Antinidatory effect of luteal phase administration of mifepristone (RU486) is associated with changes in endometrial prostaglandins during the implantation window

Abstract

Luteal phase administration of mifepristone provides a significant degree of pregnancy protection to monkeys and women. Among several proposed mediators of the antinidatory action of luteal phase mifepristone, prostaglandins (PG) at the endometrial level appear important, and was examined in the present study using the rhesus monkey as the primate model. To this end, the concentrations of PGE 2 and PGF 2α in endometrium and the profiles of cyclooxygenase (COX) and 15-hydroxy prostaglandin dehydrogenase (PGDH) were examined in untreated control animals, in animals subjected to mifepristone treatment (2 mg/day) alone or along with diclofenac (25 mg/day), or along with a PGE 1 analog (100 μg misoprostol), in animals subjected to diclofenac alone treatment, and in animals treated with misoprostol alone on cycle days 16, 17, and 18. Tissue samples were collected on day 20 of treatment cycles from animals with discernible corpora lutea. Early luteal phase treatment with diclofenac did not result in any remarkable change in endometrial prostaglandin concentrations, however, there was an increase in the profile of COX. Animals exposed to misoprostol in the prereceptive stage, on the other hand, exhibited decreased expression of endometrial COX. The concentrations of PGF 2α and PGE 2, as well as the ratios of PGF 2α to PGE 2 concentrations, were increased along with a decrease in COX and PGD in endometrial samples following luteal phase mifepristone treatment. Although the underlying cellular mechanism of regulation of COX and PGDH in mifepistone-treated endometrium remains to be examined, the decrease in PG catabolism through low PGDH may contribute to the increased PG and high ratio of PGF 2α to PGE 2 in mifepristone-exposed endometrium. It is plausible that mifepristone action on endometrial cells is mediated by an altered ratio of PGF 2α to PGE 2. Furthermore, it appears that the regulation of PG milieu by COX and PGDH activities in reproductive tissues is under complex regulatory mechanism and is temporarily correlated with specific developmental events.