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Estrogen and progestins

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Lecture Classes for BNS 1st Year
Maharajgunj Nursing Campus

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Estrogen and progestins

  1. 1. Drugs Used in Reproductive Health: Estrogen and Progestin For BNS Ist Year Dr. Pravin Prasad Ist Year Resident, MD Clinical Pharmacology Maharajgunj Medical Campus 2nd October, 2015(Asoj 15, 2072); Friday
  2. 2. Drugs Used in Reproductive Health • Estrogens, Progestins • Oral Contraceptives • Uterine Stimulants – Oxytocin – Methylergotmetrine • Uterine Relaxants
  4. 4. Estrogens: Introduction • Female sex hormone • Natural Estrogens: – Estradiol (secreted by graafian 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 E2, in liver) – Estriol (formed by hydroxylation of esterone)
  5. 5. Types of Synthetic Estrogens Estrogens: Introduction Steroidal Non-steroidal Ethinylestradiol Diethylstilbestrol (stilbestrol) Mestranol Hexestrol Tibolone Dienestrol
  6. 6. Estrogen Synthesis Ref: am_Reviews/Exam_5_Final_Review/steroid_hormone _synthesis.png
  7. 7. Regulation of Estrogen secretion
  8. 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. 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. 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 I2 (PGI2) 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. 11. Estrogen Receptors Estrogen Receptor Alpha (ERα) Estrogen Receptor Beta (ERβ) Both Subtypes Expressed by most tissues Predominates in: uterus, vagina, breast, bone, hypothalamus, blood vessels Predominates in: Prostate gland of males, ovaries in females • E2 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. 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. 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. 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. 15. Estrogen: Doses • Equivalent parenteral doses are: – Estradiol1 0.1 mg = Ethinylestradiol3 0.1 mg = Mestranol3 0.15 mg = Coniugated estrogen2 10 mg = Estriol succinate2 16 mg = Diethylstilbestrol3 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. 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 cm2 delivering 0.025, 0.05, 0.1 mg respectively for 3-4 days (postmenopausal syndrome)
  17. 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. 18. Estrogens: Indications • Hormonal Replacement Therapy (HRT) • Senile Vaginitis • Delayed puberty in girls • Dysmenorrhoea • Acne • Dysfunctional Uterine Bleeding • Carcinoma prostate
  19. 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
  21. 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. 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 (ERα 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. 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. 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. 25. PROGESTINS
  26. 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 2nd and 3rd trimester; from adrenals and testes in men (? role)
  27. 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. 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. 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 (0.5oC) Actions of Progestins (Progesterone as Prototype)
  30. 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. 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. 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. 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. 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
  36. 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. 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. 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. 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. 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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Lecture Classes for BNS 1st Year Maharajgunj Nursing Campus


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