The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome

Soulmaz Shorakae; Helena Teede; Barbora de Courten; Gavin Lambert; Jacqueline Boyle; Lisa J. Moran

doi:10.1055/s-0035-1556568

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2015; 33(04): 257-269
DOI: 10.1055/s-0035-1556568

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome

Soulmaz Shorakae

¹Monash Centre for Health Research and Implementation, Monash University, Melbourne, Australia

,

Helena Teede

¹Monash Centre for Health Research and Implementation, Monash University, Melbourne, Australia

²Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Australia

,

Barbora de Courten

¹Monash Centre for Health Research and Implementation, Monash University, Melbourne, Australia

²Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Australia

,

Gavin Lambert

³Human Neurotransmitters Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia

⁴Department of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia

,

Jacqueline Boyle

¹Monash Centre for Health Research and Implementation, Monash University, Melbourne, Australia

,

Lisa J. Moran

¹Monash Centre for Health Research and Implementation, Monash University, Melbourne, Australia

⁵The Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, The Robinson Research Institute, Australia

› Author Affiliations

Abstract

Polycystic ovary syndrome (PCOS) has become increasingly common over recent years and is associated with reproductive features as well as cardiometabolic risk factors, including visceral obesity, dyslipidemia and impaired glucose homeostasis, and potentially cardiovascular disease. Emerging evidence suggests that these long-term metabolic effects are linked to a low-grade chronic inflammatory state with the triad of hyperinsulinemia, hyperandrogenism, and low-grade inflammation acting together in a vicious cycle in the pathophysiology of PCOS. Dysregulation of the sympathetic nervous system may also act as an important component, potentially creating a tetrad in the pathophysiology of PCOS. The aim of this review is to examine the role of chronic inflammation and the sympathetic nervous system in the development of obesity and PCOS and review potential therapeutic options to alleviate low-grade inflammation in this setting.

Keywords

polycystic ovary syndrome - obesity - chronic low-grade inflammation - sympathetic nervous system

