Progestins

PROGESTINS

These are substances which convert the estrogen primed endometrium to secretory and maintain pregnancy in animals spayed after conception (Progestin = favouring pregnancy).

At the turn of the last century it became apparent that ovaries secrete two hormones, and that corpus luteum was essential for maintenance of pregnancy. Progesterone was isolated in 1929, but its full therapeutic potential has been exploited only after the 1950s when a large number of orally active synthetic progestins were developed.

Natural Progestin

Progesterone, a 21 carbon steroid, is the natural progestin and is derived from cholesterol. It is secreted by the corpus luteum (10–20 mg/day) in the later half of menstrual cycle under the influence of LH. Its production declines a few days before the next menstrual flow. If the ovum gets fertilized and implants—the blastocyst immediately starts producing chorionic gonadotropin which is absorbed and sustains the corpus luteum in early pregnancy. Placenta starts secreting lots of estrogens and progesterone from 2nd trimester till term. Men produce 1–5 mg progesterone per day from adrenals and testes— its role if any, in males is not known.

Synthetic Progestins

A number of synthetic progestins with high oral activity have been produced. These are either progesterone derivatives (21 C) or 19nortestosterone derivatives (18 C).

The progesterone derivatives are almost pure progestins, have weaker anti-ovulatory action and are used primarily as adjuvants to estrogens for HRT in postmenopausal women, threatened abortion, endometriosis, etc. for selective progestational effect. The older 19nortestosterone derivatives developed in the 195060s have additional weak estrogenic, weak androgenic, anabolic and potent anti-ovulatory action: are used primarily in combined contraceptive pills. Norgestrel has a 13ethyl substitution (termed gonane)—is more potent (especially its levo isomer levonorgestrel).

In the 1980-90s a number of other gonane 19nortestosterone compounds were introduced, of which desogestrel has been marketed in India. Desogestrel and norgestimate are prodrugs. In addition to being very potent progestins they have strong anti-ovulatory action (gestodene inhibits ovulation at as low as 40 μg/day dose), and little or no androgenic property. Therefore, they do not antagonise the beneficial action of estrogens on lipid profile and are preferable in women with hyperandrogenemia. High anti-ovulatory potency allows reduction of ethinylestradiol dose when these are combined in oral contraceptives.

The newer 19norprogesterone derivative nomegestrol has antiandrogenic property, is less anti-ovulatory, but has strong effect on endometrium.

Actions

The main function of progesterone is preparation of the uterus for nidation and maintenance of pregnancy. The latter is due to prevention of endometrial shedding, decreased uterine motility and inhibition of immunological rejection of the foetus: progesterone depresses Tcell function and cellmediated immunity (CMI).

1. Uterus

Progesterone brings about secretory changes in the estrogen primed endometrium: hyperemia, tortuocity of glands and increased secretion occurs while epithelial proliferation is suppressed. It is lack of progestational support which causes mucosal shedding during menstruation.

Continued action of progesterone (as when pregnancy occurs) brings about decidual changes in endometrium—stroma enlarges and becomes spongy, glands atrophy. It also decreases sensitivity of myometrium to oxytocin.

2. Cervix

Progesterone converts the watery cervical secretion induced by estrogens to viscid, scanty and cellular secretion which is hostile to sperm penetration.

3. Vagina

Progesterone induces pregnancy like changes in the vaginal mucosa—leukocyte infiltration of cornified epithelium.

4. Breast

Progesterone causes proliferation of acini in the mammary glands. Cyclic epithelial proliferation occurs during luteal phase, but continuous exposure to progesterone during pregnancy halts mitotic activity and stabilizes mammary cells. Acting in concert with estrogens, it prepares breast for lactation. Withdrawal of these hormones after delivery causes release of prolactin from pituitary and milk secretion starts.

5. CNS

High circulating concentration of progesterone (during pregnancy) appears to have a sedative effect.

6. Body Temperature

It causes a slight (0.5oC) rise in body temperature by resetting the hypothalamic thermostat and increasing heat production. This is responsible for the higher body temperature seen during the luteal phase.

7. Respiration

Progestins in relatively higher doses stimulate respiration, as occurs during pregnancy.

