Evidence That Estrogens Directly Alter Androgen-Regulated Prostate Development*

Abstract

Neonatal exposure to high doses of estrogen results in permanent suppression of prostate growth and reduced sensitivity to androgens in adulthood. It is unclear whether alterations in prostate growth are due to a direct effect of estrogens on the gland or are the result of hypothalamic-pituitary-gonadal axis suppression and a subsequent reduction in androgen levels. Therefore, the aim of this study was to determine whether estrogens have a direct effect on the prostate using a defined method of culturing neonatal prostates. Newborn rat ventral prostates were microdissected and cultured in the presence of testosterone, which resulted in branching morphogenesis and ductal canalization. Solid cords of epithelium differentiated into acini lined by tall columnar epithelial cells; these acini were surrounded by stromal cells, expressing smooth muscle alpha-actin. When cultured in the presence of 17beta-estradiol or diethylstilbestrol in addition to testosterone, androgen-induced prostatic growth was reduced, and differentiation was altered. Although estrogen-treated explants were smaller than controls, quantification of epithelial, stromal, and luminal volumes using unbiased stereology revealed significant changes; the proportion of epithelial cells and lumen decreased, and the proportion of stroma increased compared with control values. Concurrent with this reduced growth rate, we observed a disturbance in the branching pattern and a reduction in ductal canalization. Specifically, stromal differentiation and organization were disrupted, so that a discontinuous smooth muscle layer was observed around the epithelial ducts, and epithelial differentiation was altered. The effects of estrogens were not accompanied by a decrease in androgen response via the androgen receptor, because immunolocalization of this receptor remained constant. These data demonstrate that high doses of estrogens are growth inhibitory and have direct effects on prostate development in vitro, which may occur in vivo in addition to indirect effects via suppression of the hypothalamic-pituitary-gonadal axis.

Role of estrogens in development of prostate cancer

“…As expected, mice lacking functional ERs develop prostatic phenotypes (recently reviewed by Jarred et al [62]). Obviously, because mice with prostate-targeted inactivation of ERs are not yet available, the phenotype is not necessarily caused solely by the lack of the receptor in prostatic tissue, but may also be secondary to the altered CNS-gonadal function.…”

“…It is well known that estrogen treatment induces development of squamous epithelial metaplasia in prostate, in particular at sites where the underlying stroma expresses ER␣. This does not occur in ER␣KO mouse, indicating that this specific response is ER␣-dependent [65,62] and likely to be mediated by prostatic ER␣. Squamous epithelial metaplasia has also been observed in human prostate, particularly in the posterior periurethral region (Fig.…”

Defects of Prostate Development and Reproductive System in the Estrogen Receptor-α Null Male Mice

“…ER␣ is expressed in both prostatic fibroblasts and smooth muscle cells (30,44). Administration of estrogens has been shown to influence both fibroblast and smooth muscle cell proliferation and differentiation (30,36). In the current studies, loss of ER␣ in the mouse prostate led to decreased fibroblast cell proliferation and content but increased smooth muscle cell content, which suggested that ER␣ could have a differential effect on the two types of stromal cells and potentially be involved in the remodeling of prostate stromal cellular composition.…”

Mutations in the Helix 3 Region of the Androgen Receptor Abrogate ARA70 Promotion of 17β-Estradiol-induced Androgen Receptor Transactivation

“…Estrogen, primarily 17␤-estradiol (E2), has also been proposed to be involved in both normal and abnormal processes of male reproductive development and associated diseases (5,6). Male estrogen is synthesized by aromatization of androgen, (e.g.…”