USE OF PROGESTERONE IN

OBSTETRICS &

GYNAECOLOGY

Dr Namkha DorjiResidentDepartment of Obstetrics & GynecologyBangabandhu Sheikh Mujib Medical University

Progesterone has the chemical formula C21H30O2.

A LITTLE BIT OF HISTORY• Progesterone was first isolated from hamster

ovaries by Willard Myron Allen, who co-discovered it with his anatomy professor, George Washington Corner, at the University of Rochester Medical School.

• Allen first determined its melting point, molecular weight, and partial molecular structure.

• He also gave it the name Progesterone, derived from PROGEstational STERoidal ketONE.

• An avid mathematician, Allen recognized that the molecular weight of progesterone is 100 x π = 314 dalt.

NATURAL PROGESTERONE

Progesterone (21 carbon steroid) is derived from cholesterol

It was first isolated in 1929 Males also produce 1-5mg progesterone per

day from adrenals and testes [but role in males is not known]

PROGESTERONE Secreted by: Corpus luteum Placenta: from 2nd trimester till term Adrenal cortexAdrenal Cortex: progesterone is an

intermediate product in the formation of cortisol

Adrenal cortex & ovary: Progesterone can be converted to androgens & estrogens

Metabolised rapidly by the liverExcreted: 20% in the urine as sodium

pregnanediol glucuronide

PROGESTOGEN Compound with progesterone like

action Produces progestational changes in an

estrogen primed endometrium Transform a proliferative into a

secretary endometrium to support pregnancy

NATURAL

OR

SYNTHETIC (progestin)

Progestogens can be either

Classification of Progestogens Progesterone Derivatives

Progesterone Contents

I. Progesterone Natural Progesterone

II. Pregnane progestogensThey don’t alter carbohydrate metabolism

•17 α hydroxy progesterone caproate•Medroxyprogesterone acetate•Chlormanidone acetate•Cyproterone acetate

III. Norpregnone progestoens •Normegestrol acetate•Gestonorone caproate

IV. Steroisomer of progesterone: RetroprogesteroneThey don’t inhibit ovulation

Dydrogesterone (DUPHASTON®)

V. 19 norprogesterone derivative(norpregnanes)

•Demegestone•Promegestone•Nestorone•Trimegestone

CONTINUATION VI. Alkyl derivatives of

19 nortestosterone A. Estrone steroids They alter carbohydrate

metabolism slightly. Metabolically, they are

converted into norethisterone

•Norethisterone•Norethisterone acetate•Norethynodrel•Ethynodiol diacetate•Lynestrenol•Norgestrol

B. Gonane steroid They have excellent contraceptive efficacy and cycle control. Side effects are less. They are more potent than estrone steroids

•Levonorgestrol•Desogestrol•Etonogestrol(3ketodesoestrol)•Gestodine•Norgestimate•Norelgestromim•Dienogest

VII. Spironolactone derivatives DrospirenoneVIII. Unsaturated 19 norsteroid Gestrinone

PHYSIOLOGICAL & PHARMACOLOGICAL ACTIONS

• Endocrine system low level(+Estrogen)>FSH surge & LH secretion. High level-> Inhibit GnRH production(Inhibit ovulation).

• Reproductive Tract decreases estrogen-driven endometrial proliferation development of a secretory endometrium abrupt decline onset of menstruation.

• Endocervical glands secretion turn to scant, viscid material.• Secondary sex organs imp for maintenance of pregnancy

suppresses menstruation and uterine contractility

• 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 pregnancyacini 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 .

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 center to CO2 and leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy.

• Progesterone may have depressant and hypnotic actions in the CNS, possibly accounting for reports of drowsiness after hormone administration.

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 HDL levels.

• 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

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.

• 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

• 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 deacetylasesincreases DNA interaction with nucleosomes and renders a target promoter inaccessible to the general transcription apparatus.

• 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 .

