Semin Reprod Med 2015; 33(4): 276-286
DOI: 10.1055/s-0035-1554918
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nutrient-Induced Inflammation in Polycystic Ovary Syndrome: Role in the Development of Metabolic Aberration and Ovarian Dysfunction

Frank González
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
› Author Affiliations
Further Information

Publication History

Publication Date:
01 July 2015 (online)

Abstract

A pathophysiology paradigm shift has emerged with the discovery that polycystic ovary syndrome (PCOS) is a proinflammatory state. Despite the dogma that the compensatory hyperinsulinemia of insulin resistance is the promoter of hyperandrogenism, physiological insulin infusion has no effect on androgen levels in PCOS. The dogma also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30 to 50% of women with PCOS who are of normal weight and lack insulin resistance. Inflammation is the underpinning of insulin resistance in obesity and type 2 diabetes, and may also be the cause of insulin resistance when present in PCOS. The origin of inflammation in PCOS has been ascribed to excess abdominal adiposity or frank obesity. However, nutrients such as glucose and saturated fat can incite inflammation from circulating mononuclear cells (MNC) of women with PCOS independent of excess adiposity and insulin resistance, and can also promote atherogenesis. Hyperandrogenism activates MNC in the fasting state to increase MNC sensitivity to nutrients, and is a potential mechanism for initiating inflammation in PCOS. However, chronic ovarian androgen suppression does not reduce inflammation in normal-weight women with PCOS. Direct exposure of ovarian theca cells to proinflammatory stimuli in vitro increases androgen production. These findings may be corroborated in vivo with anti-inflammatory therapy to normal-weight insulin-sensitive women with PCOS without abdominal adiposity to observe for amelioration of ovarian dysfunction.

 
  • References

  • 1 The Rotterdam ESHRE/ASRM-Sponsored PCOS Conference Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25
  • 2 Wild RA, Carmina E, Diamanti-Kandarakis E , et al. 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 (5) 2038-2049
  • 3 Eisner JR, Barnett MA, Dumesic DA, Abbott DH. Ovarian hyperandrogenism in adult female rhesus monkeys exposed to prenatal androgen excess. Fertil Steril 2002; 77 (1) 167-172
  • 4 Daskalopoulos GN, Karkanaki A, Karagiannis A, Mikhailidis DP, Athyros VG. Is the risk for cardiovascular disease increased in all phenotypes of the polycystic ovary syndrome?. Angiology 2011; 62 (4) 285-290
  • 5 González F, Rote NS, Minium J, Kirwan JP. Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91 (4) 1508-1512
  • 6 Piotrowski PC, Rzepczynska IJ, Kwintkiewicz J, Duleba AJ. Oxidative stress induces expression of CYP11A, CYP17, STAR and 3βHSD in rat theca-interstitial cells. J Soc Gynecol Investig 2005; 12 (2, Suppl): 319A
  • 7 González F, Minium J, Rote NS, Kirwan JP. Hyperglycemia alters tumor necrosis factor-α release from mononuclear cells in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90 (9) 5336-5342
  • 8 González F, Rote NS, Minium J, Kirwan JP. In vitro evidence that hyperglycemia stimulates tumor necrosis factor-α release in obese women with polycystic ovary syndrome. J Endocrinol 2006; 188 (3) 521-529
  • 9 González F, Rote NS, Minium J, Kirwan JP. Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91 (1) 336-340
  • 10 González F, Rote NS, Minium J, Kirwan JP. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 2009; 58 (7) 954-962
  • 11 Escobar-Morreale HF, Calvo RM, Sancho J, San Millán JL. TNF-alpha and hyperandrogenism: a clinical, biochemical, and molecular genetic study. J Clin Endocrinol Metab 2001; 86 (8) 3761-3767
