Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 6, 2015

Adiposity and metabolic dysfunction in polycystic ovary syndrome

  • Susan Sam EMAIL logo

Abstract

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-age women and is associated with a high risk for metabolic disorders. Adiposity and insulin resistance are two prevalent conditions in PCOS and the likely culprits for the heightened metabolic risk. Up to 60% of women with PCOS are considered to be overweight or obese, and even among non-obese women with PCOS there is an increased accumulation of adipose tissue in abdominal depots. Insulin resistance in PCOS is unique and independent of obesity, as even non-obese women with this condition are frequently insulin resistant. However, obesity substantially aggravates the insulin resistance and the metabolic and reproductive abnormalities in women with PCOS. Recently, it has been shown that many aspects of adipose tissue function in PCOS are abnormal, and these abnormalities likely predispose to development of insulin resistance even in the absence of obesity. This review provides an overview of these abnormalities and their impact on development of metabolic disorders. At the end, an overview of the therapeutic options for management of adiposity and its complications in PCOS are discussed.


Corresponding author: Susan Sam, MD, MSc, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, USA, E-mail:

References

1. Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 2003;14:365–70.10.1016/j.tem.2003.08.002Search in Google Scholar PubMed

2. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–36.10.1056/NEJMra041536Search in Google Scholar PubMed

3. Luque-Ramirez M, Escobar-Morreale HF. Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity. Curr Hypertens Rep 2014;16:500–10.10.1007/s11906-014-0500-6Search in Google Scholar PubMed

4. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev 2012;33:812–41.10.1210/er.2012-1003Search in Google Scholar PubMed PubMed Central

5. Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev 2013;14:95–109.10.1111/j.1467-789X.2012.01053.xSearch in Google Scholar PubMed

6. Escobar-Morreale HF, San Millan JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab 2007;18:266–72.10.1016/j.tem.2007.07.003Search in Google Scholar PubMed

7. Barber TM, Franks S. Adipocyte biology in polycystic ovary syndrome. Mol Cell Endocrinol 2013;373:68–76.10.1016/j.mce.2012.10.010Search in Google Scholar PubMed

8. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–9.10.1210/jc.2003-032046Search in Google Scholar PubMed

9. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434–8.10.1210/jc.85.7.2434Search in Google Scholar

10. Targher G, Solagna E, Tosi F, Castello R, Spiazzi G, Zoppini G, Muggeo M, Day CP, Moghetti P. Abnormal serum alanine aminotransferase levels are associated with impaired insulin sensitivity in young women with polycystic ovary syndrome. J Endocrinol Invest 2009;32:695–700.10.1007/BF03345743Search in Google Scholar PubMed

11. Seow KM, Tsai YL, Hwang JL, Hsu WY, Ho LT, Juan CC. Omental adipose tissue overexpression of fatty acid transporter CD36 and decreased expression of hormone-sensitive lipase in insulin-resistant women with polycystic ovary syndrome. Hum Reprod 2009;24:1982–8.10.1093/humrep/dep122Search in Google Scholar PubMed

12. Manneras-Holm L, Leonhardt H, Kullberg J, Jennische E, Oden A, Holm G, Hellstrom M, Lonn L, Olivecrona G, Stener-Victorin E, Lonn M. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab 2011;96:E304–11.10.1210/jc.2010-1290Search in Google Scholar PubMed

13. Huang ZH, Manickam B, Ryvkin V, Zhou XJ, Fantuzzi G, Mazzone T, Sam S. PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity. J Clin Endocrinol Metab 2012;98:E17–24.10.1210/jc.2012-2697Search in Google Scholar PubMed PubMed Central

14. Pasquali R, Casimirri F, Cantobelli S, Labate AM, Venturoli S, Paradisi R, Zannarini L. Insulin and androgen relationships with abdominal body fat distribution in women with and without hyperandrogenism. Horm Res 1993;39:179–87.10.1159/000182732Search in Google Scholar PubMed

15. Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2012;18:618–37.10.1093/humupd/dms030Search in Google Scholar PubMed

16. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257–66.10.2337/diab.41.10.1257Search in Google Scholar PubMed

17. Horejsi R, Moller R, Rackl S, Giuliani A, Freytag U, Crailsheim K, Sudi K, Tafeit E. Android subcutaneous adipose tissue topography in lean and obese women suffering from PCOS: comparison with type 2 diabetic women. Am J Phys Anthropol 2004;124:275–81.10.1002/ajpa.10364Search in Google Scholar PubMed

18. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 1983;57:304–10.10.1210/jcem-57-2-304Search in Google Scholar PubMed

19. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20–34.10.1093/ajcn/4.1.20Search in Google Scholar PubMed

20. Bjorntorp P. Hyperandrogenicity in women – a prediabetic condition? J Intern Med 1993;234:579–83.10.1111/j.1365-2796.1993.tb01016.xSearch in Google Scholar PubMed

21. Wells JC. Sexual dimorphism of body composition. Best Pract Res Clin Endocrinol Metab 2007;21:415–30.10.1016/j.beem.2007.04.007Search in Google Scholar PubMed

22. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, Partington C. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women – a clinical research center study. J Clin Endocrinol Metab 1996;81:2198–203.Search in Google Scholar

23. Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ. Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab 1997;82:2044–7.10.1210/jc.82.7.2044Search in Google Scholar

24. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel, SF; Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006;91:4237–45.10.1210/jc.2006-0178Search in Google Scholar PubMed

25. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol 2013;373:29–38.10.1016/j.mce.2012.10.009Search in Google Scholar PubMed PubMed Central

26. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 1998;95:14956–60.10.1073/pnas.95.25.14956Search in Google Scholar PubMed PubMed Central

27. Sam S, Legro RS, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4797–802.10.1210/jc.2004-2217Search in Google Scholar PubMed PubMed Central

28. Sam S, Legro RS, Essah PA, Apridonidze T, Dunaif A. Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome. Proc Natl Acad Sci USA 2006;103:7030–5.10.1073/pnas.0602025103Search in Google Scholar PubMed PubMed Central

29. Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:2134–8.10.1210/jcem.87.5.8387Search in Google Scholar PubMed PubMed Central

30. Sam S, Coviello AD, Sung YA, Legro RS, Dunaif A. Metabolic phenotype in the brothers of women with polycystic ovary syndrome. Diabetes Care 2008;31:1237–41.10.2337/dc07-2190Search in Google Scholar PubMed PubMed Central

31. Corton M, Botella-Carretero JI, Lopez JA, Camafeita E, San Millan JL, Escobar-Morreale HF, Peral B. Proteomic analysis of human omental adipose tissue in the polycystic ovary syndrome using two-dimensional difference gel electrophoresis and mass spectrometry. Hum Reprod 2008;23:651–61.10.1093/humrep/dem380Search in Google Scholar PubMed

32. Corton M, Botella-Carretero JI, Benguria A, Villuendas G, Zaballos A, San Millan JL, Escobar-Morreale HF, Peral B. Differential gene expression profile in omental adipose tissue in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:328–37.10.1210/jc.2006-1665Search in Google Scholar PubMed

33. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617–23.10.1056/NEJM199608293350902Search in Google Scholar PubMed

34. Mai K, Bobbert T, Reinecke F, Andres J, Maser-Gluth C, Wudy SA, Mohlig M, Weickert MO, Hartmann MF, Schulte HM. Intravenous lipid and heparin infusion-induced elevation in free fatty acids and triglycerides modifies circulating androgen levels in women: a randomized, controlled trial. J Clin Endocrinol Metab 2008;93:3900–6.10.1210/jc.2008-0714Search in Google Scholar PubMed

35. Bellanger S, Battista MC, Fink GD, Baillargeon JP. Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells. Steroids 2012;77:347–53.10.1016/j.steroids.2011.12.017Search in Google Scholar PubMed PubMed Central