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

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)

INDICATIONS IN OBSTETRICS

• Threatened abortion • Recurrent abortion• Preterm Labour

INDICATIONS IN GYNAECOLOGY • Disorders of menstruation & ovulation1. Amenorrhoea2. DUB3. Spasmodic dysmenorrhoea4. PMS5. LPD• LPS in ART• HRT• Endometriosis• Contraception• Cancer & Breast condition

ROUTES OF ADMINISTRATION

• Oral • Vaginal suppositories• Deep intramuscular injections• Implant• Intrauterine system

SIDE EFFECTS OF PROGESTATIONAL AGENT

• Natural(micronized) progesterone Fatigue Somnolence • Synthetic progestins

AcneAlopecia Anxiety Hirsutism Depression Hoarse voice Myalgia Fluid retention Oedema Abdominal bloating

CONTRAINDICATION (BNF 50th edition) Liver tumours & severe liver impairment Genital or breast cancer: unless used for

treatment Severe arterial disease Undiagnosed vaginal bleeding Porphyria History during pregnancy of idiopathic jaundice,

severe pruritus, or pemhigoid gestationis Missed or incomplete abortion Hypersensitivity

CAUTIONS Condition that may worsen fluid retention

(epilepsy, hypertension, migraine, cardiac or renal dysfunction)

Susceptible to thromboembolism Liver impairment History of depression Progesterone decrease glucose tolerance &

diabetes should be monitored closely

DATA ON PROGESTERONE AND PRETERM LABOUR

Many studies have examined the use of progesterone for prevention of preterm labour. Mackenzie et al. found 735 such studies, which showed that the use of progestins in women at risk for preterm labour reduced its occurrence by 43%

Mackenzie R, Walker M, Armson, A, Hannah, ME. Progesterone for the prevention of preterm birth among women at increased risk: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol 2006;194(5):1234–42.

Meta-analyses by Dodd et al. concluded that women who received progesterone were statistically significantly less likely to give birth before 37 weeks (RR 0.58; 95% CI 0.48–0.70), to have an infant with birth weight of > 2.5 kg (RR 0.62; 95% CI 0.49–0.78), or to have an infant diagnosed with intraventricular hemorrhage (RR 0.25; 95% CI 0.08–0.82). Their analysis showed no apparent benefit to early start of the progesterone administration or in the use of higher doses. Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev 2006;1:CD004947

PRETERM LABOUR(SOGC TECHNICAL UPDATE NO. 202, JAN 2008)

Lack of available data for many neonatal outcome variables and about the lack of comparative data on dosing and route of administration.

Indication for prophylactic progesterone therapy : Previous

spontaneous preterm labour and/or short cervix (< 15 mm at 22–26 weeks’ gestation) on transvaginal ultrasound.

The therapy should be started after 20 weeks’ gestation and stopped when the risk of prematurity is low.

Following dosages: History of previous PTL: 17 alpha-hydroxyprogesterone 250 mg IM

weekly or progesterone 100 mg daily vaginally. Short cervix of <15 mm detected on transvaginal ultrasound at

22–26 weeks: progesterone 200 mg daily vaginally. Farine, Dan, et al. "The use of progesterone for prevention of preterm birth." Journal of Obstetrics and Gynaecology Canada 30.1 (2008): 67-71.

PROGESTOGEN FOR TREATING THREATENED MISCARRIAGE.

The use of progestogens is effective in the treatment of threatened miscarriage with no evidence of increased rates of pregnancy-induced hypertension or antepartum haemorrhage as harmful effects to the mother, nor increased occurrence of congenital abnormalities on the newborn.

However, the analysis was limited by the small number and the poor methodological quality of eligible studies (four studies) and the small number of the participants (421), which limit the power of the meta-analysis and hence of this conclusion.