Full Text

References

References
1 Centres for Disease Control and Prevention. Prevalence of Overweight and Obesity Among Adults: United States, 2003–2004. US Department of Health and Human Services; 2003
2 Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood) 2009; 28 (5) w822-w831
3 Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000; 894: i-xii , 1–253
4 Yamashita S, Nakamura T, Shimomura I , et al. Insulin resistance and body fat distribution. Diabetes Care 1996; 19 (3) 287-291
5 Reverchon M, Ramé C, Bertoldo M, Dupont J. Adipokines and the female reproductive tract. Int J Endocrinol 2014; 2014 (14) 232454
6 Naderpoor N, Shorakae S, Joham A, Boyle J, De Courten B, Teede HJ. Obesity and polycystic ovary syndrome. Minerva Endocrinol 2015; 40 (1) 37-51
7 Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011; 378 (9793) 815-825
8 Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15 (11) 2792-2800
9 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444 (7121) 860-867
10 Carmina E. Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 2013; 40: 40-50
11 Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines and low-grade chronic inflammation in PCOS. Reproduction 2015; 149 (5) 219-227
12 Engström G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgärde F. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 2003; 52 (8) 2097-2101
13 Seematter G, Binnert C, Martin J-L, Tappy L. Relationship between stress, inflammation and metabolism. Curr Opin Clin Nutr Metab Care 2004; 7 (2) 169-173
14 March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25 (2) 544-551
15 Shorakae S, Boyle J, Teede H. Polycystic ovary syndrome: a common hormonal condition with major metabolic sequelae that physicians should know about. Intern Med J 2014; 44 (8) 720-726
16 Deligeoroglou E, Vrachnis N, Athanasopoulos N , et al. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol Endocrinol 2012; 28 (12) 974-978
17 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 (2) 95-109
18 Barber TM, Franks S. Adipocyte biology in polycystic ovary syndrome. Mol Cell Endocrinol 2013; 373 (1-2) 68-76
19 Stepto NK, Cassar S, Joham AE , et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod 2013; 28 (3) 777-784
20 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012; 33 (6) 981-1030
21 Ebejer K, Calleja-Agius J. The role of cytokines in polycystic ovarian syndrome. Gynecol Endocrinol 2013; 29 (6) 536-540
22 Samy N, Hashim M, Sayed M, Said M. Clinical significance of inflammatory markers in polycystic ovary syndrome: their relationship to insulin resistance and body mass index. Dis Markers 2009; 26 (4) 163-170
23 Zhuang XF, Zhao MM, Weng CL, Sun NL. Adipocytokines: a bridge connecting obesity and insulin resistance. Med Hypotheses 2009; 73 (6) 981-985
24 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
25 González F. Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 2012; 77 (4) 300-305
26 Ojeda-Ojeda M, Murri M, Insenser M, Escobar-Morreale HF. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Curr Pharm Des 2013; 19 (32) 5775-5791
27 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
28 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 (10) 1257-1266
29 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18 (6) 774-800
30 Randeva HS, Tan BK, Weickert MO , et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev 2012; 33 (5) 812-841
31 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) 1048-1058.e1 , 2
32 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
33 Toulis KA, Goulis DG, Mintziori G , et al. Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod Update 2011; 17 (6) 741-760
34 Escobar-Morreale HF, Botella-Carretero JI, Villuendas G, Sancho J, San Millán JL. Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity. J Clin Endocrinol Metab 2004; 89 (2) 806-811
35 Kaya C, Pabuccu R, Berker B, Satiroglu H. Plasma interleukin-18 levels are increased in the polycystic ovary syndrome: relationship of carotid intima-media wall thickness and cardiovascular risk factors. Fertil Steril 2010; 93 (4) 1200-1207
36 Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman's long-term health using data linkage. J Clin Endocrinol Metab 2015; 100 (3) 911-919
37 Sirmans SM, Weidman-Evans E, Everton V, Thompson D. Polycystic ovary syndrome and chronic inflammation: pharmacotherapeutic implications. Ann Pharmacother 2012; 46 (3) 403-418
38 Meyer C, McGrath BP, Cameron J, Kotsopoulos D, Teede HJ. Vascular dysfunction and metabolic parameters in polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90 (8) 4630-4635
39 Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J Clin Endocrinol Metab 2005; 90 (10) 5711-5716
40 Kravariti M, Naka KK, Kalantaridou SN , et al. Predictors of endothelial dysfunction in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90 (9) 5088-5095
