Hormonal and molecular consequences of androgen replacement on the prostate

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DESCRIPTION (provided by applicant): Dr. Page's career goal is to become an independent clinician-investigator proficient in the design and conduct of research evaluating the use of existing and novel selective androgens in aging men. Androgen replacement in older men with low serum testosterone levels is becoming increasingly commonplace, yet the effect this may have on prostate health is unknown. Having gained some experience in designing and conducting clinical research relating to the uses of androgens in men, Dr. Page proposes mentored research and didactic training to evaluate the effects of testosterone replacement on the prostate at the molecular level in older men. In her initial placebo controlled study, older men with low serum testosterone (T) levels will be treated with placebo, T, T plus a potent 5-alpha-reductase inhibitor (dutasteride) which blocks the conversion of T to the more potent androgen dihyrotestosterone (DHT), or DHT gel. Prostate biopsies will be conducted after one month of drug treatment. Careful analyses of intraprostatic tissue concentration and gene expression will allow Dr. Page to determine the effect of these hormone manipulations on prostate hormone levels and to determine the optimal dosage and treatment number for further study. In a subsequent study, testosterone deficient older men will undergo an initial prostate biopsy prior to treatment with either placebo, T, or T and dutasteride for six months followed by a second biopsy procedure. Tissue hormone levels, cell proliferation, and tissue specific gene expression will be analyzed. Long-term androgen-responsive endpoints such as bone mineral density, body composition and serum cholesterol will be followed to ascertain the impact of the addition of a potent 5-alpha-reductase inhibitor to these secondary endpoints. Data from these studies may eventually guide the design of larger, more definitive trials of androgen replacement in older men with low serum T. William J. Bremner MD, PhD, Chairman of the Department of Medicine, and Director of the Center for Research in Reproduction and Contraception, Alvin M. Matsumoto MD, Director, Clinical Research Unit VA Puget Sound Health Care System and Professor of Medicine (Gerontology), University of Washington School of Medicine, and Peter S. Nelson, MD, Associate Professor of Medicine (Oncology), University of Washington School of Medicine will co-mentor this award.