ENDOMETRIAL EFFECTS OF RU486 IN PRIMATES - ANTIPROLIFERATIVE ACTION DESPITE SIGNS OF ESTROGEN ACTION AND INCREASED CYCLIN-B EXPRESSION

Continuous antiprogestin administration to hormone replaced, castrate monkeys inhibits estrogen-induced endometrial proliferation through me chanisms which remains unclear. To elucidate the molecular mechanisms of RU486-induced endometrial suppression, we treated six intact female cynomolgus monkeys on cycle days 2-22 sequentially with placebo, RU48 6 (1mg/kg/day) and levonorgestrel (LNG) (2 mu g/kg/day) intramuscularl y (i.m.), with uterine wedge sections and endometrial biopsies collect ed on day 22 of each cycle. The uterine sections were evaluated for mo rphology, mitosis and proliferating cell nuclear antigen (PCNA) immuno histochemistry. Changes in the mRNA levels of ER, PR, cyclin-B and tum our suppressor gene p21 were assessed using co-amplification with beta -actin by reverse transcriptase-polymerase chain reaction (RT-PCR). Ad ministration of RU486 uniformly resulted in characteristic suppression of endometrium with few mitosis, dense stroma and simple glands, wher eas the effects of LNG were less uniform. Following RU486 administrati on, the levels of endometrial ER and PR mRNA were comparable to prolif erative phase endometrium, and significantly higher than those seen in the secretory endometrium, indicating that some of the biological act ions of E(2) were not inhibited during RU486 treatment. Despite scarce mitosis, PCNA was readily detectable in all samples. Curiously, in co mparison to secretory phase controls, the levels of cyclin-B, but not p21, mRNA were markedly increased following RU486. The effects of LNG on the levels of these mRNA species varied, with mean levels falling b etween those of the secretory phase controls, and RU486-treated specim ens. The increase in cyclin-B mRNA and lack of mitosis suggests that a nti-proliferative actions of RU486 in the primate endometrium might be associated with a cell-cycle block at the G2-M interphase. Whether me chanisms similar to these are associated with the beneficial clinical effects of RU486 seen in the treatment of various hormone dependent ma ladies remains to be determined. Copyright (C) 1996 Elsevier Science L td.