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Progestins

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Natural progestin – progesterone 21C steroid , derive from cholesterol , secreted by corpus luteum* / placenta*
Synthetic progestins – high oral activity
-progesterone derivatives (21C) – apart from progesteronal activity it have weaker antiovulatory acton

Publicada em: Saúde e medicina
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Progestins

  1. 1. PROGESTINS Dr Suyash Bharat MD Pharmacology GMC haldwani
  2. 2. Introduction • Progestin  favouring pregnancy. • Natural progestin – progesterone 21C steroid , derive from cholesterol , secreted by corpus luteum* / placenta* • Synthetic progestins – high oral activity -progesterone derivatives (21C) – apart from progesteronal activity it have weaker antiovulatory axn
  3. 3. Blastocyst secrete Placenta secrete E & P from 2nd trimester WITHDRAWL OF E & P coz release of prolactin from pitutary milk secretion starts
  4. 4. • 19-nortestosterone derivatives  Estranes(18 C) - progesteronal activity, potent antiovulatory * axn , weak estrogenic, androgenic, anabolic axn. • Estranes with a 13–ethyl substitution  Gonanes increase potency antiovulatory * axn & reduced androgenic activity. • * Suppress GnRH
  5. 5. Physiological and Pharmacological Actions • Neuroendocrine Actions decreasing the frequency of GnRH pulses. • Reproductive Tract decreases estrogen- driven endometrial proliferation  l/t development of a secretory endometrium  abrupt decline  onset of menstruation. • Endocervical glands secretion turn to scant, viscid material. • Progesterone  imp for maintenance of pregnancy suppresses menstruation and uterine contractility
  6. 6. ====
  7. 7. • Mammary Gland. Development requires both estrogen & progesterone. • During pregnancy acting with estrogen, brings proliferation of the acini of the mammary gland. Toward the end of pregnancyacini fill with secretions & vasculature of the gland increases • After the levels of estrogen and progesterone decrease at parturition does lactation begin. • Under influence of progesterone mitotic activity in the breast epithelium is very low in the follicular phase and then peaks in the luteal phase .
  8. 8. CNS Effects. • During a normal menstrual cycle, an increase in basal body temperature of about 0.6°C (1°F) at mid-cycle correlates with ovulation. • Progesterone also increases the ventilatory response of the respiratory centers to CO2 and leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy. • Progesterone also may have depressant and hypnotic actions in the CNS, possibly accounting for reports of drowsiness after hormone administration.
  9. 9. Metabolic Effects • Progesterone  increases basal insulin levels & the rise in insulin after carbohydrate ingestion, but it does not normally alter glucose tolerance. • Long-term administration of more potent progestins decrease glucose tolerance. • Progesterone stimulates lipoprotein lipase activity and seems to enhance fat deposition. • Progesterone & analogs (MPA) increase LDL & no/little reductions in sr HDL levels.
  10. 10. • 19-norprogestins (androgenic activity) effects on plasma lipids • Micronized progesterone does not significantly affect beneficial estrogen effects on either HDL or LDL profiles. • Progesterone diminish effects of aldosterone in the renal tubule and cause a decrease in Na+ reabsorption  increase mineralocorticoid secretion from the adrenal cortex.
  11. 11. Mechanism of Action • Single gene encodes two isoforms of the progesterone receptor (PR): PR-A and PR-B. The first 164 N-terminal amino acids of PR-B are missing from PR-A. • The ratios of the individual isoforms vary in reproductive tissues as a consequence of tissue type, developmental status, and hormone levels. • Both PR-A and PR-B have AF-1 and AF-2 transactivation domains, but the longer PR-B also contains an additional AF-3 that contributes to its cell- and promoter-specific activity.
  12. 12. • Ligand-binding domains  PR isoforms are identical. • In the absence of ligand, PR is present in the nucleus in an inactive monomeric state bound to heat-shock proteins (HSP-90, HSP-70, and p59). • Binding progesterone, HSPs dissociate  receptors are phosphorylated  form dimers (homo- and heterodimers) that bind with high selectivity to PREs (progesterone response elements) located on target genes