8. Metabolism

Prolonged use of oral contraceptives impairs glucose tolerance in some women. This has been ascribed to the progestational component. Progestins, especially those with androgenic activity (19nortestosterone derivatives) tend to raise LDL and lower HDL levels. This may reduce the beneficial effect of estrogen used concurrently in HRT or in contraceptives. Micronized oral progesterone formulation (referred to as ‘natural progesterone’ introduced recently has been shown not to counteract the beneficial effect of estrogen on LDL and HDL.

9. Pituitary

Progesterone is a weak inhibitor of Gn secretion from pituitary. It decreases the frequency of LH pulses by action on hypothalamic pulse generator but increases the amount of LH secreted per pulse. Administration of progestin during follicular phase suppresses the preovulatory LH surge and prevents ovulation; synergises with estrogen for this action. The gonane 19nortestosterone derivatives are potent anti-ovulatory drugs.

Mechanism Of Action

Unlike other steroid receptors, the progesterone receptor (PR) has a limited distribution in the body: confined mostly to the female genital tract, breast, CNS and pituitary. The PR is normally present in the nucleus of target cells. Analogous to ER, upon binding the hormone PR undergoes dimerization, attaches to progesterone response element (PRE) of target genes and regulates transcription through coactivators. The anti-progestins also bind to PR, but the conformation assumed is different from agonist bound receptor and opposite effects are produced by interaction with corepressors.

The PR exists in a short (PRA) and a longer (PRB) isoforms. The two have differing activities, but because the ligand binding domain of both is identical, all agonists and antagonists display similar binding properties for them. Tissue selective modulation of PR has not yet been possible, as has been in the case of ER. Progesterone also acts on cell membrane receptors in certain tissues and produces rapid effects, but they are probably not important physiologically.

Estrogens have been shown to increase PR density, whereas progesterone represses ER and enhances local degradation of estradiol.

Pharmacokinetics

Progesterone, unless specially formulated, is inactive orally because of high first-pass metabolism in liver. It is mostly injected i.m. in oily solution. Even after an i.m. dose it is rapidly cleared from plasma, has a short t½ (5–7 min). It is nearly completely degraded in the liver—major product is pregnanediol which is excreted in urine as glucuronide and sulfate conjugates. However, effects of progesterone last longer than the hormone itself.

A micronized formulation of progesterone has been developed for oral administration. Microfine particles of the drug are suspended in oil and dispensed in gelatin capsules. Absorption occurs through lymphatics. Though bioavailability is low, effective concentrations are attained in the body.

Most of the synthetic progestins are orally active and are metabolized slowly; have plasma t½ ranging from 8–24 hours.

Preparations And Dose

1. Progesterone: 10–100 mg i.m. (as oily solution) OD; PROGEST, PROLUTON, GESTONE 50 mg/ml inj., 1 and 2 ml amp; 100–400 mg OD oral: NATUROGEST, OGEST 100, 200, 400 mg caps containing micronized oily suspension.

2. Hydroxyprogesterone caproate: 250–500 mg i.m. at 2–14 days intervals; PROLUTON DEPOT, MAINTANE INJ, PROCAPRIN 250 mg/ml in 1 and 2 ml amp.

3. Medroxyprogesterone acetate: 5–20 mg OD–BD oral, 50–150 mg i.m. at 1–3 month interval; FARLUTAL 2.5, 5, 10 mg tab., PROVERA, MEPRATE, MODUS 2.5, 10 mg tab, DEPOTPROVERA 150 mg in 1 ml inj. (as contraceptive). Has weak androgenic and antiestrogenic property.

4. Dydrogesterone: 5–10 mg OD/TDS oral; DUPHASTON 5 mg tab. It has poor anti-ovulatory action: may be preferred when contraceptive effect is not required.

5. Norethindrone (Norethisterone): 5–10 mg OD–BD oral; PRIMOLUTN, STYPTIN, REGESTRONE, NORGEST 5 mg tab; REGESTRONE HRT, NORETA HRT 1 mg tab (for HRT); NORISTERAT 200 mg/ml inj (as enanthate) for contraception 1 ml i.m every 2 months; has androgenic, anabolic and antiestrogenic activity.

