PROSTATIC DIFFERENTIATION & SEX HORMONE METABOLISM

我们最近已经证明，同时服用睾丸素(T) 雌二醇-17β(E_2)对正常高贵(NB)大鼠16wk的诱导作用 仅位于前列腺背侧(DP)的导管内发育不良。其他人则有 据报道，相当数量的这种不典型增生随后演变为 浸润性癌。这与性激素对正常大鼠的损伤密切相关 类似于人类腺体中的导管发育不良，被认为是 前列腺癌的前驱病变。 而另一些人报告说，这种损害可以由慢性治疗引起 可芳香化T或雌酮的大鼠，本身我们一直无法引起 单独慢性治疗动物后的不典型增生 非芳香化5α-二氢睾酮(DHT)的药理剂量 或雌二醇组。因此，我们的目标将是确定其发病机制是否 发育不良可能与激素的直接相互作用有关 雄激素-雌激素，还是发生癌前病变 需要雄激素支持的雌激素激活才有可能 致癌代谢物；如儿茶酚。调查……的作用 雌激素在异型增生的发生中的作用，我们将使用类固醇 雌激素受体的不同生物效价和结合亲和力 (呃)，它们形成儿茶酚的能力不同。这些 雌激素会单独或在16周内注射给正常大鼠。 与DHT联合应用。雄激素支持的雌激素受体状态和/或改变 DP和肝微粒体中儿茶酚的形成将在不同的时间进行测定 治疗期间的时间间隔。特定情况下的时间扰动 生化参数将与有丝分裂的改变相关 指数，并在激素介导的分化变化中发现 进化中的发育不良病变。我们的多学科研究将涉及 雄激素和雌激素代谢，受体分析，免疫组织化学， 电子显微镜和病理学。 我们的研究将对理解关键的 自发性前列腺癌发病机制的相关因素 长期以来，类固醇一直被怀疑在引发这种疾病的过程中发挥了重要作用 以及这种肿瘤的发展。异型增生的诱因 在我们的NB大鼠模型中，E2和T的组合是特别有趣的 由于可能有利于雌激素的性类固醇循环系统失衡 据报道，在靶器官采取行动的男性和女性 前列腺癌患者。

We have shown recently that simultaneous administration of testosterone (T) and estradiol-17Beta (E2) to intact Noble (Nb) rats for 16 wk induces intraductal dysplasia exclusively in the dorsal prostate (DP). Others have reported a significant number of these dysplasias subsequently evolve into invasive carcinoma. This sex hormone-induced lesion of Nb rats closely resembles ductal dysplasia in the human gland which is believed to be the antecedent lesion of prostatic carcinoma. While others report that the lesion can be induced by chronic treatment of rats with aromatizable T or estrone, per se, we have been unable to cause dysplasia following separate chronic treatment of animals with pharmacological doses of non-aromatizable 5Alpha-dihydrotestosterone (DHT) or E2. Therefore, our goal will be to determine if the pathogenesis of dysplasia can be linked to direct hormonal interactions of androgen-estrogen, or whether development of the pre-neoplastic lesion requires androgen-supported activation of estrogen to potentially carcinogenic metabolites; eg catechols. To investigate the role of estrogen in the genesis of dysplasia, we will utilize steroids with differing biological potencies and binding affinities for estrogen receptor (ER), and which differ in their capacity to form catechols. These estrogens will be administered for 16 wk to Nb rats, alone or in combination with DHT. Alterations in androgen-supported ER status and/or catechol formation in DP and hepatic microsomes will be assayed at varying time intervals during treatment. Temporal perturbations in specific biochemical parameters will be correlated with alterations in mitotic indices, and with hormone-mediated changes in differentiation found in the evolving dysplastic lesions. Our multidisciplinary studies will involve androgen and estrogen metabolism, receptor assays, immunohistochemistry, electron microscopy, and pathology. Our studies will be of particular importance to understanding critical factors involved in the pathogenesis of human prostatic carcinoma since sex steroids have long been suspected of playing a major role in the initation and progression of this neoplasm. The induction of dysplasia by combinations of E2 and T in our Nb rat model is of particular interest since imbalances in circulating sex steroids which could favor estrogen action at the target organ have been reported in agging men and in individuals with prostatic cancer.