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Reactive Oxygen Species-Induced Oxidative Stress in the Development of Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome

Department of Reproductive Biology (F.G., N.S.R., J.M.), Department of Medicine and Schwartz Center for Metabolism and Nutrition (J.P.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44109

Address all correspondence and requests for reprints to: Frank González, MetroHealth Medical Center, Department of Obstetrics and Gynecology, Hamann S4-44, 2500 MetroHealth Drive, Cleveland, Ohio 44109. E-mail: fgonzalez{at}metrohealth.org.

Context: Insulin resistance and chronic low level inflammation are often present in women with polycystic ovary syndrome (PCOS).

Objective: The purpose of this study was to determine the effects of hyperglycemia on reactive oxygen species (ROS) generation from mononuclear cells (MNCs) in PCOS.

Design: This was a prospective controlled study.

Setting: The study was conducted at an academic medical center.

Patients: The study population consisted of 16 women with PCOS (eight lean, eight obese) and 15 age- and body composition-matched controls (eight lean, seven obese).

Main Outcome Measures: Insulin sensitivity was derived from a 2-h, 75-g oral glucose tolerance test (IS_OGTT). ROS generation and p47^phox protein expression were quantitated from MNCs obtained from blood drawn fasting and 2 h after glucose ingestion.

Results: IS_OGTT was lower in PCOS, compared with controls (3.1 ± 0.3 vs. 6.3 ± 0.9, P < 0.003). The percent change in ROS generation from MNCs was higher in lean and obese PCOS, compared with lean controls (138.8 ± 21.3 and 154.2 ± 49.1 vs. 0.6 ± 12.7, P < 0.003). The percent change in ROS generation from MNCs correlated positively with glucose area under the curve (r = 0.38, P < 0.05), and plasma levels of testosterone (r = 0.59, P < 0.002) and androstenedione (r = 0.50, P < 0.009). The percent change in p47^phox from MNCs was also higher in lean and obese PCOS, compared with lean controls (36.2 ± 18.2 and 39.1 ± 8.0 vs. –13.7 ± 8.7, P < 0.02), and correlated negatively with IS_OGTT (r = –0.39, P < 0.05).

Conclusion: ROS generation from MNCs in response to hyperglycemia is increased in PCOS independent of obesity. The resultant oxidative stress may contribute to a proinflammatory state that induces insulin resistance and hyperandrogenism in women with this disorder.

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