func- 12. PRL. plasma urine osmolality (Uosm).13 This converts to 1. The owner is provided with written instructions and urine osmolality (Posm and Uosm) are measured every 2 h. Urine is collected at 2 h intervals during weight.13 12. they should be shipped on dry ice by an overnight mail service. cortisol. Differentiation of central diabetes insipidus. Uosm measurements are prefer- cause EDTA inhibits this reaction. When Posm 욷 310 mOsm/kg of 24 hours and the samples are sent to the laboratory for and there is 쏝 5 % increase in Uosm between consecutive col- measurement of Uosm.1) for measurement of ACTH.004. the response to a vasopressin analogue can be late vasopressin release. progesterone).4 Sample handling tional) nephrogenic diabetes insipidus.12 Marked fluctuations in Uosm and any values higher than 1000 mOsm/kg indicate good renal concentrating ability. Performance Performance Urine samples are collected at home while water is available Following 12 h of fasting. blood samples are collected in EDTA. i.2 Modified water deprivation test Indication First step in differentiating central diabetes insipidus. cortisol. be. (2) If Uosm remains low with little osmolality (Posm) is increased by water deprivation to stimu- variation. and 10 µg TRH/kg. specific gravity. the test is stopped.14). Interpretation showing the polyuria to be the result of variations in water in- The results are compared with those in healthy control dogs take. test than when its releasing hormone GnRH is administered central diabetes insipidus is indicated by prompt cessation of alone. If the samples cannot be brought immedi. They are well correlated centrifuge. measured at each interval. 1 µg GHRH/kg.14 Uosm calculated from Usg has been reported to be within ± 200 mOsm/kg of the measured value in 84. Also.2. Heparin-coated tubes should be used for samples (r = 0.2 Pituitary posterior lobe pletely unsuited for estimating Usg.2. electrolyte balance are related to osmolality rather than to 12 ately to the laboratory where the assays are performed. primary polydipsia. TSH. and Interpretation LH. Plasma should be stored at able because homeostatic mechanisms maintaining water and or below –20 °C.1 Serial measurements of urine osmolality 12. water is withheld and then plasma ad libitum. Blood samples are collected urine samples at 2 h intervals.1. for T4. and eleven small labeled tubes in a suitable box for mailing or hourly if the polyuria is severe.1. the owner re- Immediately after collection of the zero blood sample from ceives a second set of tubes and a dropper bottle of desmo- the jugular vein. 1.. nephro. at the times given for the CRH test (chapter 12. 306 Protocols for Function Tests Performance If Uosm remains low throughout the first test. mopressin in the conjunctival sac three times daily for four ing order and doses: 1 µg CRH/kg. Principles (1) In dogs with primary polydipsia. The owner administers one drop of des- catheter in the cephalic vein within 30 seconds. 2. When the loss of body to the laboratory. and primary polydipsia. Urine specific gravity (Usg) measured by refractometry coated ice-chilled tubes and are centrifuged in a cooled can be used in place of Uosm. 10 µg days and on the fourth day repeats the collection of the eleven GnRH/kg. If Uosm does not exceed 1000 mOsm/kg after desmopressin. 1).20 Maximal stimulation of the thyroid is achieved with 100 µg or even 50 µg rhTSH Indication per dog. of Performance which less than 1/10 is needed per dog. Comments. This can occur in severe systemic illness. Posm should be measured in the samples immediately ister rhTSH on three consecutive days to produce an increase and when it reaches ~ 350 mOsm/kg the hypertonic saline in plasma T4 concentration. it remains low.17 Suspicion of deficient TSH secretion.3) but can also be used to test for the paradoxi- . 100 µg recombinant human TSH (rhTSH).1) is administered intravenously.. and fig. In cats the use of an in- dwelling urinary catheter may be necessary. the diagnosis is unresolved. If post-TSH T4 is between 20 This may be necessary to determine whether water depriva. Post-TSH T4 values urine volume is small. and 32 nmol/l or is 쏜 32 nmol/l but 쏝 1.3 Thyroid by 50 % or more following the administration of DDAVP and is 쏜 650 mOsm/kg (~ sg 1. (chapter 12. there is usually complete Interpretation emptying of the bladder at each micturition and it is usually In healthy dogs plasma T4 rises above 32 nmol/l and is at least not difficult to collect a sample during micturition. the results are not always conclusive.5x the basal T4 concentration.3.19 4 Comments 12. hypertonic saline infusion which was used in the past. are similar. See also fig.3.2. When 1.20 sopressin secretion. One ampule of the highly purified recombinant form of human TSH contains 1100 µg of lyophilized rhTSH.22 Posm are obtained at 20 min intervals. Fortunately.1. Interpretation The slope of the regression line for Posm and Pvp is used as 12. When urine volume is very large. Suspicion of hypothyroidism.2 TRH-stimulation test a measure of the sensitivity of the osmoregulatory system. 2. Uosm is The test requires very close observation and monitoring of measured again 1 h and 2 h later. particularly when basal plas- acter of the test. In both nephrogenic diabetes insipidus and central diabetes insipidus.33). 21 Higher doses do not increase the T4 response and Suspicion of deficient vasopressin release or inappropriate va. 2. the 90 % Indication range for sensitivity was 0.5 × the basal T4. In complete central diabetes insipidus it rises 12. catheterization may be needed to ob. Posm. tion can and should be continued. Measurement of Usg is suitable in the initial urine examin. fig. and the fact that vasopressin is very sensitive to proteolytic breakdown. 2. The test is a com- The 90 % range for the threshold of the system was 276– ponent of the combined anterior pituitary function test 309 mOsm/kg. Thyroid 307 sopressin analogue DDAVP (see also treatment section of Comment chapter 2.5 × the basal T4 concentration are tain a sample and /or ascertain that the bladder is emptied.1 TSH-stimulation test insipidus the increase in Uosm is 욷 15 %. 쏝 20 nmol/l and 쏝 1.3.16 In part because of the indirect char. the recon- The euhydrated and fasted animal is infused for 2 h via the stituted rhTSH can be stored at 4 oC for 4 weeks and at –20 jugular vein with 20 % NaCl solution at a rate of 0.2.34. 2. In partial central diabetes 12. responses to a fixed dose do not vary with body weight. This.3. body weight per minute. 2. but not for the water deprivation test Blood is collected for measurements of plasma T4 immedi- (chapter 12.020).3. in which decisions are made on the basis of ately before and 4–6 h after the intravenous injection of changes of 5 %.17 ma T4 and TSH concentrations are not conclusive (chap- ter 3. infusion should be stopped. In the nomogram developed by Biewenga et al. diagnostic of hypothyroidism. Because there is the risk of inducing critical hypertonicity in a severely polyuric In secondary hypothyroidism it may be necessary to admin- animal.24–2. Performance ation for polyuria.35.47 pmol/ml per mOsm/kg.18.18 Quantitative measurement of thyroidal uptake of 12 99mTcO – can be helpful in resolving the diagnosis.03 ml/kg oC for at least eight weeks without loss of biological activity.1).31. In primary polydipsia Uosm gradually rises to 쏜 1000 mOsm/kg during water deprivation. In nephrogenic diabetes insipidus DDAVP causes little or no increase in Indication Uosm (figs. makes it advisable that the test be per- Interpretation formed in institutions having experience with it.3 Vasopressin measurements during The biological activities of rhTSH and bovine TSH (bTSH). Samples for plasma VP (Pvp) and allowing for several TSH-stimulation tests per ampule.32. because dexame- TRH is administered intravenously in a dose of 10 µg per kg thasone is not measured in cortisol assays. in spontaneous primary hypothyroidism basal TSH cortisol is low and. 0.28. as a result of the development of thyrosoma.73).3. ticism and below the level of detection in secondary hypoad- totroph pituitary cells (chapter 3.32 If the values at either 4 h and/or 8 h are at least .3. CI: 0.6). sufficiency it usually increases 쏝 50 nmol/l above the low ondary hypothyroidism. Interpretation In healthy dogs the maximum plasma TSH concentration Interpretation (mean ± SEM.01 mg dexamethasone per kg trilostane (chapter 4. there is often no significant increase in plasma T4 after 12.2.4. 5. ter 3. given.3.1). and may not be increased by TRH (chap. In healthy dogs. plasma cortisol concentration rises to jection.26 ± 0. as occurs after hypophysectomy. This is not necessary if de- Performance xamethasone is used rather than cortisone. 4. Differentiation between primary and secondary adreno- thyroidism respond to TRH administration by an increase cortical insufficiency can be confirmed by measuring plasma in plasma GH concentration (mean ± SEM at 10 min: ACTH.1. in the differential diagnosis.1).1 ACTH-stimulation test Indication Suspicion of hypercortisolism.25 mg) of synthetic ACTH.4. but the high result of 0. 30. In dogs the finding of plasma cortisol 쏜 40 nmol/l at 8 h tered intravenously and blood is collected immediately before after dexamethasone confirms hypercortisolism with a pre- and at 60 min after the injection for measurement of plasma dictive value of a positive test result of 0. the morning dose of cortisone is postponed on the test day until the test is completed. Performance Interpretation Synthetic ACTH (cosyntropin or tetracosactrin) is adminis. with cortisol in nmol/l and Comment ACTH in pmol/l. 1. 308 Protocols for Function Tests cal GH response that may occur in pituitary hyperplasia due If treatment for adrenocortical insufficiency is already being to primary hypothyroidism (chapter 3.31 The measurements at 0 and cost prompted re-evaluation of the dose and 5 µg/kg was 4 h are not needed for the diagnosis per se but may be useful found to be sufficient for maximal adrenocortical stimu. depending on the severity and duration of concentration may also be below the upper limit of the refer.26 Although the low and suppression test (iv-LDDST) variable responses to TRH make it of no value for identifying dogs with hypothyroidism. It was customary in the past to administer the full val.3. A high value at 8 h after a lower lation.3.96). those with primary hypo. 20.25 renocorticism.4 Adrenal cortex ism. In secondary adrenocortical insufficiency plasma However.9 ± 3.2 Low-dose dexamethasone TRH administration in healthy dogs.2. However.24 Comment In contrast to healthy dogs. In healthy dogs the reference range for the cortisol/ACTH ratio (CAR). body weight intravenously.23 basal value. Collect blood for cortisol assay immediately before and at 4 h cortical reserve to guide treatment of hypercortisolism with and 8 h after administering 0. treatment for more than three days can by itself result in a sub- and 45 min.22 µg/l) occurs at 10 min after in.5 µg/l). the insufficiency.92 (confidence inter- cortisol.29 value at 4 h indicates escape from the suppression by dexame- thasone. In primary adrenocortical in- of increase after TRH administration is consistent with sec. and a predictive value of a negative test contents of a vial (0. The sensitivity of the hypothalamic-pituitary-adrenocortical axis to suppression by glucocorticoids is tested by administer- ing a low dose of a potent glucocorticoid that causes suppres- sion in healthy animals but not in those with hypercortisol- 12. Indication Suspicion of decreased adrenocortical reserve (primary or Performance secondary adrenocortical insufficiency) and testing of adreno. absent.4.43–0.30 Studies have been undertaken to determine whether the plasma T4 response to TRH might be helpful in the diagnosis 12 of primary hypothyroidism.85–0.1). 12. the increase after ACTH is subnormal or ence range.19. For sample handling see chapter 12. has been reported to be 1–26.12 A low basal plasma TSH concentration and lack 270–690 nmol/l after ACTH.59 (CI: 0. contrary to expec- tations. which is extremely high in primary hypoadrenocor- 11.27 a definite increase in T4 after Principle TRH might exclude hypothyroidism.1). 10. normal response via induction of secondary hypocortisolism (chapters 4. Glucocorticoid body weight and blood is collected at –15. Urinary cortisol is related to urinary creatinine to correct for cretion usually cannot be suppressed with the high dose of differences in urine concentration.. chapter 4. or due to ectopic ACTH excess (chapter 4. so that the stopper is not sults.1 mg per kg body weight) at 8 h intervals.4).3). Increasing the dose of dexamethasone to 0.1: vulsant treatment with phenobarbital does not affect the re. . Plasma cortisol levels in animals The cortisol in the morning urine reflects the production with functional adrenocortical tumors. The owner collects morning urine samples at home at the same Interpretation time (e. the impairment of glucocorticoid feedback varies Suspicion of hypercortisolism and differentiation between hy- considerably with the size of the pituitary and large corticot.3 High-dose dexamethasone suppression test (iv-HDDST) Principle and indication 12. or ectopic ACTH se. chapter.3.2). Figure 12. differentiate between a corticotroph adenoma of the anterior lobe of the pituitary and other causes of hypercortisolism.3.4. the hypercortisolism is pitui- tary dependent. After collecting the second urine sample. be- cause of the low incidence of hypercortisolism in this species. 