Cochrane Database Syst Rev. 2011 Dec 7;(12):

A RANDOMIZED TRIAL OF PROGESTERONE IN WOMEN WITH RECURRENT MISCARRIAGES(PROMISE TRIAL)

This large multicenter, randomized, placebo-controlled trial showed that progesterone therapy in the first trimester of pregnancy did not result in a significant increase in the rate of live births among women with a history of unexplained recurrent miscarriages.

Coomarasamy, Arri, et al. "A randomized trial of progesterone in women with recurrent miscarriages." New England Journal of Medicine 373.22 (2015): 2141-2148.

PROGESTOGEN FOR PREVENTING MISCARRIAGE (REVIEW)

Subgroup analysis of four trials, 225 women: recurrent miscarriages (three or more consecutive miscarriages)

Progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment

Poorer methodological quality. No significant differences in the rates of preterm birth, neonatal

death, or fetal genital anomalies/virilization were found between progestogen therapy versus placebo/control

Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003511.

HORMONES & MENSTRUAL CYCLE Estrogen levels increases gradually during the follicular phase and fall just before ovulation

Estrogen levels maintained during the luteal phase and fall before the menstrual phase

Progesterone levels increase during the luteal phase and fall sharply just before the menstrual phase.

AMENORRHOEA

Primary Secondary

Priming with oestrogen is essential

Progesterone may be given alone but is usually combined with estrogen

DYSFUNCTIONAL UTERINE BLEEDING: FIRST LINE TREATMENT

Progestogens are the first-line treatment for DUB, particularly when associated with anovulation. There is no significant difference among various types of progestogens with regard to effectiveness in treating DUB. However, some believe that medroxyprogesterone is associated with less unfavourable effects on blood lipids

Anovulation results in continuous unopposed oestrogen stimulation of the endometrium. In cases of chronic anovulation disorders, particularly polycystic ovary syndrome (PCOS), the use of progestogens is helpful for treating DUB as well as preventing the development of endometrial hyperplasia and serious complications such as endometrial carcinoma

May be delivered through progesterone-containing IUDs and contraceptive implants.

SECOND LINE THERAPY• Combined oestrogen & progestogen: when progestogen alone is not

associated with an adequate response• Formulations: monophasic pill or triphasic pill• Combined oestrogen and progestogen is effective in restoring menstrual

bleeding (withdrawal bleeding) in most cases of DUB whether anovulatory or ovulatory. Sometimes higher doses are needed initially, for example, 2 or 3 pills every day during the first few days until bleeding stops.

• In addition to cycle regulation, this approach has the advantage of also offering effective contraception

• Continuous administration of the COCP is licensed for up to 3 consecutive months with withdrawal bleeding at the end of the 3 months of treatment. This approach is particularly beneficial in those with DUB-associated anaemia.

PRMARY DYSMENORRHEA • First line: Most patients with primary dysmenorrhea show

subjective improvement with NSAID treatment(64 to 100%).

• Second line: OCP provides another effective and well-studied choice for therapy, especially in women desiring birth control(effective in about 90%).

• Non responder (10%): laparoscopic surgery to acupuncture, although with much less evidence to support their use.

• lack of pain relief should increase suspicion of a secondary cause of dysmenorrhea.

PREMENSTRAL SYNDROME

“A condition which manifests with distressing physical, behavioural and psychological symptoms, in the absence of organic or underlying psychiatric disease, which regularly recurs during the luteal phase of each menstrual (ovarian) cycle and which disappears or significantly regresses by the end of menstruation”

POSSIBLE TREATMENT REGIMEN FOR THE MANAGEMENT OF SEVERE PMS

First Line Exercise, cognitive behavioural therapy, vitamin B6 Combined new-generation pill, such as Yasmin®, Cilest® (cyclically or continuously) Continuous or luteal phase (day 15–28) low-dose SSRIsSecond Line Estradiol patches (100 micrograms) + oral progestogen such as duphaston 10 mg D17-D28 or Mirena® Higher-dose SSRIs continuously or luteal phase

Third Line GnRH analogues + addback HRT (continuous combined estrogen + progestogen or tibolone)Fourth Line Total abdominal hysterectomy and bilateral oophorectomy + HRT (including testosterone)

RCOG Green-top Guideline No. 48drospirenone and ethinyl estradiol Yasmin®

PREMENSTRUAL SYNDOME

• Newer contraceptive pill types may represent effective treatment for PMS and should be considered as one of the first-line pharmaceutical interventions.

