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.

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

“…In the dorsal and lateral lobes, not only is growth reduced but severe branching deficiencies exist such that elongating ducts fail to develop secondary and tertiary branch points and complex morphology (50). While reduced growth is in part a function of reduced circulating T levels following neonatal estrogen exposure (48), organ culture studies also demonstrated a direct effect of estrogens in growth retardation as well as altering prostate differentiation (51,52).…”

Oestrogens and prostate cancer.

“…As there is increasing evidence that the prostate is a target for direct oestrogenic activity (Jarred et al 2000, Putz et al 2001, it is important to determine whether or not aromatase is expressed locally and to identify any changes that may occur with prostate disease. To date, aromatase expression in the prostate is contentious because the detection of enzymic activity or gene expression is equivocal; numerous reports have detected or failed to detect aromatase in prostatic tissue (Smith et al 1982, Kaburagi et al 1987, Stone et al 1987, Brodie et al 1989, Matzkin & Soloway 1992, Tsugaya et al 1996, Hiramatsu et al 1997, Negri-Cesi et al 1998, 1999.…”

Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice

“…18,21,43,44 Previous studies from conventional ER KO mice revealed that ERa, not ERb, is the critical receptor to mediate the estrogens response in those processes. 7,8,19,21 To investigate the in vivo roles of ERb in mouse prostate development, the neo-ERbKO mouse model was applied. The neo-ERbKO male mice from Chapel Hill revealed a hyperplastic prostate, 13 while the same transgenic mice housed at Karolinska Institute presented with prostatic intraepithelial neoplasia.…”

“…5,6 In contrast, higher doses of estrogens permanently suppress the neonatal rat or mouse prostate growth and prostatic branching morphogenesis by reducing testosterone (T) production, suppressing AR expression, and inducing prostatic epithelial regression. [7][8][9][10] Estrogen's actions can be mediated by estrogen receptor alpha (ERa) and ERb, 11,12 encoded by two distinct genes. Studies conducted with conventional neomycin (Neo) gene knockin and ER knockout (KO) mice suggested that ERa, but not ERb, acts as a dominant receptor of estrogen signaling in males for the development of prostate and for maintenance of normal reproductive functions.…”