which is not easy to achieve. Late luteal phase administration will suppress the corpus luteum and cause bleeding, but it appears to require prostaglandins as well as the antiprogestin for high effectiveness.

There are no data on the contraceptive efficacy or safety of continuous long-term administration of low-dose antiprogestins. Of interest, however, are data derived from a number of studies using mifepristone to treat endometriosis, leiomyomas, meningiomas, and Cushing's syndrome. These studies suggest that long-term use of this compound would inhibit ovulation and induce consistent amenorrhea (Yen, Appendix B8; Nieman, Appendix B10). In one study reported at the IOM workshop, with perhaps the longest continuous use of mifepristone, 15 women with meningiomas (3 of whom were premenopausal and 12 postmenopausal) were treated for meningiomas with 200 mg daily for six months to five years (Grunberg et al., 1991a, b). During the study, the three premenopausal women became amenorrheic. Toxicity experienced by these women was minimal; reported side effects included fatigue, hot flashes, breast tenderness, thinning of hair, and rash. At low doses (less than 25 mg/day) used for up to six months to treat subjects with uterine leiomyomas, the antiglucocorticoid activities of the compound were not manifest (Yen, Appendix B8), even though doses as low as 5 mg/day were effective at inhibiting ovulation. These data substantiate the fact that mifepristone is more potent as an antiprogestin than as an antiglucocorticoid; however, pure antiprogestins without any associated antiglucocorticoid activity would remain preferable for contraceptive purposes.

In studies to evaluate potential contraceptive efficacy, experience with continuous low-dose mifepristone appears to be limited to only 30 days of treatment and doses of 2 to 10 mg/day of mifepristone (see Baird, Appendix B4; Ledger et al., 1992; Croxatto et al., 1993). The 2-mg/day dose consistently suppressed ovulation; a 1-mg dose did not. A possible advantage of continuous, low-dose mifepristone administration is that it appears to "spare" estrogen despite the inhibition of ovulation. Serum estrogen levels similar to those seen in late follicular phase were noted in these studies (see Baird, Appendix B4, and Croxatto et al., 1993, referenced therein), suggesting that such estrogen-affected factors as bone density, lipids, and sense of well-being should be well maintained. However, the few samples of endometrial tissue that have been obtained from women using mifepristone do not show proliferative effects, nor do they show a progestin-induced secretory effect. If changes in the endometrium caused by mifepristone are sufficient to prevent implantation, then a dose lower than the 2 mg daily required to suppress ovulation may be adequate. Endometrial changes associated with mifepristone require further study. Evaluation of possible ovarian follicular cysts, which have been reported to occur, and the recognized antiglucocorticoid effects will also require study.

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