Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment.

CONTEXT Insulin resistance plays a significant role in the pathogenesis of the polycystic ovary syndrome (PCOS) and represents a link to the unfavorable cardiovascular risk profile frequently found in affected patients. The endogenous nitric oxide synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is associated with atherosclerosis and represents an independent marker for cardiovascular morbidity and mortality. OBJECTIVE We investigated ADMA levels among other cardiovascular, metabolic, and hormonal parameters in women with PCOS and the effects of metformin treatment on these parameters. DESIGN A cross-sectional study and clinical trial were performed. PATIENTS AND PARTICIPANTS Women with PCOS (n = 83) compared with a control group of healthy women (n = 39) were studied. INTERVENTIONS In a subgroup of patients with PCOS (n = 21), the effect of metformin was assessed after 6 months of treatment. MAIN OUTCOME MEASURES ADMA, intima media thickness (IMT), metabolic and hormonal parameters, and markers of inflammation were investigated. RESULTS ADMA levels were significantly higher in the PCOS group compared with controls (0.57 +/- 0.15 vs. 0.50 +/- 0.11; P = 0.024). Androgens, C-reactive protein, fasting C-peptide, area under the curve (AUC) insulin, AUC glucose, homeostatic assessment of insulin resistance, fasting insulin, glycosylated hemoglobin, cholesterol, low-density lipoprotein cholesterol, triglycerides, and IMT were significantly higher in women with PCOS compared with controls. In PCOS patients ADMA was found to be positively correlated with body mass index (BMI), waist to hip ratio, parameters of insulin sensitivity, hyperandrogenemia (free testosterone, free androgen index), and IMT. Treatment with metformin ameliorated hyperandrogenemia and decreased ADMA levels (0.53 +/- 0.06 vs. 0.46 +/- 0.09, P = 0.013). Decrease in ADMA levels subsequent to metformin treatment did not correlate with change in BMI or metabolic parameters. CONCLUSIONS ADMA amd parameters of insulin sensitivity are elevated in women with PCOS and the degree of insulin resistance confers the greatest influence on ADMA level. Metformin treatment led to improvement of hormonal and metabolic parameters and decreased ADMA levels possibly independent of BMI and metabolic changes.

[1]  T. Imaizumi,et al.  Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery: an epidemiological study. , 2007, Atherosclerosis.

[2]  B. Zinman,et al.  Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. , 2006, The New England journal of medicine.

[3]  M. Wolzt,et al.  Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With Advanced Peripheral Artery Disease , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[4]  J. Lekakis,et al.  Inflammatory and endothelial markers in women with polycystic ovary syndrome , 2006, European journal of clinical investigation.

[5]  E. Bixler,et al.  Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea. , 2006, Metabolism: clinical and experimental.

[6]  J. Lekakis,et al.  Association of dehydroepiandrosterone-sulfate with endothelial function in young women with polycystic ovary syndrome. , 2006, European journal of endocrinology.

[7]  E. Diamanti-Kandarakis,et al.  Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. , 2006, Human reproduction.

[8]  P. Tsao,et al.  Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss. , 2006, The Journal of clinical endocrinology and metabolism.

[9]  J. Kirwan,et al.  Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome. , 2006, The Journal of clinical endocrinology and metabolism.

[10]  James L. Young,et al.  Metformin Inhibits Proinflammatory Responses and Nuclear Factor-&kgr;B in Human Vascular Wall Cells , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[11]  R. Pasquali,et al.  Insulin-sensitizing agents in polycystic ovary syndrome. , 1998, European journal of endocrinology.

[12]  N. Bukan,et al.  The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. , 2005, Human reproduction.

[13]  C. Stehouwer,et al.  Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure. , 2005, Kidney international.

[14]  H. Teede,et al.  Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. , 2005, The Journal of clinical endocrinology and metabolism.

[15]  G. Chrousos,et al.  Predictors of endothelial dysfunction in young women with polycystic ovary syndrome. , 2005, The Journal of clinical endocrinology and metabolism.

[16]  R. Azziz,et al.  Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. , 2005, The Journal of clinical endocrinology and metabolism.

[17]  J. Cameron,et al.  Vascular dysfunction and metabolic parameters in polycystic ovary syndrome. , 2005, The Journal of clinical endocrinology and metabolism.

[18]  N. Sattar,et al.  Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. , 2005, The Journal of clinical endocrinology and metabolism.

[19]  A. Pfeiffer,et al.  Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women , 2005, International Journal of Obesity.

[20]  Jun-Lin Jiang,et al.  Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity , 2005, Naunyn-Schmiedeberg's Archives of Pharmacology.

