This document discusses several key topics related to gonadal hormones: 1. It reviews the major classes of natural and synthetic gonadal hormones including estrogens, progestogens, androgens, and their inhibitors. 2. It describes the physiological effects and clinical uses of important hormones like estrogen, progesterone, and testosterone. 3. It also discusses hormonal contraceptives and performance enhancing drugs that are abused in sports. 4. The summary briefly mentions a reproductive health bill in the Philippines that aims to promote family planning but faces opposition from the Catholic Church.

1. Gonadal Hormones and Inhibitors Ma. Victoria Matias-Villarica, M.D. Dept. of Pharmacology Fatima College of Medicine

2. Objectives: Review gonadal hormone secretion and their functions Identify the uses of these hormones

3. Estrogen Natural Estrogen a. 17-β-estradiol b. Estrone c. Estriol Synthetic Estrogen a. Ethinyl estradiol b. Quinestrol c. Mestranol

4. Estrogen (cont.) Non-steroidal Synthetic Estrogen a. Methestrol b. Dienestrol c. Benzestrol d. Hexistrol e. Diethylstilbestrol f. Chlorotrianisene g. Methallenestril Anti-Estrogen a. Tamoxifen b. Clomiphene

5. Progesterone Natural Progestin - Progesterone Synthetic Progestin a. Norgestrol b. Medroxyprogesterone c. Norethindrone Anti-progestin a. Danazol b. Mifepristone

6. Androgens Natural Androgen - Testosterone Synthetic Androgen a. Methyltestosterone b. Fluoxymesterone Anabolic Steroid a. Oxandrolone b. Stanozolol

7. Androgens (cont.) Androgen Antagonist a. Finasteride b. Flutamide c. Cyproterone d. Ketoconazole e. Spirinolactone

8. Ovary - Quiescent - Gonadarche - Menarche - Menopause - Disturbances of ovarian function: a. emotional and environmental stress b. anovulatory cycles c. organic causes – pituitary adenomas, arrhenoblastoma, Leydig cell tumors

10. Estrogen: Secreted by the theca cells, corpus luteum, placenta and adrenals and testes Intracellular receptors for lipid soluble agents Bounded by SHBG Metabolites: cathecol estrogen -> neurotransmitters -> converted to 2- and 4-methoxycompounds by COMT Enterohepatic circulation

11. Estrogen: Physiologic effects Female maturation - stimulate the development of vagina, uterus, uterine tubes - breast: stromal development, ductal development - growth: accelerated; closure of epiphysis of long bones - growth of axillary/pubic hair - typical female body contour

12. Estrogen: Physiologic effects (cont.) on sexual organs (primary and secondary sexual characteristics) ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy uterus: endometrial growth vagina: cornification of epithelial cells with thickening and stratification of epithelium cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)

13. Estrogen: physiologic effects (cont) Endometrial effects – hyperplasia with abnormal bleeding patterns Cardiovascular effects: - ↑HDL, ↓LDL; ↓antithrombin III; ↑ Fx II, VII, IX, X; ↑plasminogen levels, ↓platelet adhesiveness

14. Estrogen: physiologic effects (cont) Other effects: - influence behavior and libido - loss of fluid from intravascular into the extravascular space (edema) - induce synthesis of progesterone receptors - electrolytes: retention of Na+, Cl- and water by the kidney - cholesterol: hypocholesterolemic effect - skin:increase in vascularization, development of soft, textured and smooth skin - bone:increase osteoblastic activity

15. Estrogen: Clinical uses Post-menopausal hormonal therapy -reduction of MI (50%), fatal strokes (40%) -prevent fractures -0.3mg D1-D21 monthly + medroxyprogesterone acetate -S/P hysterectomy – 5 days/week -atrophic vaginitis - topical Oral contraceptives Hypogonadism – 0.3mg D1-D21 monthly Osteoporosis Infertility Dysmenorrhea Prostate Ca

16. Natural estrogens Conjugated estrogenic substances: an amorphous preparation containing water soluble conjugated forms of mixed estrogens from the urine of pregnant mares (Premarin, Cenestin - synthetic conjugated estrogens) estradiol : oral : Estrace transdermal: Climara, Alora, Vivelle, Vivelle-Dot, Estraderm, FemPatch

17. Natural estrogens estrone: Kestrone 5 (injectable only) esterified estrogen (75-85% sodium estrone sulfate and 6- 15% sodium equilin sulfate) Estratab; Menest estropipate (piperazine estrone sulfate) Ogen; Ortho-Est

18. Natural estrogens Sustained-release injectables: estradiol valerate in oil (Delestrogen; Valergen) estradiol cypionate in oil (depGynogen; DepoGen) duration of action from 3 to 8 weeks esterified at C-17 hydroyl group

19. Estrogen products

20. Estrogen: Contraindications Estrogen dependent neoplasm (breast, endometrium) Undiagnosed genital bleeding History of thromboembolic disorders Pregnant women

