The University of Colorado is uniquely positioned to be an active and valuable unit in the Cooperative Reproductive Medicine Network (RMN) ofthe NICHD. This proposal takes advantage of our extensive experience in clinical protocol development and a highly successful record as effective contributors to many large multicenter trials including the existing RMN since 2000. The geographic and population diversity represented by our location as one of the very few academic reproductive medicine centers in the Rocky Mountain region is an additional important asset that we bring to the RMN. Our concept proposal is entitled "Male Obesity Hypothesis for Infertility: Treatment Options". Male obesity reduces fertility regardless of the body mass of the female partner. Observational studies have clearly demonstrated that obese men exhibit a compromise in reproductive hormones and semen parameters. A gap in knowledge exists as no clinical trials have been conducted to address treatments for obesity-related male Infertility. Use of aromatase inhibitors in men leads to improvement of compromised sperm parameters and reproductive hormones but pregnancy data is sparse. The central hypothesis of this proposal is that an abnormal endocrine milieu found in obese infertile men negatively impacts reproductive function and can be reversed with aromatase inhibitors. We seek to conduct a multi-center, randomized, double-blind, placebo-controlled trial of an aromatase inhibitor, letrozole, in infertile obese men. Guided by available observational data, this hypothesis will be tested by pursuing three specific aims: 1) To compare the efficacy of an aromatase inhibitor, letrozole, to placebo for the treatment of subfertility in obese men, using live birth as the primary outcome and clinical pregnancy as the secondary outcome;2) To determine which prospective parameters characterize response to letrozole; and 3) To determine if dietary lipid intake (assessed by red blood cell membrane fatty acid composition) is associated with success of fertility treatment in obese men. The mechanistic approach aimed at correcting the underlying hormonal imbalance represents a novel therapeutic strategy and we shall attempt to further correlate attributes ofthe treated males with metabolic outcomes of their offspring.

Public Health Relevance

The proposed research is relevant to public health because obesity is increasingly one ofthe most significant sources of morbidity in the United States. Discoveries made in this study may yield insights that will benefit other areas of obesity research, particularly those having to do with diet and hormonal interactions. This project will advance the goal of ameliorating the impact of obesity on human health.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZHD1-DSR-L (55))
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De Paolo, Louis V
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University of Colorado Denver
United States
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Legro, Richard S; Brzyski, Robert G; Diamond, Michael P et al. (2014) The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial. Fertil Steril 101:258-269.e8
Legro, Richard S; Brzyski, Robert G; Diamond, Michael P et al. (2014) Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 371:119-29
Legro, Richard S; Chen, Gang; Kunselman, Allen R et al. (2014) Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype. Hum Reprod 29:2680-6
Legro, Richard S; Kunselman, Allen R; Brzyski, Robert G et al. (2012) The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 33:470-81
Diamond, Michael P; Kruger, Michael; Santoro, Nanette et al. (2012) Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol 119:902-8
Jones, Michelle R; Chua, Angela K; Mengesha, Emebet A et al. (2012) Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids 77:317-22
Aubuchon, Mira; Kunselman, Allen R; Schlaff, William D et al. (2011) Metformin and/or clomiphene do not adversely affect liver or renal function in women with polycystic ovary syndrome. J Clin Endocrinol Metab 96:E1645-9
Krawetz, Stephen A; Casson, Peter R; Diamond, Michael P et al. (2011) Establishing a biologic specimens repository for reproductive clinical trials: technical aspects. Syst Biol Reprod Med 57:222-7
Trussell, J C; Christman, Gregory M; Ohl, Dana A et al. (2011) Recruitment challenges of a multicenter randomized controlled varicocelectomy trial. Fertil Steril 96:1299-305
Schlaff, William D; Zhang, Heping; Diamond, Michael P et al. (2011) Increasing burden of institutional review in multicenter clinical trials of infertility: the Reproductive Medicine Network experience with the Pregnancy in Polycystic Ovary Syndrome (PPCOS) I and II studies. Fertil Steril 96:15-8

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