Luteal contraception

The impact of oral administration of RU 486 on the ongoing functional activity of the hypothalamic-gonadotropin-corpus luteum-endometrial (H-P-CL-E) axis was assessed during the mid-luteal (MLP) and the late-luteal phase (LLP) with and without hCG-induced pseudopregnancy. Longitudinal studies with daily dosing and frequent blood sampling were conducted during three consecutive cycles (control/treatment/recovery). During MLP, uterine bleeding occurred in all subjects within 36-72 h of the first dose of RU 486, but no histological changes were discernible on endometrial biopsy taken 12-24 h before bleeding. There was a significant decrease in LH secretion, pulse amplitude but not frequency. Response to GnRH on the last day of treatment was impaired. This was followed 3 days later by a rebound LH secretion lasting for 5 days. These events were accompanied by an initial decline of estradiol, but not progesterone, and a second peak of 5 days' duration for both estradiol and progesterone. Hence corpus luteum function was prolonged by 5 days, and second bleeding ensued following the spontaneous luteolysis. Recovery cycles were normal. During LLP, a single dose of RU 486 induced uterine bleeding in all cases. This was associated with a decreased LH pulse amplitude and frequency, and a faster decline of both estradiol and progesterone as compared to control cycles. Rescue of corpus luteum function by the administration of incremental doses of hCG failed to prevent the uterine bleeding after a single dose of RU 486. Recovery cycles were normal. While the antiprogesterone effect of RU 486 at the endometrial level was predictably expressed, its effects at the H-P-CL-E axis were also demonstrated. These findings provide important clues for the design of once-monthly contraceptive methods.