POLYCYSTIC OVARY SYNDROME Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy Helena J. Teede, Ph.D., a,b Caroline Meyer, Ph.D., b Samantha K. Hutchison, M.B., B.S., a Sophia Zoungas, Ph.D., a,b Barry P. McGrath, M.D., c and Lisa J. Moran, Ph.D. a a The Jean Hailes Foundation for Women’s Health, Monash Institute of Health Services Research, Monash University, Melbourne; b Diabetes Unit, Southern Health, Melbourne; and c Department of Vascular Sciences and Medicine, Centre for Vascular Health, Monash University, Clayton, Victoria, Australia Objective: To assess the interaction between insulin resistance and endothelial function and the optimal treatment strategy addressing cardiovascular risk in polycystic ovary syndrome. Design: Randomized controlled trial. Setting: Controlled clinical study. Patient(s): Overweight age- and body mass index–matched women with polycystic ovary syndrome. Intervention(s): Six months metformin (1 g two times per day, n ¼ 36) or oral contraceptive pill (OCP) (35 mg ethinyl E 2 –2 mg cytoproterone acetate, n ¼ 30). Main Outcome Measure(s): Fasting and oral glucose tolerance test glucose and insulin levels, endothelial function (flow-mediated dilation, asymmetric dimethylarginine, plasminogen activator inhibitor-1, von Willebrand factor), inflammatory markers (high-sensitivity C-reactive protein), lipids, and hyperandrogenism. Result(s): The OCP increased levels of glucose and insulin on oral glucose tolerance test, high-sensitivity C-re- active protein, triglycerides, and sex-hormone binding globulin and decreased levels of low-density lipoprotein cholesterol and T. Metformin decreased levels of fasting insulin, oral glucose tolerance test insulin, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. Flow-mediated dilation increased only with met- formin (þ2.2%  4.8%), whereas asymmetric dimethylarginine decreased equivalently for OCP and metformin (0.3  0.1 vs. 0.1  0.1 mmol/L). Greater decreases in plasminogen activator inhibitor-1 occurred for the OCP than for metformin (1.8  1.6 vs. 0.7  1.7 U/mL). Conclusion(s): In polycystic ovary syndrome, metformin improves insulin resistance, inflammatory markers, and endothelial function. The OCP worsens insulin resistance and glucose homeostasis, inflammatory markers, and tri- glycerides and has neutral or positive endothelial effects. The effect of the OCP on cardiovascular risk in polycystic ovary syndrome is unclear. (Fertil Steril Ò 2010;93:184–91. Ó2010 by American Society for Reproductive Medi- cine.) Key Words: Polycystic ovary syndrome, insulin resistance, endothelial function, oral contraceptive pill, metformin Polycystic ovary syndrome (PCOS) affects approximately 6.6% of women of reproductive age and presents with reproductive manifestations including anovulation, infertil- ity, and hyperandrogenism. It is recognized as a metabolic condition with insulin resistance (IR) a key pathophysiologic component contributing to hyperandrogenism and the repro- ductive and metabolic features of PCOS (1). Overweight or obesity affects 50% to 80% of women with PCOS and exac- erbates IR and the reproductive and metabolic features of PCOS (2). Polycystic ovary syndrome also is associated with increased cardiovascular risk factors including the met- abolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, endothelial dysfunction, and subclinical atheroscle- rosis (3). Addressing these complications is thus advisable and offers a potential to prevent future metabolic disease in this population. Received April 3, 2008; revised September 5, 2008; accepted September 6, 2008; published online November 18, 2008. H.J.T. has nothing to disclose. C.M. has nothing to disclose. S.K.H. has nothing to disclose. S.Z. has nothing to disclose. B.P.M. has served on the Cardiovascular Advisory Boards of Boehringer Ingelheim and Solvay Pharmaceuticals. L.J.M. has nothing to disclose. This work was an investigator-initiated trial supported by a competitive Cardiovascular Lipid (CVL) Research Grant sponsored by Pfizer Aus- tralia and through internal department funds. H.J.T. received a National Health and Medical Research Council Career Development Award. L.J.M. received the Jean Hailes Fellowship. Presented at the Endocrine Society of Australia National Meeting, Christ- church, New Zealand, September 2–5, 2007, and the American Endo- crine Society Annual Meeting, San Francisco, California, June 15–18, 2008. Reprint requests: Lisa J. Moran, Ph.D., The Jean Hailes Foundation for Women’s Health, Monash Institute of Health Services Research, Locked bag 29, Monash Medical Centre, 246 Clayton Rd., Clayton, Vic- toria 3168, Australia (FAX: 61-03-9594-7554; E-mail: lisa.moran@med. monash.edu.au). Fertility and Sterility â Vol. 93, No. 1, January 2010 0015-0282/10/$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2008.09.034 184