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  1. 1. INTRODUCTION• These are substances which convert estrogen primedendometrium to secretory and maintain pregnancy• In addition to estrogens, progestins are importantfemale sex hormones. Progesterone is mainhormone produced in the ovaries, testes and theadrenal glands.• Progestin’s are hormones which favorspregnancy
  2. 2. NATURAL PROGESTINPROGESTERONE (21 CARBON STEROID) is derived fromcholesterolIt was first isolated in 1929It is secreted by corpusluteum (10-20mg/day) in later half ofmenstrual cycle under influence of LH. If ovum gets fertilizedand implants-the blastocyst immediately starts producingchorionic gonadotropin which is absorbed and sustains thecorpus luteum in early pregnancy. Secretion of progesteronestarts from placenta from 2nd trimester till termMales also produce 1-5mg progesterone per day from adrenalsand testes[BUT ROLE IN MALES IS NOT KNOWN]
  3. 3. Biosynthesis of Progesterone
  4. 4. Synthetic progestinsProgesteronederivatives-These are pure progestinsThey have weaker anti-ouvlatory action and areused primarily as adjutantsto estrogens forHRT, threatenedabortions, endometriosis19-nortestosteronederivatives-they have weakestrogenic androgenicand anabolic action buthave potent antiovulatory action.theyare mainly used incombined contraceptivepills.Like Desogestrel andNorgestimate (prodrug)
  5. 5. 1PROGESTERONEDERIVATIVESMedroxyprogesterone acetateMegestrolacetateDydrogestroneHydroxyprogesterone caproate219-NORTESTOSTERONEDERIVATIVES (OLD)NorethindroneLynestrenolAllylestrenolLevonorgestrel(gonane)319-NORTESTOSTERONEDERIVATIVES (NEW)DesogestrelNorgestimateGestodene
  6. 6. ACTIONSIt prepares uterus for nidation and helps in maintance ofpregnancy by preventing endometrial shedding, decreasesuterine motility and inhibiting immunological rejection of fetus( T cell function and cell mediated immunity)Specific actions• Uterus- secretory changes in estrogen primed endometrium(hyperemia, tortuocity of glands and increased secretion).Continued action of progesterone cause decidual changes inendometrium (stroma enlarges, becomes spongy, glandsatrophy and decreases sensitivity of myometrium to oxytocin)• Cervix-converts watery secretion (estrogen produced) toviscid, scanty and cellular which is hostile to sperm penetration• Vagina- induces pregnancy like changes in the mucosa-leukocyte infiltration of cornified epithelium
  7. 7. Continued…• Breast - it causes proliferation of acini in the mammarygland. Acting along with estrogen which prepares the breastfor lactation• CNS - may have sedative effect• Body temperature -causes slight (0.5 C) rise in bodytemperature.• Respiration -may stimulate respiration at high doses• Metabolism -prolonged use of OCP impairs glucosetolerance. They also tend to raise LDL and lower HDL(ie.19-nortestoserone derivatives)• Pitutary -progesterone is a weak inhibitor of Gonadotrophinsecretion
  8. 8. Mechanism of actionThe progesterone receptors (PR) has limiteddistribution in the body confined mainly to thefemale genital tract, breast, CNS and pitutary.Upon hormone binding PR undergoesdimerization, attaches to progesterone responseelement (PRE) of target genes and regulatetranscription through coactivators.
  9. 9. AR = Androgen receptor; ER = Estrogen receptor;GR = Glucocorticoid receptor; MR = Mineralocorticoid receptor;PR = Progesterone receptor.
  10. 10. Pharmacokinetics Progesterone is orally inactive because of high first passmetabolism in liver. Hence mostly given by i.m in oilysolution. I.m doses are rapidly cleared from plasma with ashort t1/2 (5-7 mins) and nearly completely degraded in liver(major product pregnananediol excreted in urine asglucuronide and sulphate conjugates). However the effectsof progesterone lasts longer Micronized formulation has been developed for oraladministration which contains micro fine particles ofprogesterone suspended in oil and dispensed in gelatincapsules. Its absorption occurs through lymphatics Most synthetic progestins are orally active, metabolizedslowly, and have plasma t1/2 btw 8-24hrs
  11. 11. Adverse effects Breast engorgement, head ache, rise in bodytemp, edema, esophageal reflex, acne and mood swingsmay occur with higher doses Irregular bleeding (amenorrhoea) may occur if givencontinuously 19-nortestosterone derivatives lower plasma HDL level thereby may promote atherogenesis ( not seen in progesteroneand its derivatives) Long term use in HRT may increase risk of breast cancer Blood sugar may rise and diabetes may be percipitated bylong term use (levonorgestrel) Intramuscular injections of progesterone are painful If given in early pergnancy they can cause masculinization offemale foetus or other congenital abnormalities
  12. 12. UsesI. As contraceptive- postcoital contraceptive (mifepristone-600mg within 72hrs), once a month contraceptive(mifepristone- 200mg 2 days after mid cycle)II. Hormone replacement therapy (HRT)-used in non-hysterectomised post menopausal women estrogen therapy issupplemented with a progestin for 10-12 days each month toreduce the risk of endometrial carcinomaIII. DUB ( dysfunctional uterine bleeding)- progestin in large dose(norethindrone 20-40mg/day) promptly stops the bleeding andkeeps it abeyance as long as thearpy is given . Cyclic treatmentregularizes and normalizes menstrual flow.IV. Threatened habitual abortion- a pure progestin withoutestrogenic or androgenic activity may show efficacy inpreventing premature delivery in high risk pregnancy
