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Progesterone in gynecology
Progesterone is a steroid hormone produced mainly by the corpus luteum. It has various physiological roles including preparing the endometrium for implantation, suppressing ovulation, and maintaining pregnancy. Progesterone exists in natural and synthetic forms, and is used diagnostically in challenge tests and therapeutically for contraception, dysfunctional uterine bleeding, endometriosis, and other conditions. It acts primarily by binding to intracellular progesterone receptors to exert its effects on target tissues.
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Progesterone in gynecology
- 1. Progesterone in gynecology Dr. M.GOKUL RESHMI, post graduate, Obg.
- 2. Introduction… • Progesterone isa C 21 steroid hormone. • produced mainly by the theca lutein cells of the corpus luteum and also in small amount from adrenal cortex. • Progesterone also known as P4 (pregn-4-ene-3,20-dione) • Progesterone is made from pregnenolone, which is in turn product of cholesterol. • The word progesterone is derived from the Latin word ‘Gestare’ meaning to ‘bear’ or ‘carry’.
- 3. Introduction… • Progesterone producessecretory changes in an estrogen primed endometrium. • It circulates throughout the body binding to receptors in the brain, the cardiovascular tissue, breast tissue and more. • The term progestagens or progestogens include endogenous, natural as well as the synthetic steroids. • Progestin: progesterone that mimics the actions of endogenous progesterone.
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- 8. Progesterone derivative Progesteronecontent i. Progesterone natural progesterone ii. Pregnane progestogens They do not alter carbohydrate metabolism • 17α hydroxy progesterone caproate • medroxyprogesterone acetate • chlormanidone acetate • cyproterone acetate iii. Norpregnane progestogens • nomegestrol acetate • Gestonorone caproate iv. stereoisomer of progesterone: retroprogesterone They do not inhibit ovulation • Dydrogesterone v. 19 norprogesterone derivatives (norpregnanes) Demegestone • Promegestone • nestorone • Trimegestone
- 9. Progesterone derivative Progesteronecontent vi. alkyl derivatives of 19 nortestosterone a. Estrone steroids They alter carbohydrate metabolism slightly metabolically, they are converted into norethisterone . b. Gonane steroids They have excellent contraceptive efficacy and cycle control. side effects are less. They are more potent than the estrone steroids • norethisterone • norethisterone acetate • norethynodrel • ethynodiol diacetate • lynestrenol • norgestrel • levonorgestrel • Desogestrel • etonogestrel (3 ketodesogestrel) • Gestodine • norgestimate • norelgestromin • Dienogest vii. spironolactone derivatives • Drospirenone viii. unsaturated 19 norsteroid • Gestrinone
- 10. Progestogens Progestational activity Androgenic activityAntiandrogenic activity Levels of SHBG ↓ Progesterone 1 _ + _ cyproterone acetate 4 _ +++ _ medroxy progesterone 4 + _ + norethosterone 4 + _ _ norgestimate 4 + _ _ Drospirenone 4 _ + _ Dienogest 4 _ + _ nomegestrol 5 _ + _
- 11. Progestogens Progestational activity Androgenic activityAntiandrogenic activity Levels of SHBG ↓ levonorgestrel 6 ++ _ ++ Desogestrel 8 + _ _ Gestodene 9 + _ + nestorone 10 _ _ _ Trimegestone 10 _ + ?
- 12. Pregnanes… • Medroxyprogesterone acetatehas a similar action as the natural compound with lesser endometrial, stromal asynchrony. It is ideal for endometrial protection. Due to prolonged axis suppression it is not ideal for withdrawal bleeding.
- 13. Pregnanes… • Dydrogesterone inducesproduction of progesterone induced blocking factor , thereby decreasing harmful Th 1 cells and increasing Th 2 cells which increase clinical pregnancy rates. Advantages : • Being a diuretic it prevents sodium retention. • No adverse effect - B.P, weight, blood clotting factors and lipoproteins. • Adrenal and renal functions are unaffected.
