Antigestogens are compounds which inhibit the synthesis of progesterone or antagonise its biological action. The progesterone antagonist mifepristone (RU 486) binds with high affinity to progesterone receptors throughout the body, blocking the action of endogenous progesterone. In the last 10 years it has been demonstrated that mifepristone, in combination with a suitable prostaglandin, is a safe, effective alternative to vacuum aspiration for termination of pregnancy in the first two months. Preliminary trials suggest that antigestogens may be useful true contraceptives by inhibiting ovulation or by preventing implantation as once a month pills and postcoital agents. In late pregnancy, by sensitising the uterus to prostaglandins and by promoting cervical dilatation, they may induce labour and facilitate lactation. In non-pregnant women mifepristone may have application in the treatment of hormone-dependent conditions such as endometriosis, fibromyomata, meningioma and breast cancer. The availability of hormone antagonists to oestrogens, androgens and progesterone offers the possibility of new methods of regulating reproductive function in health and disease.
PIP: Antigestogens inhibit the synthesis of progesterone or antagonize its biological action. The action of mifepristone and its clinical application are reviewed. The progesterone antagonist mifepristone (RU-486) binds with high affinity to progesterone receptors, blocking the action of endogenous progesterone. The most plausible explanation of the mechanism is the failure of the antagonist-receptor complex to induce the necessary to unmask the DNA binding sites on the receptor molecule. In clinical application for inhibition of ovulation, 200-600 mg of RU-486 in single doses or for a few days halts follicular growth. A lower daily dose of 25 mg also suspends ovulation for 21 days, and it could provide a novel contraceptive in combination with cyclical gestogen. It was recently reported that no pregnancies occurred in 402 women who were given 600 mg RU-486 for postcoital contraception within 72 hours of unprotected intercourse, compared to 4 pregnancies in women given conventional Yuzpe regimen of 200 mcg ethinyl estradiol and 1 mg DL-norgestrel. Although RU-486 was associated with fewer minor side effects, such as nausea and vomiting, the menses were delayed by more than 3 days in 30% of women. RU-486 in combination with a suitable prostaglandin is a safe alternative to vacuum aspiration for termination of early pregnancy. Pretreatment with RU-486 offers advantages for induction of abortion by prostaglandins later in pregnancy. In women with a dead or severely handicapped fetus in the third trimester of pregnancy, RU-486 results in rapid delivery. A preliminary study reported that 18 out of 31 normal women given 200 mg RU-486 per day went into labor within 72 hours compared to only 7 of 31 controls. Preliminary studies have suggested that regression of endometriosis and fibromyomata may be induced by RU-486, as fibroids and endometrium contain high concentrations of progesterone receptors. RU-486 also inhibits the growth of a progesterone-dependent breast cancer cell line in vitro.