Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility among women, and women with PCOS are at increased risk for pregnancy complications such as gestational diabetes and pre-eclampsia. PCOS results in a significant health care burden to our economy with an estimated $500 million spent annually in the U.S. on infertility treatment alone. Both hyperandrogenism (HA) and obesity exacerbated insulin resistance (IR) are characteristic of the syndrome, and are targets for treatment, but which should be the predominant focus is unknown. We hypothesize that the key to improving the live birth rate in infertile women with PCOS is to correct HA, and the key to avoiding later pregnancy complications is to improve IR with an intense weight loss program. Phase I will be a randomized trial of three preconception interventions (lasting 4 mos.) in infertile women with PCOS (N=246, ~150 at Penn State and ~100 at U Penn): A) a combined intervention of medication (sibutramine), meal replacements, and lifestyle modficiation to improve IR B) continuous OCP for 4 months to improve HA and C) the combination of both to improve HA and IR. This will be followed by ovulation induction with clomiphene citrate in all subjects for up to 4 cycles (Phase II). All treatment arms will follow standardized diet and exercise regimens at this point. The primary outcome of the trial will be the cumulative live birth rates of the three treatment groups (and secondarily ovulation rates) which we propose will increase stepwise from Treatment A thru C. We will also examine changes in the PCOS phenotype during Phase I and II and will study all pregnant subjects by trimester in pregnancy for changes in glucose tolerance and blood pressure in the two treatment arms (Phase III). The goal of this trial is to establish the relative roles of HA versus IR and in combination in treating infertility and preventing pregnancy complications in women with PCOS. We will adapt existing medications and treatments with an established favorable risk benefit ratio to the treatment of infertile women with PCOS. Our trial is novel and important because we are studying women with PCOS across the continuum from pre-conception to conception to delivery. This project has assembled a unique multidisciplinary team bridging vast experience in their respective areas, and fulfills the mandates of the NIH roadmap to develop clinical interventions that improve patient oriented outcomes.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women in the U.S. and is the leading cause of infertility in women. The best treatment for this disorder is unknown and this proposal will examine the effects of weight loss, reducing female androgens with the birth control pill, and using both in combination on pregnancy rates and pregnancy complication rates in women with PCOS. Our goal is to develop safe and effective treatments to improve the treatment of infertility in women with PCOS, but the findings can be generalized to all women with PCOS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Eisenberg, Esther
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Pennsylvania State University
Obstetrics & Gynecology
Schools of Medicine
United States
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Legro, Richard S (2012) Superovulation and multiple birth: in search of kryptonite. Fertil Steril 97:793-4
Dmitrovic, Romana; Kunselman, Allen R; Legro, Richard S (2012) Continuous glucose monitoring during pregnancy in women with polycystic ovary syndrome. Obstet Gynecol 119:384
Dmitrovic, Romana; Katcher, Heather I; Kunselman, Allen R et al. (2011) Continuous glucose monitoring during pregnancy in women with polycystic ovary syndrome. Obstet Gynecol 118:878-85
Pasquali, Renato; Stener-Victorin, Elisabet; Yildiz, Bulent O et al. (2011) PCOS Forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrinol (Oxf) 74:424-33
Dapuzzo, Lisa; Seitz, Faith E; Dodson, William C et al. (2011) Incomplete and inconsistent reporting of maternal and fetal outcomes in infertility treatment trials. Fertil Steril 95:2527-30
Jones, Michelle R; Chua, Angela; Chen, Yii-Der I et al. (2011) Harnessing expression data to identify novel candidate genes in polycystic ovary syndrome. PLoS One 6:e20120
Ewens, Kathryn G; Jones, Michelle R; Ankener, Wendy et al. (2011) FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS One 6:e16390
Ewens, Kathryn G; Jones, Michelle R; Ankener, Wendy et al. (2011) Type 2 diabetes susceptibility single-nucleotide polymorphisms are not associated with polycystic ovary syndrome. Fertil Steril 95:2538-41.e1-6
Legro, Richard S (2010) Metformin during pregnancy in polycystic ovary syndrome: another vitamin bites the dust. J Clin Endocrinol Metab 95:5199-202
Legro, Richard S; McAllister, Jan M (2009) Heirarchical clustering and beyond in PCOS endometrium: brave new world. J Clin Endocrinol Metab 94:1084-5

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