- 14. Pregnanes… • Cyproterone Acetate- derivative of 17OHP with potent progestational and anti-androgen activity. • Nomegestrol Acetate - strong inhibitor of gonadotropin secretion without androgenic activity.
- 15. Pregnanes… • Norethisterone levonorgestrelDesogestrel Drospirenone • Norethynodrel d-norgestrel Gestodene • Gonane Norgestimate Ist Generation IInd Generation IlIrd Generation IVnd Generation (---)pituitary gonadotrop hins & hemostatic activity effective contraceptiv es lipid friendly & potent antiovulato ry agents antiminera locorticoid effects analogu e of Spironol actone. each generation has been designed to have progressively less androgenic effect.
- 16. Micronized progesterone… • Itis a natural progesterone. • Decreasing the particle size increases absorption & bioavalability • Dose dependent increase of serum progesterone can be achieved . • To fully protect endometrium- 300mg/day in divided doses is required. • ( 100 mg – 0 – 200mg ) as sedation is a side effect.
- 17. Micronized progesterone… • Maximumabsorption after food than on an empty stomach. Short acting and needs multiple doses Lipid friendly. • Favours diuresis - useful in HRT as cardio-protective. • Suitable for treatment of LPD, DUB, HRT, premenstrual syndrome and for progesterone challenge test.
- 18. Chemistry… • Progesterone isa compound with a 21carbon atom chain derived from cholesterol. • It consists of four interconnected cyclic hydrocarbons, ketone and oxygenated functional groups, as well as two methyl branches. • It is hydrophobic.
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- 22. Source… • Progesterone isproduced in the ovaries, by the corpus luteum, the adrenal glands and during pregnancy, in the placenta. • Progesterone is also stored in adipose tissue. • During pregnancy, progesterone is produced initially from the corpus luteum and “rescued” by the HCG from the conceptus.
- 23. Source… • After the8th week, production of progesterone shifts to the placenta. An additional source of progesterone is milk products. • After consumption of milk products, the level of bioavailable progesterone goes up. • Progesterone can be produced from this diosgenin . The human body is not able to make progesterone from diosgenin, so eating wild yam or soy will not boost one’s progesterone levels.
- 24. Advantages *Disadvantages • Bypassesfirst pass metabolism, • Rapid hepatic inactivation * Androgenic ill effects. • Good oral absorption * Fluid retention . • Good haemostat * Decreases HDL. • Good contraceptive * PMS like symptoms Not able to convey many of the biological benefits of native progesterone.
- 25. DIFFERENT DRUG DELIVERYSYSTEMS … • Oral Route – OCC/ POP. • Intramuscular injections • subcutaneous DMPA • Implants • suppository contains progesterone in a wax base. • Tablets are effervescent and they dissolve in vaginal secretions. • Gel helps to coat the vaginal walls.
- 26. Pharmacokinetics… Preparations T1/2 • DMPA2-3 days • Dydrogesterone 4-5 hrs • LNG 16 hrs • Gestodene 12-18hrs • Desogestrel 12 hrs • Norethindrone 8hrs
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- 29. Levels… • Progesterone levels- Low - preovulatory phase (< 2 ng/ml) Rise - after ovulation (> 5 ng/ ml) Elevated - luteal phase.
- 30. Levels… • Progesterone levelsare relatively low in children and in postmenopausal women - declines to less than 1% of the premenopausal level. • Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
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- 32. progesterone receptor… • Theprogesterone receptor has three major forms, mainly the A, B, and C receptors. • The three isoforms are expressed by a single gene on chromosome 11 at q22–23
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- 35. Physiological mechanisms... • Progesterone- primary action through the intracellular progesterone receptor, although a distinct, membrane bound progesterone receptor has also been postulated.
- 36. The mechanism includes… (1)steroid hormone diffusion across the cell membrane, (2) steroid hormone binding to receptor protein, (3) interaction of a hormone-receptor complex with nuclear DNA, (4) synthesis of messenger RNA (mRNA), (5) transport of the mRNA to the ribosomes, and finally, (6) protein synthesis in the cytoplasm that results in specific cellular activity. In addition, progesterone is a highly potent antagonist of the mineralocorticoid receptor (MR). It reduces the sodium-retaining activity of aldosterone
- 37. Effects… • It causessuppression of H-P-O axis, inhibits preovulatory surge and thereby ovulation. • Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. • Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis).