7 A.33 The same dose of dexamethasone is used and the same criteria are applied for the diagnosis.1).1 mg/kg has been proposed but would lead to an increase in false-negative test results.M.34 Stress from other procedures such as ultraso- nography performed during the test may also override the suppressive effect of dexamethasone. together with directions for collecting urine at home from cats. to sensitivity to glucocorticoid feedback. integrating the fluctuations in plasma cortisol. in pituitary-dependent hypercortisolism in cats. 쏝 50 % indicates that the hypercortisolism is ACTH inde.1).4.. the owner gives the three oral doses of dexamethasone pendent (primarily adrenocortical tumor. as in dogs. corticotroph adeno.4. Indication However. In cats there is much less experience with the iv-LDDST. or (0. Adrenal cortex 309 50 % lower than the 0 h value. Consequently.) on the that the hypercortisolism is pituitary dependent.g.) on three consecutive days.36. the instruction sheet for the owner is given as an annex to this ter 4.M.3.37 expelled by freezing. A decrease of preceding evening. Nevertheless. The test includes the oral dexamethasone. in a cushioned box for sone per kg body weight. resistance to glucocorticoid feedback ranges from slight to complete (see also chapter 12. Box with cushion lining for sending three urine samples to the laboratory for cor- tisol assay. An example of pituitary dependent but dexamethasone resistant (chap. after taking the A decrease in plasma cortisol of 쏜 50 % in this test indicates dog for its last walk at the same time (e.38 ism. The fourth tube contains the dexamethasone tablets for the suppression test.35 Long-term anticon. a one with dexamethasone tablets.1 mg dexametha. The tubes should be no more than half filled. Comment The stress of disease and hospitalization can cause false-posi- tive results.4 Urinary corticoid:creatinine ratios Although the iv-LDDST reveals the sensitivity of the pitu. percortisolism due to corticotroph adenoma of the anterior roph tumors may be associated with complete resistance to pituitary and dexamethasone-resistant forms of hypercortisol- dexamethasone. 12. 11 P.g. the iv-HDDST is indicated administration of high doses of dexamethasone to assess the after the diagnosis hypercortisolism has been established. 12. mailing the urine tubes to the laboratory (fig. Performance Performance Blood for cortisol assay is collected immediately before and The owner is provided with three tubes for urine samples and 3–4 h after intravenous administration of 0. mas arising from the pars intermedia. during ~ 8 h. the system is usually suppressible with a Principle high dose of dexamethasone. with high-dose suppression test itary-adrenocortical system to be decreased in most cases of (UCCR + o-HDDST) 12 hypercortisolism due to a functional corticotroph adenoma in the anterior lobe. teal (ovarian) tissue but values 쏝 3 nmol/l do not exclude it.3–8. and 60 min.00 h for measurement of the UCCR.2). for it higher discriminatory power than the iv-LDDST. For estradiol. blood is collected at –40.00 h for measurement of UCCR. CI 12 0.4. CI 0.77. cificity.or heparin-coated tubes (see also chapter 12. hospital visit and an invasive test procedure.00 h and 14.1. –40. 310 Protocols for Function Tests Interpretation empty its bladder and the third urine sample is collected at In our laboratory the basal UCCR in healthy pet dogs is 16. FSH.3 × 10–6 39 and in healthy cats it is 8. More importantly.45 However. 0.1 ml GnRH/kg body weight (Fertagyl® or Receptal®).00 h to . ministration than after intravenous administration. If the ism the UCCR following dexamethasone was 쏜 1.1 GnRH-stimulation test The UCCR is also very useful for monitoring the result of treatment following hypophysectomy or adrenalectomy as Indication well as treatment with o. (1) Suspicion of decreased secretory capacity of gonadotroph cocorticoid and /or mineralocorticoid should be omitted the cells. see chapter 12.05. The urine samples should be col. without the stresses of a elevates cortisol excretion. Capsules were pre- concluded that the UCCR has high sensitivity but lacks spe. above dexamethasone was triturated with lactose and micro- thyroidism.88–1. and 120 min. with low-dose suppression test in EDTA.0 × 10–6.5 Urinary corticoid:creatinine ratios Blood is collected before and after intravenous administration of 0. For LH and FSH.p'-DDD. For progesterone one basal sample have been inconclusive or negative but in which there is still (–40 or 0 min) suffices. Performance 12. blood is collected at suspicion of hypercortisolism. After collection of the second urine sample.88.1.93) and that of a negative UCCR (0. respectively).44 From studies in such populations it has been crystalline cellulose was used as a diluent. and 90 min.5. in the appropriate populations – animals and 0.40 The reference values of the laboratory performing the assays Interpretation should be used.0 × 10–6. and the UCCR is similar (0. Both complete adrenocortical ab. (2) Search for functional ovarian or testicular tissue.0 × calculated and values exceeding the upper limit in healthy 10–6. blood is collected at 0. pared with the following doses: 0.80–0. 0. in addition readily activates the pituitary-adrenocortical axis and thus to which the test is done at home.46.73 and 0. and /or testosterone. The sampling scheme depends on the hormones Indication of interest. the predictive value of a positive UCCR (0.31 12.4. Dogs in which results of the UCCR and /or the iv-LDDST 10.2 kg body weight. bitches with primary anestrus due to hermaphroditism50 or rectly after it is collected.0–42. 0.01. This series of capsules facili- suspected of hypercortisolism – the specificity of the LDDST tated dosage with an accuracy of 0. incomplete ovariectomy. Performance The owner collects urine on two consecutive mornings at Interpretation 8.41–43 The high sensitivity of the UCCR not only reveals In both the iv and the oral LDDST the dosage of dexametha- stress responses but also increased cortisol production associ.49 UCCR of the third urine sample is 쏝 50 % of the mean of the first two the hypercortisolism is pituitary-dependent.00 h was 쏝 1.01 mg dexamethasone per kg body weight orally. 30. For Comments the interpretation of post-dexamethasone UCCRs 쏜 50 % The bioavailability of dexamethasone is lower after oral ad- of the mean basal values. progesterone. 60.47 The replacement glu.005.49 lected by the owner at home under conditions free of stress. (4) Suspicion of anorchism or cryptorchidism in male dogs. (3) Detection of hormonal abnor- lation and hypophysectomy result in UCCRs 쏝 2.001 mg dexamethasone.48 In dogs with mild pituitary-dependent hypercortisol- dogs or cats provides the diagnosis of hypercortisolism.40.01 mg dexamethasone per kg body weight is Comments still sufficient to suppress the system in healthy pet dogs. 0.98. without changing the Plasma progesterone 쏜 3 nmol/l indicates the presence of lu- feeding regimen. as in night before the urine sample is collected and resumed di.4. the owner administers 0. The dog is walked at 12. 5. estradiol.3. 0. For the studies of the o-LDDST mentioned ated with diseases such as malignant lymphoma and hyper. The mean of the two basal UCCR values is In seven healthy pet dogs the UCCR at 16. but the oral dose of 0. 0. 20.00) compare well with these variables for the LDDST 12. malities in the pituitary-gonadal axis in cases of infertility. This Stress (including hospitalization) during or prior to the urine lower exposure to dexamethasone may give the o-LDDST a collection should be avoided as much as possible.25. For testosterone.1–0.4) (UCCR + o-LDDST) for measurement of LH.0 × 10–6. 60. sone is critical.5 Ovary and Testis (chapter 12. 0. GnRH stimulation induced Comment a moderate increase in plasma estradiol that did not return to If remnant ovarian tissue is suspected after ovariectomy of a pretreatment values during 160 min following stimulation queen.52 plasma testosterone concentration is low and does not change Following GnRH stimulation..6 ± 0.7 ± 1. clines slowly. Following stimulation the In six healthy female dogs mean basal plasma LH (~ 2. 1994. 40 min (fig.6 µg/l (range 2.8 U/l in late anestrus (see also fig. 12.2: Basal plasma estradiol concentration in ovariectomized Mean LH (blue) and estradiol (green) responses to GnRH (0.54 In six healthy male dogs mean (± SEM) basal plasma LH and testosterone concentrations were 4.2). ting the results of the GnRH-stimulation test. ceptal®) is injected during estrus behavior and plasma pro- vanced anestrus than in early anestrus. with values done at 60 and /or 90 min (fig. The LH and estradiol responses were greater in ad.1 ± 0.5 µg/l and 9. peak LH concentrations of after GnRH administration.56.2 U/l in early anestrus.1 ml Fertagyl® per kg body weight) in six healthy male dogs.3 ± 0.2). .55 Sampling for testosterone may also be creased significantly during progression of anestrus. Ovary and Testis 311 Figure 12. 1993.7 µg/l) did mean (± SEM) plasma LH was 57 ± 13 µg/l at 20 min and not change significantly during the progression of anestrus.3).3 ± 1. GnRH administration did not induce a significant rise in plasma FSH concentration in four ovariectomized bitches. (Adapted from Knol et al. A value that the stage of anestrus must be taken into account in interpre. 12.1 ml/kg body weight of Fertagyl® or Re- (fig. 12.53 Figure 12.)55 In four healthy anestrous bitches the median basal FSH con- centration was 5.57 In female dogs and castrated male dogs trus.3: Mean LH (blue) and testosterone (red) responses to GnRH (0.6 U/l in mid-anes.8–13.9 µg/l) and GnRH ad- ministration resulted in peak values ranging from 18 to 27 µg/l at 10 min. 쏜 3 nmol/l indicates the presence of ovarian tissue.51 These findings indicate gesterone is measured seven to ten days later. 7. However.1 ml Fertagyl® per kg bitches overlaps that in anestrous bitches.3) as the concentration de- of 6.)51 centration if ovarian tissue is present. 7. In the mean (± SEM) plasma testosterone was 16 ± 4 nmol/l at contrast. respectively.. mean (± SEM) basal plasma FSH concentration in. ~ 42 µg/l (early anestrus) and ~ 50 µg/l (advanced anestrus) oc- curred after 5–20 min (fig. but GnRH admin- body weight) in six healthy female dogs during early (upper panel) and advanced istration only causes a significant rise in plasma estradiol con- (lower panel) anestrus. GnRH (0. Their basal plasma FSH concen- trations (range 40–108 µg/l) did not overlap with the GnRH- 12 induced FSH peak values in the anestrous bitches.7 nmol/l. and 9.16). (Adapted from Van Haaften et al. 12. suggesting that measurement of FSH in a single plasma sample may be sufficient to verify neuter status in bitches. but please do not fill them above the mark For cats. Res Vet Sci 2006. TSGAM. RIJNBERK A. ALTSZULER N. GALAC S. RUTTEMAN GR.131:413–421. gravel. The desmopressin stimu. J Endocrinol 1997. there is also a litter specifically designed for urine we can then examine the control of the adrenal cortex in collection in cats.81:24–30. CROUGHS RJM. BEVERS MM. VAN DEN BERG G. SELMAN PJ. morning the urine is taken up with a syringe or pipette and poured into the tube through gauze. VAN DEN INGH adrenocorticism. Domest gesterone acetate. MOL JA. MEIJ BP. RIJNBERK A.154:505–512. as litter does. 5. Hyperadreno- corticism in a dog due to ectopic secretion of adrenocorticotropic 10.00 hours tablet(s) morning. KOOISTRA HS. RIJNBERK A. RIJNBERK A. Make the collection at about the same time each 24. MOL JA. Am J Vet Res 1981. The gravel does not remain unrefrigerated for more than a day. insulin- in beagle dogs: Rapid sequential intravenous administration of four like growth factor I and glucose homeostasis. The tablets can be spectively. urine is collected by replacing the litter box for because this can cause the stopper to be forced out when the night with one containing aquarium gravel that has the urine is frozen. 1996. BHATTI SFM. . HITTMAIR KM. OKKENS AC. dogs with pituitary-dependent hyperadrenocorticism. Responsiveness to corticotropin-re- ment in the bitch.00 hours tablet(s) the morning sample is from urine produced during the night. 08. MEIJ BP. Pulsatile plasma profiles of 3. 