  • 12 Villuendas G, San Millán JL, Sancho J, Escobar-Morreale HF. The -597 G—>A and -174 G—>C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. J Clin Endocrinol Metab 2002; 87 (3) 1134-1141
  • 13 Peral B, San Millán JL, Castello R, Moghetti P, Escobar-Morreale HF. Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab 2002; 87 (8) 3977-3983
  • 14 Escobar-Morreale HF, Calvo RM, Villuendas G, Sancho J, San Millán JL. Association of polymorphisms in the interleukin 6 receptor complex with obesity and hyperandrogenism. Obes Res 2003; 11 (8) 987-996
  • 15 Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril 2011; 95 (3) 1048-58.e1 , 2
  • 16 Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107 (3) 391-397
  • 17 Boulman N, Levy Y, Leiba R , et al. Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease. J Clin Endocrinol Metab 2004; 89 (5) 2160-2165
  • 18 Tarkun I, Arslan BC, Cantürk Z, Türemen E, Sahin T, Duman C. Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J Clin Endocrinol Metab 2004; 89 (11) 5592-5596
  • 19 Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49 (21) 2129-2138
  • 20 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112 (12) 1796-1808
  • 21 Cinti S, Mitchell G, Barbatelli G , et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46 (11) 2347-2355
  • 22 Groemping Y, Lapouge K, Smerdon SJ, Rittenger K. Understanding activation of NADPH oxidase: a structural characterization of p47phox. Biophys J 2003; 84: 356A
  • 23 Chanock SJ, el Benna J, Smith RM, Babior BM. The respiratory burst oxidase. J Biol Chem 1994; 269 (40) 24519-24522
  • 24 Baldwin Jr AS. The transcription factor NFκB and human disease. J Clin Invest 2001; 107: 3-6
  • 25 Fain JN, Bahouth SW, Madan AK. TNFα release by nonfat cells of adipose tissue. Int J Obes 2004; 28: 616-622
  • 26 Rui L, Aguirre V, Kim JK , et al. Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 2001; 107 (2) 181-189
  • 27 Holmes AG, Mesa JL, Neill BA , et al. Prolonged interleukin-6 administration enhances glucose tolerance and increases skeletal muscle PPARalpha and UCP2 expression in rats. J Endocrinol 2008; 198 (2) 367-374
  • 28 Franckhauser S, Elias I, Rotter Sopasakis V , et al. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 2008; 51 (7) 1306-1316
  • 29 Romano M, Sironi M, Toniatti C , et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 6 (3) 315-325
  • 30 Mohanty P, Ghanim H, Hamouda W, Aljada A, Garg R, Dandona P. Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells. Am J Clin Nutr 2002; 75 (4) 767-772
  • 31 Deopurkar R, Ghanim H, Friedman J , et al. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care 2010; 33 (5) 991-997
  • 32 Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004; 110 (12) 1564-1571
  • 33 Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 2001; 19 (5) 378-387
  • 34 Emanuelli B, Peraldi P, Filloux C , et al. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 2001; 276 (51) 47944-47949
  • 35 Stephens JM, Pekala PH. Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Regulations is coordinate and independent of protein synthesis. J Biol Chem 1992; 267 (19) 13580-13584
  • 36 Moshage HJ, Roelofs HM, van Pelt JF , et al. The effect of interleukin-1, interleukin-6 and its interrelationship on the synthesis of serum amyloid A and C-reactive protein in primary cultures of adult human hepatocytes. Biochem Biophys Res Commun 1988; 155 (1) 112-117
  • 37 Carlos T, Kovach N, Schwartz B , et al. Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Blood 1991; 77 (10) 2266-2271
  • 38 Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001; 103 (9) 1194-1197
  • 39 Goodarzi MO, Korenman SG. The importance of insulin resistance in polycystic ovary syndrome. Fertil Steril 2003; 80 (2) 255-258
  • 40 Carmina E, Bucchieri S, Esposito A , et al. 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 (7) 2500-2505