- 38. Effects… • Progesterone convertsthe endometrium to its secretory stage to prepare the uterus for implantation. • At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable to sperms.
- 39. Effects… • If nopregnancy - progesterone levels will fall, leading to menstruation. • Normal menstrual bleeding is progesterone-withdrawal bleeding. • If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.
- 40. Progesterone Metabolism… • Peripheralconversion of steroids to progesterone is not seen in the nonpregnant female. • The progesterone production rate = secretion from the adrenal + the ovaries. • The blood production rate: * preovulatory phase < 1 mg/day. *luteal phase 20–30 mg/day. • The metabolic fate of progesterone, as expressed by its many excretion products, is more complex than estrogen.
- 41. Progesterone Metabolism… • About10–20% of progesterone is excreted as pregnanediol. • Pregnanediol glucuronide is present in the urine in concentrations less than 1 mg/day until ovulation. • Postovulation pregnanediol excretion reaches a peak of 3–6 mg/day, which is maintained until 2 days prior to menses. • The assay of pregnanediol in the urine now has little clinical use.
- 42. Metabolic effects… Fat metabolism- stimulates lipoprotein lipase, promotes fat deposition and decreases HDL, increases triglycerides but has no effect on LDL. Carbohydrate metabolism - increases basal insulin levels, increases insulin response to glucose, promotes glycogen storage (liver) and promotes ketogenesis. Protein metabolism – no significant effect.
- 43. Effects of progesterone… •It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen. • Progesterone decreases synthesis of oestrogen receptors in the endometrium. • • It inhibits mitotic activity of the endometrial cells . • It induces the enzyme oestradiol dehydrogenase — which degrades oestradiol in the endometrium into estrone which is a milder estrogen .
- 44. Effects of progesterone… •Progesterone plays an important role in the signalling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes · • It competes with aldosterone at the renal tubules: decreasing sodium reabsorption. • It promotes increased adrenocortical aldosterone secretion
- 45. Effects of progesterone… •It causes alveolobular development of the breast secretory apparatus. • By acting on testosterone receptors, it decreases SHBG and is responsible for acne and hirsutism . • It stimulates osteoblastic mediated bone formation.
- 46. Effects of progesterone… •Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually dimorphic proportions of these organs.
- 47. Functions of progesterone… •Progesterone acts primarily as an antagonist to estrogen. • It brings about the changes in endometrium, enabling the implantation of a fertilized ovum. • It serves to promote survival and development of embryo and fetus. • It prevents contractions of the uterus and helps in maintaining pregnancy.
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- 49. Diagnostic… • Progesterone challengetest: • To investigation of pathological amenorrhea, this test is employed. • withdrawal bleeding occurs if • (i) intact hypothalamopituitary ovarian axis, • (ii) there is adequate endogenous estrogen (>40 pg/ml), • (iii) the endometrium is responsive • (iv) the uterovaginal canal is patent. The individual is likely to respond to ovulation induction drugs .
- 50. Diagnostic… • Dose: • Medroxyprogesteroneacetate 10 mg daily for 5 days is given orally.
- 51. Therapeutic… • Contraception • DysfunctionalUterine Bleeding (DUB) • Endometriosis • Dysmenorrhea • Luteal phase defect (LPD) • endometrial hyperplasia and endometrial carcinoma • Premenstrual syndrome • Luteal support • Postponement of menstruation • Hormone replacement therapy (HRT) • Idiopathic hirsutism.
- 52. Contraception… Combined Estrogen -ProgesteroneContraceptive: • Recent OCPs contains low dose estrogen and new progestins. • Because of less androgenicity, they do not cause weight gain, acne and hirsutism. • New progestins do not impair carbohydrates tolerence. • They also have a favourable lipoprotein profile & thus protects against cardiovascular diseases.