  13. 13. • Transcriptional activation by PR occurs primarily via recruitment of co-activators such as SRC-1, NcoA-1, or NcoA- 2. • The receptor-co-activator complex then favors further interactions with additional proteins such as CBP and p300, which have histone acetylase activity remodeling of chromatin  increases the accessibility of general transcriptional proteins, including RNA polymerase II, to the target promoter. • Progesterone antagonists also facilitate receptor dimerization and DNA binding, but conformation of antagonist-bound PR is different from that of agonist-bound PR. • This different conformation favors PR interaction with co- repressors such as NcoR/SMRT, which recruit histone deacetylasesincreases DNA interaction with nucleosomes and renders a target promoter inaccessible to the general transcription apparatus.
  14. 14. • In most cells, PR-B mediates the stimulatory activities of progesterone; PR-A strongly inhibits this action of PR-B and is also a transcriptional inhibitor of other steroid receptors. • PR-A antiproliferative effect • PR-B mediating hormone effects in the mammary gland . • Progesterone increased Ca2+ mobilization in sperm (membrane-bound progesterone receptors).  spermatozoa and oocyte maturation .
  15. 15. Mechanism of Action • PR nucleus of target cell(Female genital tract, breast , CNS , Pituitary) • P binding the PR undergoes DIAMERIZATION • Attaches to Progesteron Response Element(PRE) of target gene. • Regulates transcription through co-activators
  16. 16. Absorption, Fate, and Excretion • Rapid first-pass metabolism • IN PLASMA, bound by albumin and corticosteroid-binding globulin. • Elimination half-life 5 minutes eliminated in the urine • 19-nor steroids have good oral activity  ethinyl substituent at C17  slows hepatic metabolism • Synthetic progestins longer half-lives (7 -24 Hrs)
  17. 17. Therapeutic Uses • Contraception • hormone therapy of postmenopausal women • Secondary amenorrhea, abnormal uterine bleeding in patients without underlying organic pathology (e.g., fibroids or cancer), • Luteal-phase support to treat infertility, and premature labor • Progesterone can be used diagnostically to test for estrogen secretion and for responsiveness of the endometrium. • Highly efficacious in decreasing the occurrence of endometrial hyperplasia and carcinoma caused by unopposed estrogens • Hormone releasing IUD decrease estrogen-induced endometrial hyperplasia • Palliative measure for metastatic endometrial carcinoma • Megestrol acetate 2nd-line treatment for breast cancer.
  18. 18. ANTI-PROGESTINS AND PROGESTERONE-RECEPTOR MODULATORS • Mifepristone- derivative of the 19- norprogestin norethindrone progesterone- receptor modulator (PRM) • Competes with both progesterone & glucocorticoids for binding to their respective receptors. • Onapristone, asoprisnil
  19. 19. • Pharmacological Actions. Mifepristone  competitive receptor antagonist for both progesterone receptors BUT exhibits some agonist activity . • Early stages of pregnancy, mifepristone causes decidual breakdown (blockade of PR) detachment of the blastocyst decreases hCG productionThis coz decrease in progesterone secretion from the corpus luteum accentuates decidual breakdown. • Sensitizes myometrium contractile actions. Mifepristone cervical softening • facilitates Expulsion of Blastocyst.
  20. 20. • Delay or prevent ovulation • If administered for one or several days in the mid- to late luteal phase, mifepristone impairs the development of a secretory endometrium and produces menses.
  21. 21. Absorption, Fate, and Excretion • Mifepristone  orally active with good bioavailability. • plasma t1/2 of 20 - 40 hrsbound by a1-acid glycoprotein. • Metabolites mono- and di-demethylated products formed via CYP3A4-catalyzed reactions. • Drug  hepatic metabolism and enterohepatic circulation
  22. 22. Therapeutic Uses • Mifepristone 600 mg  f/b 48 Hr later Misoprostol (PGE1) 400mg Termination of early pregnancy Success rate  >90% among women with pregnancies of 49 days. • Cervical ripening- • Postcoital contraceptives
  23. 23. • Adverse effect Vaginal bleeding (lasts from 8 to 17 days ) , abdominal pain and uterine cramps, nausea, vomiting, and diarrhea • CI Women receiving chronic glucocorticoid therapy (anti-glucocorticoid activity) Patient anemic or receiving anticoagulants. Women with cardiovascular risk factors
  24. 24. Ulipristal(selective progesterone receptor modulator) • Use- Emergency contraceptive Inhibit ovulation (suppress LH surge) Interfere with implantation
  25. 25. Thank you

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