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This version published online on October 21, 2004
Endocrinology, doi:10.1210/en.2004-1132
A more recent version of this article appeared on February 1, 2005
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Submitted on August 25, 2004
Accepted on October 13, 2004

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

Pascale V. Nantermet, Patricia Masarachia, Michael A. Gentile, Brenda Pennypacker, Jian Xu, Daniel Holder, David Gerhold, Dwight Towler, Azriel Schmidt, Donald B. Kimmel, Leonard P. Freedman, Shun-ichi Harada, and William J. Ray*

Department of Molecular Endocrinology and Bone Biology, Merck Research Labs, West Point PA, 19401; Department of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, Barnes-Jewish Hospital North Campus, St. Louis, Missouri 63110; Department of Laboratory Science and Investigative Technology, Merck Research Labs, West Point PA, 19401; Department of Biometrics Research, Merck Research Labs, West Point PA, 19401

* To whom correspondence should be addressed. 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. Non-aromatizable AR-selective agonists potently stimulate hypertrophy and induce significant myometrial expansion distinct from that induced by 17{beta}-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{alpha}-dihydrotestosterone (DHT) were compared. 491 genes were differentially expressed following 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 insulin-like growth factor-1 (IGF-1) and epithelial secretory genes such as uterocalin. In estrogen receptor (ER){alpha} knockout mice, DHT cannot induce uterine growth, suggesting a key role for ER{alpha}. However DHT appears not to activate ER{alpha} directly, as DHT induction of IGF-1 is blocked by the AR antagonist bicalutamide, and multiple genes regulated directly by ER{alpha} were not induced by DHT. The similarity between estrogens and androgens instead could reflect general trophic signaling in reproductive tissues, since 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.
Key words: Uterus • Androgen Receptor • Estrogen Receptor • Insulin-like growth factor-1 • Uterocalin • prostate • microarray




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