TY - JOUR
T1 - Androgenic induction of growth and differentiation in the rodent uterus involves the modulation of estrogen-regulated genetic pathways
AU - Nantermet, Pascale V.
AU - Masarachia, Patricia
AU - Gentile, Michael A.
AU - Pennypacker, Brenda
AU - Xu, Jian
AU - Holder, Daniel
AU - Gerhold, David
AU - Towler, Dwight
AU - Schmidt, Azriel
AU - Kimmel, Donald B.
AU - Freedman, Leonard P.
AU - Harada, Shun Ichi
AU - Ray, William J.
PY - 2005/2
Y1 - 2005/2
N2 - 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 17β-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 5α-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)α knockout mice, DHT cannot induce uterine growth, suggesting a key role for ERα. However, DHT appears not to activate ERα directly because DHT induction of IGF-I is blocked by the AR antagonist bicalutamide, and multiple genes regulated directly by ERα 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.
AB - 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 17β-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 5α-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)α knockout mice, DHT cannot induce uterine growth, suggesting a key role for ERα. However, DHT appears not to activate ERα directly because DHT induction of IGF-I is blocked by the AR antagonist bicalutamide, and multiple genes regulated directly by ERα 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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U2 - 10.1210/en.2004-1132
DO - 10.1210/en.2004-1132
M3 - Article
C2 - 15498879
AN - SCOPUS:19944431453
SN - 0013-7227
VL - 146
SP - 564
EP - 578
JO - Endocrinology
JF - Endocrinology
IS - 2
ER -