9. DUCHATEAU L. DE VLIEGER SP. PAGITZ M.. in a small piece of meat). re. MOL JA. MOL JA.130:410–416. Domest Animal Endocrinol 2005. The tubes can be filled to less than the mark. SELMAN PJ. ZEUGSWETTER F. In order to measure the production of corti. I. Domest Anim Endocrinol 1994. Anim Endocrinol 2003. we need three morning urine samples. HOYER MT.28:338–348. MOL JA. Take the dog out to uri- nate fairly late in the evening before each sample so that 16. BEVERS MM. Domest Anim Endo.13:161–170. Fill the tube only half-full (below the mark) and given with or without food (e. Theriogenology 2008. Alterations in anterior pituitary function of dogs with pituitary-dependent hyper- 4. and so should absorb cortisol from the urine. So excessive production of the hormone cortisol from the ad.70:179–185. MEIJ BP. LEE WM. Eur J Endocrinol hypothalamic releasing hormones.34:254–260.g. PETERSON ME.42:1881–1883. VAN HAM LML. BEIJERINK NJ. 2. brought to the laboratory. MOL JA. RIJN. Assessment of a combined anterior pituitary function test gestin treatment in the dog. MOL JA. then place it in the freezer or freezer compartment of the It is likely that the dog will drink more and urinate more refrigerator until all three samples can be mailed or than usual for about a day following the tablets.58 12 References 1. KOOISTRA HS. 6. roughly according to sol. VAN WIJK PA. MOL JA. KOOISTRA HS. 312 Protocols for Function Tests Client information for UCCR + o-HDDST Your dog has symptoms and signs that could be caused by the third sample. about 8 hours after the last tablet(s). Pro- BERK A. BEIJERINK NJ. BHATTI SFM. the following schedule: Please collect a sample during the dog’s first morning uri. HAZEWINKEL HAW.00 hours tablet(s) nation on three successive days. after dexamethasone has been given.32:63–78. WOLFSWIN- FSH and LH before and during medroxyprogesterone acetate treat- KEL J. KOOISTRA HS. OKKENS AC. DUCHATEAU L. BHATTI SFM. Pulsatile secretion pattern of growth hormone in Adenohypophyseal function in bitches treated with medroxypro. Suppression of growth hor- hormone. 7. Effects on growth hormone. collecting the second urine sample. VAN HAM LML. MEIJ BP.) mone secretion in spontaneous hyperadrenocorticism and its rever- sal after treatment. leasing hormone and vasopressin in canine Cushing’s syndrome Eur J Endocrinol 1994. Ghrelin-stimulation test in the diagnosis of ca- crinol 2008. The next not be mailed just before the weekend. Hence the third morning urine sample will be collected Place the urine sample in the tube numbered 1. 2 or 3. Domest Anim Endocrinol 2007. VOORHOUT G. DIELEMAN SJ. The samples should not be allowed to been washed with tap water and dried. BENESCH T. In place of aquarium Using the first two samples to measure cortisol production. KOOISTRA HS. BHATTI SFM. you administer the enclosed tablets of dexamethasone after renal cortex. 8. THALHAMMER JG. nine pituitary dwarfism. lation test in dogs with Cushing’s syndrome. DIELEMAN SJ.24:59–68. 11. 20:556–561. RIJN- thyroxine concentration.30: 20.22:1070–1073. 28. HOSGOOD GEFFEN C. . Tijdschr Diergeneesk 1995. 29. of different breeds. Evaluation of a poadrenocorticism in dogs. DUCHATEAU L. Biochemical characterization of pituitary-dependent hyperadreno. MAY ER. FAVROT C. VOORHOUT G. Thyrotropin-releasing hormone-induced growth mone and combined administration of four hypothalamic releasing hormone secretion in dogs with primary hypothyroidism. Effect of phenobar- itary function after transsphenoidal hypophysectomy in dogs with bitone on the low-dose dexamethasone suppression test and the pituitary-dependent hyperadrenocorticism. WOFSHEIMER KJ. FOSTER SF. DAMINET S. 13. HENDRIKS HJ. FRANK LA. 78:19–23. REUSCH CR. hypothy. Transsphenoidal hypophysectomy for treatment of pitu- itary-dependent hyperadrenocorticism in 7 cats. clinical refractometer: a useful tool for the determination of specific gravity and osmolalilty in canine urine. FRANK LA.120:400–402. ment of specific gravity in canine urine).32:481–487. Assessment of thyroid function in dogs with low plasma 33. VAN 36. KOOISTRA HS. J Vet Intern Med 2000.34:176–181.65:267–270. WILLI B. WATSON ADJ. J Endocrinol 1997. responses after single administration of thyrotropin-releasing hor. TESKE E. Can Vet J 2000. Change in serum thy. BIEWENGA WJ. Assessment of dose Evaluatie van een teststrook voor de bepaling van het soortelijk ge. MOL JA. WALKER MJ. J Small wicht van urine van de hond (Evaluation of a test strip for measure. KOOISTRA HS. Residual pitu. MOL JA. Correlation between impairment of glucocorticoid feedback and tration of thyrotropin-releasing hormone to healthy dogs. GRUFFYD-JONES TJ. mock ultrasonographic procedure on cortisol concentrations dur- stimulating hormone for thyrotropin stimulation test in euthyroid ing low-dose dexamethasone suppression testing in clinically nor- dogs.13: Anim Endocrinol 2008. J Vet Intern Med 2006. BORETTI FS. Effects of a 21. DOSSIN O. Effect of storage of reconstituted re- G. 27. PEETERS ME. SIEBER-RUCKSTUHL NS. CHURCH DB. RIJNBERK A. MEIJ BP. RIJNBERK A. BRUYETTE DS. MÜLLER PB. IVERSEN L. VAN DEN BROM WE. KEMPPAINEN RJ. DE BRUIJNE JJ. HNILICA KA. TABOADA J. Comparison of thyrotropin-releasing hormone (TRH) to thyrotropin (TSH) stimulation for evaluating thyroid 14. 23. and euthyroid dogs with concurrent disease. VAN VONDEREN IK. 26. The function in dogs. DE BRUIJNE JJ. MOL JA. CHASTAIN CB. J Am Vet Med Ass 2006. REUSCH CE.169:1327–1330. Domest hormones in beagle dogs. References 313 12.77:111–118. BOER P. 31. BEHREND EN. Evaluation of 1988. Use of recombinant human thyroid. niques of evaluation of urine dilution /concentration in the dog. 38. SCOTT-MONCRIEFF JC. Assessment of two tests 18. Am J Vet Res 2006.229:528–530.36:245–251.14:157–164. CROUGHS RJM. BERK A. J Vet Med A 2003. J Endocrinol 1978. KOOISTRA HS. RIJNBERK A. dogs. RIJNBERK A. KOOI- STRA HS. modified water-deprivation test for diagnosis of polyuric disorders in dogs. J Endocrinol 1997. CARMICHAEL N. Comparison of the biological activity of recombinant human thyroid-stimulating hor.103:1065–1068. J Vet Intern Med 2006. GERMAIN C. J Am Vet peradrenocorticism. VAN WEES A. DE ROOVER K.122:178–180. J Am Vet Med Ass 1976. SIEBER-RUCKSTUHL NS. GLEADHILL A. 30. EVANS H. 2006. LUTZ for the diagnosis of canine hyperadrenocorticism Vet Rec H. LATHAN P. recombinant human thyroid-stimulating hormone to test thyroid function in dogs suspected of having hypothyroidism. J Vet Intern Med 2008. MULNIX JA. 72–86. BEVERS MM. Front Horm Res 1987.22:435–442. ZAMBON S. DE BRUIJNE JJ. 34. Tijdschr Diergeneesk 1978. stimulation testing in dogs. MADSEN mone with bovine thyroid-stimulating hormone and evaluation of RW. GASCHEN FP. MEIJ BP. J Am Anim Hosp Assoc 1986.67:1169–1172. MOORE GE. 24. MOL JA. 37. GALAC S. GANJAM VK. VAN DEN INGH TSGAM.67:2012–2016. Aldosterone-to-renin and cortisol-to-adrenocor- 17. RIJNBERK A. Evaluation of the hypothalamic pituitary-adrenal axis in clini- recombinant human thyroid-stimulating hormone in healthy dogs cally stressed dogs. MEIJER JC. WOTTON PR. Use of a low-dose ACTH-stimulation test for diagnosis of hy- 16. J Am Anim Hosp Ass 1996.20:812–817. roid-stimulating hormone concentration in response to adminis. HOFMANN-LEHMANN R. GALAC S. HENDRIKS HJ. ROBBEN JH. RIJNBERK A. mal adult dogs. PARADIS M. HOFMANN-LEHMANN R. NELSON RW. YWEA. 12 19. DIAZ ESPIÑEIRA MM. SCOTT-MONCRIEFF JC.21:25–32. J Vet Intern Med 2007. the size of the pituitary gland in dogs with pituitary-dependent hy- roid dogs. Aust Vet J 2000. Am J Vet Res 32. BORETTI FS. LUTZ H. POLLAK corticism in the dog. and time responses to TRH and thyrotropin in healthy dogs. SPARKES AH. Vasopressin ticotropic hormone ratios in healthy dogs and dogs with primary in polyuric syndromes in the dog. MOL JA. KOOISTRA HS. SAUVÉ F. MEIJ BP.144: urinary corticoid:creatinine ratio in dogs. Effects of long-term phe- combinant human thyroid-stimulating hormone (rhTSH) on thy- nobarbital treatment on the thyroid and adrenal axis and adrenal roid-stimulating hormone (TSH) response testing in euthyroid function tests in dogs.41:215–219. Med Ass 1998. Am J Vet Res 2004. PARTINGTON BP. MOL JA. VAN DIJK JE. Thyroid-stimulating hormone 25. 22. 465–468. MOL JA. BRAUN JP. 531–539.17: hypoadrenocorticism.213:1435–1438. Domest Anim Endocrinol 1996. VAN DEN BROM WE. JAVADI S.152:387–394. Vet Surg 2001.50:322–325. Intramuscular administration of a low dose of ACTH for ACTH- 15. VOORHOUT G. 139–148. 35. DIAZ ESPIÑEIRA MM. RIJNBERK A. Comparison of the tech. RIJNBERK A. LANE IF. Anim Pract 1995. BUSCH K. FRANKLIN RT. BUIJTELS JJCWM. DIELEMAN SJ.22:315–320. BUIJTELS JJCWM.12:431–435. ZIMMER C. BELANGER A. BEIJERINK JN. BEIJERINK NJ. TRIP MRJ. Results of non-selective adrenocorticolysis by 12 o. VOORHOUT G. 314 Protocols for Function Tests 39. DELPORT PC. GROVES E. RIJNBERK A. and testosterone. The urinary corticoid:creatinine ratio (UCCR) and follicle-stimulating hormone during different phases of the es- in healthy cats undergoing hospitalization. RIJNBERK A. Prognostic factors for outcome after trans- testosterone response to hCG and the identification of a presumed sphenoidal hypophysectomy in dogs with pituitary-dependent hy- anorchid dog. GALAC S. Vet Rec 2007. Minimal external masculinization in a SrY-negative 41. VAESSEN MMAR. GIEGER TL. 55. MAN SJ.60: 2003. High urinary corticoid /creatinine ratios in cats with hyperthyroidism.155: 518–521. 57. VAN HAAFTEN B. DANK G. J Vet Intern Med 2003. KOOISTRA HS. J Vet Intern Med miniature poodles in association with high urinary corticoid:creati- 1997. OKKENS AC. LLOYD DH. J Reprod Fertil 1994. DEN HERTOG E. ENGLAND GCW.145:323–328. CHURCH DB. TESKE E. OKKENS AC. BUIJTELS JJCWM. 47. WALLACK ST. Diagnosis of hyperadrenocorticism in dogs. VELDHUIS KROEZE EJB. TREMBLAY Y. MOL JA. 53. 58. OKKENS AC. KOOISTRA HS. Therioge- nology 2007.22:2–11. Clin 54. a non-invasive method for collecting cat urine for phosphate determination. WITT AL. GALAC S. Evaluation of the STRA HS. HS. VAN DEN BROM WE. SCHOE- 43. POPP- SNIJDERS C. 52. ZIJLSTRA C. 45. . CERUNDOLO R. KNOL BW.107:830–840. Effects of gonadotrophin-releasing hor- mone administration on the pituitary-ovarian axis in anoestrous vs 46. after single administration of hCG or LHRH agonist analogue in Urinary corticoid:creatinine ratios in healthy pet dogs after oral dog and rat. 49. FELDMAN EC. KOOI- phoma as a model for chronic illness: Effects on adrenocortical STRA HS. 42.11:30–35. Increasing sensitivity of the pituitary to GnRH from early to late Kreatinin-Verhältnis in Urin (UCC) bei gesunden Katzen (Urinary anoestrus in the beagle bitch. J Small Anim Pract 1989. Vet Rec 2004. BEVERS MM. WILLEMSE AH. DIELEMAN SJ. KOOISTRA HS. TESKE E. BEVERS MM. VAESSEN MMAR. Katkor cat litter. DIELE- Tech Small Anim Pract 2007. 51. Changes in plasma steroid levels 48.5:329–333.41:555–561. Biol Reprod 1999. Vet Rec 1999. HANSON JM. TRA HS. OKKENS AC. Schweiz Arch Tierheilk 2003. DIELEMAN SJ. Alopecia in pomeranians and gravity in healthy pet dogs of various ages. RIJNBERK A. J Reprod Fertil 1993. FOURIE LJ. BEVERS MM. MOL JA. BRAAKMAN JCA. REUSCH CE. J S Afr Vet Assoc 2005. KOOIS- Vet Intern Med 2004. In. VAN DEN BROM WE. DIELEMAN SJ. KOOISTRA HS. VAN SLUIJS FJ. KOOI- 56. J 50. low-dose dexamethasone suppression tests. Concurrent pulsatile secretion of luteinizing hormone T. VAN VONDEREN IK. Reprod Domest Animals 2009: Epub ahead fluence of veterinary care on the urinary corticoid:creatinine ratio of print. NEIGER R. VAN HAAFTEN B. VAN HAEFTEN T. ALLEN E.p'-DDD in 129 dogs with pituitary-dependent hyperadrenocorti. J Vet Intern Med 1998. KOOISTRA HS. J Steroid Biochem 1985. PETERSON ME. J Neurosurg 2007.160:393–397. and interindividual variation in urine osmolality and urine specific KOOISTRA HS. in dogs. Basal and GnRH-induced secretion of function. Reprod Domest Anim 2006.18:152–155. MARTINEZ MAKER J. Lym. cortisol /creatinine ratio in healthy cats). VAN VONDEREN IK. PORTER DJ. RIJNBERK A. 40. KOOISTRA ovariectomized bitches. SPEE B. DE LANGE MS. peradrenocorticism. Untersuchungen zum Kortisol.98:159–161. RIJNBERK A.17:154–157 FSH and LH in anestrous versus ovariectomized bitches. Intra.76:233–234. nine ratios and resistance to glucocorticoid feedback. MEIJ BP. XX male Podenco dog. KOOISTRA HS.144:12–17. 65–71.101:221–225. DE GIER J.67:1039–1045.30:441–443. OKKENS AC. GnRH in the male dog: dose-response relationships with LH cism. J Feline Med Surg trus cycle and anestrus in beagle bitches. 44. CAUVIN AL. long term remission). This is most likely due to vasopressin resistance caused by hypercor- tisolism. the abrupt ces. 315 13 Treatment Protocols The preceding chapters have covered diagnostic procedures 쎱 Immediately following removal of the pituitary gland: and modes of treatment for endocrine disturbances in dogs – Hydrocortisone. Once food intake is resumed. The owner is instructed to try reducing the fre- the first 24–48 h after surgery is essential for a successful out. anticipated and treated. 쎱 Antibiotic therapy consists of intravenous administration tions have proved to be very useful to owners in carrying out of 20 mg amoxycillin /clavulanic acid per kg body weight this somewhat complicated protocol. and glucose and plasma osmolality are measured before and im- 13. chloride. Meij In case blood samples are collected for 4 h after hypophysec- The total hypophysectomy that is performed in dogs and cats tomy to monitor the immediate post-surgical decline of the for the treatment of pituitary tumors leads to immediate ces. 1 mg/kg every 6 h. tisone is gradually lowered over a period of four weeks to mediate postoperative treatment concentrates on fluid 0. Consequently.45 % sodium chloride In healthy dogs this protocol prevents postoperative hyper- (NaCl) and 2. The results together with continuous monitoring 13. the im. parenteral administration of supraphysiological doses doses of 15 µg/kg twice daily. cortisol substitution is too difficult to administer desmopressin in the conjunctival given orally and is gradually reduced to a physiological dose. plasma ACTH concentration (which is a prognosticator for sation of the release of both adenohypophyseal and neurohy.5 mg/kg every 12 h. This chapter adds treatment protocols requiring – Desmopressin.5 % glucose solution with 20 mmol/l natremia. for patients that undergo hypophysectomy greatly benefit from two to three weeks.1 mg tablets. cortisone is only started after the last blood sample has been sopressin deficiency would be life threatening if not correctly collected. every 8 h. 