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(442) SYNERGISTIC ACTION OF RU486 AND AN AROMATASE INHIBITOR, AMINOGLUTETHIMIDE, SUPPRESSES DECIDUALIZATION IN THE RAT. Given, Randall1, Glasser, Stanley3, Shi, Leili1, Purcell, Tracy2, Garfield, Robert2, 1 Department of Anatomy and Neurosciences, Galveston, TX3 Department of Molecular and Cellular Biology, Houston, TX2 Department of Obstetrics and Gynecology, Galveston, TX ABSTRACT- The peri-implantation endometrial response to the developing embryo involves stromal reorganization and differentiation of the antimesometrial stromal cells and vasculature. This process is regulated by both progesterone (P) and estrogen (E2). This decidual response can be mimicked by oil installation into the uterine lumen of an ovariectomized rat programmatically maintained on P and E2. Our objective was to examine the effects of inhibitors and/or antagonists of these hormones on the regulation of endometrial function and decidualization. Sprague-Dawley rats were ovariectomized and 7-10 days later were given a daily regimen of P (2mg, s.c., day 1) and P + E2 (100ng, s.c., days 2-5). Arachis oil was instilled (day 3) in one uterine horn to stimulate an artificial decidual response. RU486 at low or high doses (0.1 or 0.3 mg/day, s.c.) was given with or without simultaneous administration of aminoglutethimide (AG, 5mg, s.c.) on days 3-5. The decidual response was evaluated on day 5 by comparison of the weight and vascular alteration of the treated and contralateral uterine horns. High doses of the P antagonist (RU486) significantly inhibited the decidual response (>% 80) whereas the low dose of RU486 had little effect (<15% decrease). Treatment with AG alone had no significant effect on decidualization (<5% decrease). However, when combined the administration of the low dose RU486 together with AG resulted in the effective blockage (>90% inhibition) of the decidual cell response. When the study was extended to treatment of intact pregnant rats these dosages also blocked decidual development and embryo implantation. In each case vascular permeability, as measured by extravasation of albumin-bound Evans blue dye was proportional to the decidual cell response. These results demonstrate a synergistic action of the P antagonist and aromatase inhibitor on P and E function in the endometrial response during decidualization and implantation. These results may provide further insight into the regulatory biology of implantation and may suggest possible new contraceptive strategies. Supported by funds from the Contraceptive Research and Development Program (CONRAD). KEY WORDS: decidualization, RU486, aminoglutethimide, rat |
