Estrogens, Progestins and Androgens

1. Estrogens, Progestins and Androgens Becky Worthylake bworth@lsuhsc.edu

2. Outline • Overview • Estrogens – General • Estrogens & Modifiers – Therapeutic Formulations & Uses • Progestins – Therapeutic Formulations & Uses • Contraception • Androgens – General • Androgens – Uses & Therapeutic Formulations

3. Overview: Endocrine Physiology Hypothalamus (GnRH) & Pitutary Luteinizing Hormone & Follicle Stimulating Hormone Ovaries & Testes Reproduction

4. Overview: Molecular Mechanisms

5. Overview: Molecular Mechanisms

6. Outline • Estrogens – General • Synthesis • Physiology • Regulation

7. Synthesis 24 28 21 22 CH 2 CH 3 CH CH 3 20 2 Cholesterol CH CH 18 2 CH 2 25 12 CH 3 23 17 CH 3 11 16 13 19 D 27 C CH 3 1 14 2 9 15 10 8 A B 3 7 5 OH 4 6 Pregnenolone Progesterone DHEA Androstenedione Androstenedione OH Testosterone aromatase OH Estradiol

8. Reproductive Tissues Growth of Ovarian Vaginal Mammary follilcle Gland Epithelium Growth of endometrium Sperm transport Lowers Decreases Plasma cholesterol rate of bone ESTROGENS resorption Behavioral effects Reduces Bowel motility Liver synthesis of Transport Proteins Maintains normal Increases blood coagulability skin structure Non-reproductive Tissues Physiology

9. Regulation: Feeback Loops FSH, LH Same a Different b

10. Regulation : Circulating Levels

11. Regulation: Impact on Reproductive Tissues Luteal Follicular

12. Outline • Estrogens & Estrogen Modifiers – Therapeutic Formulations and Uses • Therapeutic Estrogens • SERMs (selective estrogen receptor modulators) • Estrogen Synthesis Inhibitors

13. Therapeutic Estrogens • Indications • Primary Hypogonadism • Postmenopausal Hormonal Therapy • Oral Contraceptives • Suppress ovulation in patients with intractable dysmenorrhea or hirsutism • Fertility treatments

14. Therapeutic Estrogens Cont’ Side effects Nausea, fluid retention, breakthrough bleeding, change in menstrual flow, breast tenderness. Adverse Effects: Thrombolytic complications; endometrial carcinoma; breast carcinoma; and hypertension. In men - feminization of genitalia & impotence. Contraindications: Pregnancy, incomplete bone growth, undiagnosed genital bleeding; stroke, thrombophlebitis, or thromboembolic disease., heart disease. Women with family history of breast or uterine cancer (BRCA gene) Drug Interactions: efficacy of oral anticoagulants and hypoglycemic agents  adverse effects of tricyclic antidepressants  the effects of oxytocin on the uterus. St. John's wort may cause loss of contraceptive or hormonal-replacement efficacy of estrogens

15. Hot Flashes HDL/LDL ratio Uses: HRT – Symptoms of Menopause  LH, FSH Estroneis major Estrogen Postmenopausal Normal, Midcycle GnRH GnRH Normal

16. Uses : HRT – Effects of Treatment (Increased risk of MI and stroke, especially in the first year)

17. Uses: HRT - Formulations • Early HRT used estrogen alone: increased risk of uterine (endometrial) cancer. As a result, addition of progestins is now used to limit endometrial hyperplasia • Medroxyprogesterone(MPA) acetate is most commonly used • Various regimens are used: estrogen for 25 days with inclusion of MPA during last 10-13 days of estrogen, 5-6 days with no hormones • Combination formulations: • PREMPRO(PREMARIN plus MPA) given at fixed dose daily; • PREMPHASE(PREMARIN for 28 days and MPA for days 14-28) • Newer combos of estrogens with progestins: • FEM HRT (estradiol plus norethindrone acetate) • ORTH PREFEST (estradiol plus norgestimate) • Vaginal creams (PREMARIN) or a ring device (ESTRING) can be used instead of oral doses . Reduces vaginal dryness, yeast infections and urinary tract infections.

