The Gonadal Hormones and Inhibitors Presentation. 2011. DAVIS 1

2/24/12Gonadal Hormones and Inhibitors Gina Davis, Pharm.D. 2012 Idaho State University Hypothalamus   GnRH   Anterior  Pituitary   FSH  and  LH   Ovary   Estrogen  and  Progesterone   FEMALES Reference:  Hansen  L,  Gunning  K.    Disorders  Related  to  the  Menstrual  Cycle.  In:  Koda-­‐Kimble  et  al.    Applied  TherapeuJcs;   The  Clinical  Use  of  Drugs,  Ninth  EdiJon.  LippincoN  Williams  &  Wilkins,  2009:  47-­‐1  to  47-­‐27.   1 Katzung.  LippincoN   Williams  &  Wilkins. Susan B. 2 . Editors: Betram G. New York. —  The estrogen inhibits FSH release and may cause regression of the immature follicles.2/24/12 Reference:  Hansen  L.   The Female Cycle ž  Follicular Phase —  FSH stimulates a number of follicles (each containing an ovum) begin to develop —  After 5 to 6 days.    Disorders  Related  to  the  Menstrual  Cycle.  Ninth  EdiJon. Anthony J. (2009) Mcgraw-Hill. Trevor. Chrousos G. The LH surge leads to ovulation.  In:  Koda-­‐ Kimble  et  al. 11th edition. In: Basic & Clinical Pharmacology. Masters.    Applied  TherapeuJcs. NY. The Gonadal Hormones & Inhibitors. a dominant follicle forms —  The theca cells and granulosa cells of this dominant follicle multiply and synthesize and release estrogens.  The  Clinical  Use  of  Drugs. —  Estrogen peaks just before midcycle and causes an LH and FSH surge.  Gunning  K.  2009:  47-­‐1  to  47-­‐27. (2009) Mcgraw-Hill. Anthony J.2/24/12 The Female Cycle ž  Luteal Phase —  The theca cells and granulosa cells form the corpus luteum. Katzung. Trevor. Estrogens •  Estradiol is the major secretory hormone of the ovary •  Estrone and estriol are mostly formed in the liver or in the peripheral tissues Necessary for: 1. Masters. The Gonadal Hormones & Inhibitors. New York. —  The corpus luteum produces estrogen and progesterone.  Endometrial lining 3. Chrousos G. 11th edition. the corpus luteum degenerates and stops producing hormones. NY. Editors: Betram G. This decline in hormones leads to endometrium shedding. In: Basic & Clinical Pharmacology.  Metabolic and Cardiovascular Effects 4.  Female Maturation 2. —  If pregnancy does not occur.  Blood coagulation 3 . Susan B. 2/24/12 Estrogens ž  Clinical Uses: —  Estrogen Replacement Therapy —  Failure of ovary development —  Premature menopause —  Castration —  Menopause Estrogens: Clinical Uses Continued ○  Post Menopausal —  Give estrogen to help with vasomotor symptoms -  Benefit=Helps to stop bone loss —  Declined estrogen levels cause a rise in LDLs -  Acceleration of atherosclerotic cardiovascular disease —  Women’s Health Initiative Study -  Estrogen plus progestin (Prempo) orally Increased risk of coronary heart disease Increased risk of blood clots Increased risk of stroke Increased risk of breast cancer 4 . decrease TC ○  Increases clotting factors —  Patch or topical ○  No first pass effect in liver ○  Little to no change in lipid levels or coagulation parameters compared to oral ○  May have decreased risk of DVT compared to oral —  Vaginal administration ○  Use for genital atrophy only ž  ž  FDA safety warnings on all estrogen: Can increase risk of MI.2/24/12 Clinical Use: Estrogen for post-menopause Examples: —  Estradiol containing products ○  Human. Estraderm —  Conjugated estrogen-containing products ○  Plant-derived. breast cancer. synthetic —  ie. Climara. gels. Cenestin ○  Preganant mare urine-derived —  Ie. Ogen Clinical Use: Estrogen for post-menopause ž  Forms: Oral. Synthetic —  ie.synthetic —  ie. Synthetic —  ie. sprays. Premarin —  Esterified estrogen-containing products ○  Soybean-derived. stroke. vaginal ring —  Oral ○  Undergoes first pass metabolism in the liver ○  Can increase Triglycerides. but can increase HDL. decrease LDL. estrace. thromboembolism Dosing: Use the lowest dose for shortest amount of time 5 . Menest —  Estropipate containing products ○  Human. Patch. Clinical Use: Estrogen for post-menopause ž  Contraindications —  Endometrial cancer —  Breast cancer —  Liver disease —  