쎱 Analgesia with 0. sudden cessation Maintenance therapy of cortisol excess would lead to collapse within hours after Drinking is allowed as soon as the animal is awake and when it surgery and death within 24–36 h. the dose of cor- pertonicity. Antibiotics (amoxycillin /clavulanic acid) and analgesia (Tramadol) are continued orally for two Treatment during hypophysectomy and the immediate weeks after surgery. Particularly in animals that have been in a state of hypercortisolism for a long time. The dog’s water intake is recorded by the strict anesthesia and immediate postoperative care protocols owner for at least four weeks after surgery and if severe poly- that prevent mistakes that may have dramatic consequences. These instruc. every 8 h. and cats.1 Pituitary mediately after surgery and then at 8. and administration of a vasopressin analogue. After the dog is discharged. potassium. Björn P. it is Close monitoring of these patients in an intensive care unit in resumed. uria and polydipsia occur when desmopressin is stopped.1 Hypophysectomy of fluid balance are used to adjust fluid administration and electrolyte supplementation. causing brain damage. sac.2 but mild and occasionally severe immediate post- potassium chloride (KCl) is started at maintenance operative hypernatremia may develop after hypophysectomy rate (10 ml/kg/hour).4 .1 intravenous administration of hydro- pophyseal hormones. The in the conjunctival sac. cortisone acetate 1 mg/kg is given 13 sation of vasopressin secretion would lead to severe plasma hy. Plasma concentrations of sodium. quency of administration after several weeks. and 48 h post- operatively. begins to eat and drink. 1 drop (~ 5 µg) three times daily. postoperative period 쎱 From the onset of the surgical procedure: Comments – Intravenous infusion of a 0.p'-DDD. tablet three times daily. in dogs with pituitary-dependent hypercortisolism. L-thyroxine is given orally in therapy. treated for hypercortisolism with o.3.25–0. If it proves to be come. orally every 12 h. as required. 24.1. Similarly. Desmopressin is administered of cortisol. it can be given orally in the form of 0. 1 drop (~ 5 µg) in the conjunctival sac further elaboration.3 µg buprenorphine per kg body weight It concludes with the instructions for owners for dogs being every 8 h. one and oral thyroxine substitution is also begun. The resulting hypocortisolism and va. such as that caused by significant illness or severe excitement Hypocortisolism is corrected by adding hydrocortisone and anxiety. The fluid therapy de. Treatment with trilostane is started at 2 mg/kg daily in one or two portions given with food. the equivalent of 10–15 % of body weight during the first 4–8 h and 100 ml/kg/24 h thereafter. xamethasone). dose of 0. Maintenance therapy 13.025 mg/kg is usually sufficient to maintain 13 Emergency treatment normal electrolyte concentrations. However.2.6).1 g/kg body weight per day. dration – often amounting to 10–15 % of body weight – and 쎱 Sodium chloride: Table salt is added to the dog’s food in a electrolyte disturbances. on initial and lifelong glomerular filtration results in adequate kaliuresis.5 mg/kg) is administered sub- cutaneously every 6 h. The dose of the povolemic shock resulting from mineralocorticoid deficiency. This is accompanied by monitoring of physical cardiovascular variables. Monitoring for possible recurrence of hypercortisolism is achieved by measuring UCCR in morning urine samples The hypoaldosteronism is corrected by subcutaneous admin- collected at home (chapter 12.1 Primary hypoadrenocorticism 쎱 Glucocorticoid: Cortisone acetate in a daily dose of 0. with trilostane sium into cells with restoration of metabolic acidosis.1–0. Kooistra should be monitored closely.2 Adrenal cortex The following oral maintenance medication is divided into at least two portions per day: 13.5 cause neurological disorders and thus fluid with a lower so- dium concentration may be preferable. even if the medications. The even. and measurement of plasma thyroxine. dose of 2 mg/kg every three weeks or desoxycorticosterone ing dose of cortisone is omitted prior to each sample and the acetate in oil in a dose of 0. the infusion is continued to provide drinking water or as tablets.2 Treatment of hypercortisolism creases hyperkalemia by (1) dilution. urea. Each follow-up consists of physical examination. and tration too rapidly in patients with severe hyponatremia may ACTH.9 % NaCl has been used for initial fluid ther. xamethasone phosphate (0.4) at two and eight weeks after istration of desoxycorticosterone pivalate (Percorten® V) in a hypophysectomy and every six months thereafter. these mineralocorticoids is available but hydrocortisone is available for glucocorticoid replacement. Alternatively. cortisone during every period of moderate to severe stress. 316 Treatment Protocols At hospital discharge enough time is taken to inform the tion of circulating volume and the consequent increase in owner. dose of 2 mg/kg every three weeks. in the or intraosseous dose of fluid. hydrocortisone event that the cortisone cannot be given orally for any reason. acetate (5 mg/kg) or prednisolone succinate (1 mg/kg) or de- The owner must also be provided with injectable hydrocorti. The dose is subsequently ad- Traditionally.0125–0. Thereafter. Hans S. and central venous pressure. justed according to the clinical response and the results of apy because it provides the needed water and sodium but ACTH-stimulation tests. cortisone can be doubled to make use of its slight intrinsic physectomy and then once yearly for the remainder of the mineralocorticoid activity (lacking in prednisolone and de- dog’s life. After the initial resuscitation by in. It may provoke vo- travenous or intraosseous administration of fluid (see below) miting of the meal and the salt can then be given with the in a dose of 100 ml/kg. the dose of hydro- Follow-up examinations are made at eight weeks after hypo. liver enzymes. the years. sodium. 0.5–1. the efficacy of treatment no potassium to exacerbate the hyperkalemia (see also is monitored by clinical signs and measurements of plasma chapter 4. However. mineralocorticoid may have to be increased slightly over The first and often life-saving step is correction of the dehy. (1 mg/kg) or prednisolone (0. In addition. and (3) increased renal excretion of potassium. urine pro- duction.2 mg/kg) to the initial intravenous sone and syringes and needles if traveling with the dog. Furthermore.1 mg/kg once daily.1.15 mg/kg. corticosterone pivalate can be given subcutaneously in a corticism admitted as an emergency are primarily those of hy. potassium.2. creatinine. Kooistra 쎱 Mineralocorticoid: Fludrocortisone acetate in a daily dose of 0. this should be changed as soon as routine biochemistry. raising plasma sodium concen. with written instructions. (2) movement of potas. and to continue this for the duration of the stress. restora- .0 mg/kg or prednisolone in a daily dose of Joris H. The owner is instructed to double the dose of infused fluid contains some potassium. desoxy- The symptoms and signs in a dog with primary hypoadreno. for hypokalemia can develop during this phase.4 possible to the orally administered mineralocorticoid fludro- cortisone with supplemental salt (see below). If neither of morning dose is delayed until after the sample is collected. Plasma potassium Hans S. 13. Robben 0. 2. 쎱 After Somogyi reaction or overt hypoglycemia. urine culture).6 dicated. the post-ACTH plasma cortisol concentration is 쎱 Give the owner written instructions.1). Reusch 쎱 Repeat history. check his / her technique. 350–450 µmol/l. 쎱 Repeat history. Consider administration of a 쎱 If clinical manifestations of hypercortisolism have not progesterone receptor blocker such as aglepristone if the ceased and the post-ACTH plasma cortisol concentration bitch cannot undergo surgery or has recently received is 쏜 150 nmol/l.3 Endocrine pancreas on all relevant technical aspects (duration at least 0. uria and polydipsia have ceased and the post-ACTH 쎱 Treatment may be started in the hospital for one to two plasma cortisol concentration is 40–150 nmol/l. as after one week. in cats by 0. 쎱 Prescribe dietary management: 쎱 If clinical manifestations of hypercortisolism have ceased – dogs: high-fiber diet but the post-ACTH plasma cortisol concentration is – cats: high-protein.3. 쎱 History. blood glucose measured close to the time of insulin elevated fructosamine). If necessary. fructosamine. and the dog’s condition is considered satisfactory but 쎱 Instruct the owner (duration at least 1 hour). the dose of trilostane is 쎱 Begin treatment of concurrent problems (e. intravenous fluid and cortico. Vetsulin®.g. blood bio. well. the dose of trilostane is not changed but that dietary management of another disease does not the dog is monitored closely for signs of possible recur. trilostane treatment is remainder of the day.5 IU/kg BID 쎱 If clinical manifestations of hypercortisolism such as poly. 쎱 Cessation of diabetogenic drugs. 쎱 Castration if intact bitch. concentration is 40–150 nmol/l. glucosuria. and the dose of insulin is decreased if blood glucose is 쎱 If clinical manifestations of hypercortisolism have not de. and dose adjustment.5 1. Initial presentation BGC may not be required if animal appears to be doing 쎱 Diagnosis of diabetes mellitus (hyperglycemia. . fructosamine. formed 2–3 h after a dose. 10–25 %. by ~ 1 mg/kg. and fructosamine is 쎱 Laboratory evaluation (routine hematology. administration is 5–10 mmol/l. 쎱 Radiographs. and dose adjustment. tient to the clinic as soon as possible. 쎱 Measure blood glucose concentration every 1–2 h for the such as lethargy and anorexia. the daily dose of trilostane is increased progestins. both Intervet/Schering Plough): is determined as follows: – dogs: 0. the first test approximately two 쎱 Start intermediate-acting insulin (lente insulin. Endocrine pancreas 317 The maximal lowering of plasma cortisol concentration oc. have priority rence of hypercortisolism. body weight. physical examination. than one portion. BGC.1 Treatment of diabetes mellitus performs a BGC once per month. body weight. 쎱 If owner performs HM. – cats: 1–2 IU/cat BID. physical examination. Blood glucose is measured three to four times daily of trilostane is left unchanged. TLI. Hence treatment is evaluated by ACTH-stimulation tests per. stopped immediately and an ACTH-stimulation test is 쎱 Measure blood fructosamine. – if overweight. Treatment may also be started without hos- creased or ceased but the post-ACTH plasma cortisol pitalization. as after one week. 쎱 Introduce owner to home monitoring (HM) and instruct 13. the dose days. The dog is then reexamined one Reevaluation three weeks after diagnosis month later and at intervals of three to six months thereafter. 쎱 Adjust insulin dose if required: in dogs increase by steroids are started (see chapter 13. physical examination. provided 150–250 nmol/l. blood glucose curve (BGC). body weight. 쏝 40 nmol/l. cPLI if in- curs between 2 and 6 h after oral administration of trilostane. Adjustment of the dose lin®. urinary increased slightly or given in two portions daily rather tract infection.. or b) decreased Reevaluation one week after diagnosis by ~ 1 mg/kg if there was no response to ACTH. stomatitis/gingivitis). Caninsu- weeks after the start of the treatment. chemistry. aim for 1 % weight loss per week 쎱 If clinical manifestations of hypercortisolism have ceased – give food just before insulin administration. reduce Follow-up examinations are repeated at intervals of two to dose by at least 50 %. urinalysis.5 h) 쎱 Owner measures fasting blood glucose twice weekly and 13. three weeks and the dose is adjusted as required until the response is satisfactory. 13 쎱 If there are signs suggesting adrenocortical insufficiency. low-carbohydrate diet. the dose of trilostane is a) not changed if plasma cortisol was increased by ACTH. performed. examined at monthly intervals. The dog 쎱 Owner gives food and insulin at home and then brings pa- is monitored closely for signs of hypocortisolism and re. 쏝 5 mmol/l. abdominal ultrasonography.0 IU/injection. in dogs and cats Reevaluation six to eight weeks after diagnosis Claudia E.25–0. or even in coma. space with correction of the metabolic acidosis. to avoid cardiac arrhythmias. The duration of 13 miting. up to the stage at the time of presentation and usually include vo. The cotrans- 쎱 Maintenance of fructosamine at 350–450 µmol/l. The lack of insulin con- tributes to the loss of intracellular potassium. is adjusted according to plasma sodium concentration and matotropism) if there are suggestive symptoms and /or fluid balance. al.1–2.1: treated with 0. and hyperventilation is usually equivalent to In most cases. and ketonuria.6–5. The fluid loss via osmotic diuresis.8 mmol/l in cats. electrolyte supplemen- tation. correction of hypovolemia will also restore the 10–12 % of body weight. and weight loss. Hence bicarbonate supplementation emergencies and its treatment is demanding. be supplemented in virtually all patients with diabetic ke- toacidosis. acid-base balance quickly. port of potassium with glucose is amplified by insulin therapy though fructosamine is the least important variable for and if hypokalemia is severe. 