18. SERMs (Selective Estrogen Receptor Modulators) • Selectivity is possible because • ER- and/or ER- show differential tissue expression. • Conformation dependent binding to DNA and transcription factors • Tissue dependent responses ranging between pro-estrogenic, partially estrogenic and anti-estrogenic effects

19. SERMs: Tamoxifen – Breast Cancer 2-3 fold increased risk of deep vein thrombosis & pulmonary embolism

20. SERMs: Tamoxifencontinued • - Most effective in treatment of tumors that are ER-positive (50% response) or ER + PR positive (70-80% response rates). Responses of ER-negative tumors is < 10%. • Adjuvant therapy with chemo or radiation in treatment • - Preventative agent for women at high risk for breast cancer. • Resistance is usually developed in 5 years, which may, in part, reflect alterations in the ER receptors in the tumors.

21. SERMs: Other • Raloxifene(EVISTA): • - High affinity for both ER- and ER- • Treatment of osteoporosis in post-menopausal women. • Does not cause proliferation of the endometriumor breast tumor cells • Side effects: 2-3 fold  risk of deep vein thrombosis and pulmonary embolism • Interactions: Ampicillin absorption • Raloxifene warfarin efficacy

22. Anti-Estrogens • ClomipheneWeak agonist and strong antagonist for ER- or ER-. • Oppose the negative feedback effects of endogenous estrogen. amplitude of the LH and FSH pulses • - Major use: induction of ovulation in women with an intact hypothalamic-pituitary-ovarian axis • Adverse effects: multiple births, ovarian cysts • ICI 182,870Fulvestrant (FASLODEX) • - pure estrogen antogonist • - effective in treating tamoxifen-resistant tumors

23. Estrogen Synthesis Inhibitors • Steroidal: exemestane(AROMASIN) • Non-steroidal: anastrozole (ARIMIDEX), letrozole (FEMARA) • - Specifically block the local production of estrogens in hormonally-responsive tissues. • - Second-line treatment for breast cancer in patients whom tamoxifen therapy is unsuccessful, but new studies rapidly proving its efficacy and promoting earlier use • - Aromatase inhibitors do not have the bone protecting activity of tamoxifen, and adjuvant therapies to prevent bone loss are in trials

24. Outline • Progestins – Therapeutic Formulations & Uses • Therapeutic Progestins • anti-Progesterones

25. Progestins – Therapeutic Progesterone • Naturally occurring progesterone (low oral bioavailability) • - Micronized particles suspended in oil and packaged in gelatin capsules (PROMETRIUM) • - Vaginal gel (CRINONE) • - Slow-release intrauterine device (PROGESTASERT) • 17-a-hydroxy-progesterone derivatives have substitutions at C17 that slow hepatic metabolism : medroxyprogesterone(MPA) (PROVERA) • 19-nor testosterone derivatives display primarily progestational rather than androgenic activity : norethindrone • Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are more potent progestins and less androgenic: norgestrel, nomegestrol

26. Progestinscontinued • Mechanism of Action: Interacts with PR to mimic the stimulatory affects of progesterone • Physiological Target: Reproductive Tract • Decreasesestrogen-driven endometrial proliferation • Establishment and maintenance of pregnancy • Common Uses: • - Oral contraceptives • - HRT to limit estrogen’s effects on the endometrium • - Uterine Bleeding disorders • Premature labor (decrease uterine contractions) • Stimulate Appetite in AIDS or cancer patients

27. Progestins: anti-Progesterones • Mifepristone (RU 486) (mifeprex): PR antagonist • Used in first trimester to terminate pregnancy (along with prostaglandins to increase uterine contractions) • Post-coital contraceptive (prevent implantation) • Investigational: induction of labor after fetal death and treatment of endometriosis. • Adverse Effects: vaginal bleeding, abdominal pain and cramping • Contraindicated in patients with vaginal bleeding, adrenal dysfunction or asthma (due to anti-glucocorticoid actions) • Interactions: • Decreases efficacy of anticoagulants. • Inhibits hepatic metabolism by CYP3A4 (eg.anti-retroviral protease inhibitors, calcium-channel blockers, carbamazepine)