36. Despres JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, Rodes-Cabau J, Bertrand OF, Poirier P. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008;28:1039–49.10.1161/ATVBAHA.107.159228Search in Google Scholar PubMed

37. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, Vasan RS, Murabito JM, Meigs JB, Cupples LA, D’Agostino RB Sr, O’Donnell CJ. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007;116:39–48.10.1161/CIRCULATIONAHA.106.675355Search in Google Scholar PubMed

38. Fox CS, Hwang SJ, Massaro JM, Lieb K, Vasan RS, O’Donnell CJ, Hoffmann U. Relation of subcutaneous and visceral adipose tissue to coronary and abdominal aortic calcium (from the Framingham Heart Study). Am J Cardiol 2009;104:543–7.10.1016/j.amjcard.2009.04.019Search in Google Scholar PubMed PubMed Central

39. Bray GA, Jablonski KA, Fujimoto WY, Barrett-Connor E, Haffner S, Hanson RL, Hill JO, Hubbard V, Kriska A, Stamm E, Pi-Sunyer FX. Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program. Am J Clin Nutr 2008;87:1212–8.10.1093/ajcn/87.5.1212Search in Google Scholar PubMed PubMed Central

40. Sam S, Haffner S, Davidson MH, D’Agostino RB Sr, Feinstein S, Kondos G, Perez A, Mazzone T. Relation of abdominal fat depots to systemic markers of inflammation in type 2 diabetes. Diabetes Care 2009;32:932–7.10.2337/dc08-1856Search in Google Scholar PubMed PubMed Central

41. Sam S, Haffner S, Davidson MH, D’Agostino RB Sr, Feinstein S, Kondos G, Perez A, Mazzone T. Relationship of abdominal visceral and subcutaneous adipose tissue with lipoprotein particle number and size in type 2 diabetes. Diabetes 2008;57:2022–7.10.2337/db08-0157Search in Google Scholar PubMed PubMed Central

42. Sam S, Haffner S, Davidson MH, D’Agostino RB Sr, Feinstein S, Kondos G, Perez A, Mazzone T. Hypertriglyceridemic waist phenotype predicts increased visceral fat in subjects with type 2 diabetes. Diabetes Care 2009;32:1916–20.10.2337/dc09-0412Search in Google Scholar

43. Jensen MD. Role of body fat distribution and the metabolic complications of obesity. J Clin Endocrinol Metab 2008;93:S57–63.10.1210/jc.2008-1585Search in Google Scholar

44. Arner P. Not all fat is alike. Lancet 1998;351:1301–2.10.1016/S0140-6736(05)79052-8Search in Google Scholar

45. Rebrin K, Steil GM, Mittelman SD, Bergman RN. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J Clin Invest 1996;98:741–9.10.1172/JCI118846Search in Google Scholar

46. Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 2000;11:351–6.10.1016/S1043-2760(00)00323-4Search in Google Scholar

47. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847–50.10.1210/jc.83.3.847Search in Google Scholar

48. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab 2005;90:2282–9.10.1210/jc.2004-1696Search in Google Scholar PubMed

49. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997;46:860–7.10.2337/diab.46.5.860Search in Google Scholar PubMed

50. Festa A, D’Agostino R Jr, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 2001;25:1407–15.10.1038/sj.ijo.0801792Search in Google Scholar PubMed

51. Lemieux I, Pascot A, Prud’homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 2001;21:961–7.10.1161/01.ATV.21.6.961Search in Google Scholar

52. Lihn AS, Bruun JM, He G, Pedersen SB, Jensen PF, Richelsen B. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol 2004;219:9–15.10.1016/j.mce.2004.03.002Search in Google Scholar PubMed

53. Fabbrini E, Magko F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 2009;106:15430–5.10.1073/pnas.0904944106Search in Google Scholar PubMed PubMed Central