0. Phosphate should be supplemented if plasma phos- Claudia E. tral venous catheter and a urine catheter in place. its potassium content must be taken into account. especially if there is no food intake after initial Joris H. so that administration of bicarbon- ate to correct metabolic acidosis is often unnecessary and can Diabetic ketoacidosis is one of the most complex metabolic even be detrimental.3.2 Management of diabetic Phosphate supplementation ketoacidosis Hypophosphatemia can develop during the first few days of treatment. aggravated by Continuing reevaluations every four months vomiting.9 % NaCl (ml/kg/h) with intravenous fluid (30–90 ml/h). It is supplemented by continuous intravenous infusion at a rate of The clinical manifestations of diabetic ketoacidosis depend on 0. The type of solution * If any other crystalloid solution is used.06 mmol/kg/h for 6 h. Table 13. This requires (1) maintenance fluid (~ 2 ml/kg/h).5 mmol/l in dogs or 쏝 0. ism due to the hypovolemia. potassium must 쎱 Urine culture at least once yearly.5 30 16 dehydration). Plasma potas- 쎱 Resolution of polyuria. Bicarbonate supplementation vomiting. rected to near normal before insulin therapy is started. hyperso.12 mmol/kg/h. The animals are infusion is determined by measuring plasma phosphate every often severely hypovolemic and may be presented in a state of 6 h. correction of acid-base balance. 13. Intra- venous administration of potassium should not exceed 0. Fluid balance is monitored closely. . (2) correction of the fluid deficit (= amount of 3. and secondary hyperaldosteron- 쎱 Repeat all measures as at six to eight weeks. rapidly lowered by dilution and osmotic diuresis. It requires 24 h surveillance with frequent reevaluation of physical and lab- oratory variables and appropriate adjustments of therapy. are sometimes necessary. ke- tonemia. Fluid therapy is started with a solution having a 2. osmotic diuresis. Laboratory findings include reduced if potassium phosphate is used for the infusion.9 % NaCl* Fluid therapy Plasma potassium mmol KCl added Maximum rate Hypovolemia and shock should be treated as soon as possible (mmol/l) per liter of 0. and correction of the hyperglycemia.0 80 6 (154 mmol/l. Reusch phate is 쏝 0.03–0. plasma potassium should be cor- evaluation of metabolic control.0 40 11 and polyuria.1). polyuria. with a cen- signs. lethargy. hyperglycemia (sometimes severe). Dehydration is usually 3. depending on the plasma sodium concentration and the state of hydration. 318 Treatment Protocols 쎱 Test for underlying disease (hypercortisolism. Potassium supplementation Reevaluation ten to twelve weeks after diagnosis The potassium deficit can be severe even though plasma po- 쎱 Repeat all measures as at six to eight weeks.1: Potassium supplementation in diabetic ketoacidosis Table 13. and polyphagia and sium is measured again after 2 h of fluid therapy.5 mmol/kg/h.1–3. polydipsia. Higher infusion rates. 쎱 Maintenance of blood glucose between 15 mmol/l at the potassium shifts from the extracellular to the intracellular time of insulin administration and 5 mmol/l at the nadir.6–3.0 20 24 resolved within 12–24 h. The initial dose depends on the pretreatment Goals of therapy plasma potassium concentration (table 13. since it is return to normal body weight. Treatment consists of fluid therapy. and (3) replacement of losses due to vomiting 2. tassium is normal or even elevated.5 60 8 sodium concentration of 140 mmol/l or slightly higher 쏝 2. Consequently. Simultaneous supplementation of potassium should be sopor or stupor. In addition.9 %). metabolic acidosis. NaCl 0. Robben treatment. Add the appropriate amount of 50 % glucose to the main- Regular crystalline insulin can be administered intermittently tenance fluid to make a 5 % solution. reduce os. The goal in either case is to glucose can be administered via a dedicated syringe pump reduce the hyperglycemia in a controlled manner. (mmol/l) administration (ml/h) fourth the maintenance rate. and there is con. 쎱 Repeat steps two and three until glucose is 쏝 15 mmol/l. Acid-base balance 5 ml/h in cats or 10 ml/h in dogs. the blood glucose concentration should be decreased by After the patient has been stabilized.5 IU/kg to 50 ml of 0. Aim at a blood glucose concentration of 9–12 mmol/l. comitant renal failure.1 IU/kg IM in dogs 쏜 10 kg.9 % NaCl. and improve acid-base status. can be initiated.2: Glucose infusion adjustments with continuous rate infusion administer insulin! Measure blood glucose every hour and Table 13. its condition improved. (mmol/l)]). add the dose for 0. which often lowers blood glucose by di. Total fluid administration should be calculated and infusion 쏜 15 Maintenance fluid 10 5 rates of other solutions reduced accordingly. and a central line at one-fourth the maintenance rate. continuous rate infusion of regular insulin (table 13.3 × body weight (kg) × (24 – [bicarbonate (cat) or 0. after injection. administered over ~ 6 h. since most patients are anorexic at this stage. and 0. to 50 ml of 0. 20 % or as a continuous rate infusion. with 5 % glucose drated. at one. Add an amount of 50 % glucose to the main- tenance fluid to result in a 5 % glucose solution. administer glucose to prevent hypoglycemia. Administer at a rate of carbonate deficit. 쏝 10 kg. to avoid large shifts in osmolality which can and it has begun to eat.5 쎱 When blood glucose reaches 8–15 mmol/l and the patient with 5 % glucose is rehydrated. treatment with longer-acting insulin 13 have detrimental neurological effects. Intermittent. dehy. 쎱 When regular insulin is given SC. intramuscular (IM) technique 쎱 After the patient is stable and rehydrated. hypokalemia (쏝 3. glucose falls below 15 mmol/l (see step 5 of the intermit- lution. and 0.2: of regular insulin adjust the glucose infusion rate accordingly.25 IU/kg IM in dogs 쏜 10 kg.5 mmol/l). continue IM administration of insulin. while adjustments are being made in the tissues. and improved uptake of glucose in peripheral tent technique). which simplifies adjustments in glucose administration. administer 1 IU of regular insulin IM per cat or dog 쏝 10 kg. 쎱 If blood glucose is still 쏜 15 mmol/l. Adjust the dose in steps of 10–20 % to maintain with 5 % glucose blood glucose at 6–8 mmol/l.9 % NaCl solution before adding insulin prevents adhesion of insulin to the synthetic material of Insulin and glucose therapy the syringe and tubing. solution after 1 h. insulin-containing solution. It is often helpful to plot . 500 ml flask or bag of 0. If the patient is not yet rehy. discard the with severe diabetic ketoacidosis. The bicarbonate deficit in mmol can be calculated by: Continuous rate infusion 쎱 First administer regular insulin at a rate of 0. motic diuresis. Alternatively. For this purpose. diuresis.2).5 IU of regular insulin/kg every 9–12 Maintenance fluid 5 2. 12–15 Maintenance fluid 7 3. 쎱 Measure blood glucose after 1 h. Adding 2 ml of plasma is determined at least every 3 h. It may be Blood glucose Glucose Regular crystalline insulin more convenient to administer 20 % glucose.05 IU/kg/h NaHCO3 = 0. and then refill the system with a fresh dration. Do not Table 13. Ideally. Endocrine pancreas 319 should be considered only if blood gasses can be measured blood glucose concentration measured hourly for 6–8 h during treatment. hypovolemic shock.1 IU/kg/h (dog) by means of a syringe pump. regular insulin Start regular insulin if blood glucose is 쏜 15 mmol/l: can be administered SC three to four times /day (see steps 쎱 Administer 2 IU of regular insulin IM per cat or dog 6 and 7 of the intermittent technique).5 6–8 h SC instead of IM.1. to determine the duration of action. via a dedicated intravenous Dog Cat syringe pump and a central intravenous catheter. 쎱 If blood glucose is 쏝 8 mmol/l. The patient is first stabilized by administering intravenous 쎱 The continuous rate infusion of glucose is started if blood fluids and potassium.9 % NaCl in a syringe or the dose for 5 IU/kg to a The initial dose is one-fourth to one-half the calculated bi. determine its maximum 6–9 Maintenance fluid 5 2. give 0. and hyperglycemia. the initial pH is 쏝 7. fill the syringe and Insulin therapy should be postponed for 2–4 h in patients tubing with insulin-containing solution. Alternatively.5 with 5 % glucose effect by measuring blood glucose 2–3 h after adminis- 쏝6 Maintenance fluid Stop insulin infusion tration. 3 mmol/l/h. Both drugs have a slow onset of action and should be ripheral vessels. because the 쎱 In animals with refractory or persistent hypoglycemia due patient is having seizures).5–5 % glucose at 1.5–1 mg/kg added to intravenous fluids 쎱 Continuous rate infusion of 20 % or 50 % glucose should and administered over 6 h) or diazoxide (5–30 mg/kg be via a central venous catheter. resulting in 쎱 As soon as intravenous injection is possible. molar solutions can cause phlebitis if administered in pe. 쎱 Patients with severe. for the longer the period convulsants have a relatively short half-life.5 to two times the glycemic state..g. These anti- postpone emergency treatment. The the first five days and then every other day. If blood tric tube. immediately start a continuous cause insulinoma patients have adapted to a chronic hypo- rate infusion of 2. it is probably (5–10 min) administer a bolus of glucose: 6–12 ml of better to avoid high blood glucose concentrations in pa- 20 % glucose or 2.p'-DDD therapy in dog7 In your dog excessive amounts of the hormone cortisol are The initial treatment of your dog consists of: tablets produced by adrenocortical tissue. 320 Treatment Protocols 13.5 mmol/l is often sufficient. but continue blood glucose. If blood glucose decreases control symptoms: 2. 쎱 If intravenous injection is not possible (e. an additional bolus must be given. fludrocortisone. Do not pour syrup into the patient’s mouth. the infusion rate is increased by 25–50 %. sulin-secreting pancreatic tumor (insulinoma). the dose of cortisone is kept higher than the normal requirement for the first week after o. for deficiency of these day the replacement of the adrenocortical hormones is hormones can result in a life-threatening crisis. given as soon as possible. If the patient is unable or unwill- 13 justed by serial measurements of blood glucose every ing to swallow.p'-DDD is given. On the third followed carefully and completely. be- 15–30 min after the bolus. The target of treatment is a normal blood glucose concen- tration. It is very import- ant that the instructions for the replacement hormone be For the first two days only o. apply glucose syrup to the oral to insulin overdosage or an insulin-secreting pancreatic mucosa. so the neuro- of hypoglycemia. Consequently. Time given to effect if the patient still has seizures after normal- required for measurement of blood glucose should never ization of the blood glucose concentration. For good ab- requirement for the hormones normally produced by ad. Adjustment of the dose is based on measurements of not. the counterregulatory hormone glucagon can be may be aspirated. be given with food.5–5 ml of 50 % glucose for a cat or tients with a tentative diagnosis of insulinoma. BID) can also be considered to control hypoglycemia. not hyperglycemia.p'-DDD therapy. slowly rebound hypoglycemia.3. 쎱 Dexamethasone (0.p'-DDD is given daily for tical tissue (including adrenocortical tumor tissue). the tablets should always renocortical tissue is then provided by lifelong adminis. stopping the medication. The treatment with of o. for it tumor.8–3.3 Treatment of hypoglycemia 쎱 The patient must be fed as soon as possible after stabiliz- ation. The rate of continuous infusion is ad. To allow a more gradual change from the ex- cessive hormone production. and ordinary salt. tration of replacement hormone tablets. the greater the risk of irreversible brain logical status of the patient can be examined shortly after damage. Client information for o. administered. glucose is very low. trying to raise blood glucose concentration via the oral 쎱 Hyperglycemia may stimulate insulin release from an in- mucosa. Joris H. sorption and to prevent vomiting. maintenance rate. because these hyperos.p'-DDD aims at complete destruction of all adrenocor. . The o. acute symptoms and signs related to 쎱 Diazepam (1 mg/kg) or propofol (2–6 mg/kg) can be hypoglycemia should be treated immediately. begun with the addition of cortisone. If they do min. administer diazepam rectally (1 mg/kg). daily for in total 25 days. if necessary by force feeding or enteral tube feeding. If blood glucose falls below the reference powder can be dissolved in water and administered by gas- range. and 20–35 ml of 20 % glucose or 8–15 ml of mal blood glucose concentrations may not be needed to 50 % glucose for a large dog. Even nor- small dog. diazoxide capsules can be opened and the 20–60 min. Start with a 50 ng/kg bolus followed by a 쎱 Serious neurological symptoms such as seizures should continuous rate infusion at an initial rate of 5–10 ng/kg/ decrease within 1–2 min after giving glucose.p'-DDD (= Lysodren® or Mitotane®) times o. Robben Parenteral feeding should be considered if the enteral route is not available. After this. The first warning is often loss of appetite. and notify the veterin. injectable medications ment doses of fludrocortisone and salt are correct. Their purpose is to be certain that the replace. also take the inject- usually be resolved without difficulty. without complications. should be started. but be sure to con. incoordination. Follow-up Special circumstances in replacement therapy The first follow-up examination is at one month after the beginning of o. This can occur after several months or even after four to five years. but there can be complications as- sociated with the o.2. but once this begins. tinue the replacement medications. administration is continued but simply spread out more over the day. able medications. The recovery of the coat takes longer.p'-DDD immediately. even if you have not yet had to use them yourself. The Complications DOC injections are continued until the dog can again With the above treatment instructions. These signs usually disappear if jections. such as nausea. symptoms of the disease reappear. stop the o.p'-DDD completely. 