ANTI-IMPLANTATION ACTIVITY OF LUTEAL-PHASE MIFEPRISTONE ADMINISTRATION IS NOT MIMICKED BY PROSTAGLANDIN SYNTHESIS INHIBITOR OR PROSTAGLANDIN ANALOG IN THE RHESUS-MONKEY

The use of mifepristone as an anti-implantation agent in the primate h as been explored in the rhesus monkey with two specific aims: (i) to d etermine the contraceptive efficacy of very low-dose mifepristone admi nistered on mated cycle days 16, 27, and 28; and (ii) to test the hypo thesis that alteration in endometrial prostaglandin milieu by using ei ther prostaglandin analogue or prostaglandin synthesis inhibitor can i ntervene the antifertility effect induced by mifepristone. Thirty fema le monkeys were randomly assigned to one of the six treatment groups. Five monkeys in the control group (group 1) were subjected to mating d uring 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 d ays after ovulation. In group 2, 12 mated cycles were studied in Jive monkeys, mifepristone [RU486, 2 mg/day/animal, s.c, in 2 mi vehicle (1 :4, benzyl benzoate:olive oil, v/v)] was given on cycle days Ib, 27, a nd 28. In this group, no pregnancy was observed, thus providing comple te pregnancy protection. Though there was an apparent extension of tre atment cycle lengths in five cases with no incidence of inter-menstrua l bleeding or spotting, there were no significant changes in serum est radiol (E) and progesterone (P). In group 3, four monkeys received pro staglandin (PG) synthesis inhibitor, diclofenac sodium (D, 25 mg/day/a nimal, i.m.) on cycle days 26, 27, and 18 in seven ovulatory menstrual cycles. Four of these cycles (57%) resulted in normal pregnancies; ho wever, mCG detection (16.8 +/- 1.2 days after ovulation) was significa ntly (p < 0.05) delayed as compared to group 1. In group 4, four monke ys received 100 mu g misoprostol (M), a PGE, analogue, by gavage on ma ted cycle days 16, 17, and 28. Four pregnancies occurred in five treat ment cycles (80%) with normal profiles of serum E and P; 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 26, 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 26, 17, and 18. One pr egnancy occurred; evaluation of E and P levels showed that the drug wa s given in the preovulatory period, which delayed ovulation and implan tation, 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 f or luteal phase and post-coital emergency contraception. However, the hy hypothesis that altered endometrial prostaglandin milieu may be res ponsible for mediating the anti-implantation effect of RU486 does not appear to be tenable based on our results in the rhesus monkey. (C) 19 97 Elsevier Science Inc.