22. Progesterone: Synthesized in the ovary, testes, adrenals Produced primarily by corpus luteum Males: 1-5mg daily or 0.03ug/dl plasma level Kinetics: rapidly absorbes; t1/2 – 5mins; completely metabolized in the liver

23. PROGESTERONE Natural hormone secreted by the corpus luteum and the placenta ( a C-21 steroid) it is also an important intermediate in steroid biogenesis in all tissues that produce steroids (testes, adrenal cortex) Intestinal absorption is quite erratic; must be micronized for most effective absorption (Prometrium)

24. Progesterone: Physiologic effects: Affects carbohydrate metabolism Compete with aldosterone ↑ body temperature Breast: alveolobular development of the secretory apparatus of the breast Endometrium: maturation and secretory changes ↓plasma levels of amino acids

25. Progesterone: Clinical uses Hormonal replacement therapy Contraception Diagnosis: estrogen secretion Dysmenorrhea Endometriosis

26. Progesterone: CI/AE Increase BP Decrease plasma HDL

27. Other androgens secreted by the ovary: Testosterone Androstenedione DHEA (dehydroepiandrosterone) Inhibin Activin Relaxin

28. Testes: Functions: sperm production (FSH) testosterone synthesis (LH) 8mg testosterone daily Weak androgen: androstenedione, dehydroepiandrosterone Active androgen: dihydrotestosterone (5-α-reductase) Testosterone is converted to estradiol by p450 aromatase

29. Natural androgens

31. Testosterone: Physiologic effect Changes in the skin (pubic, axillary, beard) Larynx Skeletal growth ↑lean body mass Male development Anabolic effect on muscle and bone mass: ↑ CHON synthesis, ↓ CHON breakdown Other effects: erythrocyte production, musculinization in females

32. Testosterone: Clinical Uses Androgen replacement therapy Gynecologic disorders Protein anabolic agent Refractory anemia Osteoporosis Growth stimulators Abused in sports “Slows” aging

33. Other Uses for Androgens Replacement therapy in hypogonadism delayed puberty cryptorchidism metastatic breast cancer in women postpartum breast pain/engorgement male climacteric

34. Testosterone: Contraindication Pregnant women Ca of the prostate, breast Adverse effect: Musculinizing effect in women Alteration of serum lipid profile Hepatocellular Ca

35. Testosterone products testosterone in aqueous suspension (short-acting) testosterone propionate in oil testosterone enanthate in oil (Delatestryl) testosterone cypionate in oil (Depotest) testosterone pellets (Testopel) testosterone transdermal system (Androderm)

36. Anti-Estrogen Clomiphene - partial agonist at estrogen receptors - act as competitive inhibitors - stimulates ovulation by preventing feedback inhibition - AE: hot flashes, eye symptoms, ovarian cyst, skin rxn, multiple births - 50mg OD x 5days; 100mg OD x 5days; 100mg OD x 5days

37. Anti-Estrogen: Tamoxifen - Act as competitive inhibitor - For breast Ca - AE: hot flashes, N and V, vulvar pruritus, menstrual irregularities - 10-20mg BID (35% ↓ but not >5yrs) □ Toremifene – prevent bone loss, ↓atherosclerosis; (+) uterus □ Raloxifene - prevent bone loss, ↓atherosclerosis; (-) uterus

38. AROMATASE INHIBITORS aromatase is a cytochrome P450 enzyme that catalyzes the conversion of adrenal androgen androstenedione to estrone in both pre- amd post menopausal women reaction occurs in the liver, muscle, adipose and breast tissue in post-menopausal women, aromatization is responsible for the majority of circulating estrogen aminoglutethimide was used but has now been replaced by more selective drugs drugs may be steroidal (testolactone, emestane) or non-steroidal (anastrozole, letrozole) estrogen deprivation through aromatase inhibition is an effective and selective treatment for some post-menopausal patients with hormone-dependent breast cancer

40. AROMATASE INHIBITORS both of these drugs are used in the treatment of advanced breast cancer in post-menopausal women with disease progression following tamoxifen therapy

41. Exemestane (Aromasin) 6-methylenandrosta-1,4-diene-3,17-dione structurally related to androstenedione acts as an irreversible (suicide) inhibitor of aromatase has no effect on other enzymes involved in steroidogenesis indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy

42. Anti-Progestin Mifepristone – RU 486 - inhibits activity of progesterone - post-coital contraceptive (600mg SD), abortifacient (400-600mg x 4days/ 800mg/day x 2days (85%) or 600mg SD + misoprostol 1mg (95% 7wks); Cushing’s syndrome - AE: heavy bleeding, N and V, anorexia, abd. pain

44. Anti-Progestin Danazol - suppress ovarian function; inhibits mid-cycle surge of LH, FSH - endometriosis (600mg/d) - fibrocystic dis. of the breast - AE: weight gain, edema, acne, cramps - CI: pregnancy, breastfeeding

