Abstract
Androgens are known regulators of the growth and differentiation of the prostate gland and are effective during development and maturity as well as in disease. The role of estrogens is less well characterized, but dual direct and indirect actions on prostate growth and differentiation have been demonstrated, facilitated via both ERα and ERβ. Previous studies using animal models to determine the role of ERβ in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERα that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERβ. Our alternate approach was to use the estrogen-deficient aromatase knockout (ArKO) mouse and the method of tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Firstly, utilizing homo- and heterotypic tissue recombinants, we demonstrate that stromal aromatase deficiency results in the induction of hyperplasia in previously normal prostatic epithelium and that this response is the result of local changes to the paracrine interaction between stroma and epithelium. Secondly, using tissue recombination and an ERβ-specific agonist, we demonstrate that the activation of ERβ results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERα. Finally, using intact ArKO mice this study demonstrates that the administration of an ERβ-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERβ-specific agonist does not. Therefore, in the absence of stromal aromatase gene expression, epithelial proliferation, leading to prostatic hypertrophy and hyperplasia, may result from a combination of androgenic stimulation of proliferation and failed activation of ERβ by locally synthesized estrogens. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguish them from those that adversely alter prostate growth and differentiation. This indicates the potential of antiandrogens and SERMS, as opposed to aromatase inhibitors, for the management of prostate hyperplasia and hypertrophy.
Note: Some data and images presented in this manuscript were presented in the article entitled “Essential role for estrogen receptor β in stromal-epithelial regulation of prostatic hyperplasia” by McPherson SJ, Ellem SJ, Simpson ER, Patchev V, Fritzemeier KH and Risbridger GP. This paper was accepted and published online in the journal Endocrinology on October 26, 2006.
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McPherson, S.J., Ellem, S.J., Patchev, V., Fritzemeier, K.H., Risbridger, G.P. (2007). The Role of ERα and ERβ in theProstate: Insights from Genetic Models and Isoform-Selective Ligands. In: Korach, K.S., Wintermantel, T. (eds) Tissue-Specific Estrogen Action. Ernst Schering Foundation Symposium Proceedings, vol 2006/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2006_020
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DOI: https://doi.org/10.1007/2789_2006_020
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