1 mg/ml) in a dose of ml 13 period of excessive scaling and some itching. the dose of cortisone remains un- arian. severe physical stress. con- NaCl (salt): × daily gram tinue the replacement medications. a very thick coat usually develops. for not all veterinarians may have these medi- In the beginning of treatment there may be mild side ef. the problems can home for more than one or two days. It is then necessary to repeat the treatment with 쎱 The cortisone tablets are replaced by subcutaneous in- o. Endocrine pancreas 321 During the first two months your dog receives as replace. also make provision for the possible need for the in- slight disorientation. If the dog refuses to eat or eats almost noth. This can be once daily or of desoxycorticosterone pivalate in a relieved by a treatment with shampoo once or twice a dosage of ml once every three weeks. If If you take your dog on vacation or on a trip away from you notify the veterinarian in time. after about 쎱 The fludrocortisone tablets and salt are replaced two months. Many dogs with the disease have an excessive appetite. You should stop o. most dogs recover swallow and also retain the fludrocortisone and salt. At this time the dose of It is extremely important to give the replacement medi- cortisone is usually reduced by half. and a Fludrocortisone acetate: × daily tablets decrease in appetite is an expected sign of recovery. The re. and this instruc- tion sheet.1) is available. syringes. the ing. Yet there may be situations examination will be used to determine whether the doses in which your dog cannot or will not take anything orally of fludrocortisone and salt need to be adjusted. tions are continued until the dog can again swallow and ing the o. It is far better to contact the veterinarian before a Cortisone acetate: × daily tablets of mg crisis occurs. If follow-up examinations are usually made once every six for any reason your dog cannot take or retain the tablets months.p'-DDD or the replacement therapy. jections of hydrocortisone acetate (50 mg/ml) in a dose of ml twice daily. and obtain the veterin- arian’s advice promptly. by subcutaneous injections of desoxycorticosterone covery of the skin and coat may be preceded by a short acetate (DOCA. A deficiency in replacement medications can lead to a life- ment therapy: threatening crisis and emergency treatment may be required. The hydrocortisone injec- The first signs of recovery are often already apparent dur.p'-DDD therapy. or cannot retain the medications because of vomiting. How- of mg ever.p'-DDD therapy. an almost complete refusal to eat should be recognized as a warning. Some. or injury. and salt for two times in succession. you should double the dose of hydrocortisone. while the dose of fludrocortisone and salt may have to be adjusted by the veterinarian. diminish and the dog’s endurance increases. If you leave the dog in the care of someone fects from o.p'-DDD. or else. With these exceptions.p'-DDD. The salt is not needed when DOC injections are used. . ment that requires anesthesia. This also applies if your dog must be times. in spite of the destructive action of o. cations at hand.p'-DDD on fasted before being brought to the veterinarian for treat- adrenocortical tissue. Results of blood cations without interruption. In cases of anesthesia. dose of cortisone should be doubled for one or two days. If neither week. and needles. DOCA nor DOC pivalate (chapter 13. The excessive thirst and hunger retain the cortisone tablets. changed for life. MEIJ BP. Efficacy of transsphenoidal dal hypophysectomy for the treatment of pituitary-dependent hy. NEIGER R. Philadelphia: WB Saunders Co 1992:345–349.27:246–261. fects of trilostane treatment on the pituitary-adrenocortical and NEZY Y. adrencorticotropic hormone predicts recurrence after transsphenoi. Current Veterinary Therapy XI. HARA Y. FUJITA Y.007.tvjl. MEIJ BP. Prophylactic efficacy of desmopressin renin-aldosterone axis in dogs with pituitary-dependent hypercor- acetate for diabetes insipidus after hypophysectomy in the dog. Med Sci 2003.65:17–22. GALAC S. RIJNBERK A. Results of transsphe. In: Kirk RW. KOOISTRA HS. MOL JA. versity 2007:131–145. Hanson. TESKE E. KOOISTRA HA. J Vet tisolism. VOORHOUT G. 322 Treatment Protocols References 1. VAN ’T HOOFD MM.10. noidal hypophysectomy in 52 dogs with pituitary-dependent hy- peradrenocorticism.19:687–694. Birmingham.208. hypophysectomy in treatment of dogs with pituitary-dependent hy- peradrenocorticism in dogs. 7. HAZE. BELSHAW BE. J Vet Int Med 2005. MASUDA H. Vet J 2008. Bon- agura JD eds. 6. doi:10. MEIJ BP. RIJNBERK A. 24 hour cortisol values in dogs with hy- 3. In: Thesis J. Utrecht Uni. Proceed British Small Anim Vet WINKEL HAW. TAGAWA M. 2001:549. HASEGAWA D. O.M. peradrenocorticism. 13 . Peri-operative plasma profile of 4. peradrenocorticism on trilostane. TESKE E.p'-DDD treatment of canine hyperadrenocorticism: an alternative protocol. Ef- 2. HURLEY K. HANSON JM. VOORHOUT G. Assoc Congress. 5. Vet Surg 1998. HANSON JM. TAODA T.1016/j. MOL JA. BUIJTELS JJCWM. VAN DEN INGH TSGAM. The plasma P4 concentrations (1 nmol/l = 0.4 Weight loss in spite of Other than kidney disease.3). The information needed for good management of breeding ciency may also cause alopecia (chapter 2. The second step is a urinalysis. this algorithm can be used after the onset of severity and duration of the endocrine disturbance.4 If the history and physical examination do not reveal clues If the routine laboratory examinations reveal no abnor- suggesting an endocrine disturbance. which lead to increased the absence of other problems such as PU/ PD. assay standards used. Polycythemia and hyperaldoste- by specific examinations. especially when associated with hepatic encephalo- pathy.32 ng/ml) used in this algorithm are based on measurements by radioimmu- 14. it can be tested oratory profile for PU/ PD. but the alope. vaginal discharge. The history and physical examin. ronism may also cause PU/ PD in dogs. pri. secretion of ACTH and subsequently cortisol excess.2. If an animal with a considered to occur at plasma P4 concentrations above seemingly convincing history of PU/ PD is found to produce 13 nmol/l and immediate mating is advised when plasma P4 urine with a high osmolality (Uosm) or specific gravity (Usg). centration.3). measurement of plasma use of a standard form for these steps may be helpful. water con. with a radioimmu- crine disorder as the cause of the polyuria /polydipsia noassay using radioiodine-labeled progesterone. the vagino- cias that have been ascribed to acquired growth hormone deficiency do not seem to fit in this category (see chap- scopic appearance of the vaginal mucosa.3 Breeding management Endocrine disturbances may cause atrophy of the skin and ad. the cytological find- ings in a vaginal smear. includes the appearance of the vaginal discharge.1 When calcium and phosphate should always be included in the lab- suspicion of an endocrine disturbance arises. In the dog the classical causes of alopecia are hy. Growth hormone defi. and hyperestrogenism (section 8. alopecia proestrus.4). and the sical examination (section 9.3). If the routine labora. ultrasonography. and tration in peripheral blood may require working with slightly physical examination may reveal a reason to suspect an endo. ences in specificity of the antibodies in the two assays or in the mary polydipsia must be considered. hepatic failure may also cause good appetite polyuria. serial measurements of urine osmolality tory examinations reveal no abnormal values.3). pothyroidism (section 3.2). A high Uosm or Usg in an ani- mal with PU/ PD may also be due to glucosuria.2. the next step is labora. 14. mal values suggesting the cause of the PU/ PD.2. characterized by swelling of the vulva and bloody may develop.2. and vasopressin measurements during hypertonic saline infusion (chapter 12. history. reaches 26 nmol/l. Depending upon the normalities. abdominal tory examination of urine and blood.5 These differences may be due to differ- indicating that the kidneys are able to concentrate urine. Atrophy of hair follicles results in slow.2). Algorithms 323 14 Algorithms Hans S.2. the modified water deprivation test (chap- imaging and work-up at specialist level may be required. ovulation is (PU/ PD). causing hypercalcemia may not have been detected by phy- ation are aimed at the detection of endocrine disease. hypercortisolism (section 4. For example. ter 12. 14. Skin atrophy may also manifest itself by If the general and gynecological examinations reveal no ab- stagnant regrowth of hair after clipping. Alternatively. sumption may be increased because the owner has changed the animal’s diet to a dry food. The use of other reliable methods for the determination of the P4 concen- In the first part of this algorithm the signalment.2 As phasis is on associated symptoms and signs that may point to parathyroid tumors are usually very small and a malignancy an endocrine disturbance. In this condition abnormal metabolism of amino acids This algorithm can be used when an animal loses weight in gives rise to »false« neurotransmitters. diagnostic (chapter 12. of the bitch nexa. Kooistra Ad Rijnberk In these step-by-step procedures for problem solving the em.1). different P4 concentrations. or absent hair growth. or diar- .3) may be required.1 Endocrine alopecia 14. fever.3. abnormal (dull).2 Polyuria and polydipsia noassay with tritium-labeled progesterone. and the plasma progesterone (P4) con- 14 ter 2. VOORHOUT G. Chronic glucocor- homa increase energy demand. ROTHUIZEN J. Domest Animal Endocrinol 2001. BIEWENGA WJ. Medical history and physical examination in companion animals. Endocrine glands. MOL JA.11: 300–303. as do cardiac abnormalities ticoid excess and impaired osmoregulation of vasopressin release in that result in tachycardia. VAN VONDEREN IK. 324 Algorithms rhea. VAN DEN BROM WE. 4. KRAUS JS. Saunders Elsevier 2009:207–212. The first step is to carefully evaluate food intake. RIJNBERK A. RIJNBERK A. BOER P. J Reprod Fertil 2001. Domest Anim Endocrinol orders weight loss is rarely seen as the primary problem and in 1995.20:227–240. dogs with hepatic encephalopathy. most of them the appetite is poor. 5. In: Rijnberk energy expenditure. Edinburgh. IJZER J. J Vet Intern Med 1997. BOER WH. KOOISTRA HS. MOL JA.12:13–24. Large and widespread malignancies such as malignant lymp- 2. in patients with these dis. eds. Influence of litter size and breed on the duration of gestation in dogs. A. However. 14 . Some References owners feed strictly according to the recommendations of the manufacturer or seller of the food. Aldosteronoma in a dog with polyuria as the leading symptom. VAN SLUIJS FJ.57 (Suppl):193–197. MEYER HP. KOOISTRA HS. KOOISTRA HS. Polyuria and polydipsia and disturbed vasopressin release in 2 dogs with secondary polycythemia. VAN DEN INGH TSGAM. KOOISTRA HS. VAN OSCH W. Van Sluijs FJ. VAN VONDEREN IK. OKKENS AC. DIELEMAN SJ. not taking account of 1. TEUNISSEN JM. 3. 1 . Algorithms 325 14 Figure 14. 2a . 326 Algorithms 14 Figure 14. 2b . Algorithms 327 14 Figure 14. 3a . 328 Algorithms 14 Figure 14. 3b . Algorithms 329 14 Figure 14. 330 Algorithms 14 Figure 14.3c . 3d . Algorithms 331 14 Figure 14. 332 Algorithms 14 Figure 14.4 . 219. 268 Cremaster muscle 242 . 161 Aminoglutethimide 125 circumference 300 hyperplasia 196 Adenohypophysis 14 AMP-activated protein kinase condition scoring system Convulsions 174 Adipocyte differentiation 299 113 299 Corpora lutea 208 Adipokines 160 Amylin 157. 160 treatment 72 ACTH 93. 97. C-PTH fragments 256. 167 size 19 Corticosteroid Adipose tissue 158. 26 Calciotropic hormones 253 Corticotropin-like inter- 129. 65. 102 clinical manifestations 72 progestin-induced 27 action 102 B diagnosis 72 radiation therapy 27 nonepithelial actions 103 b-cell(s) 155. 28. 217. 212 117 regulation 98 (in) growth hormone excess Calcinosis cutis 112. 197 Body Congenital adrenocortical Addison’s disease 104. 305 ACTH-stimulation test 107. 103. Index 333 Index Bold page numbers indicate figures and tables. 259. 269 noncortisol-secreting 130 see also AMH 261. 278 mediate-lobe peptide 97 causing hypercortisolism 125 primary 190. 