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PRESENTED BY V.SUNITHA(10T21S0118)<br /> M.Pharm (Pharmacology)<br /> UNDER THE GUIDENCE OF<br /> MR.J.ANOOP ASST .PROFESSOR<br />PROGESTINS<br />

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<ul><li>Compounds with biological activities similar to those of progesterone have been variously referred to in the literature as progestins, progestational agents, progestagens, progestogens, gestagens, or gestogens. </li></ul>DEFENITION<br />

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History<br />

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<ul><li>There is a single gene that encodes two isoforms of the progesterone receptor (PR): PR-A and PR-B

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Since the ligand-binding domains of the two PR isoforms are identical, there is no difference in ligand binding

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However, the biological activities of PR-A and PR-B are distinct and depend on the target gene in question

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PR-B mediates the stimulatory activities of progesterone

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PR-A strongly inhibits this action of PR-B</li></ul>The Progestin Receptor<br />

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Neuroendocrine Actions: Progesterone produced in the luteal phase of the cycle has several physiological effects including decreasing the frequency of GnRH pulses, which is the major mechanism of action of progestin-containing contraceptives.<br />Physiological and Pharmacological Actions<br />

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Under normal circumstances, estrogen antecedes and accompanies progesterone in its action upon the endometrium and is essential to the development of the normal menstrual pattern<br />Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility, but other effects also may be important.<br />Based on a recent report that premature labor in high-risk mothers was diminished by weekly intramuscular administration of 17-hydroxyprogesterone (DELALUTIN), this indication is being re-evaluated<br />Reproductive Tract<br />

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During pregnancy and to a minor degree during the luteal phase of the cycle, progesterone, acting with estrogen, brings about a proliferation of the acini of the mammary gland. Toward the end of pregnancy, the acini fill with secretions and the vasculature of the gland notably increases; however, only after the levels of estrogen and progesterone decrease at parturition does lactation begin<br />Mammary Gland<br />

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During a normal menstrual cycle, an increase in basal body temperature of about 0.6˚C (1˚F) may be noted at mid-cycle; this correlates with ovulation. This increase is due to progesterone, but the exact mechanism of this effect is unknown.<br />Progesterone also increases the ventilatory response of the respiratory centers to carbon dioxide and leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy<br />Progesterone also may have depressant and hypnotic actions in the CNS, possibly accounting for reports of drowsiness after hormone administration. This potential untoward effect may be abrogated by giving progesterone preparations at bedtime, which may even help some patients sleep.<br />CNS Effects<br />

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Progesterone itself increases basal insulin levels and the rise in insulin after carbohydrate ingestion, but it does not normally alter glucose tolerance. However, long-term administration of more potent progestins, such as norgestrel, may decrease glucose tolerance<br />Progesterone stimulates lipoprotein lipase activity and seems to enhance fat deposition. Progesterone and analogs such as MPA have been reported to increase LDL and cause either no effects or modest reductions in serum HDL levels. <br />Progesterone also may diminish the effects of aldosterone in the renal tubule and cause a decrease in sodium reabsorption that may increase mineralocorticoid secretion from the adrenal cortex.<br />Metabolic Effects<br />

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Progesterone : If given orally, it is quickly destroyed by liver. A micronized form is available orally for HRT since it escapes first pass hepatic metabolism. <br />Synthetic progestins : <br /> Oral progestins have improved oral bioavailability Unlike progesterone, they stabilize endometrium but do not support early pregnancy<br /> Preparations :<br />

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<ul><li>Medroxyprogesterone acetate (Provera) :</li></ul> Oral tablets, or <br /> IM depot preparation (depot provera)<br /> It has also androgenic effects <br /><ul><li> Dydrogesterone : Oral tabs. No androgenic effects

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19-Nortestosterone derivatives :</li></ul> Norethindrone (Norethisterone) <br /> L -norgestrel <br /> Both also have androgenic effect <br /><ul><li>New generation agents : Desogestrel, Norgestimate ; they have much less or no androgenic effects.</li></li></ul><li>Therapeutic uses<br />A. Contraception :<br />With estrogens in combined contraceptive tabs OR<br />Alonein progestin-only contraceptive tabs <br /> Progestinsact by :<br />1.Interfering with endometrial implantation <br />of fertilized ovum :by making endometrium <br /> out of phase (by antagonizing estrogen effect).<br />

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. Fertilization is prevented due to interference with passage of spermatozoa from vagina to uterus bymaking secretions of the cervix <br />thick and viscid, so difficult to be penetrated by spermatozoa. <br /> Secretions of fallopian tube also become viscid.<br />3. With large doses or with some preparation, Gn secretion is inhibited, so ovulation is inhibited. <br /> This occurs in ~ 50% of cases, butalways with Depot preparations <br />

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Menstrual disorders : such as:<br />PrimaryDysmenorrhea : ( At first, NSAIDs e.g. mefenamic acid are used; if these fail , then dydrogesterone or combined contraceptive tabs. are employed).<br />Dysfunctional uterine bleeding with menorrhagia <br /> : Norethindrone (oral) or IM Depot provera <br />C. Endometriosis :<br /> Inhibits ectopic endometrial tissue by antagonizing estrogen and by inhibiting Gn secretion which leads to inhibition of ovarian function, including estrogen secretion.<br /> - Medroxyprogesterone acetate IM (Depot provera) <br />

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Habitual abortions: Recurrent pregnancy loss or Recurent Miscarriage can be treated by progesterone therapy<br /><ul><li>Premature labour: progesterone, often given in the form of 17-hydroxy progesterone caproate, relaxes the uterine musculature, maintains cervical length, and has anti-inflammatory properties, and thus exerts activities expected to be beneficial in reducing preterm birth</li></li></ul><li>Progestin-Only Contraceptives<br />They contain progestins only, termed “mini pills”<br />Slightly less effective, with 99% efficacy<br />Forms<br />Pills<br />Injectables<br />Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration and impairs implantation<br />

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Emergency Contraceptives<br />PLAN-B includes 2 doses of levonorgestrel separated by 12 hours (progestin-only)<br />

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Many side effects were found to be dose dependent, hence the development of the current low-dose preparations<br />Side effects include:<br />Cardiovascular effects (hypertension, myocardial infarction, hemorrhagic stroke, venous thrombosis)<br />Breast, Hepatocellular, and Cervical Cancers<br />Endocrine and Metabolic effects<br />Currently, its found that the low-dose preparations pose minimal health risks in women who have no predisposing risk factors<br />Side Effects<br />

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Anti-progestin, first discovered in 1981, is mifepristone, used to terminate pregnancy<br />In the presence of progesterone, mifepristone acts as a competitive receptor antagonist for both progesterone receptors<br />When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blocking uterine progesterone receptors, which leads to detachment of the blastocyst.<br />Anti-progestins<br />

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With the advancement of technology microcrystaline progestins were developed which are cost effective and easy to administer which is the major draw back of progestin depots.<br />NOTE<br />