54. Aydogdu A, Tasci I, Kucukerdonmez O, Tapan S, Aydogdu S, Aydogan U, Sonmez A, Yazici M, Azal O. Increase in subcutaneous adipose tissue and fat free mass in women with polycystic ovary syndrome is related to impaired insulin sensitivity. Gynecol Endocrinol 2013;29:152–5.10.3109/09513590.2012.708802Search in Google Scholar PubMed

55. Borruel S, Fernandez-Duran E, Alpanes M, Marti D, Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 2013;98:1254–63.10.1210/jc.2012-3698Search in Google Scholar PubMed

56. Jones H, Sprung VS, Pugh CJ, Daousi C, Irwin A, Aziz N, Adams VL, Thomas EL, Bell JD, Kemp GJ, Cuthbertson DJ. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab 2012;97:3709–16.10.1210/jc.2012-1382Search in Google Scholar PubMed

57. Battaglia C, Battaglia B, Mancini F, Paradisi R, Fabbri R, Venturoli S. Ultrasonographic extended-view technique for evaluation of abdominal fat distribution in lean women with polycystic ovary syndrome. Acta Obstet Gynecol Scand 2011;90:600–8.10.1111/j.1600-0412.2011.01124.xSearch in Google Scholar PubMed

58. Carmina E, Bucchieri S, Esposito A, Del Puente A, Mansueto P, Orio F, Di Fede G, Rini G. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol Metab 2007;92:2500–5.10.1210/jc.2006-2725Search in Google Scholar PubMed

59. Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 2001;16:1255–60.10.1093/humrep/16.6.1255Search in Google Scholar PubMed

60. Hutchison SK, Stepto NK, Harrison CL, Moran LJ, Strauss BJ, Teede HJ. Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2011;96:E48–56.10.1210/jc.2010-0828Search in Google Scholar PubMed

61. Barber TM, Golding SJ, Alvey C, Wass JA, Karpe F, Franks S, McCarthy MI. Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93:999–1004.10.1210/jc.2007-2117Search in Google Scholar PubMed

62. Oh JY, Lee JA, Lee H, Oh JY, Sung YA, Chung H. Serum C-reactive protein levels in normal-weight polycystic ovary syndrome. Korean J Intern Med 2009;24:350–5.10.3904/kjim.2009.24.4.350Search in Google Scholar

63. Dolfing JG, Stassen CM, van Haard PM, Wolffenbuttel BH, Schweitzer DH. Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS. Hum Reprod 2011;26:1495–500.10.1093/humrep/der070Search in Google Scholar

64. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 2011;121:2094–101.10.1172/JCI45887Search in Google Scholar

65. Villa J, Pratley RE. Adipose tissue dysfunction in polycystic ovary syndrome. Curr Diab Rep 2011;11:179–84.10.1007/s11892-011-0189-8Search in Google Scholar

66. Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C, Creatsas G. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol Endocrinol 2012;28:974–8.10.3109/09513590.2012.683082Search in Google Scholar

67. Diamanti-Kandarakis E. Role of obesity and adiposity in polycystic ovary syndrome. Int J Obes (Lond) 2007;(31 Suppl 2):S8–13; discussion S31–2.10.1038/sj.ijo.0803730Search in Google Scholar

68. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–74.10.2337/diab.38.9.1165Search in Google Scholar

69. Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ, Henry RR. Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. J Clin Endocrinol Metab 2009;94:157–63.10.1210/jc.2008-1492Search in Google Scholar

70. Ciaraldi TP, el-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 1992;75:577–83.Search in Google Scholar

71. Ciaraldi TP, Morales AJ, Hickman MG, Odom-Ford R, Olefsky JM, Yen SS. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 1997;82:1421–5.10.1210/jc.82.5.1421Search in Google Scholar

72. Marsden PJ, Murdoch A, Taylor R. Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome. Metabolism 1994;43:1536–42.10.1016/0026-0495(94)90013-2Search in Google Scholar

73. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993;264:E197–202.10.1152/ajpendo.1993.264.2.E197Search in Google Scholar PubMed

74. Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, Chen BS, Chazenbalk G, Azziz R. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 2013;62:2278–86.10.2337/db12-0963Search in Google Scholar PubMed PubMed Central

75. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–56.10.1210/jc.2004-0395Search in Google Scholar PubMed

76. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011;121:2111–7.10.1172/JCI57132Search in Google Scholar PubMed PubMed Central

77. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008;118: 2992–3002.10.1172/JCI34260Search in Google Scholar PubMed PubMed Central

78. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011;29:415–45.10.1146/annurev-immunol-031210-101322Search in Google Scholar PubMed

79. Mathieu P, Poirier P, Pibarot P, Lemieux I, Despres JP. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension 2009;53:577–84.10.1161/HYPERTENSIONAHA.108.110320Search in Google Scholar PubMed

80. Sam S, Mazzone T. Adipose tissue changes in obesity and the impact on metabolic function. Transl Res 2014;164:284–92.10.1016/j.trsl.2014.05.008Search in Google Scholar PubMed

81. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821–30.10.1172/JCI200319451Search in Google Scholar

82. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–808.10.1172/JCI200319246Search in Google Scholar

83. Oh DY, Morinaga H, Talukdar S, Bae EJ, Olefsky JM. Increased macrophage migration into adipose tissue in obese mice. Diabetes 2012;61:346–54.10.2337/db11-0860Search in Google Scholar

84. Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008;8:301–9.10.1016/j.cmet.2008.08.015Search in Google Scholar

85. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005;54:2277–86.10.2337/diabetes.54.8.2277Search in Google Scholar

86. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O’Brien PE, Harrison LC. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010;59:1648–56.10.2337/db09-0287Search in Google Scholar

87. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A. Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 1993;268:26055–8.10.1016/S0021-9258(19)74276-8Search in Google Scholar

88. Tao T, Li S, Zhao A, Zhang Y, Liu W. Expression of the CD11c gene in subcutaneous adipose tissue is associated with cytokine level and insulin resistance in women with polycystic ovary syndrome. Eur J Endocrinol 2012;167:705–13.10.1530/EJE-12-0340Search in Google Scholar PubMed

89. Manneras-Holm L, Benrick A, Stener-Victorin E. Gene expression in subcutaneous adipose tissue differs in women with polycystic ovary syndrome and controls matched pair-wise for age, body weight, and body mass index. Adipocyte 2014;3:190–6.10.4161/adip.28731Search in Google Scholar PubMed PubMed Central

90. Toulis KA, Goulis DG, Farmakiotis D, Georgopoulos NA, Katsikis I, Tarlatzis BC, Papadimas I, Panidis D. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update 2009;15:297–307.10.1093/humupd/dmp006Search in Google Scholar PubMed

91. Chazenbalk G, Trivax BS, Yildiz BO, Bertolotto C, Mathur R, Heneidi S, Azziz R. Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{α}. J Clin Endocrinol Metab 2010;95:935–42.10.1210/jc.2009-1158Search in Google Scholar PubMed PubMed Central

92. Mlinar B, Marc J. New insights into adipose tissue dysfunction in insulin resistance. Clin Chem Lab Med 2011;49:1925–35.10.1515/CCLM.2011.697Search in Google Scholar PubMed

93. Wang L, Li S, Zhao A, Tao T, Mao X, Zhang P, Liu W. The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. J Steroid Biochem Mol Biol 2012;132:120–6.10.1016/j.jsbmb.2012.02.003Search in Google Scholar PubMed

94. Pedersen SB, Fuglsig S, Sjogren P, Richelsen B. Identification of steroid receptors in human adipose tissue. Eur J Clin Invest 1996;26:1051–6.10.1046/j.1365-2362.1996.380603.xSearch in Google Scholar PubMed

95. Corbould A. Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. J Endocrinol 2007; 192:585–94.10.1677/joe.1.07070Search in Google Scholar PubMed

