Hormonal and molecular consequences of androgen replacement on the prostate

描述(由申请人提供)：佩奇博士的职业目标是成为一名独立的临床医生兼调查员，精通研究的设计和实施，评估现有的和新的选择性雄激素在老年男性中的使用。在血清睾酮水平较低的老年男性中，雄激素替代治疗正变得越来越普遍，但这可能对前列腺健康产生的影响尚不清楚。在设计和进行与男性使用雄激素有关的临床研究方面获得了一些经验，佩奇博士建议进行指导性研究 和说教训练，从分子水平评估睾酮替代治疗对老年男性前列腺的影响。在她最初的安慰剂对照研究中，血清睾酮(T)水平较低的老年男性将接受安慰剂、T，T加上一种有效的5-α还原酶抑制剂(度他雄胺)的治疗，该抑制剂可阻止T转化为更有效的雄激素二氢睾丸酮(DHT)或DHT凝胶。在药物治疗一个月后，将进行前列腺活检。对前列腺组织浓度和基因表达的仔细分析将使佩奇博士能够确定这些激素操作对前列腺素水平的影响，并确定进一步研究的最佳剂量和治疗次数。在随后的研究中，睾丸激素缺乏的老年男性将接受最初的前列腺活检，然后使用安慰剂、T或T和度他雄胺治疗6个月，然后进行第二次活检程序。将分析组织激素水平、细胞增殖和组织特异性基因表达。将跟踪长期雄激素反应终点，如骨密度、身体成分和血清胆固醇，以确定向这些次级终点添加有效的5-阿尔法还原酶抑制剂的影响。这些研究的数据最终可能会指导在血清水平较低的老年男性中进行雄激素替代试验的更大规模、更明确的试验。T.William J.Bremner MD，博士，医学系主席兼生殖与避孕研究中心主任，Alvin M.MatSumoto MD，华盛顿大学医学院VA Puget Sound医疗保健系统临床研究部主任，医学(老年学)教授Alvin M.MatSumoto MD和华盛顿大学医学院医学(肿瘤学)副教授Peter S.Nelson医学博士将共同指导这一奖项。

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.