[21]  P. Flatt,et al.  Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[22]  A. Tavridou,et al.  Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. , 2005, The Journal of clinical endocrinology and metabolism.

[23]  M. Wolzt,et al.  Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease. , 2005, The Journal of clinical endocrinology and metabolism.

[24]  Sang Hoon Lee,et al.  Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment. , 2005, The American journal of cardiology.

[25]  F. Manguso,et al.  Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. , 2005, The Journal of clinical endocrinology and metabolism.

[26]  M. Wolzt,et al.  Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women. , 2004, The Journal of clinical endocrinology and metabolism.

[27]  H. Arnesen,et al.  Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. , 2004, Metabolism: clinical and experimental.

[28]  M. Hanefeld,et al.  Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. , 2004, The Journal of clinical endocrinology and metabolism.

[29]  C. Duman,et al.  Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. , 2004, The Journal of clinical endocrinology and metabolism.

[30]  A. Aljada,et al.  Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. , 2004, The Journal of clinical endocrinology and metabolism.

[31]  F. Orio,et al.  Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. , 2004, The Journal of clinical endocrinology and metabolism.

[32]  A. Seifalian,et al.  Intima-media thickness of elastic and muscular arteries of young women with polycystic ovaries. , 2004, Atherosclerosis.

[33]  M. Wolzt,et al.  Acute Escherichia coli endotoxaemia decreases the plasma l-arginine/asymmetrical dimethylarginine ratio in humans. , 2004, Clinical science.

[34]  O. Zinder,et al.  Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease. , 2004, The Journal of clinical endocrinology and metabolism.

[35]  A. Pfeiffer,et al.  The polycystic ovary syndrome per se is not associated with increased chronic inflammation. , 2004, European journal of endocrinology.

[36]  J. L. San Millán,et al.  Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity. , 2004, The Journal of clinical endocrinology and metabolism.

[37]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[38]  A. Ruokonen,et al.  Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. , 2003, The Journal of clinical endocrinology and metabolism.

[39]  J. Cooke,et al.  Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia: Role of Asymmetric Dimethylarginine , 2003, Circulation.

[40]  E. Minar,et al.  Impact of Weight Loss on Inflammatory Proteins and Their Association With the Insulin Resistance Syndrome in Morbidly Obese Patients , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[41]  G. Brabant,et al.  Oral L-arginine improves endothelial function in healthy individuals older than 70 years , 2003, Vascular medicine.

[42]  R. Böger.  Association of Asymmetric Dimethylarginine and Endothelial Dysfunction , 2003, Clinical chemistry and laboratory medicine.

[43]  T. Saeki,et al.  Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. , 2002, Biochemical and biophysical research communications.

[44]  P. Tsao,et al.  Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. , 2002, Metabolism: clinical and experimental.

[45]  R. Nijveldt,et al.  Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. , 2002, Analytical biochemistry.

[46]  P. Tsao,et al.  Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. , 2002, JAMA.

[47]  T. Lehtimäki,et al.  Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine , 2001, The Lancet.

[48]  E. Diamanti-Kandarakis,et al.  Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. , 2001, The Journal of clinical endocrinology and metabolism.

[49]  A. Hamsten,et al.  Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. , 2001, Journal of the American College of Cardiology.

[50]  J. Connell,et al.  Low grade chronic inflammation in women with polycystic ovarian syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[51]  A. Baron,et al.  Polycystic Ovary Syndrome Is Associated With Endothelial Dysfunction , 2001, Circulation.

[52]  H. Knapp,et al.  Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. , 2001, Clinical science.

[53]  A. de Leiva,et al.  Assessment of insulin sensitivity and beta-cell function from measurements in the fasting state and during an oral glucose tolerance test , 2000, Diabetologia.

[54]  J. Connell,et al.  Insulin action is associated with endothelial function in hypertension and type 2 diabetes. , 2000, Hypertension.

[55]  C. Luley,et al.  Serum homocysteine increases after therapy with fenofibrate or bezafibrate , 1999, The Lancet.

[56]  P. Dandona,et al.  Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. , 1999, Metabolism: clinical and experimental.

[57]  W. Dodson,et al.  Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. , 1999, The Journal of clinical endocrinology and metabolism.

[58]  P. Tsao,et al.  Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. , 1998, Circulation.

[59]  A. Dunaif,et al.  Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. , 1997, Endocrine reviews.

[60]  B. Vester,et al.  High Performance Liquid Chromatography Method for Rapid and Accurate Determination of Homocysteine in Plasma and Serum , 1991, European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies.

[61]  H. Graf,et al.  Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus. , 1986, Diabete & metabolisme.