96. Corbould A. Effects of spironolactone on glucose transport and interleukin-6 secretion in adipose cells of women. Horm Metab Res 2007;39:915–8.10.1055/s-2007-993156Search in Google Scholar PubMed

97. Kovacs P, Stumvoll M. Fatty acids and insulin resistance in muscle and liver. Best Pract Res Clin Endocrinol Metab 2005;19:625–35.10.1016/j.beem.2005.07.003Search in Google Scholar PubMed

98. Ek I, Arner P, Bergqvist A, Carlstrom K, Wahrenberg H. Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J Clin Endocrinol Metab 1997;82:1147–53.10.1210/jc.82.4.1147Search in Google Scholar

99. Faulds G, Ryden M, Ek I, Wahrenberg H, Arner P. Mechanisms behind lipolytic catecholamine resistance of subcutaneous fat cells in the polycystic ovarian syndrome. J Clin Endocrinol Metab 2003;88:2269–73.10.1210/jc.2002-021573Search in Google Scholar PubMed

100. Arner P. Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome. Biochimie 2005;87:39–43.10.1016/j.biochi.2004.11.012Search in Google Scholar PubMed

101. Dicker A, Ryden M, Naslund E, Muehlen IE, Wiren M, Lafontan M, Arner P. Effect of testosterone on lipolysis in human pre-adipocytes from different fat depots. Diabetologia 2004;47:420–8.10.1007/s00125-003-1324-0Search in Google Scholar PubMed

102. Ek I, Arner P, Ryden M, Holm C, Thorne A, Hoffstedt J, Wahrenberg H. A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 2002;51:484–92.10.2337/diabetes.51.2.484Search in Google Scholar PubMed

103. Trottier A, Battista MC, Geller DH, Moreau B, Carpentier AC, Simoneau-Roy J, Baillargeon JP. Adipose tissue insulin resistance in peripubertal girls with first-degree family history of polycystic ovary syndrome. Fertil Steril 2012;98:1627–34.10.1016/j.fertnstert.2012.08.025Search in Google Scholar PubMed PubMed Central

104. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012;33:981–1030.10.1210/er.2011-1034Search in Google Scholar PubMed PubMed Central

105. Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome. Brit J Obstet Gynecol 2006;113:1203–9.10.1111/j.1471-0528.2006.00973.xSearch in Google Scholar PubMed

106. Cascella T, Palomba S, De Sio I, Manguso F, Giallauria F, De Simone B, Tafuri D, Lombardi G, Colao A, Orio F. Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome. Hum Reprod 2008;23:153–9.10.1093/humrep/dem356Search in Google Scholar PubMed

107. Dunaif A, Finegood DT. β-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942–7.Search in Google Scholar

108. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96:520–7.10.1172/JCI118064Search in Google Scholar PubMed PubMed Central

109. Legro RS, Kunselman AR, Dodson WC, Dunaif A. 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. J Clin Endocrinol Metab 1999;84:165–9.10.1097/00006254-199906000-00019Search in Google Scholar

110. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141–6.10.2337/diacare.22.1.141Search in Google Scholar PubMed

111. Vrbikova J, Hill M, Fanta M. The utility of fasting plasma glucose to identify impaired glucose metabolism in women with polycystic ovary syndrome. Gynecol Endocrinol 2014;30: 664–6.10.3109/09513590.2014.912265Search in Google Scholar PubMed

112. Salley KE, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome – a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007;92:4546–56.10.1210/jc.2007-1549Search in Google Scholar PubMed

113. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010;95:2038–49.10.1210/jc.2009-2724Search in Google Scholar PubMed

114. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, Kelestimur F, Macut D, Micic D, Pasquali R, Pfeifer M, Pignatelli D, Pugeat M, Yildiz B. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 2014;171:P1–29.10.1530/EJE-14-0253Search in Google Scholar

115. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;37:119–25.10.1111/j.1365-2265.1992.tb02295.xSearch in Google Scholar

116. Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1985;61:946–51.10.1210/jcem-61-5-946Search in Google Scholar