6. Lynestrenol (Ethinylestrenol): 5–10 mg OD oral; ORGAMETRIL 5 mg tab. Has additional androgenic, anabolic and estrogenic activity.

7. Allylestrenol: 10–40 mg/day; GESTANIN, FETUGARD, MAINTANE 5 mg tab. Has been especially used for threatened/habitual abortion, PROFAR 25 mg tab.

8. Levonorgestrel: 0.1–0.5 mg/day; DUOLUTONL, OVRAL 0.25 mg+ ethinylestradiol 0.05 mg tab. Has androgenic, anabolic and antiestrogenic property.

9. Desogestrel 150 μg + ethinylestradiol 30 μg (NOVELON) tab, 1 tab OD 3 week on 1 week off cyclic therapy. (Other preparations are given with oral contraceptives).

Adverse Effects

Ø Breast engorgement, headache, rise in body temperature, edema, esophageal reflux, acne and mood swings may occur with higher doses.

Ø Irregular bleeding or amenorrhoea can occur if a progestin is given continuously.

ØThe 19nortestosterone derivatives lower plasma HDL levels—may promote atherogenesis, but progesterone and its derivatives have no such effect.

Ø Long-term use of progestin in HRT may increase the risk of breast cancer.

Ø Blood sugar may rise and diabetes may be precipitated by long-term use of potent agents like levonorgestrel.

Ø Intramuscular injection of progesterone is painful.

Ø Given in early pregnancy, progestins can cause masculinization of female foetus and other congenital abnormalities.

Their use for diagnosis of pregnancy is now contraindicated.

Uses

a. As contraceptive Most common use (see later).

b. Hormone replacement therapy (HRT) In nonhysterectomised postmenopausal women estrogen therapy is supplemented with a progestin for 10–12 days each month to counteract the risk of inducing endometrial carcinoma. A progesterone derivative lacking androgenic activity is preferred.

c. Dysfunctional uterine bleeding It is often associated with anovular cycles. Continued estrogenic action on endometrium (causing hyperplasia) without progesterone induction and withdrawal resulting in incomplete sloughing leads to irregular, often profuse bleeding. A progestin in relatively large doses (norethindrone 20–40 mg/ day or equivalent) promptly stops bleeding and keeps it in abeyance as long as given. Subsequently cyclic treatment regularizes and normalizes menstrual flow. A progestin with inherent estrogenic action is preferred; often supplemental dose of estrogen is combined.

d. Endometriosis It is due to the presence of ectopic endometrium; manifestations are dysmenorrhoea, painful pelvic swellings and infertility. Continued administration of progestins induces an anovulatory, hypoestrogenic state by suppressing Gn release. The direct action on endometrium prevents bleeding in the ectopic sites by suppressing menstruation. Treatment for a few months causes atrophy and regression of the ectopic masses; therapy can be withdrawn in many cases after 6 months without reactivation. Fertility returns in a good percentage. Progestin treatment of endometriosis is cheap and generally well tolerated, but not all cases respond and recurrences are frequent. Danazol is an effective alternative. Other drugs used are GnRH agonists and antiprogestins.

e. Premenstrual syndrome/tension Some women develop headache, irritability, fluid retention, distention and breast tenderness a few days preceding menstruation. When depression predominates, it has been labelled ‘premenstrual dysphoric disorder’. Fluoxetine and other SSRIs given daily on symptom days dampen irritability and mood changes in majority of women. If severe, premenstrual syndrome requires suppression of ovulation by combined estrogen-progesterone treatment given cyclically. Relatively higher dose of progestin is generally used. Progestins are added to estrogen when it is used for severe dysmenorrhoea.

f. Threatened/habitual abortion In most such patients there is no progesterone deficiency; administration of excess hormone is of no benefit. Progestin therapy may be considered in those patients who have established deficiency. However, progestins are briskly promoted and almost routinely prescribed in India. There is some recent evidence of its efficacy in preventing premature delivery in high risk pregnancy. If such use is made—a pure progestin without estrogenic or androgenic activity should be employed.

e. Endometrial carcinoma Progestins are palliative in about 50% cases of advanced/ metastatic endometrial carcinoma. High doses are needed.