Dr. Kaukab Azim. MBBS, PhD

1. Gonadal Hormones &Inhibitors Dr. Kaukab Azim. MBBS, PhD

2. Hypogonadism in males and females • Precocious puberty, leiomyoma, endometriosis, dysmenorhea • Hormonal contraceptives • Menopausal replacement therapy • Infertility • SERMs • Medical abortion • Gonadal hormones agonist and antagonists • Hormonal drugs for some cancers

3. Gonadal Hormones and Inhibitors

4. Key concepts of Pharmacology of Gonadal Hormones: Effects of GnRH release frequency on gonadotropin release. Interaction between estrogen and the pituitary gland. Tissue selectivity of estrogen agonists and antagonists. Various strategies to antagonize the effect of endogenous sex hormones. Hypothalamus-Pituitary-Gonadal Axis (Ovulation inducer)

5. Gonadotropin releasing hormone (GnRH) released in “pulsalite manner”from the hypothalamus and acts on Pituitary to stimulate the secretion of gonadotropins- FSH & LH

6. Short-acting analogs Gonadorelin (t1/2 = 4 min.) It can be used in “Pulsatile”manner to stimulate pituitary to secrete FSH and LH. Uses: Diagnostic purpose In infertility: Hypothalamic amenorrhea Long-acting analogs Goserelin Nafarelin- nasal spray Leuprolide After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion. (down-regulation) GnRH analogs

7. Long-acting GnRH analogs Goserelin Nafarelin Leuprolide After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion. Therapeutic Uses: For Medical castration: In precocious puberty Breast Ca Prostate Ca Leiomyoma Endometriosis GnRH analogs

8. GnRH analogs: Adverse effects Adverse effects of long-acting analogs: • Gonadal steroidal inhibition in females can cause: • Hot flashes • Vaginal atrophy • Decreased bone density

9. GnRH antagonist • Ganirelix • Cetrorelix These are pure GnRH antagonists and do not cause initial increase in gonadotropin secretion.

10. Gonadotropins: FSH & LH Gonadotropin preparations: Menotropins (LH + FSH) Recombinant FSH and LH hCG (Human chorionic gonadotropin)

11. Estrogens Physiological Role: • Secondary sexual characteristics • Menstrual cycle • During follicular phase it cause endometrium to grow • For normal mineralization and osteoid formation • Deficiency of estrogens cause osteoporosis

12. Estrogens Natural estrogens • Estradiol • Estriol • Estrone Synthetic estrogens • Ethinylestradiol • Mestranol

13. Estrogens • Oral: • Estradiol: micronized form • Conjugated estrogens: conjugated equine estrogens • Ethinyl estradiol & Mestranol (synthetic estrogens) • IM:aqueous or oil based esters of estradiol and estrione • Transdermal preparations: estradiol

14. Uses of Estrogens • Hormone Replacement therapy: • Primary hypogonadism • Premature ovarian failure; surgical removal of ovaries • Menopause • Oral contraception • Osteoporosis • Atrophic vaginitis

15. Estrogens: Adverse effects • Nausea, vomiting • Thromboembolic problems • Myocardial infarction • Breast Ca • Endometrial Ca • Postmenopausal uterine bleeding • Diethylstilbestrol: Clear cell Ca (cervical & vagina)

16. Progestins • Physiological role: • helps maintaining pregnancy • They are often combined with estrogen in various formulations to counteract the harmful effects of estrogens • Estrogen can cause endometrial carcinoma

17. Progestins Natural progestins: • Progesterone, 17-alpha hydroxyprogesterone Synthetic progestins: • Hydroxyprogesterone (IM, every 1-2 weeks) • Medroxyprogesterone (Oral-daily, IM every 1-3 months) • Norethindrone: belongs to 19-nortestoserone analogs • Norgestrel, Levonorgestrel • Norgestimate(less androgenic) • Desogestrel(less androgenic)

18. Progestins: Uses • As contraceptive and menopausal hormone therapy • Combined with estrogen (in COCPs & menopausal hormonal therapy) • Progestin only contraceptive preparations • As postcoital contraception • Dysmenorrhea • Dysfunctional uterine bleeding • Endometriosis