  • 41 González F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor α in normal-weight women with polycystic ovary syndrome. Metabolism 1999; 48 (4) 437-441
  • 42 Sayin NC, Gücer F, Balkanli-Kaplan P , et al. Elevated serum TNF-alpha levels in normal-weight women with polycystic ovaries or the polycystic ovary syndrome. J Reprod Med 2003; 48 (3) 165-170
  • 43 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 (2, Pt 1) E197-E202
  • 44 Corbould A, Kim YB, Youngren JF , et al. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005; 288 (5) E1047-E1054
  • 45 Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980; 50 (1) 113-116
  • 46 Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83 (6) 2001-2005
  • 47 Micic D, Popovic V, Nesovic M , et al. Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease. J Steroid Biochem 1988; 31 (6) 995-999
  • 48 Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 1989; 83 (1) 23-29
  • 49 Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989; 38 (9) 1165-1174
  • 50 Nelson D, Cox MM. Lehninger Principles of Biochemistry. 4th ed. New York: WH Freeman; 2005: 648-649
  • 51 Tan AS, Ahmed N, Berridge MV. Acute regulation of glucose transport after activation of human peripheral blood neutrophils by phorbol myristate acetate, fMLP, and granulocyte-macrophage colony-stimulating factor. Blood 1998; 91 (2) 649-655
  • 52 Carman GM, Han G-S. Regulation of phospholipid synthesis in yeast. J Lipid Res 2009; 50 (Suppl): S69-S73
  • 53 Inoguchi T, Li P, Umeda F , et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C—dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49 (11) 1939-1945
  • 54 Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336 (15) 1066-1071
  • 55 González F, Sia CL, Abdelhadi OA, Melvin RM, Garrett TJ. Lipid-induced reactive oxygen species generation is related to ovarian androgen hyperresponsiveness to HCG stimulation in normal weight women with polycystic ovary syndrome. Reprod Sci 2013; 20 (3, Suppl): 79A
  • 56 Abdelhadi OA, Shepard MK, Sia CL, Garrett TJ, González F. Activation of nuclear factor κB in response to cream ingestion is related to ovarian androgen hypersecretion in polycystic ovary syndrome. Fertil Steril 2013; 100 (2, Suppl): S63
  • 57 Abdelhadi OA, Considine RV, Acton AJ, Shepard MK, González F. Cream ingestion promotes the expression of toll-like receptor-4 and suppressor of cytokine signaling-3 in polycystic ovary syndrome. Reprod Sci 2014; 21 (3, Suppl): 126A-127A
  • 58 González F, Rote NS, Minium J, Kirwan JP. In vitro evidence that hyperglycemia stimulates increased IL-6 release from mononuclear cells of obese women with polycystic ovary syndrome. Fertil Steril 2006; 86 (2, Suppl): S449-S450
  • 59 Abdelhadi OA, Considine RV, Acton AJ, Sia CL, González F. Lipid-stimulated TNFα release from mononuclear cells is related to ovarian androgen hyperresponsiveness to HCG administration in polycystic ovary syndrome. Proceedings from the 11th meeting of the Androgen Excess and Polycystic Ovary Syndrome Society, 2013;Prog pg 37
  • 60 Meijer CA, Le Haen PA, van Dijk RA , et al. Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study. Clin Sci (Lond) 2012; 122 (9) 421-428
  • 61 McCaffrey TA, Fu C, Du B , et al. High-level expression of Egr-1 and Egr-1-inducible genes in mouse and human atherosclerosis. J Clin Invest 2000; 105 (5) 653-662
  • 62 Radler-Pohl A, Gebel S, Sachsenmaier C , et al. The activation and activity control of AP-1 (fos/jun). Ann N Y Acad Sci 1993; 684: 127-148
  • 63 Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85 (1) 1-31
  • 64 Cui MZ, Parry GC, Oeth P , et al. Transcriptional regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and EGR-1. J Biol Chem 1996; 271 (5) 2731-2739
  • 65 Moreno PR, Bernardi VH, López-Cuéllar J , et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 1996; 94 (12) 3090-3097