117. Dejager S, Pichard C, Giral P, Bruckert E, Federspield MC, Beucler I, Turpin G. Smaller LDL particle size in women with polycystic ovary syndrome compared to controls. Clin Endocrinol (Oxf) 2001;54:455–62.10.1046/j.1365-2265.2001.01245.xSearch in Google Scholar

118. Talbott E, Clerici A, Berga SL, Kuller L, Guzick D, Detre K, Daniels T, Engberg RA. Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol 1998;51:415–22.10.1016/S0895-4356(98)00010-9Search in Google Scholar

119. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001;111:607–13.10.1016/S0002-9343(01)00948-2Search in Google Scholar

120. Berneis K, Rizzo M, Lazzarini V, Fruzzetti F, Carmina E. Atherogenic lipoprotein phenotype and low-density lipoproteins size and subclasses in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:186–9.10.1210/jc.2006-1705Search in Google Scholar PubMed

121. Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 2007;18:280–5.10.1016/j.tem.2007.07.004Search in Google Scholar PubMed

122. Sidhwani S, Scoccia B, Sunghay S, Stephens-Archer CN, Mazzone T, Sam S. PCOS is associated with atherogenic changes in lipoprotein particle number and size independent of body weight. Clin Endocrinol (Oxf) 2011;75:76–82.10.1111/j.1365-2265.2011.04015.xSearch in Google Scholar PubMed PubMed Central

123. Lo JC, Feigenbaum SL, Yang J, Pressman AR, Selby JV, Go AS. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1357–63.10.1210/jc.2005-2430Search in Google Scholar PubMed

124. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:48–53.10.1210/jc.2005-1329Search in Google Scholar PubMed

125. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90: 1929–35.10.1210/jc.2004-1045Search in Google Scholar PubMed

126. Hu WH, Qiao J, Wang LN, Tong J. Clinical features of the metabolic syndrome in patients with polycystic ovary syndrome. Beijing Da Xue Xue Bao 2010;42:159–63.Search in Google Scholar

127. Weerakiet S, Bunnag P, Phakdeekitcharoen B, Wansumrith S, Chanprasertyothin S, Jultanmas R, Thakkinstian A. Prevalence of the metabolic syndrome in Asian women with polycystic ovary syndrome: using the International Diabetes Federation criteria. Gynecol Endocrinol 2007;23:153–60.10.1080/09513590701214158Search in Google Scholar PubMed

128. Hahn S, Tan S, Sack S, Kimmig R, Quadbeck B, Mann K, Janssen OE. Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2007;115:130–5.10.1055/s-2007-967093Search in Google Scholar PubMed

129. Markou A, Androulakis II, Mourmouris C, Tsikkini A, Samara C, Sougioultzis S, Piaditis G, Kaltsas G. Hepatic steatosis in young lean insulin resistant women with polycystic ovary syndrome. Fertil Steril 2010;93:1220–6.10.1016/j.fertnstert.2008.12.008Search in Google Scholar PubMed

130. Economou F, Xyrafis X, Livadas S, Androulakis II, Argyrakopoulou G, Christakou CD, Kandaraki E, Palioura E, Diamanti-Kandarakis E. In overweight/obese but not in normal-weight women, polycystic ovary syndrome is associated with elevated liver enzymes compared to controls. Hormones 2009;8:199–206.10.14310/horm.2002.1236Search in Google Scholar PubMed

131. Tasali E, Van Cauter E, Ehrmann DA. Relationships between sleep disordered breathing and glucose metabolism in polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:36–42.10.1210/jc.2005-1084Search in Google Scholar PubMed

132. Mokhlesi B, Scoccia B, Mazzone T, Sam S. Risk of obstructive sleep apnea in obese and nonobese women with polycystic ovary syndrome and healthy reproductively normal women. Fertil Steril 2012;97:786–91.10.1016/j.fertnstert.2011.12.024Search in Google Scholar PubMed PubMed Central