28. Outline • Contraception • Therapeutic Estrogens & Progesterones • Oral Contraceptive Formulations • Emergency Contraception • Extended-Regimen Contraception • Mechanism of Action • Effects

29. Hypothalamus GnRH Oral Contraceptives GnRH analogs Pituitary LH FSH Ovary Estradiol Progesterone ovum Fallopian Tube Tubal Ligation Ovum transport IUD Progestin only contraceptive Uterus Implantation Sperm transport Barrier Methods Natural family planning Cervix and Vagina Contraception

30. Oral Contraceptives: History • 1950: Pincus et al (progesterone prevents ovulation) • 1959: 1st pill appeared in USA • 1960: mini pill (progesterone alone) • 1970: Introduction low dose or second generation of OCS • 1980: biphasic or triphasic regimens • 1990: 3rd generation OCs e.g, norgestimate 0.25mg or desogestrel 0.15 mg)

31. Contraception: Therapeutic Estrogens 1.Estrogens: mestranol and ethinyl estradiol • Absorbed efficiently in GI tract. Mestranol is biologically inactive and must be metabolized to ethinyl estradiol. Peak plasma levels within 1 hr after oral administration • Clearance is ~ 60% 24 hr after oral dose • Ethinyl estradiol is 2X more potent than mestranol Hepatic Metabolism

32. OH C CH H OH H H O AC O H NORETHINDRONE C CH H H H O H H 19-NORTESTOSTERONE O AC ETHYNODIOL DIACETATE Contraception: Therapuetic Progestins • 19-NOR Steroids :Progestins • Removal of 19-carbon changed major hormonal effect from an androgen to progestin while maintaining oral activity • Estranes: have some androgenic activity as well as estrogenic/anti- estrogenic actions. Rapidly absorbed (Norethindrone)

33. OH H C 3 CH C CH 2 H H H O NORGESTREL H C OCOCH 3 3 C CH CH 2 H H H HON NORGESTIMATE Contraception: Therapuetic Progestins cont’ • Gonanes: More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives • (Norgestrel, Norgestimate, Desogestrel) OH H C 3 CH C CH 2 H2C H H H O DESOGESTREL

34. Therapeutic Estrogen & Progestin Combinations • • 1st generation: products containing mestranol • Low dose OCs: products containing < 50 mcg ethinylestradiol • • 2nd generation “Low-Dose” : products containing gonanes (levonorgestrel, norgestimate) and other members of norethindrone family and 20, 30, or 35 mcg ethinylestradiol • • 3rd generation: desogestrel or gestodene (new progestins) with 20, 30, or 35 mcg ethinylestradiol

35. Contraception: Formulations Monophasic: The concentrations of estrogens and progestins are fixed in the pill, which is taken for 21 days followed by 7 days of “hormone-free” pills. mestranol (50 µg) + norethindrone (1.0 mg) (ORTHO-NOVUM 1/50, NORINYL 1+50) b.ethinylestradiol (20-30 µg) + a progestin (estranes or the gonanes, 0.15-1.5 mg). Include ORTHO-NOVUM 1/35, NORDETTE, ORTHO-CEPT , LOESTRIN)

36. Contraception: Formulations Biphasics: • ethinyl estradiol (fixed concentration) + norethindrone (lower concentration in the first 7-10 days and then higher concentration for the next 11-14 days). • (Include ORTHO-NOVUM 10/11, JENEST-28) • The rationale is to limit exposure to the higher concentration of the progestin.

