Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers

Women with polycystic ovarian syndrome (PCOS) have evidence of subclinical cardiovascular disease (CVD). However, insulin resistance, an important factor in the development of CVD in adults, is common in adolescents with PCOS, yet data in adolescents are limited. Therefore, we sought to measure insulin resistance and CVD markers in obese youth with and without PCOS. Thirty-six PCOS and 17 non-PCOS adolescent girls who were obese, sedentary, and non-hypertensive were recruited from clinics located within the Children’s Hospital Colorado. Following 3 days of controlled diet and restricted exercise, fasting plasma samples were obtained prior to a hyperinsulinemic euglycemic clamp. PCOS girls were more insulin resistant than controls (glucose infusion rate 5.24±1.86 mg/kg/min vs 9.10±2.69; p<0.001). Girls with PCOS had blood pressure in the normal range, but had greater carotid intima–media thickness (cIMT) (0.49±0.07 mm vs 0.44±0.06; p=0.038), beta stiffness index (5.1±1.3 U vs 4.4±0.9; p=0.037), and reduced arterial compliance (1.95±0.47 mm2/mmHg × 10−1 vs 2.13±0.43; p=0.047). PCOS girls had a normal mean lipid profile, yet had a more atherogenic lipoprotein cholesterol distribution and had persistent elevations of free fatty acids despite hyperinsulinemia (68±28 μmol/mL vs 41±10; p=0.001), both potential contributors to CVD. Free fatty acid concentrations correlated best with all CVD markers. In summary, adolescent girls with PCOS have greater cIMT and stiffer arteries than girls without PCOS, perhaps related to altered lipid metabolism, even when clinical measures of blood pressure and cholesterol profiles are ‘normal’. Therefore, management of adolescent PCOS should include assessment of CVD risk factor development.

[1]  C. Kaya,et al.  Evaluation of cardiac risk marker levels in obese and non-obese patients with polycystic ovaries , 2017, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[2]  F. Giallauria,et al.  Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a randomized controlled trial , 2016, Clinical endocrinology.

[3]  J. Regensteiner,et al.  Youth with type 1 diabetes have worse strain and less pronounced sex differences in early echocardiographic markers of diabetic cardiomyopathy compared to their normoglycemic peers: A RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) Study. , 2016, Journal of diabetes and its complications.

[4]  Y. Taşçı,et al.  The Predictive Role of Serum Cystatin C Levels in Polycystic Ovary Syndrome in Adolescents. , 2016, Journal of pediatric and adolescent gynecology.

[5]  V. Štich,et al.  Acute hyperlipidemia initiates proinflammatory and proatherogenic changes in circulation and adipose tissue in obese women. , 2016, Atherosclerosis.

[6]  C. Fardella,et al.  Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension , 2016, International journal of molecular sciences.

[7]  J. Hokanson,et al.  Lipoprotein subfraction cholesterol distribution is more atherogenic in insulin resistant adolescents with type 1 diabetes , 2016, Pediatric diabetes.

[8]  M. Deveer,et al.  Serum Copeptin, Pentraxin 3, Anti-Mullerian Hormone Levels With Echocardiography and Carotid Artery Intima-Media Thickness in Adolescents With Polycystic Ovary Syndrome , 2015, Journal of clinical medicine research.

[9]  Yuan-Lin Guo,et al.  Distribution of High-Density Lipoprotein Subfractions and Hypertensive Status , 2015, Medicine.

[10]  Melonie P. Heron Deaths: Leading Causes for 2012. , 2015, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[11]  F. Keleştimur,et al.  Metformin improves endothelial function and carotid intima media thickness in patients with PCOS , 2015, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[12]  Victor Mor-Avi,et al.  Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2015, European heart journal cardiovascular Imaging.

[13]  D. Macut,et al.  Cardiovascular risk factors and events in women with androgen excess , 2015, Journal of Endocrinological Investigation.