- 53. Contraception… Combined Estrogen -ProgesteroneContraceptive: • But a WHO collaborative study has shown 2.6 times greater risk of venous thromboembolism with OCPs containing desogestrel and gestodene than the OCPs containing levonorgestrel. • This inference may be due to some confounding factors like prescribing new progestins to smokers, new users, carriers of factor V Leiden mutation, women with family history of thrombosis.
- 54. Contraception… • Progesterone OnlyContraceptives: • They are preferably used in lactating women, women over age 40, diabetics, hypertensive women and women with history of thromboembolism. • Levonorgestrel 75 µg, norethisterone 350 µg, desogestrel 75 µg, lynestrenol 500 µg or norgestrel 30 µg, to be taken daily from the first day of the cycle.
- 55. Contraception… • Mechanism ofaction: • It works mainly by making cervical mucus thick and viscous, thereby prevents sperm penetration. • Endometrium becomes atrophic, so blastocyst implantation is also hindered. • In about 2 percent of cases ovulation is inhibited and 50 percent women ovulate normally.
- 56. Contraception… Advantages: • safe inlactation and so often called “Lactation Pill” . • Safe in hypertension, fibroid, diabetes, epilepsy, smoking and history of thromboembolism • Reduces the risk of PID and endometrial cancer.
- 57. Contraception… Disadvantages: • Acne, mastalgia,headache, breakthrough bleeding, or at times amenorrhea in about 20–30 percent cases. • Simple cysts of the ovary. • Failure rate - 0.5–2 per 100 women years of use. • Contraindications: Pregnancy, unexplained vaginal bleeding , recent breast , thromboembolic disease.
- 58. Contraception… Depo-subQ Provera 104a new low dose depot medroxyprogesterone acetate (DMPA) is being administered subcutaneously. • Subcutaneous DMPA showed complete ovulation inhibition for 13 weeks along with decrease in anemia, PID, ectopic pregnancy and endometrial cancer. • It also benefits patient of sickle cell disease by inhibiting sickling and increasing hemoglobin level.
- 59. Contraception… Progesterone containing IUCDs: • Mirena, levonorgestral releasing intrauterine system (LNG-IUS) contains 52 mg LNG releasing 20µg /day for 5 years. • Fibroplant, a new shorter device releasing 14µg LNG per day is being developed for the treatment of endometrial hyperplasia and menorrhagia in the peri-and post menopausal women.
- 60. Contraception… Emergency Contraception: • Levonorgestrelalone in 2 doses of 0.75 mg 12 hours apart is better than the combined estrogen-progesterone pills. • Single dose of 1.5 mg levonorgestrel is also equally effective
- 61. Contraception… drug dose Pregnancyrate (%) Levonorgestrel 0.75 mg stat and after 12 hours 0-1 ethinyl estradiol 50 µg + norgestrel 0.25 mg 2 tab stat and 2 after 12 hours 0-2
- 62. Contraception… Post partum Contraception: •POPs can be a good choice after 3 weeks postpartum. • LNG-IUS is an equally effective alternative. It can be used even during cesarean section.
- 63. Abnormal Uterine Bleeding(AUB) • Progesterone are more effective in anovulatory AUB. • Progesterone therapy is ideal in puberty, adolescent and women approaching menopause.
- 64. Dysfunctional Uterine Bleeding(DUB) • The common preparations used are norethisterone acetate and medroxyprogesterone acetate. Mechanism of antiestrogenic action of progestins : • It stimulates - 17-β-hydroxy steroid dehydrogenase - converts estradiol to estrone. • Inhibits induction of estrogen receptor. • It has antimitotic effect on the endometrium. • Anovular DUB - Isolated progestins ; ovular DUB - combined oral pills/ Dydrogesteron 1 tab 10 mg OD/BD .15th -25th day course .
