PROSTATIC DIFFERENTIATION & SEX HORMONE METABOLISM

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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.