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

ABSTRACT

PIP: Luteal phase administration of mifepristone has been reported to induce several changes in the progesterone-dominated endometrium. The present study investigated the involvement of prostaglandins (PGs) in the process of implantation and their role in mediating the anti-implantation activity of RU-486 in the rhesus monkey. Concentrations of PGE and PGF in endometrium and the profiles of enzymes responsible for their synthesis (cyclooxygenase, COX) and degradation (15-hydroxy prostaglandin dehydrogenase, PGDH) were examined after treatment with the following regimens: mifepristone (2 mg/day), alone or along with the PG synthesis inhibitor diclofenac (25 mg/day) or the PGE analog misoprostol (100 mcg); diclofenac alone; and misoprostol alone. Tissue samples were collected on day 20 of treatment cycles from monkeys with discernible corpora lutea. Early luteal phase treatment with diclofenac did not produce any significant change in endometrial PG concentrations; however, there was an increase in the profile of COX. Monkeys exposed to misoprostol in the prereceptive stage exhibited decreased expression of endometrial COX. PGF2alpha and PGE2 concentrations and their ratios were increased along with a decrease in COX and PGDH in endometrial samples after luteal phase mifepristone treatment. The decrease in PG catabolism through low PGDH may contribute to the increased PG and high ratio of PGF2alpha to PGE2 in mifepristone-exposed endometrium. Moreover, mifepristone action on endometrial cells may be mediated by an altered ratio of PGF2alpha to PGE2.