- 65. Dysfunctional Uterine Bleeding(DUB) MOA: * It reduces vascularity & enhances fibrinolysis. *It provides local stromal support. *It prevents glandular growth by antagonising estrogen action. *It increases thromboxane A2 leading to platelet aggregation. *It prevents endogenous ovarian steroid production
- 66. Uterine fibroid… • LNG-IUSreduces menstrual blood loss and dysmenorrhea upto 50% in patients of uterine fibroids. • There is decrease in uterine volume but hemoglobin and serum iron level rises. • Estrogen Progesterone combination when added with GnRH agonists for long term use in fibroid, there is no reduction in the bone mass density.
- 67. Endometriosis… • Progesterone inducesa hyperprogestogenic hypoestrogenic state causing decidualization of endometrium. • Progestins are first choice for treatment of endometriosis because comparable effectiveness as danazol or GnRH analogue. • LNG-IUS has beneficial - by reducing pain, better suppression than the GnRH agonists with fewer side effects and providing ongoing contraception.
- 68. Endometriosis… MOA: • Progestins reducethe frequency and increase the amplitude of pulsatile GnRH release, resulting in a reduction in FSH and LH secretion. • Their continuous application leads to a suppression of ovarian steroidogenesis with anovulation and low serum levels of ovarian steroids.
- 69. Endometriosis… • The hypoestrogenicand hypergestagenic status causes decidual transformation of the eutopic endometrium. • secretory changes in ectopic lesions were followed by decidual transformation and atrophy. • As continuous progestin therapy results in low serum estradiol levels, breakthrough bleeding is a common occurrence.
- 70. Endometriosis… Endometriosis Associated Pain: • In a prospective, randomized trial with MPA, there was a 50% regression rate of ectopic implants and 13% partial regression with scar formation. • Pain reduction with MPA was as effective as danazol.
- 71. Endometriosis… • In deep-infiltratingrectovaginal endometriosis, the guidelines recommend complete excision, but it is also possible to treat with progestins symptomatically. • In a prospective randomized controlled trial using norethisterone acetate (NETA) versus a combination of estrogen and cyproterone acetate (CPA) - dyschezia, pelvic pain, deep dyspareunia and dysmenorrhea were reduced significantly with both treatment regimens. CPA monotherapy for 6 months versus OCs improved quality of life and psychiatric profile significantly in treated women.
- 72. Endometriosis… • In conclusion,different progestins have different effects on the different types of endometriotic foci. Pain relief using adequate dosages of progestins is identical with the medication of danazol or GnRH analogues. Infertility: • Pregnancy rates following MPA, lynestrenol or norethisterone acetate regimens vary from 5 to 90% depending on the stage of endometriosis and whether they were surgically corrected or not.
- 73. Endometriosis… • Dydrogesterone doesnot inhibit ovulation it can be used for symptomatic treatment of pain and for reduction of bleeding problems. • Long-term follow-up shows recurrence rates above 50% in general.
- 74. PREMENSTRUAL SYNDROME… • Alogical treatment for severe PMS, is to suppress ovulation and the ensuring cyclical endocrine/ biochemical changes that cause the distressing symptoms. • Progesterone - natural antidepressant, restoring libido, normalizing blood sugar, facilitating thyroid hormone, serving as a natural diuretic, restoring proper cell oxygen levels, protecting against fibrocystic breasts, helping use fat as fuel and normalizing zinc and copper levels.
- 75. PREMENSTRUAL SYNDROME… • Assuranceand life style and diet modifications . • Combined oral and contraceptive pills – esp. those containing anti- mineralcorticoid and anti-androgenic progestogen, drospirenone has been effective. • Cyclical progesterones- from 5th day of the cycle for 20 days - A recent meta analysis showed no significant benefit for the treatment of severe pms with progestogens and progesterone.
- 76. PREMENSTRUAL SYNDROME… • Depomedroxyprogesteroneacetate (DepoProvera), etonorgestrel rod (Implanon) and anovulation suppression ‘progestogen-only pill’ (Cerazette) - all have ovulation suppressant activity. • cyclical symptoms are often replaced with continuous low-grade symptoms due to the PMS like side effects of synthetic progestogens . • Levonorgestrel intrauterine system - progestogenic PMS like physical and psychological side effects is less.
