Estrogen and progestins

Lecture Classes for BNS 1st Year
Maharajgunj Nursing Campus

1. Drugs Used in Reproductive Health: Estrogen and Progestin For BNS I st Year Dr. Pravin Prasad I st Year Resident, MD Clinical Pharmacology Maharajgunj Medical Campus 2 nd October, 2015( Asoj 15, 2072); Friday

2. Drugs Used in Reproductive Health Estrogens, Progestins Oral Contraceptives Uterine Stimulants Oxytocin Methylergotmetrine Uterine Relaxants

3. Estrogens

4. Estrogens: Introduction Female sex hormone Natural Estrogens: Estradiol (secreted by g raafian follicles, corpus luteum and placenta in females and by aromatization of testerone in testes and extraglandular tissues in males; most active/potent), Esterone ( oxidised form of estradiol E 2 , in liver) Estriol (formed by hydroxylation of esterone ) ??

5. Types of Synthetic Estrogens Estrogens: Introduction Steroidal Non-steroidal Ethinylestradiol Diethylstilbestrol ( stilbestrol ) Mestranol Hexestrol Tibolone Dienestrol ??

6. Estrogen Synthesis Ref: http://www.apsubiology.org/anatomy/2010/2010_Exam_Reviews/Exam_5_Final_Review/steroid_hormone_synthesis.png

7. Regulation of Estrogen secretion

8. Actions of Estrogens Sex organs: Responsible for pubertal changes Growth of uterus, fallopian tubes and vagina Mensturation in anovulatory cycles Enhances sperm penetration Deficiency leads to atrophic changes in female reproductive tract Secondary Sex Characters: Breasts: proliferation of ducts and stroma , accumulation of fat Pubic and axillary hair appears Feminine body contours and behaviours ??

9. Anabolic , weaker than testosterone Responsible for pubertal growth spurt in both boys and girls Bone Mass : Retards bone resorption ; Promotes fusion of epiphyses Water and salt retention : edema treatable by diuretics; Blood pressure may rise on prolonged use Glucose tolerance (high doses as in combined OCPs): impaired, normal blood sugar not affected, diabetes precipitated, control lost Lipid Profile : decreased plasma LDL cholestrol , increase HDL and TG levels; raised HDL:LDL ratio Actions of Estrogens: Metabolic Effects

10. Blood Coagulability : increased due to induction of synthesis of clotting factors (factors II, VII, IX and X); Fibrinolytic activity increases (lowering of plasminogen -activator inhibitor-I, PAI-I) Vascular Endothelium : Nitric oxide synthase and Prostaglandin I 2 (PGI 2 ) production  promotes vasodilatation, Gallbladder : increases lithogenicity (increased cholesterol secretion and decresed bile salt secretion) Hormone Binding Globulins : increases plasma Sex Hormone Binding Globulin (SHBG), Thyroxine Binding Globulin (TBG), Cortisol Binding Globulin (CBG) Actions of Estrogens: Metabolic Effects

11. Estrogen Receptors Estrogen Receptor Alpha (ER α ) Estrogen Receptor Beta (ER β ) Both Subtypes Expressed by most tissues Predominates in: uterus, vagina, breast, bone, hypothalamus, blood vessels Predominates in: Prostate gland of males, ovaries in females E 2 bind to both receptors with equal affinity; Certain ligands (types of estrogens) have differing affinity These receptors have different pattern of interaction(different activity) with coactivators and corepressors

12. Estrogen: Mechanism of Action Genomic Actions: Binds to specific nuclear receptors (Estrogen receptors, ER)  conformational changes (receptor dimerization leading to interaction with Estrogen Response Elements, ERE, of target genes)  regulates protein synthesis Nongenomic Actions: ERs located on the cell membrane ??

13. Estrogen: Mechanism of Action Ref:   Laurentino S, Pinto P, Correia S, Cavaco JE, Canário AVM, Socorro S. Structural variants of sex steroid hormone receptors in the testis: from molecular biology to physiological roles. OA Biotechnology 2012 Dec 17;1(2):4. ??

14. Estrogen : Pharmacokinetics Pharmacokinetic Parameters Profile Absorption Well absorbed orally as well as transdermally Natural estrogen inactivated due to rapid metabolism in liver when given orally Distribution Natural estrogens are largely plasma protein bound (SHBG and albumin) Metabolism Converted to Esterone and vice versa in liver Esterone converted to estriol Phase I reaction: Conjugation with glucuronic acid Phase II reaction: sulfation Excretion Due to deconjugation in intestines: considerable enterohepatic circulation Mainly excreted in urine, may be excreted in bile

15. Estrogen : Doses Equivalent parenteral doses are: Estradiol 1 0.1 mg = Ethinylestradiol 3 0.1 mg = Mestranol 3 0.15 mg = Coniugated estrogen 2 10 mg = Estriol succinate 2 16 mg = Diethylstilbestrol 3 10 mg 1: inactive orally, 2: partially metabolised, 3: similar activity of both dosage forms Preferred Route Oral; Intramuscular used when high dose is required (Ca. prostate)

