EFFECTS OF LUTEAL-PHASE ADMINISTRATION OF MIFEPRISTONE (RU486) AND PROSTAGLANDIN ANALOG OR INHIBITOR ON ENDOMETRIUM IN THE RHESUS-MONKEY

Early luteal phase administration of a potent anti-progestin like mife pristone (RU486) inhibits blastocyst implantation and the establishmen t of pregnancy without marked changes in menstrual cyclicity and ovari an steroid hormone profiles; however, the underlying mechanism is not very clear. In the present study, a hypothesis that prostaglandins (PG ) are involved in the anti-gestatory action of luteal phase mifepristo ne was tested. Endometrial changes in rhesus monkeys were examined fol lowing luteal phase administration of mifepristone, a prostaglandin sy nthesis inhibitor (diclofenac) and a prostaglandin analogue (misoprost ol) either alone or in combination. Twenty-five monkeys were randomly assigned to six groups: group 1 (n = 4), normal control group; group 2 (n = 4), mifepristone (2 mg, daily, s.c.) treated group; group 3 (n = 4), diclofenac (25 mg, daily, i.m.) treated group; group 4 (n = 4), m isoprostol (100 mu g, daily, oral) treated group; group 5 (n = 5), mif epristone and diclofenac (same dosages as for groups 2 and 3) treated group; group 6 (n = 4), mifepristone and misoprostol (same dosages as for groups 2 and 4) treated group. All treatments were given to monkey s on days 16-18 of mated cycles and endometrial tissue samples were co llected on day 20, With diclofenac alone (group 3), marginal changes w ere observed in glandular, stromal and vascular compartments, and ther e were few apoptotic bodies in gland cells; partial inhibition and del ay in implantation was earlier reported. Significantly higher oestroge n receptor expression in glandular epithelial cells as compared with a ll other treatment groups was found after treatment with misoprostol a lone (group 4) and was associated with normal fecundity, The anti-nida tory action of luteal phase antiprogestin treatment alone or in combin ation with diclofenac or misoprostol was associated with altered endom etrial histometric features characterized by glandular apoptosis, regr ession in secretory functions, decreased oedema, extravasation and a h igher degree of stromal leukocytic infiltration. In these three groups (groups 2, 5 and 6) receptors for oestrogen and progesterone receptor s were significantly higher in stromal cells, and lower in vascular ce lls, while glandular cells showed significantly higher progesterone re ceptors compared with the control group, The anti-nidatory activity of mifepristone and associated endometrial changes could not be accentua ted or attenuated with co-administration of PGE or diclofenac, nor cou ld these be mimicked by these agents alone.