Evidence that estrogens directly alter androgen-regulated prostate development

Neonatal exposure to high doses of estrogen results in permanent suppressio n of prostate growth and reduced sensitivity to androgens in adulthood. It is unclear whether alterations in prostate growth are due to a direct effec t of estrogens on the gland or are the result of hypothalamic-pituitary-gon adal axis suppression and a subsequent reduction in androgen levels. Theref ore, the aim of this study was to determine whether estrogens have a direct effect on the prostate using a defined method of culturing neonatal prosta tes. Newborn rat ventral prostates were microdissected and cultured in the presence of testosterone, which resulted in branching morphogenesis and duc tal 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 17 beta-estradiol or diethylstilbestrol in addition to testosterone, and rogen-induced prostatic growth was reduced, and differentiation was altered . Although estrogen-treated explants were smaller than controls, quantifica tion 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 val ues. 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 discon tinuous smooth muscle layer was observed around the epithelial ducts, and e pithelial differentiation was altered. The effects of estrogens were not ac companied by a decrease in androgen response via the androgen receptor, bec ause immunolocalization of this receptor remained constant. These data demo nstrate that high doses of estrogens are growth inhibitory and have direct effects on prostate development in vitro, which may occur in vivo in additi on to indirect effects via suppression of the hypothalamic-pituitary-gonada l axis.