Undiagnosed vaginal bleeding —  History or presence of thromboembolic disorder (venous or arterial) —  Heavy smokers 6 .2/24/12 Clinical Use: Estrogen for post-menopause ž  Need to give estrogen with a progestational agent if patient has uterus to protect against endometrial hyperplasia and endometrial cancer. Depo-Provera. Mirena Intrauterine Device (IUD) —  Produces ovarian suppression for other reasons Hormonal Contraception ž  Combined Hormonal Contraception (CHC) —  Estrogen plus progesterone ○  Pills ○  Patch ○  Ring ž  Progesterone only options —  Pills (POP) —  IM or SQ —  Implanon —  IUD 7 . Micronor.2/24/12 Progesterone ž  Necessary for: —  Maturation and shedding of the endometrium lining ž  Levels phase are increased during the Luteal ž  Uses —  Hormone replacement ○  ie. medroxyprogesterone —  Hormonal contraception ○  ie. 2/24/12 Combined Hormonal Contraception (CHC) ž  MOA: —  Stop ovulation —  Change of cervical mucus —  Change in uterine endometrium Some Advantages of CHC —  ↓ heavy menstrual bleeding (menorrhagia) ○  Progressive thinning of the lining of the endometrium ↓ painful menstration (dysmenorrhea) Protection from endometrial cancer Protection from ovarian cancer and suppression of development of ovarian cysts —  Reduced risk of benign breast disease —  Decreased incidence of ectopic pregnancy —  Acne improvements —  —  —  8 . MI ↑ TG ↑ Blood pressure ↑ benign hepatocellular adenomas ↑ breast cancer ? ↑ cervical cancer Contraindications of CHCs ž  Many contraindications —  Some of the contraindications or precautions include presence or a history of: •  •  •  •  •  •  •  •  •  •  •  Age  35  or  older  and  smokes   Heart  aNack  or  stroke   Blood  clots  (ie.  PE)   Chest  pain  (angina)   HPTN     Diabetes  with  vascular  complicaJons  or  more  than  20  years   duraJon   Headaches  with  focal  neurological  symptoms  or  personal   history  of  stroke   Breast  cancer   Liver  disease  or  tumor   Heart  valve  disorder   ImmobilizaJon   9 .2/24/12 Disadvantages of CHC ○  ○  ○  ○  ○  ○  ○  ○  Compliance No STD protection ↑ in VTE.  DVT. stroke. 2/24/12 Common Complaints ž  Estrogen Excess —  —  —  —  —  ž  Progestin Excess —  —  —  —  Nausea Bloating / Edema Hypertension Migraine HA Breast tenderness / fullness ž  Breast tenderness Headache Fatigue Changes in mood Progestin Deficiency —  Late breakthrough bleeding —  Amenorrhea —  Hypermenorrhea ž  Estrogen Deficiency —  Early or mid-cycle breakthrough bleeding ž  Androgen excess —  —  —  —  Increased appetite Weight gain Acne. therefore. which decrease serum levels of estrogen by interfering with enterohepatic recirculation 10 . decrease combined oral contraceptive efficacy ž  Some antibiotics can kill GI bacteria. oily scalp Hirsutism CHC: Drug Interactions ž  Medications that induce Cyt P450 3A4 will increase metabolism and. HTN. history of thromboembolic disease ○  Protection against endometrial cancer 11 . Micronor) —  Advantages ○  Can be used in women whom are: —  Post partum period —  Lactation (start 6 weeks postpartum) —  Avoidance of estrogen ADR: -  Migraines. smokers. CV risk.2/24/12 Contraception: ž  Progesterone Only Options Progesterone Only Pills (ie. not able to discontinue immediately -  Breakthrough bleeding -  Weight gain -  Office visits -  May ↓ BMD 12 . severe cirrhosis.PE (not on anticogulation) ○  Systemic Lupus Erythematosus (positive antiphospholipid antibody) ○  Breast CA (current or past) ○  Active viral hepatitis.2/24/12 Progesterone Only Pills (ie. liver tumors ○  Undiagnosed vaginal bleeding Depo-Provera (Medroxyprogesterone) —  IM & SQ formulations (Depo-SubQ Provera) —  Q 3 month administration —  Advantages -  ↓ failure rate -  ↓ or no menses -  Every 3 months —  Disadvantages -  Delayed return to fertility -  If side effects occur. Micronor) —  Disadvantages ○  Less effective than COC ○  Irregular and unpredictable bleeding ○  Compliance crucial —  Avoid in: ○  Current DVT. pelvic pain. diarrhea. Mifepristone —  Uses: ○  Strong inhibitor of progesterone receptor ○  Abortifacient —  Side effects: vomiting.75 mg —  Take 1 tablet ASAP. then take the 2nd tablet 12 hours later Plan B One-Step®: 1 tablet of levonorgestrel 1.5 mg OTC status for women 17yo and older Prescription for those <17yo ž  Availability: ○  ○  ž  CARE program (Convenient Access.2/24/12 Emergency Contraception: Levonorgestrel ž  Plan B (“the morning-after pill”) —  Products: ○  ○  Next ChoiceTM: 2 tablets of levonorgestrel 0. or vaginal bleeding 13 . Responsible Education) —  —  Sold behind the pharmacy counter Must have a pharmacist on duty and available for counseling when product is sold. abdominal pain. bones.2/24/12 Selective estrogen receptor modulator (SERM) ž  Tamoxifen —  MOA: competitive partial agonist inhibitor of estradiol —  Uses: ○  Treatment and Prevention (in high risk women) of breast cancer —  May increase risk of endometrial cancer —  May increase risk of arterial and venous thromboembolism ○  Agonist=on lipid. endometrium ○  Antagonist=on breast tissue ž  Raloxifene —  Uses: ○  prevention of postmenopausal osteoporosis ○  prophylaxis of breast cancer in women with risk factors —  MOA: —  May increase risk of arterial and venous thromboembolism ○  Agonist=on lipid and bone ○  Antagonist= on the endometrium or breast tissue Clomiphene ž  Ovulation-inducing agent ž  Partial estrogen agonist ž  Inhibits estradiol’s negative feedback effect on the gonadotropins at the hypothalamus. leading to ovulation ž  Will not help in patients with ovarian or pituitary failure ž  Uses: Stimulate ovulation ž  Adverse effects: hot flushes 14 . 2/24/12 Males ž  The most important androgen secreted by the testis is testosterone. ž  65% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) ž  In many target tissues. testosterone is converted to dihydrotestosterone. Testosterone ž  Some Clinical Uses: —  Replacement therapy in men 15 . erythrocytosis. gynecomastia. acne. Androgel ž  Transdermal Patches= Androderm ž  Injectables= Depo-Testosterone ž  Oral products should not be used because can cause liver problems Testosterone ž  Adverse Effects: —  In women=hirsutism. sleep apnea. hepatic dysfunction 16 . edema (not common). azoospermia —  Sodium retention. deep voice —  In men=acne. amenorrhea.2/24/12 Testosterone Products ž  Buccal Tablet= Striant ž  Transdermal gels= Testim. 2/24/12 Contraindications and Cautions ž  Pregnancy ž  Carcinoma of the breast or prostate ž  Infants and children ž  Conditions with edema 5α reductase inhibitor ž  Finasteride (Proscar. Propecia) ž  Dutasteride (Avodart) Testosterone 5α reductase Dihydrotestosterone 17 . Calis KA. 18 . et al. a pathophysiolgical approach. Applied Therapeutics: the clinical use of drugs. a pathophysiolgical approach. (2009) Mcgraw-Hill. Diaz VA. Contraception. Inc. et al. Shrader SP. 2008:1313-1343. The McGraw Hill Companies. In: Basic & Clinical Pharmacology. Inc. 2009:45-1 to 45-28.eds. In: Koda-Kimble MA. Pharmacotherapy. et al. Hormonal contraception. Pharmacist's Letter/Prescriber's Letter 2007. Applied Therapeutics: the clinical use of drugs. Seventh Edition. The Transition Through Menopause. Parent-Stevens L. Masters. 2009:48-1 to 48-9. (Update June 2010). Pharmacotherapy. New York.2/24/12 Receptor Inhibitors ž  ž  ž  Flutamide —  Inhibits binding of androgens at the receptor —  Used in treatment of prostate cancer —  Liver failure (black box warning) Bicalutamide (Casodex) and Nilutamide (Nilandron) —  Androgen receptor inhibitor —  Used for Prostate cancer Spironolactone —  Competitive inhibitor of aldosterone and competes with dihydrotestosterone for androgen receptors —  Treats hirsutism in women References: Chrousos G. Dickerson LM. In: Koda-Kimble MA.eds. Seventh Edition. Susan B. Trevor. The McGraw Hill Companies. Ninth Edition. Kalantaridou S. Davis S. Katzung. 11th edition.23 (12):231207. In: Dipiro. Ninth Edition. Hardman JL. The Gonadal Hormones & Inhibitors. Lipppincott Williams & Wilkins. In: Dipiro. et al. 2008:1351-1368. Editors: Betram G. Lipppincott Williams & Wilkins. Contraception. NY. Anthony J.