Insulin Resistance in Non-Obese Women with Polycystic Ovary Syndrome: Relation to Byproducts of Oxidative Stress

Abstract

To get more insight into molecular mechanisms underlying oxidative stress and its link with insulin resistance, oxidative stress parameters, as well as, antioxidant enzyme activities were studied in young, non-obese women with polycystic ovary syndrome (PCOS). Study was performed in 34 PCOS women and 23 age and body mass index (BMI)-matched healthy controls. Plasma nitrotyrosine and malondialdehyde (MDA), representative byproducts of protein and lipid oxidative damage, were determined by enzyme immunoassay. Antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPX) were studied spectrophotometrically. Insulin resistance was calculated using homeostasis assessment model (HOMA-IR). Plasma nitrotyrosine and MDA were increased, but only nitrotyrosine was signifi cantly higher (p < 0.05) in PCOS women compared to controls. Uric acid (surrogate marker of × antine oxidase) was also signifi – cantly elevated in PCOS (p < 0.05). Both plasma SOD and GPX activity showed no statistically significant difference between PCOS and controls. Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of MDA (r = 0.397 and r = 0.523, respectively; p < 0.05) as well as GPX activity (r = 0.531 and r = 0.358, respectively; p < 0.05). Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS.

Key words

polycystic ovary syndrome - oxidative stress - nitrotyrosine - lipid peroxidation

References

• 1 Azziz R, Woods KS, Reyna R. et al . The prevalence and features of the polycystic ovary syndrome in an unselected population.  J Clin Endocrinol Metab. 2004;  89 2745-2749
• 2 Balen AH, Laven JS, Tan SL. et al . Ultrasound assessment of the polycystic ovary: international consensus definitions.  Hum Reprod Update. 2003;  9 505-514
• 3 Bausenwein J, Serke H, Eberle K. et al . Elevated levels of oxidized low-density lipoprotein and of catalase activity in follicular fluid of obese women.  Mol Hum Reprod. 2010;  16 117-124
• 4 Carmina E, Orio F, Palomba S. et al . Evidence for altered adipocyte function in polycystic ovary syndrome.  Eur J Endocrinol. 2005;  152 389-394
• 5 Cussons AJ, Stuckey BG, Watts GF. Cardiovascular disease in the polycystic ovary syndrome: new insights and perspectives.  Atherosclerosis. 2006;  185 227-239
• 6 De Simone G, Devereux RB, Roman MJ. et al . Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults.  Hypertension. 1994;  23 600-606
• 7 Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus.  Am J Med. 1995;  98 33S-39S
• 8 Ferrannini E, Natali A, Bell P. et al . Insulin resistance and hypersecretion in obesity. European group for the study of insulin resistance (EGIR).  J Clin Invest. 1997;  100 1166-1173
• 9 Gonzalez F, Rote NS, Minium J. et al . Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2006;  91 336-340
• 10 Goodarzi MO, Korenman SG. The importance of insulin resistance in polycystic ovary syndrome.  Fertil Steril. 2003;  80 255-258
• 11 Hatch R, Rosenfield RL, Kim MH. et al . Hirsutism: implications, etiology, and management.  Am J Obstet Gynecol. 1981;  140 815-830
• 12 Karadeniz M, Erdogan M, Tamsel S. et al . Oxidative stress markers in young patients with polycystic ovary syndrome, the relationship between insulin resistances.  Exp Clin Endocrinol Diabetes. 2008;  116 231-235
• 13 Kaya MG, Gunebakmaz O, Zencir C. et al . An assessment of the elastic properties of the aorta in nonobese women with polycystic ovary syndrome.  Fertil Steril. 2010;  94 2402-2405
• 14 Kim JA, Montagnani M, Koh KK. et al . Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms.  Circulation. 2006;  113 1888-1904
• 15 Krieger-Brauer HI, Kather H. Human fat cells possess a plasma membrane-bound H₂O₂-generating system that is activated by insulin via a mechanism bypassing the receptor kinase.  J Clin Invest. 1992;  89 1006-1013
• 16 Kuscu NK, Var A. Oxidative stress but not endothelial dysfunction exists in non-obese, young group of patients with polycystic ovary syndrome.  Acta Obstet Gynecol Scand. 2009;  88 612-617
• 17 Laven JS, Imani B, Eijkemans MJ. et al . New approach to polycystic ovary syndrome and other forms of anovulatory infertility.  Obstet Gynecol Surv. 2002;  57 755-767
• 18 Lee YS, Kim AY, Choi JW. et al . Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress.  Mol Endocrinol. 2008;  22 2176-2189
• 19 Macut D, Damjanovic S, Panidis D. et al . Oxidised low-density lipoprotein concentration – early marker of an altered lipid metabolism in young women with PCOS.  Eur J Endocrinol. 2006;  155 131-136
• 20 Mathur RS, Moody LO, Landgrebe S. et al . Plasma androgens and sex hormone-binding globulin in the evaluation of hirsute females.  Fertil Steril. 1981;  35 29-35
• 21 Matthews DR, Hosker JP, Rudenski AS. et al . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 22 Orio Jr F, Palomba S, Cascella T. et al . Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2004;  89 4588-4593
• 23 Orio F, Vuolo L, Palomba S. et al . Metabolic and cardiovascular consequences of polycystic ovary syndrome.  Minerva Ginecol. 2008;  60 39-51
• 24 Paradisi G, Steinberg HO, Hempfling A. et al . Polycystic ovary syndrome is associated with endothelial dysfunction.  Circulation. 2001;  103 1410-1415
• 25 Rifici VA, Schneider SH, Khachadurian AK. Stimulation of low-density lipoprotein oxidation by insulin and insulin like growth factor I.  Atherosclerosis. 1994;  107 99-108
• 26 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.  Fertil Steril. 2004;  81 19-25
• 27 Sabuncu T, Vural H, Harma M. et al . Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease.  Clin Biochem. 2001;  34 407-413
• 28 Sahin Y, Unluhizarci K, Yilmazsoy A. et al . The effects of metformin on metabolic and cardiovascular risk factors in nonobese women with polycystic ovary syndrome.  Clin Endocrinol (Oxf). 2007;  67 904-908
• 29 Shin MJ, Lee JH, Jang Y. et al . Insulin resistance, adipokines, and oxidative stress in nondiabetic, hypercholesterolemic patients: leptin as an 8-epi-prostaglandin F2alpha determinant.  Metabolism. 2006;  55 918-922
• 30 Simic DV, Mimic-Oka J, Pljesa-Ercegovac M. et al . Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension.  J Hum Hypertens. 2006;  20 149-155
• 31 Song P, Wu Y, Xu J. et al . Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner.  Circulation. 2007;  116 1585-1595
• 32 Yilmaz M, Bukan N, Ayvaz G. et al . The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome.  Hum Reprod. 2005;  20 3333-3340

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