41 Burchall G, Linden MD, Teede H, Piva TJ. Hemostatic abnormalities and relationships to metabolic and hormonal status in polycystic ovarian syndrome. Trends Cardiovasc Med 2011; 21 (1) 6-14
42 Stefan N, Stumvoll M, Vozarova B , et al. Plasma adiponectin and endogenous glucose production in humans. Diabetes Care 2003; 26 (12) 3315-3319
43 Black PH. The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II. Med Hypotheses 2006; 67 (4) 879-891
44 Comim FV, Hardy K, Franks S. Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome. PLoS ONE 2013; 8 (11) e80416
45 Tao T, Xu B, Liu W. Ovarian HMW adiponectin is associated with folliculogenesis in women with polycystic ovary syndrome. Reprod Biol Endocrinol 2013; 11: 99
46 Carmina E, Bucchieri S, Mansueto P, Rini G, Ferin M, Lobo RA. Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertil Steril 2009; 91 (4, Suppl): 1332-1335
47 Itoh H, Kawano Y, Furukawa Y, Matsumoto H, Yuge A, Narahara H. The role of serum adiponectin levels in women with polycystic ovarian syndrome. Clin Exp Obstet Gynecol 2013; 40 (4) 531-535
48 Li S, Huang X, Zhong H , et al. Low circulating adiponectin levels in women with polycystic ovary syndrome: an updated meta-analysis. Tumour Biol 2014; 35 (5) 3961-3973
49 Stefan N, Vozarova B, Funahashi T , et al. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 2002; 51 (6) 1884-1888
50 Cekmez F, Cekmez Y, Pirgon O , et al. Evaluation of new adipocytokines and insulin resistance in adolescents with polycystic ovary syndrome. Eur Cytokine Netw 2011; 22 (1) 32-37
51 Wang Y, Xie X, Zhu W. Serum adiponectin and resistin levels in patients with polycystic ovarian syndrome and their clinical implications. J Huazhong Univ Sci Technolog Med Sci 2010; 30 (5) 638-642
52 Kale-Gurbuz T, Akhan SE, Bastu E, Telci A, Iyibozkurt AC, Topuz S. Adiponectin, leptin and ghrelin levels in obese adolescent girls with polycystic ovary syndrome. J Pediatr Adolesc Gynecol 2013; 26 (1) 27-30
53 Güven A, Ozgen T, Aliyazicioğlu Y. Adiponectin and resistin concentrations after glucose load in adolescents with polycystic ovary syndrome. Gynecol Endocrinol 2010; 26 (1) 30-38
54 Lee H, Oh JY, Sung YA. Adipokines, insulin-like growth factor binding protein-3 levels, and insulin sensitivity in women with polycystic ovary syndrome. Korean J Intern Med 2013; 28 (4) 456-463
55 Yilmaz M, Bukan N, Demirci H , et al. Serum resistin and adiponectin levels in women with polycystic ovary syndrome. Gynecol Endocrinol 2009; 25 (4) 246-252
56 Chang CY, Chen MJ, Yang WS , et al. Hypoadiponectinemia: a useful marker of dyslipidemia in women with polycystic ovary syndrome. Taiwan J Obstet Gynecol 2012; 51 (4) 583-590
57 Cankaya S, Demir B, Aksakal SE, Dilbaz B, Demirtas C, Goktolga U. Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome. Fertil Steril 2014; 102 (3) 826-830
58 Cassar S, Teede HJ, Harrison CL, Joham AE, Moran LJ, Stepto NK. Biomarkers and insulin sensitivity in women with PCOS: Characteristics and predictive capacity. Clin Endocrinol (Oxf) 2014;
59 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
60 Spanos N, Tziomalos K, Macut D , et al. Adipokines, insulin resistance and hyperandrogenemia in obese patients with polycystic ovary syndrome: cross-sectional correlations and the effects of weight loss. Obes Facts 2012; 5 (4) 495-504
61 Jeon YE, Lee KE, Jung JA , et al. Kisspeptin, leptin, and retinol-binding protein 4 in women with polycystic ovary syndrome. Gynecol Obstet Invest 2013; 75 (4) 268-274
62 Greisen S, Ledet T, Møller N , et al. Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells. Acta Obstet Gynecol Scand 2000; 79 (11) 931-935
63 Llaneza-Suarez D, Llaneza P, González C , et al. Assessment of follicular fluid leptin levels and insulin resistance as outcome predictors in women undergoing in vitro fertilization-intracytoplasmic sperm injection. Fertil Steril 2014; 102 (6) 1619-1625
64 Pepene CE. Evidence for visfatin as an independent predictor of endothelial dysfunction in polycystic ovary syndrome. Clin Endocrinol (Oxf) 2012; 76 (1) 119-125
65 Lajunen TK, Purhonen AK, Haapea M , et al. Full-length visfatin levels are associated with inflammation in women with polycystic ovary syndrome. Eur J Clin Invest 2012; 42 (3) 321-328
66 Dıkmen E, Tarkun I, Cantürk Z, Cetınarslan B. Plasma visfatin level in women with polycystic ovary syndrome. Gynecol Endocrinol 2011; 27 (7) 475-479
67 Jongwutiwes T, Lertvikool S, Leelaphiwat S, Rattanasiri S, Jultanmas R, Weerakiet S. Serum visfatin in Asian women with polycystic ovary syndrome. Gynecol Endocrinol 2009; 25 (8) 536-542
68 Gen R, Akbay E, Muslu N, Sezer K, Cayan F. Plasma visfatin level in lean women with PCOS: relation to proinflammatory markers and insulin resistance. Gynecol Endocrinol 2009; 25 (4) 241-245