  • 66 Lewandowski KC, Komorowski J, O'Callaghan CJ , et al. Increased circulating levels of matrix metalloproteinase-2 and -9 in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91 (3) 1173-1177
  • 67 Davies MJ. The birth, growth, and consequences of the atherosclerotic plaque. Dialog Cardiovasc Med 1999; 4: 115-178
  • 68 Kim F, Pham M, Luttrell I , et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007; 100 (11) 1589-1596
  • 69 Ritossa F. Discovery of the heat shock response. Cell Stress Chaperones 1996; 1 (2) 97-98
  • 70 Hall L, Martinus RD. Hyperglycaemia and oxidative stress upregulate HSP60 & HSP70 expression in HeLa cells. Springerplus 2013; 2: 431
  • 71 Tsan MF, Gao B. Endogenous ligands of Toll-like receptors. J Leukoc Biol 2004; 76 (3) 514-519
  • 72 Cani PD, Bibiloni R, Knauf C , et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57 (6) 1470-1481
  • 73 Creely SJ, McTernan PG, Kusminski CM , et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 2007; 292 (3) E740-E747
  • 74 Liu B, Cai LY, Lv HM , et al. Raised serum levels of matrix metalloproteinase-9 in women with polycystic ovary syndrome and its association with insulin-like growth factor binding protein-1. Gynecol Endocrinol 2008; 24 (5) 285-288
  • 75 González F, Kirwan JP, Rote NS, Minium J. Elevated circulating levels of tissue factor in polycystic ovary syndrome. Clin Appl Thromb Hemost 2013; 19 (1) 66-72
  • 76 Gao H, Meng J, Xu M , et al. Serum heat shock protein 70 concentration in relation to polycystic ovary syndrome in a non-obese Chinese population. PLoS ONE 2013; 8 (6) e67727
  • 77 González F, Kirwan JP, Rote NS, Minium J. Glucose ingestion stimulates atherothrombotic inflammation in polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2013; 304 (4) E375-E383
  • 78 González F, Considine RV, Pardue SL, Acton AJ. Cream ingestion promotes the expression of toll-like receptor-2 and matrix metalloproteinase-2 in polycystic ovary syndrome. Fertil Steril 2014; 102 (2, Suppl): e250
  • 79 Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril 2002; 77 (6) 1095-1105
  • 80 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 2003; 46 (1) 3-19
  • 81 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 (1) 520-527
  • 82 Nicol LE, Grant WF, Comstock SM , et al. Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates. J Endocrinol 2013; 217 (2) 207-213
  • 83 Ehses JA, Perren A, Eppler E , et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 2007; 56 (9) 2356-2370
  • 84 El-Assaad W, Buteau J, Peyot ML , et al. Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 2003; 144 (9) 4154-4163
  • 85 Westwell-Roper C, Nackiewicz D, Dan M, Ehses JA. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunol Cell Biol 2014; 92 (4) 314-323
  • 86 Kanat M, Norton L, Winnier D, Jenkinson C, DeFronzo RA, Abdul-Ghani MA. Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. Acta Diabetol 2011; 48 (3) 209-217
  • 87 Abdul-Ghani MA, Williams K, DeFronzo RA, Stern M. What is the best predictor of future type 2 diabetes?. Diabetes Care 2007; 30 (6) 1544-1548
  • 88 Malin SK, Kirwan JP, Sia CL, Gonzalez F. Pancreatic β-cell dysfunction in polycystic ovary syndrome: Role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation. Am J Physiol Endocrinol Metab 2015; 308 (9) E770-E777
  • 89 Malin SK, Kirwan JP, Sia CL, González F. Glucose-induced oxidative stress is inversely related to pancreatic β-cell function in polycystic ovary syndrome. J Clin Endocrinol Metab 2014; 99: 322-329
  • 90 Lindholm A, Blomquist C, Bixo M , et al. No difference in markers of adipose tissue inflammation between overweight women with polycystic ovary syndrome and weight-matched controls. Hum Reprod 2011; 26 (6) 1478-1485