45. Anti-Androgen Finasteride– inhibits 5-α – reductase (5mg/d) - BPH(5mg/D), baldness (1mg/D) Spirinolactone- ↓synthesis of testosterone on the testes Ketoconazole - ↓synthesis of testosterone on the testes - inhibits binding to androgen receptor Cyproterone– inhibits binding to androgen receptor - hirsutism in women, prostatic Ca Flutamide– inhibits binding to androgen receptor - prostatic Ca 1. Bicalutamide (150-200mg/d) 2. Nilutamide (300mg/d x 3 days)

46. Antiandrogen drugs

47. Finasteride : Proscar and Propecia

51. Hormonal Contraceptives Combination oral contraceptive I. Monophasic – provide constant amount of estrogen and progesterone (21day) II. Biphasic – provide varying amount of progestin but constant amount of estrogen III. Triphasic -provide varying amounts of estrogen and progestin Transdermal combination contraceptive

52. Examples of Oral Contraceptives 4 types: monophasic: Loestrin, Levlen, Levora, Levlite, Desogen, Lo/Ovral, Ortho-Cept, Nordette, Demulen, Ovcon, Modicon, Zovia, Loestrin, Apri, Microgestin, Yasmin, Ortho-Cept, Levora, Alesse biphasic: Ortho-Novum 10/11, Nelova 10/11, Necon 10/11, Jenest-28, Mircette triphasic: Ortho-Novum 7/7/7, Tri-Norinyl, Tri-Levlen, Triphasil, Trivora-28, Estrostep progestin-only: Micronor, Nor-QD, Ovrette

53. Adverse effect of combination oral contraceptive: Mild:nausea, mastalgia, breakthrough bleeding, changes in serum protein, transient headache, withdrawal bleeding Moderate:breakthrough bleeding, weight gain, skin pigmentation, acne, hirsutism, vaginal infections, amenorrhea Severe:vascular disorders (MI, CVA), cholestatic jaundice, depression, Ca

54. Hormonal Contraceptive Progesterone only contraceptive Oral: Norethindrone, Norgestrel Subdermal: Norgestrol, Norplant Injectable: Medroxyprogesterone Acetate/ Depoprovera Post-coital contraceptive

55. OTHER CONTRACEPTIVE PRODUCTS Levonorgestrel implants (Norplant system) intrauterine progesterone contraceptive system (Progestasert) medroxyprogesterone contraceptive injection (Depo-Provera) nonoxynol contraceptive creams and gels

58. Emergency contraceptives drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure to be effective these must be taken within 72 hours of intercourse two products are available: Plan B: 0.75 mg levonorgestrel Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this product includes a pregnancy test kit)

59. Male Contraceptive Gossypol – phenolic compound that reduces sperm density by 99% in men and impairs sperm motility - 20mg/D x 2 mos. or 60mg/wk - not continued >2yrs.

60. In summary…… Identify gonadal hormone secretion and their functions Know the uses of these hormones

61. Types of steroid hormones Glucocorticoids; cortisol is the major representative in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

62. Miscellaneous topics

64. Anabolic, androgenic, and growth hormones Anabolicrefers to muscle building (Testosterone, Dianobol, and Deca Durabolin) Androgenic refers to increased masculine characterictics (Equipoise, Masteron, and Trenbolone) (2005,march NIDA Infofacts) Growth hormones are different in nature from anabolic-androgenic steroids. (2005,march NIDA Infofacts)

65. Georgia Bureau of Investigation at 2:30 p.m. EDT on July 17, 2007

67. REPRODUCTIVE HEALTH BILL IN THE PHILIPPINES There are four bills pertaining to reproductive health and/or population management that have been filed for deliberation in both the House of Representatives and the Senate for the 14th Congress. These are House Bill No. 17 authored by Rep. Edcel Lagman, House Bill No. 812 authored by Rep. Janette Garin, Senate Bill No. 40 authored by Sen. Rodolfo Biazon and Senate Bill No. 43 authored by Sen. Panfilo Lacson.

68. The bill is controversial, as it is being opposed by the Catholic Church. The Catholic Church is against the use of artificial contraceptives House Bill No. 17, also known as the proposed "Reproductive Health and Population Development Act of 2008," will cover the following areas: information and access to natural and modern family planning; maternal, infant and child health and nutrition; promotion of breast feeding; prevention of abortion and management of post-abortion complications; adolescent and youth health; prevention and management of reproductive tract infections, HIV/AIDS and sexually transmitted diseases; elimination of violence against women; counseling on sexuality and sexual and reproductive health; treatment of breast and reproductive tract cancers; male involvement and participation in reproductive health; prevention and treatment of infertility; and reproductive health education for the youth.

69. Finally ……. The End Thank You!