37. Contraception: Formulations Triphasic: • Fixed concentration of ethinylestradiol with 3 different concentrations of norethindrone • (TRI-NORINYL ORTHO-NOVUM 7/7/7), • Fixed concentration of ethinylestradiolwith three concentrations of gonanes. • (ORTHO-TRI-CYCLEN - norgestimate; TRI-LEVLEN, TRIPHASIL -levonorgestral). • Rationale is to mimic the hormonal changes in the menstrual cycle

38. Contraception: Formulations Progestin Only: • Oral formulations ofnorethindrone (micronor) orlevonorgestrel(ovrette) taken daily • Subdermal implants of levonorgestrel(norplant) for slow-release and long-term contraceptive actions (up to five years) • IM injections ofmedroxyprogesterone(depo-provera) that provides effective contraception for 3 months • IUD that releases low amounts of progesterone locally (progestasert).

39. Emergency Contraceptives • Drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. • Emergency hormone contraceptive regimens are highly effective and decrease the risk of pregnancy by 75 percent • To be effective these must be taken within 72 hours of intercourse • May also inhibit ovulation or fertilization depending on timing of administration Alteration of the endometrium, sperm penetration, and tubal motility are also affected . ESTABLISHED PREGNANCIES ARE NOT HARMED. • Two products are available: • Plan B: 0.75 mg levonorgestrel • Preven: 0.25 mg levonorgestrel and 0.05 mg ethinylestradiol(this product includes a pregnancy test kit)

40. Extended Regimen Contraception Levonorgestrel/ ethinylestradiol0.15 mg / 0.03 mg And either placebo or ethinylestradiol tablets 0.01 mg tablets) Brand Names: Jolessa, Quasense, Seasonale, Seasonique 91-day courses of tablets Advantages • Period once every 3 months • Period last about 3 days with decreased bleeding , Side Effects: Breakthrough bleeding and spotting Seasonique: incorporates low-dose estrogen rather than placebo tablets in an effort to limit bloating, hormonal fluctuations, and breakthrough bleeding.

41. Contraceptives: MOA LH/FSH release  Follicular development & ovulation

42. Contraceptives: MOA • Progestin only: • Thick cervical mucus • Implantation of blastocystin endometrium • Contractions of uterus & F.tubes are modified

43. Effects: Benefits Initiating Method • Start First day of next menstrual period • Some suggest starting on first Sunday following onset of menses – Usually avoids menstrual period on weekends – Most clinicians recommend backup for at least 2 cycles • Other Beneficial effects • 1. Decreases Dysmenorrhea • 2. Decreases benign breast and ovarian cysts • 3. Regulates cycle in anovulatory women • 4. Decreased blood loss during menstruation • 5. 50% reduction in ovarian and endometrial cancer.

44. Effects: Drug Interactions Drugs that disrupt liver metabolism and increase oral contraceptive metabolism - anti-seizure medications, St. John’s wort - antibiotics tetracycline and ampicillin - HIV protease inhibitors - Anti-tuberculosis drugs such as rifampin Oral contraceptives effect the activity of other drugs a. anticoagulants b. benzodiazepines, c. beta-blockers d. corticosteroids, and tricyclic antidepressants

45. Effects: Contraindications Absolute a.History of thromboembolism, MI, stroke b.Impaired liver function c.Known or suspected breast cancer d.Undiagnosed abnormal vaginal bleeding e.Known or suspected pregnancy f.Smokers over age 35 (may use progestin-only) 2.Relative a.– Migraine headaches b.– Hypertension - ok if <35, or healthy, or BP controlled c.– Elective surgery: Discontinue 4wks. prior to major surgery d.– Gallstones/ Cholecystitis e.– Epilepsy: anti-seizure meds may decrease effectiveness of OCP’s f.– Diabetes: small risk or worsening vascular disease.

46. Outline • Androgens – General • Synthesis • Regulation • Physiological Effects

47. Androgens : Synthesis

48. Androgens : Regulation

49. Androgens : Regulation • Circulating testosterone and dihydrotestosterone • 1-2% Free • 65% bound to SSBG (sex steroid binding globulin) • 33-34% bound to albumin

50. Androgens : Physiology