Male infertility is a common and devastating problem, and the prevalence is increasing, much of which is related to obesity. However, non-Assisted Reproductive Technology (ART) treatment remains rudimentary and poorly studied. In Vitro Fertilization with intracytoplasmic sperm injection (IVF/ICSI), while effective, is expensive, emotionally traumatizing, and may carry significant potential risks. Empiric medical treatment (EMT) treatment with either clomiphene citrate (CC;a selective estrogen receptor modulator) or letrozole (an aromatase inhibitor) in men with oligospermia has been advocated;both act by decreasing estrogen negative feedback on the hypothalamic-pituitary axis. Letrozole may offer additional benefit to obese men by blocking peripheral androgen aromatization to estradiol. Despite prevalent use, a paucity of data exists as to efficacy of EMT, particularly in regards to live birth rates. We hypothesize that when used in conjunction with controlled ovulation induction (COI)/intrauterine insemination (lUl), EMT represents effective therapy. Our overarching hypothesis is that an eight-month course of EMT and four consecutive COH/IUIs in men with non-obstructive oligo-asthenospermia and infertility will significantly improve live birth rates. We propose an 8 month three-arm (clomiphene, letrozole, placebo) randomized study design to determine if EMT significantly improves live birth pregnancy outcomes in couples with non-obstructive male infertility We also will determine if letrozole works better in obese men independent of risk factors for metabolic syndrome. If our overall hypothesis is true then the combination of EMT and COH/IUIs may represent a cost effective and efficacious treatment for idiopathic oligospermia, especially as it pertains to obesity. If we show letrozole is the most effective therapy in obese men, this will further inform future therapeutic interventions. If the letrozole effect is independent of metabolic syndrome status, the etiology of obesity-related male factor is clarified. The potential benefits of this therapy are enormous: 1) reduced healthcare cost;2) improved pregnancy outcomes;and 3) improved quality of life for previously infertile couples.

Public Health Relevance

Effective non IVF treatment of the increasing problem of idiopathic oligospermia will reduce health care costs, allow for couples with limited means to have a family, and reduce the adverse pregnancy out comes associated with IVF/ICSI. Unequivocal demonstration of efficacy of clomiphene, and particularly letrozole offers new insights into the cause of this devastating and increasingly prevalent problem.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-L (55))
Program Officer
De Paolo, Louis V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Vermont & St Agric College
Obstetrics & Gynecology
Schools of Medicine
United States
Zip Code
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
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
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
Kuang, Hongying; Jin, Susan; Hansen, Karl R et al. (2015) Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome. Hum Reprod 30:2222-33
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

Showing the most recent 10 out of 25 publications