Anti-implantation activity of luteal phase mifepristone administration is not mimicked by prostaglandin synthesis inhibitor or prostaglandin analogue in the rhesus monkey

Abstract

The use of mifepristone as an anti-implantation agent in the primate has been explored in the rhesus monkey with two specific aims: (i) to determine the contraceptive efficacy of very low-dose mifepristone administered on mated cycle days 16, 17, and 18; and (ii) to test the hypothesis that alteration in endometrial prostaglandin milieu by using either prostaglandin analogue or prostaglandin synthesis inhibitor can intervene the antifertility effect induced by mifepristone. Thirty female monkeys were randomly assigned to one of the six treatment groups. Five monkeys in the control group (group 1) were subjected to mating during cycle days 8-22. Four out of five monkeys became pregnant in the first mated cycle (80%) with detection of serum mCG by 12.7 +/- 1.5 days after ovulation. In group 2, 12 mated cycles were studied in five monkeys, mifepristone [RU486, 2 mg/day/animal, s.c. in 1 ml vehicle (1:4, benzyl benzoate:olive oil, v/v)] was given on cycle days 16, 17, and 18. In this group, no pregnancy was observed, thus providing complete pregnancy protection. Though there was an apparent extension of treatment cycle lengths in five cases with no incidence of inter-menstrual bleeding or spotting, there were no significant changes in serum estradiol (E) and progesterone (P). In group 3, four monkeys received prostaglandin (PG) synthesis inhibitor, diclofenac sodium (D, 25 mg/day/animal, i.m.) on cycle days 16, 17, and 18 in seven ovulatory menstrual cycles. Four of these cycles (57%) resulted in normal pregnancies; however, mCG detection (16.8 +/- 1.2 days after ovulation) was significantly (p < 0.05) delayed as compared to group 1. In group 4, four monkeys received 100 micrograms misoprostol (M), a PGE1 analogue, by gavage on mated cycle days 16, 17, and 18. Four pregnancies occurred in five treatment cycles (80%) with normal profiles of serum E and Pi mCG was first detected 13.2 +/- 1.7 days after ovulation. In group 5, seven monkeys received same dosages of RU486 and D on mated cycle days 16, 17, and 18. One hundred percent pregnancy protection was observed with luteal phase lengthening in eight treatment cycles but with unaltered E and P profiles. In group 6, five monkeys in nine treatment cycles received same dosages of RU486 and M on mated cycle days 16, 17, and 18. One pregnancy occurred; evaluation of E and P levels showed that the drug was given in the preovulatory period, which delayed ovulation and implantation, as mCG was detected 19 days post-ovulation. A delay in vaginal bleeding was observed in four treatment cycles with unaltered E and P profiles. Low-dose mifepristone appears to be a potential candidate for luteal phase and post-coital emergency contraception. However, the hypothesis that altered endometrial prostaglandin milieu may be responsible for mediating the anti-implantation effect of RU486 does not appear to be tenable based on our results in the rhesus monkey.