McPherson S J, Ellem S J, Patchev V, Fritzemeier K H, Risbridger G P
Centre for Urology Research, Monash Institute of Medical Research, Monash University, 27-31 Wright Street Clayton, 3168 Victoria, Australia.
Ernst Schering Found Symp Proc. 2006(1):131-47. doi: 10.1007/2789_2006_020.
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 ERalpha, and ERbeta. Previous studies using animal models to determine the role of ERbeta in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERalpha that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERbeta. 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 ERbeta-specific agonist, we demonstrate that the activation of ERbeta results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERalpha. Finally, using intact ArKO mice this study demonstrates that the administration of an ERbeta-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERbeta-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 ERbeta 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.
雄激素是前列腺生长和分化的已知调节因子，在发育、成熟以及疾病过程中均发挥作用。雌激素的作用则不太明确，但已证实其对前列腺生长和分化具有直接和间接的双重作用，这一过程通过雌激素受体α（ERα）和雌激素受体β（ERβ）介导。以往利用动物模型确定ERβ在前列腺中作用的研究存在问题，因为通过ERα对雌激素给药的中枢介导反应会降低雄激素水平并导致上皮细胞退化，从而掩盖了ERβ对前列腺的任何直接作用。我们采用的另一种方法是使用雌激素缺乏的芳香化酶敲除（ArKO）小鼠和组织重组方法，以深入了解雌激素对前列腺生长和病理的作用。首先，利用同型和异型组织重组体，我们证明基质芳香化酶缺乏会导致先前正常的前列腺上皮细胞增生，且这种反应是基质与上皮细胞之间旁分泌相互作用局部变化的结果。其次，通过组织重组和ERβ特异性激动剂，我们证明ERβ的激活会导致抗增殖反应，该反应不受全身雄激素水平变化或ERα激活的影响。最后，使用完整的ArKO小鼠，本研究表明给予ERβ特异性激动剂可消除前列腺中现有的增生性上皮病理变化，但ERβ特异性拮抗剂则无此作用。因此，在缺乏基质芳香化酶基因表达的情况下，上皮细胞增殖导致前列腺肥大和增生，可能是雄激素刺激增殖与局部合成的雌激素未能激活ERβ共同作用的结果。这些数据证明了雌激素对前列腺正常生长的重要和有益作用，并将其与那些对前列腺生长和分化产生不利影响的作用区分开来。这表明与芳香化酶抑制剂不同，抗雄激素和选择性雌激素受体调节剂在治疗前列腺增生和肥大方面具有潜力。
