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Essential Role for Estrogen Receptor ß in Stromal-Epithelial Regulation of Prostatic Hyperplasia

Centre for Urological Research (S.J.M., S.J.E., G.P.R.), Monash Institute of Medical Research, Monash University, Clayton 3168, Australia; Prince Henry’s Institute (E.R.S.), Melbourne 3168, Australia; and Schering AG, CRBA Gynecology and Andrology (V.P., K.-H.F.), 13342 Berlin, Germany

Address all correspondence and requests for reprints to: Gail P. Risbridger, Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au.

Estrogens, acting via estrogen receptors (ER) and ß, exert direct and indirect actions on prostate growth and differentiation. Previous studies using animal models to determine the role of ERß in the prostate have been problematic because the centrally mediated response to estrogen results in reduced androgen levels and prostatic epithelial regression, potentially masking any direct effects via ERß. This study overcomes this problem by using the estrogen-deficient aromatase knockout mouse and tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Homo- and heterotypic aromatase knockout tissue recombinants revealed stromal aromatase deficiency induced hyperplasia in normal prostatic epithelium due to disruption of paracrine interaction between stroma and epithelia. Treatment of tissue recombinants with an ERß-specific agonist demonstrated that stimulation of ERß elicits antiproliferative responses in epithelium that are not influenced by alterations to systemic androgen levels or the activation of ER. Additionally, work performed with intact aromatase knockout mice demonstrated that the administration of an ERß-specific agonist ablated preexisting prostatic epithelial hyperplasia, whereas an ER-specific agonist did not. Therefore, failed activation of ERß, resulting from local stromal aromatase deficiency, in conjunction with increased androgen levels, results in increased epithelial cell proliferation and prostatic hyperplasia. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguishes them from those that adversely alter prostate growth and differentiation. This highlights the potential of selective estrogen-receptor modulators, rather than aromatase inhibitors, for the management of dysregulated prostate growth.

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