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; Dodson, William C; Kunselman, Allen R et al. (2016) Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS. J Clin Endocrinol Metab 101:2658-66
Mumford, Sunni L; Legro, Richard S; Diamond, Michael P et al. (2016) Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 101:3288-96
Hansen, Karl R; He, Amy Linnea W; Styer, Aaron K et al. (2016) Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination. Fertil Steril 105:1575-1583.e2
Pal, Lubna; Zhang, Heping; Williams, Joanne et al. (2016) Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial. J Clin Endocrinol Metab 101:3027-35
Brower, Meredith A; Jones, Michelle R; Rotter, Jerome I et al. (2015) Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 100:E182-6
Kuang, Hongying; Jin, Susan; Thomas, Tracey et al. (2015) Predictors of participant retention in infertility treatment trials. Fertil Steril 104:1236-43.e1-2
Diamond, Michael P; Legro, Richard S; Coutifaris, Christos et al. (2015) Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med 373:1230-40
Hayes, M Geoffrey; Urbanek, Margrit; Ehrmann, David A et al. (2015) Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 6:7502
Steiner, Anne Z; Diamond, Michael P; Legro, Richard S et al. (2015) Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes. Fertil Steril 104:1522-6
Diamond, Michael P; Legro, Richard S; Coutifaris, Christos et al. (2015) Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics. Fertil Steril 103:962-973.e4

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