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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 6 2668-2679
Copyright © 2001 by The Endocrine Society

Original Articles: Hormones and Reproductive Health

Progesterone Antagonists Increase Androgen Receptor Expression in the Rhesus Macaque and Human Endometrium1

Ov D. Slayden, Nihar R. Nayak, Kevin A. Burton, Kristof Chwalisz2, Sharon T. Cameron, Hilary O. D. Critchley, David T. Baird and Robert M. Brenner

Division of Reproductive Sciences (O.D.S., N.R.N., R.M.B.), Oregon Regional Primate Research Center, Beaverton, Oregon 97006; Center for Reproductive Biology (K.A.B., S.T.C., H.O.D.C., D.T.B.), University of Edinburgh, EH3 9ET Edinburgh, United Kingdom; and Schering AG (K.C.), D13342 Berlin, Germany

Address correspondence and requests for reprints to: Robert M. Brenner, Ph.D., Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006.

Abstract

Antiprogestins (APs) inhibit estradiol (E2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E2 alone, E2 + progesterone (P), E2 + mifepristone (RU 486), and E2 + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E2 significantly increased AR expression above vehicle controls; E2 + RU 486 increased binding further; E2 + P decreased AR binding; and E2 + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E2 alone, stromal AR staining was predominant, and P treatment suppressed that staining. E2 + RU 486 or E2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E2 treatment in macaques) and lowest during the late secretory phase in women (or after E2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E2 action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.




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