[14]  C. Lewis,et al.  Prospective Association of Polycystic Ovary Syndrome With Coronary Artery Calcification and Carotid-Intima-Media Thickness: The Coronary Artery Risk Development in Young Adults Women’s Study , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[15]  P. Dabadghao,et al.  Cardiovascular disease risk in young Indian women with polycystic ovary syndrome , 2014, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[16]  Z. Allameh,et al.  Does Carotid Intima-media Thickness have Relationship with Polycystic Ovary Syndrome? , 2013, International journal of preventive medicine.

[17]  D. Mozaffarian,et al.  Plasma Free Fatty Acids and Risk of Heart Failure: The Cardiovascular Health Study , 2013, Circulation. Heart failure.

[18]  M. Hsu,et al.  The relationship between carotid intima-media thickness and endogenous androgens in young women with polycystic ovary syndrome in Taiwan , 2013, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[19]  M. Kleber,et al.  Effect of Lifestyle Intervention on Features of Polycystic Ovarian Syndrome, Metabolic Syndrome, and Intima-Media Thickness in Obese Adolescent Girls , 2012 .

[20]  M. Rewers,et al.  Features of hepatic and skeletal muscle insulin resistance unique to type 1 diabetes. , 2012, The Journal of clinical endocrinology and metabolism.

[21]  L. Szydlowski,et al.  Blood pressure regulation and resting heart rate abnormalities in adolescent girls with polycystic ovary syndrome. , 2011, Fertility and sterility.

[22]  O. Dekkers,et al.  PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. , 2011, Human reproduction update.

[23]  M. Rizzo,et al.  Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. , 2011, Fertility and sterility.

[24]  H. Escobar-Morreale,et al.  Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. , 2011, Fertility and sterility.

[25]  M. Rewers,et al.  Association of insulin sensitivity to lipids across the lifespan in people with Type 1 diabetes , 2011, Diabetic medicine : a journal of the British Diabetic Association.

[26]  M. Rewers,et al.  Insulin Resistance, Defective Insulin-Mediated Fatty Acid Suppression, and Coronary Artery Calcification in Subjects With and Without Type 1 Diabetes , 2010, Diabetes.

[27]  J. Hokanson,et al.  Lipoprotein Subfraction Cholesterol Distribution Is Proatherogenic in Women With Type 1 Diabetes and Insulin Resistance , 2010, Diabetes.

[28]  K. Cusi,et al.  Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects , 2010, Cardiovascular diabetology.

[29]  J. Regensteiner,et al.  Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. , 2010, The Journal of clinical endocrinology and metabolism.

[30]  A. Genazzani,et al.  Adolescent girls with polycystic ovary syndrome showing different phenotypes have a different metabolic profile associated with increasing androgen levels. , 2009, Fertility and sterility.

[31]  D. Guzick,et al.  Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. , 2008, The Journal of clinical endocrinology and metabolism.

[32]  J. Marshall,et al.  Polycystic Ovary Syndrome in Adolescence , 2008, Annals of the New York Academy of Sciences.

[33]  E. V. van Beek,et al.  Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. , 2007, The Journal of clinical endocrinology and metabolism.

[34]  Melonie P. Heron,et al.  Deaths: leading causes for 2004. , 2007, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[35]  Chi-Ling Chen,et al.  Relationship Between Androgen Levels and Blood Pressure in Young Women With Polycystic Ovary Syndrome , 2007, Hypertension.

[36]  M. Nery,et al.  Prevalence of abnormalities of glucose metabolism in patients with polycystic ovary syndrome. , 2007, Arquivos brasileiros de endocrinologia e metabologia.

[37]  D. Jacobs,et al.  Influence of Insulin Resistance and Body Mass Index at Age 13 on Systolic Blood Pressure, Triglycerides, and High-Density Lipoprotein Cholesterol at Age 19 , 2006, Hypertension.

[38]  C. K. Hsiao,et al.  Low sex hormone-binding globulin is associated with low high-density lipoprotein cholesterol and metabolic syndrome in women with PCOS. , 2006, Human reproduction.

