Inhibition of ovulation by low-dose mifepristone (RU 486).

ABSTRACT

Mifepristone (RU 486) is a potent antigestagen and antiglucocorticoid which when given at a dose of 25-600 mg disrupts folliculogenesis, inhibits ovulation and induces menses in healthy women. This study reports the effects of much lower doses of mifepristone than used previously, given for the duration of a complete menstrual cycle. Healthy female volunteers (n = 11) with regular menstrual cycles were given mifepristone at a daily dose of 5 mg (n = 6) or 2 mg (n = 5) for 30 days, beginning immediately after an ovulatory placebo cycle. Mifepristone prevented menstruation for the duration of the treatment period, with recurrence of menses 15-29 days after replacement of mifepristone with placebo. Daily mifepristone given in either 5 mg or 2 mg doses inhibited ovulation, as indicated by the lack of a rise in urinary pregnanediol excretion. The excretion of oestrone glucuronide in urine rose during treatment, suggesting ovarian follicular development. Inhibition of ovulation appeared to result from a failure of the positive feedback effect of oestradiol on the hypothalamo-pituitary axis, as no surges of luteinizing hormone were seen despite pre-ovulatory levels of oestrone glucuronide being measured during exposure to mifepristone. The cycle immediately following treatment was shorter than the pre-treatment cycle, with lower peak levels of pregnanediol glucuronide, suggesting an inadequate luteal phase. Recovery from the effects of mifepristone treatment was more rapid after 2 mg than after 5 mg and one subject conceived in the immediate post-treatment phase, indicating adequate ovulation and luteinization.(ABSTRACT TRUNCATED AT 250 WORDS)

ABSTRACT

PIP Physicians at the Centre for Reproductive Biology in Edinburgh, Scotland, followed 11 healthy 29-39 year old women with normal menstrual cycles for 3 consecutive menstrual cycles to examine the effect of 2 mg or 5 mg doses of RU-486 taken daily during 1 menstrual cycle on concentrations of ovarian steroids and luteinizing hormone and to compare this with the menses pattern. The women took either a placebo or low-dose RU--486 daily during the first menstrual cycle. Then they took each day the item they did not take during the first cycle (second cycle). The third cycle involved taking the item they did not take during the second cycle. RU-486 prevented menstruation during the treatment period. Menstruation returned significantly later after cessation of RU-486 treatment than after placebo treatment (cycle lengths in days at 5 mg dose, 52.5 vs. 29.6, p .001; at 2 mg dose, 43.6 vs. 27.4, p .02). The lack of an increase in urinary pregnanediol excretion indicated that low doses of RU-486 inhibited ovulation. Urinary estrone glucuronide levels did rise, however, demonstrating that RU-486 did not interfere with follicular development. No rapid rises of luteinizing hormone occurred, suggesting that failure of the positive feedback effect of estradiol on the hypothalamo-pituitary axis suppressed ovulation. The post-treatment cycle was not as long as the treatment cycle and had reduced peak levels of pregnanediol glucuronide, denoting an inadequate luteal phase. Women who took 2 mg RU-486 recovered more quickly than those who took 5 mg. All the women ovulated during the post-treatment cycle. 1 woman became pregnant during the post-treatment cycle, suggesting satisfactory return to ovulation and luteinization. Pre- and post-treatment adrenocorticotrophic hormone and cortisol levels in the blood indicated that these low doses of RU-486 did not affect the pituitary-adrenal axis. These results suggest that low-dose RU-486 has the potential to be an oral contraceptive. Further studies are needed, however.