19. Progestines: Adverse effects • Edema • Depression ADRs of progestins having Androgen-like activity: • Increase the ratio of LDL to HDL cholesterol • Thrombophlebitis • Pulmonary embolism • Acne • Hirsutism • Weight gain

20. Hormonal Contraceptives • Combined Oral Contraceptive Pills (COCPs) • contain both estrogen and progesterone • Monophasic, Biphasic, Triphasic forms • Progestin only preparations • Progestin-only pills (“mini-pill”) • Progestin implants/depot (Levonorgestrel, medroxyprogesterone) • Progestin containing Intrauterine device • Postcoital contraception (emergency contraception)

21. Estrogen and progesterone causes feedback inhibition of FSH and LH secretion from the pituitary gland to inhibit ovulation. (main mechanism) Progestins thicken the cervical mucous and prevent the entry of sperm. 3. Effects on uterine tubes and endometrium decrease the likelihood of fertilization and implantation COCPs:Mechanism of action Feedback inhibition ↓ LH surge No Ovulation

22. COCPs:Adverse effects • Nausea, vomiting, mastalgia • Headache • Breakthrough bleeding • Wt. gain • Acne and Hirsutism (19-nortestosterone derivatives) • Chloasma (skin pigmentation)

23. COCPs:Serious complications • Leg vein and pulmonary thrombosis • Coronary and cerebral thrombosis • Rise in BP

24. COCPs:Contraindications COCPs are absolutely contraindicated in • Thromboembolic, coronary, cerebrovascular disease. Greater risk for : • Women > 35 years of age • Heavy smokers • Obese • Active liver disease • Suspected or overt malignancy of genitals/breast • Undiagnosed vaginal bleeding

25. COCPs:Relative contraindications • Hypertension • Migraine • Diabetes mellitus • Uterine leiomyoma • Mental illness • Gall bladder disease

26. COCPs:Drug Interactions • Enzyme inducers (Phenytoin, barbiturates, carbamazapine, Rifampin) cause contraceptive failure • Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive failure by suppressing intestinal microflora: • Decreased deconjugation of estrogens excreted in bile • Decreased enterohepatic circulation of estrogens • Blood levels of estrogens fall contraceptive failure

27. Progestin-only preparations • Progestin-only pill (“Mini-pill”) • norethindrone or levonorgestrel • Progestin implants/depot • Levonorgestrel: subcutaneous implant, 5 years • Medroxyprogesterone acetate (DMPA): IM, every 3 months. • Progestin containing Intrauterine devices • Progestasert contains progesterone & mirenacontains levonorgestrel

28. Progestin-only preparations Progestin-only preparations are suitable for women when estrogens are contraindicated : • Smokers • Age > 35 years • h/o cardiovascular disease • Migraine • Liver impairment

29. Progestin-only preparations Disadvantages of progestins: • Frequent spotting • Irregular and unpredictable menstrual cycles • Failure rate is higher as compared to combined COCPs • Unfavorable effect on lipid profile

30. Emergency contraception • Postcoitalor “morning after” contraception • Combined oral contraceptive pills: 2 pills within 72 hours of unprotected sexual intercourse and 2 exactly 12 hours later. • Progestin-only pills (Levonorgestrel): one tablet within 72 hours of unprotected sexual intercourse followed by second dose exactly 12 hrs later. • Ulipristal:a selective progesterone receptor modulator; taken within 120 hrs of unprotected sexual intercourse

31. Menopausal hormone therapy(HRT) • Estrogen deficiency symptoms: • Hot flashes, chills, night sweats, mood swings, insomnia, headache, palpitation • Vaginal and urethral atrophy • Osteoporosis (others drugs are preferred) • Lowest effective dose of estrogen for the shortest duration to relieve estrogen deficiency symptoms in postmenopausal period.

32. Selective estrogen receptor modulators(SERMs) Tamoxifen, Raloxifene These are drugs that interact with estrogen receptors but have different effects on different tissues. They can show agonism or antagonism depending upon the tissue type.