210. 96. 99. 196. 130. 96. 191. 198. 278 Clonidine 305 regulation 97 endocrine 323 Blood glucose meters 173 Combined anterior pituitary stress response 97 miniature poodle 24 Blood-brain barrier 14 function test 33. 308. 126. 236 trilostane 129 translocation of AQP-2 37 Carbimazole 57. Breeding management 228 metabolism 95 Adrenals 108 222. 102. Pomeranian 24 Blood-testis barrier 235 Compression fractures 271 110. 27. 175 moderate cortisol excess 126 Anti-Müllerian hormone 241. 26.p'-DDD 127 Aquaretic agent 45 Castration 237. 221 action 261 Cortisol 94. 78 99m TcO4– uptake 307 ultrasonography 126 urinary AQP-2 excretion ointment 78 Adrenocorticolytic drug 127 37 Carrier proteins 5 A o. 3 hyperplasia 278 diagnosis 26 Aldose reductase 161 Azoospermia 246 Central hypothyroidism hypophysectomy 27 Aldosterone 37. 162. 130 APUD cells 291 humoral manifestations 294 genase 101. 80. 167 Amyloidosis 298 Bone binding globulin 94 Adrenalectomy 127. 114 Bethamethasone 133 extra-adrenal 139 pulsatility 99 algorithm 323 Biphosphonates 275. Calcium-sensing receptor 257. 123. 283 a-cells 155 Adrenocorticotropic hormone see Arginine vasopressin 35 Cataract 161. 228 Athyreosis 61 C-cell(s) 55. 139 precursor 118 Alopecia 24. sex hormones 126. 212 clinical findings 125 prolonged 221 synthesis 261 ACTH-independent dedifferentiated 126 Angiotensin-converting enzyme Calcitonin gene-related peptide mechanisms 99 dexamethasone resistance 101 241 free fraction 94 126 Angiotensin-II 100 Calcitriol 257. 298 mass index 300 Corticomelanotropins 14 Adiponectin 160. laparoscopic 127 Androgen-binding protein 236 metabolism 262 see also UCCR Adrenaline 139 Androgen(s) 93. 317 AMH 188. pheochromocytoma 140 secretion 139 Acromegaly 25. 93. 162. 196. 113 Corticotrophs 16 Adrenocortical tumor 125. 130 Anestrus 210 Calcitonin 255. 167. 195. 225. 236 algorithm 323 withdrawal 109 adrenal medulla 139 insensitivity 198 Bromocriptine 210. 1. 265. 261 168 Agouti gene-related peptide 297 Autocrine 2. 284 target genes 101 after ADX 127 Anticonvulsants 320 direct regulation 253 urinary 95 metastases 126 Antidiuretic hormone 35 hormonal control 255 C-peptide 156. 167. 298 Amyloid 160. 100. 130 Anal sac tumor 274 hunger 268 corticoid:creatinine ratio 99. 261. 282. 139 ACE-inhibiting compounds 101 161 hyperaldosteronism 137 biosynthesis 138 Acidosis 172 Aglepristone 164. 270. regulation 99 damage 156 Cerebral edema 44 155 renin ratio 107 differentiation 157 Cervical spondylomyelopathy (and) aldosterone 100 Aldosterone synthase 94 dysfunction 160 279 burst 97 Aldosteronoma 135 failure 167 Chief cell 255 cortisol ratio 107 Algorithms 323 function 156 Chimerism 190 (and) cytokines 99 Alkaline phosphatase 271 proliferation 157 Cholecalciferol 258 feedback inhibition 99 All meat syndrome 271 tumor 176 Cholecystokinin 297 nonpituitary tumors 130 Alloxan 177 Baroreceptor 101 Chromaffin cells 93. 131 surgery 127 Aquaporins 37 mammary 20 5a-reductase 189. 265 a-glucosidase inhibitors 169 ACTH ARR (ald–renin ratio) 137 Catecholamine receptor 140 Abortion 218 Advanced glycation end products Arterial hypertension Catecholamines 3. 189. 191. 99. 160. 212 Corticosterone 94 turmorigenesis 125 receptor 189 Brucellosis 228 Corticotroph adenoma 116 ultrasonography 108 regulation 96 macroadenoma 118 Adrenergic receptor 139 Androstenedione 103 C molecular pathogenesis Adrenocortical secretion Anemia Cabergoline 34. 130.p'-DDD treatment 127 Antisperm antibodies 246 Cancer 20 259 plasma ACTH 126 Appetite regulation 297 cachexia 294 11b-Hydroxysteroid dehydro. immune response 101 ferret 130 Angiotensinogen 101 276 salivary 94 glucocorticoid substitution Anorchism 310 Calcium 253. 160. 194.25-dihydroxycholecalciferol o. 16 (and) pituitary surgery 38 Endometrium 226 Glipizide 170 Gonadotropin-releasing hormone prognosis 41 Enhancers 6 Glucagon 155. 214 receptor 101 diabetogenic action 18 insulin-dependent 159 follicular phase 204 regulation 96 excess 25. 41. DEXA (dual energy x-ray hypochondroplastic 23 Galactopoiesis 21 178 absorptiometry) 300 Dynamic endocrine tests 11 Galactorrhea 68. 40. 316 Double adenoma 26 Glycogen synthesis 158 hypersecretion 135 Dwarfism 21. 168. 38. 70 Glycoprotein hormones 14 Dexamethasone 133 Dyslipidemia 299 Gastric inhibitory polypeptide Glycosylated hemoglobin 175 bioavailability 310 157 Glycosylation 7 dosage 310 E Gastrin 155. 317. 223. 226. 215. 262 GnRH agonist 222. 238. 62 clinical manifestations 39 Eicosanoids 3 progestin-induced 291 Gonadal development 187 diagnosis 40 Endochondral ossification 262. gestational 160 214. 16 Gluconeogenesis 101. 120 hormonal syndrome 291 Gestation 211 stage of anestrus 311 central 37. 305 Gonadectomy 222. 159. Diestrus 160. Fluid balance 318 Glucose administration 236 oropharyngeal signals 36 continuous rate infusion 320 D Diiodotyrosine 57 (and) vasopressin 36 intravenous injection 320 d-cells 155 Diphosphonates 262 Fluid therapy 316. 297. 235 Glucose-dependent insulinotropic Deiodinase 58 DNES cells 291 Folliculogenesis 215. 226. 293 Growth 262 (in) dogs 161 Estradiol 204. 165. receptor 19 clinical manifestations 318 prevention 222 114 Growth hormone deficiency 24 fluid therapy 318 Estrus prevention and GH excess diagnostic imaging 115 acquired 24 insulin therapy 319 28 food-dependent 130 congenital 21 . 174. 220. 160. 280 Ghrelin 18. 208. 197. phosphate supplementation Exons 6 hypertension 115 310 318 laboratory data 115 abdominal 241 potassium supplementation F respiratory distress 114 inguinal 241 318 Feed-back control 8. 237 Diabetes mellitus 159 Epinephrine 93. 277. 242 treatment 40 Enostosis 263. 167 192 Dihydrotachysterol 265 Fludrocortisone 316 transporter 156. 204 132 deficiency 21 hypercortisolism 318 anovulatory 22 erythropoiesis 293 adult-onset 24 hypersomatotropism 318 estrus 204. 194. 65 non-insulin-dependent 159 luteal phase 204 replacement 316 hypersecretion 69 other specific types 160 metestrus 204. Cystic endometrial hyperplasia Diagnostic imaging 12 Female pseudohermaphroditism 177. 41 Endometritis 191. 217. 222 polypeptide 157 Demodicosis 114 Dopamine 139 Fragmented coronoid process Glucosuria 160. 160. 275. 227 Glargine 170 Gonadotroph cells 14. 135. 23 G Glycogenolysis 159. 168. Greenstick fractures 271 diet 317 renal insufficiency 293 278. 217.334 Index CRH-stimulation test 305 metabolic acidosis 318 Exocytosis 57 hypercoagulability 114 Cryptorchidism 22. 317 postestrus 214 Glucocorticoid deficiency 105 (of) mammary origin 19 type 1 159. 161 preovulatory luteinization Glucocorticoid excess 111. 164 218. GH-receptor antagonist 27 Gonadal dysgenesis 191 head injury 38 263. 24. 283. 114. 210. 179. 283 anti-inflammatory action anabolic effects 19 home monitoring 317 Estrous cycle 22. 226. 175. 163. 318 syrup 320 DDAVP 40. 158. 219. expression 298 Desoxycorticosterone. 212. 276. 198. 158. 210. neurohypophysis 120 195 Glucose 156 227. 237 resistance 309 Ectopic Gastrinoma 179 GnRH-stimulation test 222. 101. 9. 214 synthetic 131 (in) hypercortisolism 25 remission 170 ovulation 204 withdrawal 134 (in) luteal phase 20 treatment 170. action 101 Growth hormone 18. suppression test 118 ACTH syndrome 130 Genes 6 310 Diabetes insipidus 37. 162. 198. Grave’s disease 73 classification 159 red-cell aplasia 293 111. 162. 239. 243 homeostasis 156 Cytochrome P-450 enzymes 8. 226. 120 hormone production 9 GH-excess Goiter 59. 214 abdominal fat 112 progestin-induced 19 Diabetic ketoacidosis 172. 225 toxicity 160. 283 idiopathic 39 Endocrinology 3 GHRH-stimulation test 305 prepubertal 238 nephrogenic 37. Diazepam 320 Ferret 130 intolerance 160 94 Diazoxide 177. 283 (in) growth hormone excess Estradiol benzoate 217 134 actions 19 26 Estrogens 236. 318 Glycated hemoglobin 163 94. DOC receptor subtypes 123 170. 223. 165. 307 Dirlotapide 300 Follicle-stimulating hormone Glucose intolerance 298 Dehydroepiandrosterone 103 DNA 6 207. 263. 210. 139 administration 320 Gonads 187 blood glucose curves 165 Epiphyseal dysgenesis 62 Glucagon-like peptide-1 157 Granulosa cells 207 castration 317 Ergocalciferol 258 Glucagonoma 180 tumor 220 (in) cats 167 Erythropoietin (Epo) 293 Glucocorticoid 93. 168 Dentition delay 22 agonists 210. 318 Estrus 206 (in) cats 114 pulses 18 bicarbonate deficit 319 induction 222 clinical manifestations 112. 208. 174 Cytogenetic examination 189. 175 Cytokines 294 Dihydrotestosterone 189. 315 (in) pseudopregnancy 31 Fructosamine 163. 320 Fibroadenomatous hyperplasia nadir 163. 160. 279 GLUT-2 156 Deslorelin 237 222 Free fatty acids 172 GLUT-4 158 Desmopressin 40. 177. 160. metabolic actions 19 type 2 159. 223. Girth 300 Gonadogenesis 187 partial 37 218. 243 alternate-day administration 168. 96. 179 20. 65. 167 204 130 porcine 24 written instructions 317 proestrus 204. 134. 162. 228 Diagnostic process 10 Feminization 198. 214. 279 181 Gonadotropins 223. 178. 125. 136. 179. 267. 246. 110 Hypotonicity syndrome 44 endocrine 2 renal 270. 272. 271 primary 107 Hypovolemia 316. 160. 265. 109. 269. 173 maintenance medication 316 nonregenerative anemia 68 Home monitoring (diabetes Hyperkalemia 107. 81. 108. 221. 276 adrenocortical tumor 125 transdermal methimazole 78 Hypoprolactinemia 70 Growth-hormone responsive aminoglutethimide 125 T-S ratio 75 Hypothalamic-hypophyseal portal dermatosis 24 diagnostic imaging 120 Hypertonic saline infusion 43 system 13 Gubernaculum testis 240 diagnosis 116 Hyperviscosity 293 Hypothalamic-pituitary-thyroid Gynecomastia 244 differentiation 118 Hypervitaminosis A 272. IAPP see Islet amyloid polypeptide paracrine 2. 221. 277 Hypothermia 68 HDDST see High-dose dexa. radioiodine therapy 78 Hypophysiotropic hormones 16 lente-type 170 117. 174 99mTcO – uptake 70 4 lipidosis 300 recurrence 316 acute crisis 108 acquired juvenile 60 steatosis 160 treatment 316 atypical primary 104 acquired primary 65 Hepatoencephalopathy 39. 163 relative 110 pituitary enlargement 70 Hormone-receptor complex 5 Hypernatremia 315 secondary 109 primary 64 Hormones 3. radioiodine uptake 75 Hypophysiotropic regulation 17 preparations 164 162. 270 correction 316 Hypovitaminosis D 272. 64 action. trilostane 316 clinical manifestations 107 diagnosis 68 190 Hyperfunction 9 diagnosis 107. 168. 161. 156. 160. 168 Hypoglycemia 163. 126. 74 symptoms 173 (in) diagnosis of acromegaly storage. 284. 111 sulfonamides 60 elimination 5 Hyperparathyroidism 266 Hypoaldosteronism tertiary 64. 275 excess 9 secondary 266. 135. 268. 109. 10. 172. 159. 316 primary 103. 168. relapse 78 Hypophysis receptor 158 283 T3-suppression test 75 anatomy 13 resistance 160. 323 treatment (at the pituitary breed predisposition 105 antibodies to Tg 70 Hermaphroditism 189. 221. Index 335 Growth plate 262. 32 167. 277 Infertility 190. 263. 111 differential diagnosis 68 Herpesvirus 228 secondary 9 ECG 106 ECG 68 High-dose dexamethasone Hyperglycemia 159. 317 Iatrogenic hypercorticism 132 peptide 5 Hyperthyroidism 73. 165. 171. 160. 11 (in) pituitary apoplexy 33 (and) stress 109 secondary 24. 318 exocrine 3 surgery 268 Hypofunction 8 free 4 Hyperphosphatemia 265. 27 Hydrocortisone 315. 173. insulin-like growth Iatrotropic threshold 42 protein-bound 4 169 factor 178 IGF-1 see also Insulin-like growth resistance 10 apathetic 73 juvenile 179 factor steroid 5 (in) cats 73. 275. axis 59 food-dependent 131 284 Hypothalamus 13 H ketoconazole 124 Hypervitaminosis D 267. emergency treatment 316 hyperlipidemia 68 suppression test 117. 319 primary 135 parathyroid damage 77 Hypophosphatemia 173. release. 265. 315 administered intermittently surgical treatment 138 plasma TSH 75 cryohypophysectomy 27 319 Hypercalcemia 256. 267. 9. metabolism. 173 Incretins 157 diagnosis 137 differential diagnosis 74 Hypoparathyroidism 264. 163. 316 biochemical abnormalities 173 (in) response to treatment 27 Hyperaldosteronism 39. 116. 174. 137 clinical manifestations 73 Hypomagnesemia 173 Incidentaloma 125 (in) cats 135 diagnosis 74 Hyponatremia 44. 173 treatment 108. 71. feline 73 hypergonadotropic 237 low caloric intake 23 Human chorionic gonadotropin 99mTcO – uptake 75 hypogonadotropic 237 (and) nutritional condition 4 242 antithyroid drugs 78 Hypokalemia 130. 246 medical treatment 138 ethanol injection 79 primary 264 Inhibin 236 polyuria 135 heat ablation 79 secondary 264 Insulin 155. 171 iatrogenic 105 iodine deficiency 60 History and physical examination Hyperglycemic hyperosmolar iatrogenic secondary 132 locomotor disturbances 68 10 syndrome 162. and Hyperosmolality 172. 74 Hypoluteoidism 221. ACTH-independent 111 thyroidectomy 76 Hypopituitarism 24. 65. 104. 64. and transport (in) dogs 81 treatment 320 27 4 thyroid storm 74 Hypogonadism (in) dwarfism 23 urinary excretion 10 Hyperthyroidism. 5. 172. 110. 71 pseudohermaphroditism treatment (at the adrenal level) client instruction and clinical manifestations 64 189. 272 preoperative treatment 76 maintenance therapy 315 deficiency 160 Hypercalcitoninism 278 prognosis 79 pituitary tumor 34 efficacy 165 Hypercortisolism 39. 310 level) 120 (in) cats 105 central 64. 228 IGF-binding proteins 19 135. 164. 165. 108. 124. 3 Hypertension 299 172. 267 pathogenesis 64 mellitus) 166 Hyperlipidemia 160. 60. 63. 268. 283 Hepatic pituitary-dependent 116 105. 277. postoperative complication immediate postoperative antibodies 160 273. 309 180 hypotonic dehydration 105 iatrogenic 64 Histone 6 stress 162. 120. 160. 268. 