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Androgenic Induction of Growth and Differentiation in the Rodent Uterus Involves the Modulation of Estrogen-Regulated Genetic Pathways

Departments of Molecular Endocrinology and Bone Biology (P.V.N., P.M., M.A.G., B.P., A.S., D.B.K., L.P.F., S.-i.H., W.J.R.), Laboratory Science and Investigative Technology (J.X.), and Biometrics Research (D.H.), Merck Research Labs, West Point Pennsylvania 19401; and Department of Medicine (D.T.), Division of Bone and Mineral Diseases, Washington University School of Medicine, Barnes-Jewish Hospital North Campus, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: William J. Ray, Department of Molecular Endocrinology, Merck & Co. Inc., P.O. Box 4, WP26A1000, West Point Pennsylvania 19401. E-mail: james_ray{at}merck.com.

The androgen receptor (AR) is expressed in the uterus; however, the role of AR in female reproductive physiology is poorly understood. Here we examined the effects of androgens on uterine growth and gene expression in adult ovariectomized rats. Nonaromatizable AR-selective agonists potently stimulate hypertrophy and induce significant myometrial expansion distinct from that induced by 17ß-estradiol (E2). In the endometrium, androgens only modestly increase epithelial cell height and antagonize the trophic effects of E2. To identify underlying mechanisms, global changes in RNA levels 24 h after stimulation with E2 and 5-dihydrotestosterone (DHT) were compared. A total of 491 genes were differentially expressed after E2 treatment, including key regulators of tissue remodeling, cell signaling, metabolism, and gene expression. Of the 164 transcripts regulated by DHT, 86% were also affected by E2, including trophic genes like IGF-I and epithelial secretory genes such as uterocalin. In estrogen receptor (ER) knockout mice, DHT cannot induce uterine growth, suggesting a key role for ER. However, DHT appears not to activate ER directly because DHT induction of IGF-I is blocked by the AR antagonist bicalutamide, and multiple genes regulated directly by ER were not induced by DHT. The similarity between estrogens and androgens instead could reflect general trophic signaling in reproductive tissues because 93 of the 503 genes regulated in the uterus are similarly affected during prostate growth. Thus androgens regulate the trophic environment and architecture of the rodent uterus via a gene expression program that is overlapping but distinct from the estrogen response.

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