16. Estrogen : Preparations Estradiol : 2.5-10mg intramuscular injection Conjugated Estrogens : 0.625-1.25 mg/day, oral (Dysfunctional Uterine Bleeding) Ethinylestradiol : 0.02-0.2 mg/day, oral (postmenopausal syndrome) Mestranol: 0.1-0.2 mg/day, oral Estriol : 4-8 mg/day initially then 1-2 mg/day, oral Fosfestrol : intravenous preparation Dienestrol : 0.01%, topical preparation Estradiol -TTS: Transdermal patch of 5, 10, 20 cm 2 delivering 0.025, 0.05, 0.1 mg respectively for 3-4 days (postmenopausal syndrome)

17. Estrogen : Transdermal patch Pros and Cons Effects on menopausal symptoms, bone density, vaginal epithelium, plasma Gonadotrophin level are comparable to those of oral therapy Milder systemic side effects in comparison to oral preparations Avoids hepatic delivery: Levels of Thyroid binding globulin (TBG), Cortisol binding globulin (CBG), angiotensin and clotting factors are not raised  risk of thromboembolic phenomenon avoided Effect of serum lipid profile: less marked

18. Estrogens: Indications Hormonal Replacement Therapy (HRT) Senile Vaginitis Delayed puberty in girls Dysmenorrhoea Acne Dysfunctional Uterine Bleeding Carcinoma prostate ??

19. Estrogen: Side Effects Population Groups Side Effects Males Suppression of libido, gynaecomastia and feminization Children Fusion of epiphyses and reduction of adult stature Postmenopausal women/ on HRT Risk of irregular bleeding and endometrial carcinoma Existing Breast cancer Growth of existing breast cancer Women under long term estrogen therapy Increased incidence of gallstones, benign hepatoma Co-morbidity Worsening of Migraine, epilepsy, endometriosis Pregnant Women(esp. first trimester) Vaginal and cervical carcinoma in female offspring in childhood or early adulthood ??

20. Antiestrogens and selective estrogen receptor modulators ( serm s )

21. Antiestrogens Clomiphene Useful for infertility due to failure of ovulation, aid in vitro fertilization, oligozoospermia in males Fulvestrant Selective Estrogen Receptor Down-Regulator Used for metastatic ER positive breast cancer in postmenopausal women which has stopped responding to Tamoxifen

22. Selective Estrogen Receptor Modulators (SERMs) Exerts both estrogenic and anti-estrogenic actions in a tissue selective manner Tamoxifen Antagonist action in Breast carcinoma cells, blood vessels and some peripheral sites (ER α receptors ) Partial agonistic activity on uterus, bone, liver and pituitary. Used in treatment for breast cancer in both pre- and post-menopausal patients Early cases: Used post mastectomy for adjuvant therapy Advanced cases: part of palliative therapy Only drug approved for breast carcinoma in premenopausal women (early and advanced) Other use: primary prophylaxis of breast cancer in high-risk women, as an alternative to clomiphene in male infertility

23. Selective Estrogen Receptor Modulators (SERMs) Raloxifene : Estrogen partial agonist in bone and cardiovascular system Antagonistic action on endometrial and breast tissue Distinct DNA target “ raloxifene response element” Used as second line drug for prevention and treatment of osteoporosis in postmenopausal women

24. Aromatase inhibitors (AI) Third generation AI: Letrozole , Anastrozole , Exemestane Letrozole and Anastrozole Orally active, nonsteroidal (Type 2) compound Reversibly inhibits aromatization of testosterone and androstenedione all over body  total estrogen deprivation Used in Early breast cancer (first line adjuvant therapy post mastectomy in ER+ve postmenopausal women), Advanced breast cancer (first line as well as tamoxifen failure cases) Exemestane Orally active, steroidal and irreversible (Type 1) inhibitors

25. Progestins

26. Progestins Converts the estrogen primed proliferative endometrium to secretory and maintain pregnancy in animals spayed after conception Natural Progestin: Progesterone Secreted form corpus luteum post-ovulation and immediately after fertilization (corpus luteum sustained by chorionic gonadotrophins released by blastocyst); from placenta during 2 nd and 3 rd trimester; from adrenals and testes in men (? role) ??

27. Synthetic Progestins Progesterone Derivatives: Medroxyprogesterone acetate, Megesterol acetate, Dydrogesterone , Hydroxyprogesterone caproate ; Nomegestrol acetate 19-nortesterone Derivatives: Older Compounds: Norethindrone , Lynestrenol ( Ethinylestrenol ), Allylestrenol , Levenorgestrel ( gonanes ) Weak estrogenic, androgenic, anabolic and potent antiovulatory action Newer Compounds ( Gonanes ): Desogestrel , Norgestimate , Gestodene Very potent progestins , antiovulatory action, little or no androgenic property Preferable in women with hyperandrogenemia 19-norprogesterone Derivative: Nomesgestrol Weak antiandrogenic property, less antiovulatory , strong antiestrogenic effect on endometrium ??