33. Tamoxifen • Antiestrogenic effect: on Breast • Effective in the treatment of breast Ca in patients with tumor cells that are estrogen receptor- positive. • can be given after surgery to eradicate micrometastases • Estrogenic effect: on Endometrium • Can cause endometrial Ca • Not prescribed to treat breast Ca for longer than 3-5 years in non-hysterectomized women

34. Tamoxifen:Adverse effects • Nausea/Vomiting • Hot flashes • Vaginal bleeding • Risk of Endometrial Ca • Thromboembolic disorders

35. Raloxifene • Antiestrogenic effect: Breast, Endometrium • Estrogenic effect: Bones, lipid metabolism • Unlike Tamoxifen, it does not increase the risk of endometrial Ca. • Approved to be used for the prevention of osteoporosis in postmenopausal women

36. Estrogen antagonists • Clomiphene(Ovulation inducer): blocks estrogen receptors in the hypothalamus and anterior pituitary reduces negative feedback ↑ FSH and LH secretion ovarian follicle development and ovulation • Fulvestrant

37. Progesterone antagonist • Mifepristone (RU 486) • Progesterone receptor antagonist • Glucocorticoid receptor antagonist Therapeutic uses: • Medical termination of pregnancy (Mifepristone followed 48 hrs later by Misoprostol)

38. Aromatase inhibitors • Anastrozole, Letrozole : non-steroidal agents; competitive inhibitors • Exemestane : steroidal agent; irreversible inhibitor Estriol Estrone Estradiol

39. Aromataseinhibitors • Aromatase inhibitors block the synthesis of estrogens from androgen precursors by inhibiting aromatase enzyme. • This approach can be used to inhibit the growth of estrogen-dependent tumors e.g., breast cancer. • Used in postmenopausal women with advanced breast cancer • Unlike tamoxifen, they do not increase the risk of endometrial carcinoma or venous thromboembolism. • Endometriosis

40. Androgens Testosterone esters: • Testosterone propionate • Testosterone enanthate • Testosterone cypionate 17-alpha alkylated androgens: • Methyltestosterone • Fluoxymesterone • Oxandrolone (anabolic steroid) • Danazol (Danocrine)

41. Androgens: Therapeutic Uses • Hypogonadism: as hormonal replacement therapy. • For Anabolic effects: • Osteoporosis • severe burns • to increase lean body mass, muscle strength • Endometriosis • Hereditary angioedema

42. Danazolsynthetic derivative of 17-ethinyltestosterone • It has weak androgenic, progestational and glucocorticoid activity • Inhibits CYP450 enzymes involved in gonadal hormone synthesis Uses: • Endometriosis • Fibrocystic breast disease • Hereditary angioedema (It occurs due to deficiency of C1- esterase inhibitor)

43. Danazol: Adverse effects • Acne • Hirsutism • Menstrual irregularities • Hepatotoxicity • Thromboembolism • Teratogenic

44. Anabolicsteroids • Greater anabolic:androgenic activity • Oxandrolone (anabolic: androgenic=3:1-13-1) Adverse drug reactions: • Infertility: due to suppressed FSH and LH • Decreased testicular size and function • Feminization in men, gynecomastia • Masculinization in women: Hirsutism, deepening of voice, menstrual irregularities • Hepatic dysfunction, Cholestatic jaundice • Psychotic symptoms

45. Gonadotropin release inhibitors Androgen Receptor blockers 5a-reductase inhibitor Androgen synthesis inhibitors Antiandrogens

46. Gonadotropin release inhibitors • Long acting GnRH analogs • Leuprolide • Goserelin • Nafarelin

47. Androgen Receptor blockers • Nonsteroidalantiandrogens • Flutamide • Bicalutamide • They block the action of dihydrotestosterone on testosterone receptors and inhibit the synthesis of new proteins in prostate and prostate cancer cells. • Combined with GnRH analogs to treat inoperable prostate Ca.

48. Androgen receptor blockers: Adverse effects • Gynecomastia or nipple tenderness • Diarrhea • Hepatotoxicity • Impotence

49. 5a-reductase inhibitor • In the prostate, testosterone is converted into dihydrotestosterone (DHT) by the action of 5a-reductase • DHT acts on prostate cells to stimulate new growth • Finastride: synthetic testosterone derivative • It inhibits the synthesis of Dihydrotestosterone (DHT) by inhibiting 5a-reductase

50. 5a-reductase inhibitor Therapeutic uses: • Benign prostatic hyperplasia • Male pattern baldness