Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486

Abstract

To investigate the role of progesterone in the follicular phase, we examined the effects of RU486 in eight normal cycling women studied with daily and frequent blood sampling (every 10 min for 10 h) during three menstrual cycles (control-treatment-recovery). RU486 (3 mg/kg, orally) was administered for 3 consecutive days after ultrasound documentation of a dominant follicle. In six of the eight women, RU486 was given after emergence of the dominant follicle, while in two women, RU486 was initiated during the preovulatory period when estradiol levels had exceeded 917 pmol/L. In the six women given RU486 after emergence of the dominant follicle, RU486 significantly prolonged the follicular phase duration from 15.6 +/- 1.9 (+/- SD) to 28.6 +/- 9.3 days (P less than 0.01) and extended the treatment cycle length to 42.3 +/- 9.1 (+/- SD) days (P less than 0.01). During RU486 treatment, mean serum estradiol levels decreased from 385 +/- 43 to 228 +/- 28 pmol/L (P less than 0.01), while LH, FSH, ACTH, cortisol, and progesterone levels changed little. LH pulse frequency and amplitude on the last day of RU486 administration did not differ from control values. Collapse of the dominant follicle was evident on ultrasound after RU486 administration and was not accompanied by uterine bleeding. In the two women treated during the preovulatory period, the follicular phase was not prolonged, and RU486 failed to delay the onset of the LH surge. Our findings indicate that RU486 treatment during the follicular phase interrupts normal follicular development, resulting in a delay of ovulation and a reinitiation of follicular recruitment.

PIP: The effect of the antiprogesterone RU486 on the hypothalamic-pituitary-ovarian axis during the follicular phase of the menstrual cycle was investigated in 8 normally cycling women. Frequent, daily blood sampling was conducted during 3 cycles--control, treatment, and recovery. In 6 subjects, RU486 administration was initiated after emergence of the putative dominant follicle (documented by ultrasound). The 2 remaining subjects received RU486 during the preovulatory period when estradiol levels had already exceeded 917 pmol/L. When RU486 was administered after emergence of the dominant follicle, the duration of the follicular phase significantly increased from 15.6 + or - 1.9 days to 28.6 + or - 9.3 days, thus prolonging the intermenstrual length of the RU486 cycle from 28.9 + or - 2.7 days to 42.3 + or - 9.1 days. Endometrial breakdown did not occur during RU486 administration. RU486 further induced a significant decline in estradiol levels from 385 + or - 43 pmol/L to 228 + or - 28 pmol/L, but there was no significant change in luteinizing hormone (LH), follicle-stimulating hormone (FSH), or progesterone levels. RU486 produced a decrease in size or collapse of the putative dominant follicle in 5 of the 6 subjects who received this agent after emergence of the follicle. In the 2 women treated during the preovulatory period, the follicular phase was nor prolonged and RU486 failed to delay the onset of the LH surge. Overall, this study demonstrates that administration of RU486 in the follicular phase disrupts normal follicular development, resulting in functional demise of the dominant follicle, reinitiation of folliculogenesis, and extended menstrual cycle length. These events are not accompanied by uterine bleeding or significant alterations in LH pulsatile frequency and amplitude.