  • 91 Svendsen PF, Christiansen M, Hedley PL, Nilas L, Pedersen SB, Madsbad S. Adipose expression of adipocytokines in women with polycystic ovary syndrome. Fertil Steril 2012; 98 (1) 235-241
  • 92 González F, Sia CL, Shepard MK, Rote NS, Minium J. Hyperglycemia-induced oxidative stress is independent of excess abdominal adiposity in normal-weight women with polycystic ovary syndrome. Hum Reprod 2012; 27 (12) 3560-3568
  • 93 González F, Sia CL, Shepard MK, Rote NS, Minium J. Inflammation in response to glucose ingestion is independent of excess abdominal adiposity in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2012; 97 (11) 4071-4079
  • 94 González F, Sia CL, Shepard MK, Rote NS, Minium J. The altered mononuclear cell-derived cytokine response to glucose ingestion is not regulated by excess adiposity in polycystic ovary syndrome. J Clin Endocrinol Metab 2014; 99 (11) E2244-E2251
  • 95 González F, Rote NS, Minium J, O'leary VB, Kirwan JP. Obese reproductive-age women exhibit a proatherogenic inflammatory response during hyperglycemia. Obesity (Silver Spring) 2007; 15 (10) 2436-2444
  • 96 Holte J, Bergh T, Gennarelli G, Wide L. The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf) 1994; 41 (4) 473-481
  • 97 Ek I, Arner P, Rydén M , et al. 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 (2) 484-492
  • 98 Xu X, De Pergola G, Björntorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology 1990; 126 (2) 1229-1234
  • 99 González F, Rote NS, Minium J, Kirwan JP. Hyperandrogenism is related to reactive oxygen species generation from pre-activated leukocytes in polycystic ovary syndrome. Reprod Sci 2007; 14 (2, Suppl): 215A
  • 100 González F, Rote NS, Minium J, Kirwan JP. Insulin sensitivity and hyperandrogenism in polycystic ovary syndrome are related to activated nuclear factor κB from mononuclear cells in the fasting state. Proceedings of the 89th meeting of the Endocrine Society 2007;89:142
  • 101 González F, Kirwan JP, Rote NS, Minium J. Evidence of mononuclear cell preactivation in the fasting state in polycystic ovary syndrome. Am J Obstet Gynecol 2014; 211 (6) 635.e1-635.e7
  • 102 González F, Nair KS, Daniels JK, Basal E, Schimke JM. Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women. Am J Physiol Endocrinol Metab 2012; 302 (3) E297-E306
  • 103 González F, Nair KS, Daniels JK, Basal E, Schimke JM, Blair HE. Hyperandrogenism sensitizes leukocytes to hyperglycemia to promote oxidative stress in lean reproductive-age women. J Clin Endocrinol Metab 2012; 97 (8) 2836-2843
  • 104 González F, Sia CL, Bearson DM, Blair HE. Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. J Clin Endocrinol Metab 2014; 99 (5) E848-E854
  • 105 González F, Nair KS, Basal E, Bearson DM, Schimke JM, Blair HE. Induction of hyperandrogenism stimulates proatherogenic inflammation in lean reproductive-age women. Horm Metab Res 2015; 47 (6) 439-444
  • 106 Maliqueo M, Lara HE, Sánchez F, Echiburú B, Crisosto N, Sir-Petermann T. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2013; 166 (2) 151-155
  • 107 Dessein PH, Joffe BI, Stanwix AE. High sensitivity C-reactive protein as a disease activity marker in rheumatoid arthritis. J Rheumatol 2004; 31 (6) 1095-1097
  • 108 Linares LF, Gomez-Reino JJ, Carreira PE, Morillas L, Ibero I. C-reactive protein (CRP) levels in systemic lupus erythematosus (SLE). Clin Rheumatol 1986; 5 (1) 66-69
  • 109 González F, Sia CL, Stanczyk FZ, Blair HE, Krupa ME. Hyperandrogenism exerts an anti-inflammatory effect in obese women with polycystic ovary syndrome. Endocrine 2012; 42 (3) 726-735
  • 110 Wahrenberg H, Ek I, Reynisdottir S, Carlström K, Bergqvist A, Arner P. Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1999; 84 (6) 2182-2187
  • 111 Mannerås-Holm L, Leonhardt H, Kullberg J , et al. 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 (2) E304-E311
