The use of progesterone antagonists and progesterone receptor modulators in contraception

Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delayin g the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2-10 mg , blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy is not yet known. Nevertheless, there is evidence that daily doses of 2 or 5 mg of mifepristone have contraceptive potential. Because of anovulation, there m ay be an unopposed estrogen effect on the endometrium, although this risk m ay be mitigated by the noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs. Low doses of PAs and PRMs, which do not affect ovulatio n, retard endometrial maturation, indicating that the endometrium is exquis itely sensitive to these compounds. This raises the prospect of endometrial contraception, i.e. prevention of endometrial maturation without disturbin g ovulation or producing alterations in bleeding patterns. This approach wo rks well in monkeys but was not found to be very promising when given to wo men not using contraception. On the other hand, 200 mg mifepristone adminis tered 48 h after the LH surge, which has minimal or no effect on ovulation and bleeding patterns, is an effective contraceptive; yet, it is not a prac tical approach to contraception. Late luteal phase administration of mifepr istone produces menstrual bleeding. However, when mifepristone was administ ered every month at the end of the cycle either alone or together with pros taglandins, it was not very effective in preventing pregnancy. In contrast, a mifepristone-prostaglandin combination has been shown to be a very effec tive treatment for occasional menstrual regulation, with vaginal bleeding i nduced in 98% of pregnant women, with menses delay of 11 days or less. Mife pristone is an excellent agent for emergency contraception when used within 120 h of unprotected intercourse. It is also possible that PAs and PRMs ma y be used to reduce the occurrence of bleeding irregularities induced by pr ogestin-only contraceptive methods. Both classes of progesterone receptor l igands may also have contraceptive efficacy by having a pharmacological eff ect on the embryo or altering tubal transport or other aspects of tubal phy siology. (C) 2000 Published by Elsevier Science Inc.