PROSTATIC DIFFERENTIATION & SEX HORMONE METABOLISM

前列腺分化

• 批准号: 3164273
• 负责人: Irwin Leav
• 金额: $ 18.45万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-30 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164273
• 关键词: androgen receptor; androgens; catechols; cell differentiation; estradiol; estrogen receptors; estrogens; gene expression; histopathology; hormone metabolism; hormone regulation /control mechanism; hormone related neoplasm /cancer; in situ hybridization; laboratory rat; neoplasm /cancer genetics; organ culture; progesterone receptors; prostate preneoplastic state; protooncogene; sex hormones; stimulant /agonist; testosterone

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.

我们最近证明，同时施用睾酮 (T) 和雌二醇-17Beta (E2) 给完整的 Noble (Nb) 大鼠 16 周诱导 导管内发育不良仅发生在前列腺背侧（DP）。 其他人有 报道称，大量这些发育不良随后演变成 浸润性癌。 这与性激素引起的Nb大鼠病变密切相关 类似于人类腺体中的导管发育不良，这被认为是 前列腺癌的先行病变。 而其他人则报告说，这种病变可以通过长期治疗来诱发 具有芳香化 T 或雌酮的大鼠，就其本身而言，我们无法引起 对动物进行单独长期治疗后的发育异常 不可芳香化的 5α-二氢睾酮 (DHT) 的药理学剂量 或E2。 因此，我们的目标是确定发病机制是否 发育不良可能与荷尔蒙的直接相互作用有关 雄激素-雌激素，或肿瘤前病变是否发展 需要雄激素支持的雌激素激活才能潜在 致癌代谢物；例如儿茶酚。 调查的作用 雌激素在发育不良的发生过程中，我们将使用类固醇 雌激素受体的不同生物效力和结合亲和力 （ER），其形成儿茶酚的能力不同。 这些 雌激素将单独或与 Nb 大鼠一起施用 16 周。 与DHT结合。 雄激素支持的 ER 状态的改变和/或 DP 和肝微粒体中儿茶酚的形成将在不同的条件下进行测定 治疗期间的时间间隔。 具体的时间扰动 生化参数将与有丝分裂的改变相关 指数，以及激素介导的分化变化 不断发展的发育不良病变。 我们的多学科研究将涉及 雄激素和雌激素代谢、受体测定、免疫组织化学、 电子显微镜、病理学。 我们的研究对于理解关键问题特别重要 性别以来影响人类前列腺癌发病的因素 长期以来，类固醇一直被怀疑在启动过程中发挥了重要作用 以及这种肿瘤的进展。 不典型增生的诱导 我们的 Nb 大鼠模型中 E2 和 T 的组合特别令人感兴趣 因为循环性类固醇的不平衡可能有利于雌激素 据报道，在老年男性和 患有前列腺癌的人。