[39]  Desmond E. Williams,et al.  Dietary intake among youth with diabetes: the SEARCH for Diabetes in Youth Study. , 2006, Journal of the American Dietetic Association.

[40]  N. Goldenberg,et al.  Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents. , 2006, Metabolism: clinical and experimental.

[41]  R. Legro,et al.  Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. , 2006, The Journal of clinical endocrinology and metabolism.

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

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

[44]  T. Kılıç,et al.  Evaluation of metabolic syndrome frequency and premature carotid atherosclerosis in young women with polycystic ovary syndrome. , 2005, Human reproduction.

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

[46]  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.

[47]  Jian-Kang Chen,et al.  Androgens augment proximal tubule transport. , 2004, American journal of physiology. Renal physiology.

[48]  F. Orio,et al.  The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. , 2004, The Journal of clinical endocrinology and metabolism.

[49]  K. Moreau,et al.  Arterial intima-media thickness: site-specific associations with HRT and habitual exercise. , 2002, American journal of physiology. Heart and circulatory physiology.

[50]  C. Otto,et al.  Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. , 2002, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[51]  J. Connell,et al.  Altered vascular function in young women with polycystic ovary syndrome. , 2002, The Journal of clinical endocrinology and metabolism.

[52]  A. Oto,et al.  Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular risk in patients with polycystic ovary syndrome. , 2001, Fertility and sterility.

[53]  J F Reckelhoff,et al.  Gender Differences in the Regulation of Blood Pressure , 2001, Hypertension.

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

[55]  S. Daya,et al.  Alterations in cardiac flow parameters in patients with polycystic ovarian syndrome. , 1999, Human reproduction.

[56]  P A Cleary,et al.  Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. , 1998, JAMA.

[57]  P S Freedson,et al.  Calibration of the Computer Science and Applications, Inc. accelerometer. , 1998, Medicine and science in sports and exercise.

[58]  D. Johnston,et al.  Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries , 1996, Clinical endocrinology.

[59]  L. Kuller,et al.  Coronary heart disease risk factors in women with polycystic ovary syndrome. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[60]  N. Katsilambros,et al.  Relative androgenicity, blood pressure levels, and cardiovascular risk factors in young healthy women. , 1995, American journal of hypertension.

[61]  S. Daniels,et al.  Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. , 1992, Journal of the American College of Cardiology.

[62]  G. Conway,et al.  Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome , 1992, Clinical endocrinology.

[63]  P Pignoli,et al.  Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. , 1986, Circulation.

[64]  P. Coulson,et al.  Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. , 1985, The Journal of clinical endocrinology and metabolism.

[65]  A. Hainline,et al.  Role and methods of the central laboratory , 1983 .

[66]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[67]  E. Barinas-Mitchell,et al.  Early Biomarkers of Subclinical Atherosclerosis in Obese Adolescent Girls with Polycystic Ovary Syndrome. , 2016, The Journal of pediatrics.

[68]  T. Kawaguchi,et al.  Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study. , 2016, Metabolism: clinical and experimental.

[69]  H. Teede,et al.  Polycystic ovary syndrome , 2016, Nature Reviews Disease Primers.

[70]  Xiao-lin Li,et al.  High-density lipoprotein subfractions in relation with the severity of coronary artery disease: A Gensini score assessment. , 2015, Journal of clinical lipidology.

[71]  R. Wild Polycystic ovary syndrome: a risk for coronary artery disease? , 2002, American journal of obstetrics and gynecology.

[72]  S. Arslanian,et al.  Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. , 2001, The Journal of pediatrics.

[73]  S. Arslanian,et al.  Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease. , 2001, The Journal of clinical endocrinology and metabolism.

[74]  M. Cavaghan,et al.  Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. , 1999, Diabetes care.

[75]  R. Pate,et al.  Validation of an instrument for measurement of physical activity in youth. , 1997, Medicine and science in sports and exercise.

[76]  A. Hainline,et al.  The Coronary Drug Project. Role and methods of the Central Laboratory. , 1983, Controlled clinical trials.