• Treatment with the lowest possible dose of progestogen is recommended to minimise adverse effects.

The National Association for Premenstrual Syndrome(Guidelines on Premenstrual Syndraome)

RCOG Green-top Guideline No. 48

POSTPONEMENT OR ADVANCMENT OF MENSTRUATION

Postponement Advancement COC (1 or 2 pills daily) or progestogensStart 3-6 days before the expected onset of period and continue until the crisis is over. Flow is expected 2-3 days after the treatment is suspended.

Start treatment early in the cycle to suppress ovulation. COC once daily from D5 & continue for 14 days. When suspended, flow (anovular) begin in 2 to 3 days.

• Supplementation of progesterone can be given orally, vaginally, or by the intramuscular (IM) route.

• Currently, there is no evidence that progesterone is beneficial in natural unstimulated cycles.

• Currently, the only well documented indication for supplemental vaginal or IM progesterone is for the improvement of ART outcomes in GnRH agonist or antagonist stimulation cycles.

• Intramuscular progesterone is associated with the highest serum levels, and vaginal progesterone increases endometrial tissue levels.

• It has been agreed that oral progesterone should not be used for luteal support; only 10% of micronized progesterone is absorbed intact through the gastrointestinal tract, and pregnancy rates are lower in ART cycles in which oral progesterone is administered compared with those in which vaginal or IM progesterone is used.

• Progesterone supplementation should be administered until placental progesterone production is adequate, around 8–10 weeks of gestation

Suppression of ovarian function for 6 months reduces endometriosis-associated pain.The hormonal drugs investigated (combined oral contraceptives, danazol, gestrinone,medroxyprogesterone acetate and GnRH agonists) are equally effective but their adverse effect and cost profiles differ.

Some adverse effects limit their long-term use and oftenproduce poor compliance. Symptom recurrence is common following medical treatment of endometriosis.

Evidence suggests that the LNG-IUS reduces endometriosis-associatedpain with symptom control maintained over 3 years

ENDOMETRIAL HYPERPLASIA

Hyperplasia without atypia

Revised 2014 World Health Organization classification

Hyperplasia with atypia

HYERLASIA WITHOUT ATYPIA • Risk of progressing to endometrial cancer <5% over 20 years• Majority will regress spontaneously during follow-up.• Reversible risk factors such as obesity and the use of HRT should be

identified and addressed if possible.• Observation alone with follow-up endometrial biopsies to ensure disease

regression can be considered,• Treatment with progestogens has a higher disease regression rate

compared with observation alone.• Progestogen is indicated in who fail to regress following observation

alone and in symptomatic women with abnormal uterine bleeding.

Green-top Guideline No. 67RCOG/BSGE Joint Guideline | February 2016

• Both continuous oral and local intrauterine (levonorgestrel-releasing intrauterine system [LNG-IUS]) progestogens are effective in achieving regression of endometrial hyperplasia without atypia.

• The LNG-IUS should be the first-line medical treatment • Continuous progestogens should be used

medroxyprogesterone 10–20 mg/day or norethisterone 10–15 mg/day) decline the LNG-IUS.• Cyclical progestogens should not be used• Duration: 6 months to 5 years

Green-top Guideline No. 67RCOG/BSGE Joint Guideline | February 2016

CONTRACEPTION

• POP• COCP• Injectables• Subdermal implants • LNG IUSMechanism:

1. Inhibit ovulation2. Cervical mucus hostile to spermatozoa3. Endometrium unreceptive to fertilized ovum