  13. 13. V. Endometriosis- mainly manifests as dysmenorrhea, painfulpelvic swellings and infertility. Progestins induce anovulatoryhypoestogenic state by suppressing Gn release . Direct actionon endometrium prevents bleeding from the ectopic sites bysuppressing menstruation. Treatment is usually given for afew months which causes atrophy and regression of theectopic mass and the therapy is usually withdrawn within 6mthsVI. Premenstrual syndrome- manifested asheadache,irritability,fluid retention, distension and breasttenderness a few days preceding menstruation . Fluoxetineand other SSRIs (selective serotonin reuptake inhibitors) canbe given symptomatically. if sever PMS then suppression ofovulation by combined estrogen progesterone treatmentgiven cyclicallyVII. Endometrial carcinoma – progestins are palliative in about50 % cases of advanced or metastatic endometrial carcinoma
  14. 14. Preparations and Dose1. Progesterone : 10-100 mg i.m OD;PROGEST, PROLUTON, GESTONE, NATUROGEST, OGEST.2. Hydroxyprogestrone caproate : 250-500 mg i.m at 2-14 Daysintervals; PROLUTON DEPOT, MAINTANE INJ, PROCAPRIN.3. Medroxyprogesterone Acetate : 5-20 mg OD-BD oral, 50-150mg i.m at 1-3 months interval;FARLUTAL, PROVERA, MEPRATE, MODUS, DEPOT-PROVERA.4. Dydrogesterone : 5-10 mg OD/TDS oral; DUPHASTON.5. Norethindrone : 5-10 mg OD-BD oral; PRIMOLUT-N, STYPTIN, REGESTRONE, NORGEST, REGESTRONEHRT, NORETA HRT, NORISTERAT.6. Lynestrenol (Ethinylestrenol) : 5-10 mg OD oral; ORGAMETRIL.7. Allylestrenol : 10-40 mg/day;GESTANIN, FETUGARD, MAINTANE, PROFAR.8. Levonorgestrel : 0.1-0.5 mg/day; DUOLUTON-L, OVRAL.9. Desogestrel: 150 micro g + Ethinylestrenol 30 micro gNOVELON 1 Tab OD 3 week on 1 week off cyclic therapy.
  16. 16. Progestin-only hormone implant (Implanon)The progestin-only hormone implant releases hormonesthat prevent pregnancy for 3 years. It must be inserted andremoved by a trained health professional. The actualimplant is about the size of a matchstick and is insertedunder the skin on the inside of the upper arm
  17. 17. ANTIPROGESTINProgestational antagonistsWhat would happen if during pregnancy we introduce aprogesterone antagonist?The antagonist will bind the receptor with high affinity.It will exclude progesterone from the binding site andhence eliminate its agonist activity.Thus pregnancy which is dependent on the progesteroneactivity will no longer be able to sustain. The fetus willhence be aborted.This is the function of MifepristoneMifepristone is a progesterone antagonist.
  18. 18. MifepristoneIt is a 19-nonsteroid with potent competitive anti-progestational, anti-glucocorticoid and anti-androgenic activity.Mifeprestone is a partial agonist and competitive antagonist ofboth A and B forms of PR. In absence of progesterone it exertsweak progestational activity.
  19. 19. Mifepristone is administered during:Follicular phase : its anti progestin action causes attenuationof mid-cycle gonadotrophin surge from pituitary there byslowing follicular development and delay or failure of ovulation.Luteal phase : it prevents secretory changes caused byprogesterone .Later in the cycle : blocks progesterone support to theendometrium , unrestraint PG release from it there bystimulating uterine contraction. It also sensitizes myometrium toPG’s inducing menstruation.Implantation phase : blocks decidualization causing thedislodgement of conceptus , fall in HCG production andsecondary luteolysis .
  20. 20. Pharmacokinetics Mifeprestone is orally active with a bioavailability of25 %. Mainly metabolized in the liver and excreted in bile . It has a t ½ of 20-36hrs . It interacts with CYP3A4 inhibitors (erythromycin, ketoconazole ) and inducer of(rifampin and anti-convulsants)
  21. 21. Uses1. Termination of pregnancy : upto seven weeks- 600mg oral causescomplete abortion in 60-85% cases . To improve success rate asingle 400mg oral dose of misoprostol can be given 48hrs later. Inplace of misoprostol 1mg gemeprostpessary can be inserted intra-vaginally.{side effects :prolonged bleeding ,failedabortion, anorexia, nausea, tiredness, abdominaldiscomfort, uterine cramps etc }2. Cervical ripening: 600mg administered 24-30 hrs beforeattempting surgical abortion or induction of labour3. Post-coital contraceptive : 600mg within 72 hrs of intercourseprevents implantation4. Once a month contraceptive: 200mg administered 2days aftermid cycle each month prevents conception5. Induction of labour : action by blocking the relaxant effect ofprogestrone on uterus of late pregnancy it induces labour in casesof intra uterine fetal death and abnormal fetus6. Cushing’s syndrome : pallative effect due to its glucocorticoidreceptor blocking property
  22. 22. MTP Kit COMPOSITIONEach pack contains 5 tablets -1 tablet of Mifepristone…200 mg4 tablets of Misoprostol, each containingMisoprostol…200 mcg