28. Actions of Progestins (Progesterone as Prototype) Uterus: Secretory changes in the estrogen primed endometrium: hyperemia , tortuosity of glands, increased secretion. Continued action (as during pregnancy): decidual changes and sensitivity of myometrium to oxytocin decreased Cervix: Secretion made viscid, scanty and cellular secretion: hostile to sperm penetration Vagina: Pregnancy like changes ??

29. Breast: Leutal phase exposure: cyclic epithelial proliferation and turnover of acini in mammary glands Continuous exposure: halts mitotic activity and stabilizes mammary cells; prepares breast for lactation CNS: High concentration has sedative effect Body Temperature: Slight rise in body temperature (0.5 o C) Actions of Progestins (Progesterone as Prototype)

30. Respiration: Stimulates respiration at higher doses Metabolism: Prolong use of Oral contraceptives impairs glucose tolerance Raises LDL and lower HDL, cholesterol levels (androgenic activity; not seen with natural progesterone) Pituitary: Weak inhibitor of Gonadotrophin secretion Supresses preovulatory LH surge and prevents ovulation if given during follicular phase Actions of Progestin (Progesterone as Prototype)

31. Progesterone Progesterone Receptors: Limited distribution: female genital tract, breast, CNS, pituitary Nucleus of target cells Short (PR-A) and Long (PR-B) isoforms Mechanism of Action: Binds to Progesterone Receptor (PR) present in nucleus  Undergoes conformational changes (dimerization)  attaches to Progesterone Response elements (PRE)  regulates transcription through coactivators Cell membrane receptors: rapid effects (Ca ++ release from spermatozoa, Oocyte maturation) ??

32. Progesterone: Pharmacokinetics Pharmacokinetic Parameters Profile Absorption Inactive orally, high first pass metabolism in liver Injected intramuscularly as oily preparation Micronized formulation for oral administration; absorption through lymphatics Distribution Short half life (5-7 mins ) Metabolism Converted to Pregnanediol in liver Phase I reaction: Conjugation with glucuronic acid Phase II reaction: sulfation Excretion Excreted in urine Effects lasts longer than the hormone itself Synthetic Progestins : orally active, metabolized slowly; longer half life

33. Progesterone: Indications As Contraceptive Hormone Replacement Therapy (HRT) Nonhysterectomized postmenopausal women to counteract risk of endometrial carcinoma Dysfunctional uterine bleeding Endometriosis Premenstrual syndrome/tension Severe cases and in severe dysmenorrhoea Threatened/habitual abortion In cases with established deficiency of progesterone Endometrial carcinoma Palliative treatment ??

34. Progestins : Side Effects General: Breast engorgement, headache, rise in body temperature, edema, esophageal reflux, acne mood swings with higher doses Irregular bleeding or amenorrhoea on continuous administration Painful injection 19-nortesterone derivatives: Lowers plasma HDL levels  promotes atherogenesis Impaired glucose tolerance, precipitate diabetes Long term administration(HRT): Increase risk of breast cancer Early pregnancy: Masculinization of female foetus and other congenital abnormality ??

35. Antiprogestin

36. Antiprogestin : Mifepristone 19-norsteroid with potent antiprogestational and significant antiglucocorticoid , antiandrogenic activity Mechanism of Action: Follicular phase : attenuates mid-cycle Gonadotrophin (FSH/LH) surge from pituitary ( antiprogestin activity)  slowing of follicle development and delay/failure of ovulation Secretory/Luteal Phase : prevents secretory changes by blocking progesterone action on endometrium Later stages of cycle : blocks progesterone support to endometrium and increases Prostaglandin (PG) release  stimulates uterine contraction Sensitizes myometrium to PG and induces mensturation Post implantation : blocks decidualization  conceptus gets dislodged  human chorionic gonadotrophin ( hCG ) falls, luteolysis occurs  decreased endogenous progesterone and cervix softens  abortion

37. Mifepristone: Antiprogesterone or Progesterone Receptor Modulator? Partial agonist and competitive antagonist at both PR-A and PR-B isoforms. Weak agonistic activity seen in the absence of progesterone( anovulatory cycles or after menopause)  predecidual changes

38. Mifepristone: Pharmacokinetics Absorption: Active orally Bioavailability only 25% Distribution Half life 20-36 hrs Metabolism Liver by CYP3A4 (interaction with inhibitors and inducers seen) Excretion Mainly in bile Enterohepatic circulation seen

39. Mifepristone: Uses Termination of Pregnancy Up to 7 weeks, 600mg single oral dose (+/- 400mg misoprostol after 48 hrs) Cervical ripening Prior to attempting surgical abortion of induction of labour (600mg oral) Post-coital contraception (emergency contraception) Within 72 hrs of intercourse (600mg oral) Once a month contraceptive (?) Induction of Labour In cases of Intra uterine foetal death or abnormal foetus Cushing Syndrome (?)

40. Mifepristone: Side Effects General: Anorexia, nausea/vomiting, tiredness, abdominal discomfort, uterine cramps, loose motions When used for termination of pregnancy: Prolonged bleeding, failed abortion When used as postcoital contraceptive: Subsequent menstrual cycle is disturbed

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