MOLECULAR MECHANISM FOR THE CONTROL OF AROMATASE IN MEN

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The purpose of this project is to investigate the factors which regulate aromatase activity in order to better understand the physiology and pathology of male sexual development. The previously proposed role of estrogens in the pathogenesis of male pseudohermaphroditism, pubertal gynecomastia, benign prostatic hypertrophy, and male infertility underline the importance of studying the regulation of estrogen production. More than 80% of the circulating estrogens in normal men is derived from conversion of androgens by aromatase in extraglandular tissues. Although in vivo studies provide considerable information about the kinetics of aromatization, cell culture of tissues that are important sites of aromatization provides a unique opportunity for the study of factor which regulate the enzyme. Hence, other workers have focused on the aromatase in fibroblasts derived from adipose tissue. Recent studies in our laboratory demonstrted that the kinetics of aromatase in skin and adipose tissue fibroblasts were similar, suggesting that skin contributes to the total production of estrogens in men. Furthermore, our studies demonstrated that the regulation of aromatase in skin fibroblasts is somewhat different from from that previously described for adipose tissue cells. Therefore, the investigation of the regulation of aromatase in human skin fibroblasts grown in cell culture should provide new and valuable insights regarding the control of this enzyme. The purpose of this application will first be to define the factors which modulate baseline aromatase activity: site of skin biopsy, age of donor, plating density and passage number. Then, we will exlore the molecular mechanisms responsible for two patterns of regulation that we recently observed; the biphasic change in aromatase activity following glucocorticoid stimulation and the suppressive effects of androgens. In addition, we will compare the effects of cAMP and of steroid hormones on aromatase activity. Finally, we plan to investigate the factors responsible for the elevated levels of aromatase activity of skin fibroblasts derived from the members of an unusual kindred with familial gynecomastia due to elevated extra-glandular aromatase activity. Attempts will be made to determine the genetic transmission of this trait by studying clonal cell populations.