  • 112 Dumesic DA, Abbott DH, Eisner JR , et al. Pituitary desensitization to gonadotropin-releasing hormone increases abdominal adiposity in hyperandrogenic anovulatory women. Fertil Steril 1998; 70 (1) 94-101
  • 113 Ek I, Arner P, Bergqvist A, Carlström 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 (4) 1147-1153
  • 114 Best CL, Pudney J, Welch WR, Burger N, Hill JA. Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause. Hum Reprod 1996; 11 (4) 790-797
  • 115 Ortega I, Cress AB, Villanueva AJ, Sokalska A, Stanley SD, Duleba AJ. Resveratrol potentiates effects of simvastatin on inhibition of rat ovarian theca-interstitial cell steroidogenesis. Fertil Steril 2011; 96 (3, Suppl): S40-S41
  • 116 Winston BW, Lange-Carter CA, Gardner AM, Johnson GL, Riches DWH. Tumor necrosis factor α rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages. Proc Natl Acad Sci U S A 1995; 92 (5) 1614-1618
  • 117 Sancho-Tello M, Pérez-Roger I, Imakawa K, Tilzer L, Terranova PF. Expression of tumor necrosis factor-alpha in the rat ovary. Endocrinology 1992; 130 (3) 1359-1364
  • 118 Spaczynski RZ, Arici A, Duleba AJ. Tumor necrosis factor-alpha stimulates proliferation of rat ovarian theca-interstitial cells. Biol Reprod 1999; 61 (4) 993-998
  • 119 Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci U S A 1995; 92 (23) 10619-10623
  • 120 Duleba AJ, Banaszewska B, Spaczynski RZ, Pawelczyk L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial. Fertil Steril 2006; 85 (4) 996-1001
  • 121 Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab 2007; 92 (2) 456-461
  • 122 Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 2009; 94 (1) 103-108
  • 123 Banaszewska B, Pawelczyk L, Spaczynski RZ, Duleba AJ. Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial. J Clin Endocrinol Metab 2009; 94 (12) 4938-4945
  • 124 Piotrewski P, Kwintkiewicz J, Rzepczynska I, Duleba AJ. Simvistatin and mevastatin inhibit expression of NADPH oxidase subunits p23phoxp47phox in rat theca-interstitial cells. J Soc Gynecol Investig 2005; 12 (Suppl. 02) 319A
  • 125 Puurunen J, Piltonen T, Puukka K , et al. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2013; 98 (12) 4798-4807
  • 126 Goldfine AB, Silver R, Aldhahi W , et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci 2008; 1 (1) 36-43
  • 127 Ebstein W. Zur therapie des diabetes mellitus, insbesondere uber die anwendeng der salicylauren natron bei demselben. Berl Klin Wochen 1876; 13: 337-340
  • 128 Baron SH. Salicylates as hypoglycemic agents. Diabetes Care 1982; 5 (1) 64-71
  • 129 Sweeney JD, Hoernig LA. Hemostatic effects of salsalate in normal subjects and patients with hemophilia A. Thromb Res 1991; 61 (1) 23-27
  • 130 Pierce JW, Read MA, Ding H, Luscinskas FW, Collins T. Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J Immunol 1996; 156 (10) 3961-3969
  • 131 Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(κ)B kinase-β. Nature 1998; 396 (6706) 77-80
  • 132 Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE ; TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2010; 152 (6) 346-357
  • 133 Goldfine AB, Fonseca V, Jablonski KA , et al; Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2013; 159 (1) 1-12
  • 134 Greenblatt DJ, Abernethy DR, Boxenbaum HG , et al. Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin. Arthritis Rheum 1986; 29 (8) 971-980
  • 135 Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008; 31 (2) 289-294
  • 136 Perkin RM, Levin DL, Clark R. Serum salicylate levels and right-to-left ductus shunts in newborn infants with persistent pulmonary hypertension. J Pediatr 1980; 96 (4) 721-726
  • 137 Hundal RS, Petersen KF, Mayerson AB , et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 2002; 109 (10) 1321-1326
  • 138 Basu R, Basu A, Johnson CM, Schwenk WF, Rizza RA. Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes. Diabetes 2004; 53 (8) 2042-2050