- 77. Dysmenorrhea… • Extended regimens(84 days) are effective in treating dysmenorrhea by decreasing frequency of mensus. • Vaginal ring, Implant and LNG-IUS have demonstrated reduction in dysmenorrhic symptoms.
- 78. Acne and Hirsutism… •Oral contraceptive pills containing third generation progesterone or drospirenone show improvement in acne and hirsutism. • 50-100mg Cyproterone acetate is added to first 10 days of cycle with COCs (reverse sequential regimen) in case of severe hirsutism and acne.
- 79. Endometrial hyperplasia andendometrial carcinoma … • The medical therapy depends upon the number of estrogen and progesterone receptors. • Due to the local action on endometrium LNG-IUS is very effective in endometrial hyperplasia and menorrhagia. • The results are comparable with surgery or endometrial ablation Well differentiated grade I endometrial carcinoma are suitable for progesterone therapy.
- 80. Role of progestinsin breast cancer… • Proliferative changes in breast cancer cells are due to ovarian hormones, as one third of the patients show some response to estrogen therapy, but some are unresponsive. • So the progesterone molecule seems to be implicated in breast carcinoma.
- 81. Role of progestinsin breast cancer… • Researches are going on to determine progesterone metabolism in breast tissue and cell lines to establish whether progesterone metabolizing enzymes can alter the drugs to pro or anti-cancer moieties. • A specific cell membrane protein PGRMC-1 is found to block cell death in breast cell which is affected by progestins used in HRT.
- 82. Hormone Replacement Therapy(HRT) … • Progesterone can be given cyclically or in the form of continuous combined regimen. • If the last menstrual period has occurred less than one year prior to starting HRT, a sequential combined regimen should be started, i.e. continuous estrogen with progestogen (12– 14 days per month).This regime will allow monthly withdrawal bleed. • In women who wish to avoid a monthly withdrawal bleed and has taken a minimum of one year of HRT, or is starting HRT one year after the last menstrual period should switch to a continuous combined regimen which will allow a bleed free HRT this will also minimise the risk of endometrial hyperplasia.
- 83. Hormone Replacement Therapy(HRT) … • progesterone along with estrogen may be indicated even in hystrectomized women if: (i) Women with past history of endometriosis – because adenocarcinoma has been reported in patients with pelvic endometriosis being treated with unopposed estrogen. (ii) Supra cervical hysterectomy (iii) Endometriod tumours of the ovary. (iv) Adenocarcinoma of the endometrium
- 84. Hormone Replacement Therapy(HRT) … • Micronized progesterone and dydrogesterone generally have fewer side effects due to progesterone receptor specificity. Benefits of Progesterone in HRT : • Vasomotor Symptoms • Quality of life • Osteoporosis
- 85. Hormone Replacement Therapy(HRT) … Risks: • Breast cancer • Ovarian Cancer • Stroke Dose and route of administration: • Typically the lowest effective doses is used - 1.5 mg medroxyprogesterone acetate, 0.1 mg norethindrone acetate, 0.5 mg drospirenone, or 100 mg micronized progesterone.
- 86. Hormone Replacement Therapy(HRT) … • Oral progestogens, combined with systemic estrogen, and combined progestogen-estrogen matrix patches have demonstrated endometrial protection. • The transdermal estrogen and progesterone combination : norethidrone acetate in a daily dose of 0.140 or 0.250mg or LNG in daily dose of 0.007, 0.015 or 0.030 and 0.04mg/daily and in sequential regimenorethidrone acetate 0.250 mg or LNG 0.010mg.
- 87. • Progesterone canbe administered in a vaginal gel which allows the delivery of a very low dose that can effectively protect the endometrium with low systemic levels because of bypass effect on the uterus. • The administration of 90mg every 2 days produces secretary changes in the endometrium. • An application of the 4% commercial preparation twice weekly protects the endoemetrium and is associated with amenorrhoea in most patients.
- 88. Progesterone IUCD (MIRENA): • It protects the endometrium against hyperplasia and cancer. • There is irregular break through bleeding in the first six months and after one year approximately 60-70% of the women are amenorrheic.
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