71 anabolic 158 chemical ablation 268 hyperreninemic 104 thyroiditis 60 antibodies to 11 nutritional 271 primary 107 treatment 71 catabolic 158 primary 266 Hypocalcemia 256. 107. action 158. 246. 208 . 161. 4. 111. nonsuppressible 126 Hypervolemia 39 Hypothyroidism 23. ultrasonography 70 chemical nature 3 radiofrequency heat ablation 284 (in) young animals 60 concentrations in plasma 10 268 Hypocortisolism 107. 165 renal insufficiency 137 pertechnetate scintigrams 274. 278 76 treatment 315 continuous rate infusion 319 (of) malignancy 267. 194. 134. 278 Hypogenitalism 237 I ketogenic 159 Hypersomatotropism 160. 221. 265. methasone supression test (of ) PI origin 117 Hypoadrenocorticism 103. 195 123 follow-up 108 congenital 23 true hermaphroditism 189. 284 adhesion prevention 319 secondary 134 76 Hypophysectomy 120. 160. 110. 300 clinical manifestations 140 lipoprotein 158 306 Octreotide 177. 283 diagnosis 175 Macula densa 101 pro-fragments 292 Osteoprotegerin 257.p'-DDD 123. expression of the GH gene diagnosis 41 Ovariohysterectomy 227 211. 310 molecules 158 Mammary gland 20. 207 Interleukin-1 110 fibroepithelial hyperplasia Nerve terminals 16 Oviducts 188 Intersexuality 189 27 Neuroendocrine 13 Ovotestes 190. 210. 273 diagnostic imaging 175 Male pseudohermaphroditism Nephrocalcinosis 266. 208 Lymphoma 273 Natriuretic peptides 135. 196. Luteolysis 217 Na+K+-ATPase 68. 268 Laboratory testing 10 Metestrus 204. 40 Islet amyloid polypeptide 157. prognosis 30 Neuropathy 161. 291 Osteodystrophy 270. 139 Paragangliomas 140 Karyotyping 191 Melanocyte 97 Normetanephrine 139 Paraneoplastic endocrine Ketoacidosis 160. 168 P 298 treatment 29 Neuropeptide Y 297 Pancreas 155 Islets of Langerhans 155 Mammary tumor 222. 63 Leptin 160. 193 Intracrine 2. 223 Nonthyroidal illness 68 Paradoxical secretion 16 K Medullary thyroid carcinomas Noradrenaline 139 Parafollicular cells 261 Karyotype 222 81 Norepinephrine 93. 278 amylin 298 Penis 189 methasone suppression test Mineralocorticoid 99 appetite 297 Peptide YY 297 predictive value 308 deficiency 106 breed prevalence 297 Perchlorate 57. 167 Müllerian inhibiting substance Os clitoris 194 141 Low-dose dexamethasone 188 Osmoreceptor 43 Pheromones 3 suppression test 116. Ovarian cysts 219 treatment 176 196 278 Ovarian tumors 219 Insulin-receptor substrate (IRS) Malignant lymphoma 273 Nephrogenic diabetes insipidus Ovariectomy 218. 276 Lactotropin 18 Micro RNAs 7 Obesity 160. 207. 222. 78 owner compliance 128 induction 219 Lactotrophs 16 Methylprednisolone 133 recurrences 128 Pathological fractures 271. 221. 163 a-MSH 97 Normetanephrine–creatinine syndromes 291 hypokalemia in 318 eumelanin 97 ratio 141 Parathyroid glands 255. 275 Ketoconazole 124 pheomelanin 97 Nuclear factor-kappa B 101 anatomy 255 Ketone bodies 163. 257. 215. 277 Insulin-like peptide 3 (Insl3) 241 atrial natriuretic peptide 291 Osteomalacia 275 Insulinoma 174 M brain natriuretic peptide 291 Osteoporosis 264. 16 Pancreatic polypeptide 155 J Median eminence 14. 172. 198 Neurotransmitter 3. 267. 262 Insulin-like growth factor 19. 167. 174 Melanotroph 118 Nucleosomes 6 location 255 Ketonuria 172 adenoma 118 Parathyroid hormone 255 Kidney function 36 Melatonin 215 O Parathyroid hormone-related Klinefelter’s syndrome 191 Messenger RNA 6 o. 297 Pendrin 57 LDDST see also Low-dose dexa. 16 Neuter status 311 Pancreatitis 168 Juxtaglomerular cells 101 Medroxyprogesterone acetate Nonesterified fatty acids 299 Panosteitis 279 29. 280 synthesis 156 Luteinizing hormone 204. 140 282 structure 156 Luteinization 207 Myxedema 65 Osteochondrosis 278. 127 protein 272 Metanephrine 139 client information 320 Parathyroid hyperplasia 266 L Metergoline 210 hormone substitution 128 Parathyroid tumor 266. 180 diagnosis 140 Lipolysis 102 Monoiodotyrosine 57 scintigraphy 294 diagnostic imaging 140 Lipoprotein Monorchism 242 Oligozoospermia 246 extra-adrenal 140 HDL 299 Mosaicism 190 Oocytes 207 fine-needle aspiration 141 LDL 299 Mucometra 227 Oophoritis 221 surgery 142 VLDL 299 Müllerian ducts 188. 228 tumor 243 diagnosis 137 insulin secretion 298 Persistent Müllerian duct Lhx4 21 laboratory findings 137 lipid metabolism 299 syndrome 196 Libido 246 subtype classification 138 neutering 297. 157 Low-sodium diet 42 Multiple endocrine neoplasia Osteochondritis dissecans 279. 208 inappetence 128 Parturition 212 Lactogenesis 21 Methimazole 57. Osteoclasia 278. 7 Mammary growth hormone 291 Oxytocin 35. 196 Orchitis 246 urinary normetanephrine Lipotoxicity 160. 274. 223 Neurophysin 35 Pancreatic carcinoma 160 Masculinization 195. 35. 3 pseudopregnancy 30 diffuse neuroendocrine system Ovulation 207. 215 117. 167. 262 Phosphorylation 8 . 308. 102. 213 Introns 6. 257. 191. 297 regulation 99 cholesterol in plasma 299 Peroxisome proliferator-activated Leukozoospermia 246 Mineralocorticoid excess 134 gender 297 receptors 298 Leydig cells 188. 222 23 treatment 42 Ovary 187. 203.336 Index secretion 156. 208 41 incomplete 219 Interestrous interval 204. Mineralization 262. sensitivity 160 Luteal phase 211. 218. 191 clinical manifestations 135 insulin resistance 298 Persistent estrus 191. Multiple endocrine deficiencies Ossification centers 62 Phlebotomy 294 309 64 Osteoblasts 256. 268. 300 Phagolysosome 57 LIF-receptor gene 21 Mitochondrial respiration 294 prognosis 300 Phenoxybenzamine 142 Ligand-receptor interaction 5 uncoupling 294 proinsulin 298 Pheochromocytes 139 Lipase Mitratapide 300 thyroid hormone 298 Pheochromocytoma 140 hormone-sensitive 158 Modified water deprivation test treatment 298. 230. 219. 219 Iodide 57 excess 27 Neuroglycopenia 173 maternal behavior 35 Iodide symporter 57 (in) cats 27 Neurohypophyseal hormones milk ejection 35 Iodine deficiency 60 diagnosis 29 35 myometrial contractions 35 Iodothyronine 57 (in) dogs 28 Neurohypophysis 14. 283 therapy 163 236 N Osteoclasts 256. 114 Osteocytes 262 178. Index 337 Physical inactivity 167 Prednisolone 131. 77 Polyglandular deficiency excess 266 Skeletal remodeling 279 Thyroid hormone 55. 96 Sex reversal syndrome 192 puerperal 284 radiation therapy 34 Prop-1 21 Sexual differentiation 187 Thiazolidinediones 169. Sorbitol 161 total thyroxine 58 PP-cells 155 280 SOX9 187. Scrotum 189. 61 radiotherapy 123 Pseudohyperparathyroidism pathogenesis 44 Thyroid 55. 210. 268 Skeletal maturation 62 morphology 55 treatment 43 deficiency 264 delayed 62 scintiscan 76. 163. 117 Pregnenolone 94 intracellular 5 Spironolactone 138 anterior lobe 13. 213 14 chemical structure 56 algorithm 323 Puerperal tetany 265 Somatostatin 18. Refractometry 306 Split heat 220. 221. 14. 294 deficiency 283 dry food 44 receptor 123. 217. 218. 217. 217. 59 Prednisone 131 RANKL 257. 57 medical treatment 123 Prostate 189 clinical manifestations 44 autoantibodies 64 o. 198. 105 resistance 256. 222. 58. 35 221. 222. 226. 192 Thirst osmoreceptors 36 cortisolism 120. 208. 299 suprasellar expansion 32 Propofol 320 chromosomal sex 190 Thiocyanate 57. 59. 237. 23 Prohormones 3 Sample handling 306 Teratozoospermia 246 Pituitary reserve capacity 32 Proinsulin 156. Sodium chloride 316 antibodies 64 Polyuria 37. 110. 79. 189. 175. 196 diagnostic imaging 33 pseudopregnancy 30 Serotonin antagonist neoplasms 243 hormone deficiency 31 pulses 20 (in) pseudopregnancy 31 regulation 236 hormone substitution 34 releasing hormone 16 Sertoli cell tumor 243 torsion 244 hypophysectomy 34 Prolactinoma 31 Sertoli cells 188. 176. 174. 214. 195 Thyrocyte 57 diagnosis 118 219. 117 210. 162. 235 Pituitary tumor 31. 208. 111 termination 217 aberrant 9 spermatozoa 235 adenoma 111. 155. 14. treatment 120 273 treatment 45 261 trilostane 123 Pseudohypoparathyroidism Sick euthyroid syndrome 68 accessory tissue 61 Polycythemia 39. regulation 100 Stress 97. 13. 38. 158 defective synthesis 62 diagnostic imaging 44 Pyometra 39. 229 Rickets 275 Syndrome of inappropriate somatotrophs 18 plasma concentration 323 RNA 7 antidiuresis 44 stalk damage 41 progesterone-receptor tRNA 7 tumor 37 antagonist 30. 223 Skeletal growth 257 embryology 55 fluctuations in Uosm 42 PTH 255. 63 Pituitary-dependent hyper. 207. 223. 212. 241 descent 239 adenoma 31 215. 218 Seminiferous tubules 235 development 193 carcinoma 31 luteotropic factor 20 Seminoma 243 differentiation 194. 59. 228 CT 33 207 Renal disease 41 SRY gene 187. 21. 60. 217. Silencers 6 dysgenesis 61 diagnosis 43 215. 278 (and) prepubertal gonadectomy follicle 55 oropharyngeal signals 42 action 257 283 hyperplasia 60 satiation of thirst 42 assay 265. 34 Prolactin 16. 317 receptor 59 PPARa agonist 299 Radius curvus syndrome 277. 256 Skin atrophy 323 3. 40.5. 220. 20. 180 deiodination 58 glucocorticoid excess 38 R receptor scintigraphy 175 free T4 58 POMC 118 Radiation therapy Somatotroph 16 intrathyroidal regulation 59 unprocessed 118 pituitary tumor 34 adenoma 25. 76. 265 medical therapy 34 Pro-opiomelanocortin 14. 227 analogues 27. 293 264 Signal peptide 7 cancer 79 Polydipsia. syndrome 64. 189. 18. 194 transporters 58 . 168 PTH/PTHrP receptor 257. 162. 168. 218. 269 Skeleton 262 62. Propylthiouracil 57 gonadal sex 187. 14 Preovulatory FSH surge 207 membrane 5 Splicing 7 carcinoma 116 Preovulatory LH surge 204. Retinol 284 Superfetation 217 posterior lobe 13. 272 Somatomammotropic hormones binding globulin 58 267. 126 Prostaglandin 134 phenotypic sex 187. invasive adenoma 31 Proligestone 223 Sex determination 236.p'-DDD 123 Pseudohermaphroditism 221 diagnosis 45 Thyroglossal duct 55. 217 Rathke’s pouch 14 spermatocytes 235 dependent cell lines 14 prolonged 223 Receptors 5. 214. 298 Schmidt’s syndrome 64 Testes 187. 273 Spermatogenesis 235 Pinocytosis 57. 194 cysts 23 Preprohormones 8 failure 269 Start codon 7 dwarfism 21 Preproinsulin 156 familial 41 Steroid hormones 3 growth hormone 18 Proestrus 206 juvenile onset 41 Steroidogenesis 94 invasive adenoma 116 Progenitor cells 14 Renin 101 Streptozotocin 177 mass 32 Progestagens/Progestins 160. 208. 191. 283 mass effects 32 Promoter 6 molecular events 188 Tetany 264. 316 RANK 262. 226. 64 Polyhormonal 9 secretion 255. 42 Pseudopregnancy 30. 141 ontogenesis 14 162. 61. 235 Testosterone 189.3'-L-triiodothyronine 55 Polypeptide hormones 3 synthesis 255 Sodium channels 102 action 59 Polyphagia 162. primary 37. 123. 132. 278 Puberty 204. Thrombocytopenia 244 bilateral adrenalectomy 123 Prostaglandin F2a 212. 226 Renin-angiotensin system 99 Sulfonylureas 169 pars distalis 14 Progesterone 94. 228 SIAD 44 Thyroglobulin 55. 116 L-thyroxine 55 Portal system 139 side effects 34 Somatotropin 18 peroxidase 57 Posttranslational processing 7 Radioiodine treatment 78 Somogyi effect 165. 9 spermatogonia 235 Pituitary 13. 225 Rubber jaw 270 T vascularization 14 Prognathia 26 T3. 274. Retinoids 3 Superfecundation 217 pars intermedia 13. 212. 217. reverse 57 Pituitary apoplexy 32 Prognathism 28 S TATA box 6 Pituitary dwarfism 22. 215. 273 spermatids 235 Pit-1 21 Pregnancy 212. 309 Vitamin A 284 chemotherapy 84 TRH-stimulation test 68. 307 (in) cardiomyopathy 35 Thyroiditis 60.338 Index Thyroid storm 74 Thyrotropin 58 Ununited anconeal process 279 Vasopressin analogue Thyroid tumor Transcription factor 21 Urinary aldosterone desmopressin 305 scintiscan 60 Transdifferentiation 9. Urinary incontinence 194. canine 79 Treatment protocols 315 Urinary corticoid Visceromegaly 28 131 I therapy 84 TRH 155 creatinine ratio 116. 306 intoxication 277 diagnostic imaging 82 Trilostane 123. 124 Urolithiasis 274 metabolism 259 differential diagnosis 81 ACTH-stimulation 123 Uterus 188. 226 metabolites 259 follicular type 79 adrenocortical insufficiency receptor 261 grade of malignancy 84 317 V synthesis 258 hyperfunctioning 81 adrenocortical tumors 124 Vagina 188 Vulva 189 hyperthyroidism 81 dose 317 vaginal cytology 204. concentration 35 X autoimmune 64 294 (and) cortisol 37 X0 syndrome 191 lymphocytic 60 Tumor suppressor gene 79 during hypertonic saline XX sex reversal 193 Thyroid-stimulating hormone infusion 307 XXX syndrome 192 58 U excess 44 XXY syndrome 191 Thyroperoxidase defect 62 UACR 137 hyperresponsiveness 45 XY sex reversal 193 clinical manifestations 63 suppression 138 hypertonic stimulus 40 Xylazine 305 diagnosis 63 UCCR 116. 230 W nonhyperfunctioning 80 UCCR 123 vaginoscopy 204. 222. 175 TSH-suppressive treatment regulation 59 analogue 40 Wobbler syndrome 279 84 TSH-releasing hormone 59 antagonist 45 Wolffian ducts 188 Thyroidectomy 264 TSH-stimulation test 69. 267 Whipple’s triad 173. 118 osmotic threshold 36 treatment 63 (and) o-HDDST 309 pulsatile secretion 35 Z Thyrosomatotropic cells 70 (and) o-LDDST 310 receptor subtypes 36 Zona fasciculata 93 Thyrotrope hyperplasia 69 predictive value 310 resistance 40 Zona glomerulosa 93 Thyrotrophs 16 serial measurements 118 water deprivation test 40 Zona reticularis 93 . 72. 258. 265 clinical staging 84 paradoxical GH response 308 Urine action 261 cytological examination 82 Triamcinolone 133 osmolality 37. 39. 70 creatinine ratio 137 Vestibular disease 68 Thyroid tumor. 206. 206. 43 prognosis 84 TSH assay 69 230 Weight loss 162. 72. 306 deficiency 275 diagnosis and staging 81 Triglycerides 299 specific gravity 39. 64 Tumor necrosis factor-a 110. Water deprivation test 40. medullary 80 survival time 124 209. 209. 168 radiation therapy 84 TSH deficiency 64 Vaginal septum 228 algorithm 324 staging groups 82 TSH secretion 59 Vanillylmandelic acid 139 diets 300 treatment 82 negative feedback 59 Vasopressin 35. intoxication 284 clinical features 80 307 238 Vitamin D 253. 255.