133. Fogel RB, Malhotra A, Pillar G, Pittman SD, Dunaif A, White DP. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1175–80.10.1210/jc.86.3.1175Search in Google Scholar

134. Tasali E, Van Cauter E, Hoffman L, Ehrmann DA. Impact of obstructive sleep apnea on insulin resistance and glucose intolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:3878–84.10.1210/jc.2008-0925Search in Google Scholar PubMed PubMed Central

135. Sprung VS, Atkinson G, Cuthbertson DJ, Pugh CJ, Aziz N, Green DJ, Cable NT, Jones H. Endothelial function measured using flow-mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies. Clin Endocrinol (Oxf) 2013;78:438–46.10.1111/j.1365-2265.2012.04490.xSearch in Google Scholar PubMed

136. Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–82.10.1016/j.fertnstert.2008.09.018Search in Google Scholar PubMed

137. Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011;CD007506.10.1002/14651858.CD007506.pub3Search in Google Scholar PubMed

138. Pasquali R, Gambineri A, Cavazza C, Ibarra Gasparini D, Ciampaglia W, Cognigni GE, Pagotto U. Heterogeneity in the responsiveness to long-term lifestyle intervention and predictability in obese women with polycystic ovary syndrome. Eur J Endocrinol 2011;164:53–60.10.1530/EJE-10-0692Search in Google Scholar PubMed

139. Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, Balestra V, Melchionda N, Barbara L. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68:173–9.10.1210/jcem-68-1-173Search in Google Scholar PubMed

140. Jakubowicz DJ, Nestler JE. 17α-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss. J Clin Endocrinol Metab 1997;82:556–60.Search in Google Scholar

141. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, Fiorini S, Cognigni GE, Filicori M, Morselli-Labate AM. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:2767–74.10.1210/jcem.85.8.6738Search in Google Scholar PubMed

142. Gambineri A, Pelusi C, Genghini S, Morselli-Labate AM, Cacciari M, Pagotto U, Pasquali R. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:241–9.10.1111/j.1365-2265.2004.01973.xSearch in Google Scholar PubMed

143. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 2004;82:421–9.10.1016/j.fertnstert.2004.02.104Search in Google Scholar PubMed

144. Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C, Pagotto U, Pasquali R. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab 2006;91:3970–80.10.1210/jc.2005-2250Search in Google Scholar PubMed

145. Moran LJ, Ko H, Misso M, Marsh K, Noakes M, Talbot M, Frearson M, Thondan M, Stepto N, Teede HJ. Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet 2013;113:520–45.10.1016/j.jand.2012.11.018Search in Google Scholar PubMed

146. Gambineri A, Pelusi C, Manicardi E, Vicennati V, Cacciari M, Morselli-Labate AM, Pagotto U, Pasquali R. Glucose intolerance in a large cohort of Mediterranean women with polycystic ovary syndrome: phenotype and associated factors. Diabetes 2004;53:2353–8.10.2337/diabetes.53.9.2353Search in Google Scholar PubMed

147. Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. J Clin Endocrinol Metab 2005;90:729–33.10.1210/jc.2004-0176Search in Google Scholar PubMed

148. Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005;90:6364–9.10.1210/jc.2005-1490Search in Google Scholar PubMed

149. Harrison CL, Lombard CB, Moran LJ, Teede HJ. Exercise therapy in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2011;17:171–83.10.1093/humupd/dmq045Search in Google Scholar PubMed

150. Palomba S, Giallauria F, Falbo A, Russo T, Oppedisano R, Tolino A, Colao A, Vigorito C, Zullo F, Orio F. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study. Hum Reprod 2008;23:642–50.10.1093/humrep/dem391Search in Google Scholar PubMed

Received: 2015-1-20
Accepted: 2015-2-11
Published Online: 2015-3-6
Published in Print: 2015-2-1

©2015 by De Gruyter

Downloaded on 21.5.2024 from https://www.degruyter.com/document/doi/10.1515/hmbci-2015-0008/html
Scroll to top button