69 Panidis D, Farmakiotis D, Rousso D , et al. Plasma visfatin levels in normal weight women with polycystic ovary syndrome. Eur J Intern Med 2008; 19 (6) 406-412
70 Kowalska I, Straczkowski M, Nikolajuk A , et al. Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Hum Reprod 2007; 22 (7) 1824-1829
71 Zhang J, Zhou L, Tang L, Xu L. Plasma visfatin levels and mRNA expression of visfatin in peripheral blood mononuclear cells and peripheral blood monocyte-derived macrophages from normal weight females with polycystic ovary syndrome. Exp Ther Med 2014; 7 (5) 1215-1220
72 Farshchian F, Ramezani Tehrani F, Amirrasouli H , et al. Visfatin and resistin serum levels in normal-weight and obese women with polycystic ovary syndrome. Int J Endocrinol Metab 2014; 12 (3) e15503
73 Güdücü N, İşçi H, Görmüş U, Yiğiter AB, Dünder I. Serum visfatin levels in women with polycystic ovary syndrome. Gynecol Endocrinol 2012; 28 (8) 619-623
74 Hong Y, Zhao XM, Huang LL, Li L, Chen XL, Yang DZ. Serum visfatin is elevated in Chinese women with polycystic ovary syndrome, but might not be a reliable predictor of their glucose intolerance. J Biol Regul Homeost Agents 2012; 26 (2) 221-229
75 Seow KM, Hwang JL, Wang PH, Ho LT, Juan CC. Expression of visfatin mRNA in peripheral blood mononuclear cells is not correlated with visfatin mRNA in omental adipose tissue in women with polycystic ovary syndrome. Hum Reprod 2011; 26 (10) 2869-2873
76 Yildiz BO, Bozdag G, Otegen U , et al. Visfatin and retinol-binding protein 4 concentrations in lean, glucose-tolerant women with PCOS. Reprod Biomed Online 2010; 20 (1) 150-155
77 Plati E, Kouskouni E, Malamitsi-Puchner A, Boutsikou M, Kaparos G, Baka S. Visfatin and leptin levels in women with polycystic ovaries undergoing ovarian stimulation. Fertil Steril 2010; 94 (4) 1451-1456
78 Chan TF, Chen YL, Chen HH, Lee CH, Jong SB, Tsai EM. Increased plasma visfatin concentrations in women with polycystic ovary syndrome. Fertil Steril 2007; 88 (2) 401-405
79 Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR, Randeva HS. Increased visfatin messenger ribonucleic acid and protein levels in adipose tissue and adipocytes in women with polycystic ovary syndrome: parallel increase in plasma visfatin. J Clin Endocrinol Metab 2006; 91 (12) 5022-5028
80 Choi JH, Rhee EJ, Kim KH, Woo HY, Lee WY, Sung KC. Plasma omentin-1 levels are reduced in non-obese women with normal glucose tolerance and polycystic ovary syndrome. Eur J Endocrinol 2011; 165 (5) 789-796
81 Guzel EC, Celik C, Abali R , et al. Omentin and chemerin and their association with obesity in women with polycystic ovary syndrome. Gynecol Endocrinol 2014; 30 (6) 419-422
82 Akbarzadeh S, Ghasemi S, Kalantarhormozi M , et al. Relationship among plasma adipokines, insulin and androgens level as well as biochemical glycemic and lipidemic markers with incidence of PCOS in women with normal BMI. Gynecol Endocrinol 2012; 28 (7) 521-524
83 Orlik B, Madej P, Owczarek A, Skałba P, Chudek J, Olszanecka-Glinianowicz M. Plasma omentin and adiponectin levels as markers of adipose tissue dysfunction in normal weight and obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2014; 81 (4) 529-535
84 Mahde A, Shaker M, Al-Mashhadani Z. Study of omentin1 and other adipokines and hormones in PCOS patients. Oman Med J 2009; 24 (2) 108-118
85 Tan BK, Adya R, Farhatullah S , et al. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 2008; 57 (4) 801-808
86 Panidis D, Koliakos G, Kourtis A, Farmakiotis D, Mouslech T, Rousso D. Serum resistin levels in women with polycystic ovary syndrome. Fertil Steril 2004; 81 (2) 361-366
87 Chu Y, Cui Q, Feng G, Song Z, Jiang X. The expression of resistin in adipose tissues of patients with polycystic ovary syndrome and insulin resistance. J Huazhong Univ Sci Technolog Med Sci 2009; 29 (5) 642-645
88 Zhang J, Zhou L, Tang L, Xu L. The plasma level and gene expression of resistin in polycystic ovary syndrome. Gynecol Endocrinol 2011; 27 (12) 982-987
89 Wang Q, Guo T, Tao Y, Wang Q, Song Y, Huang W. Association between serum adipocyte factor level and insulin resistance in polycystic ovarian syndrome. Gynecol Endocrinol 2011; 27 (11) 931-934
90 Arikan S, Bahceci M, Tuzcu A, Kale E, Gökalp D. Serum resistin and adiponectin levels in young non-obese women with polycystic ovary syndrome. Gynecol Endocrinol 2010; 26 (3) 161-166
91 Escobar-Morreale HF, Villuendas G, Botella-Carretero JI , et al. Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study. Hum Reprod 2006; 21 (9) 2257-2265
92 Seow KM, Juan CC, Wu LY , et al. Serum and adipocyte resistin in polycystic ovary syndrome with insulin resistance. Hum Reprod 2004; 19 (1) 48-53
93 Lewandowski KC, Szosland K, O'Callaghan C, Tan BK, Randeva HS, Lewinski A. Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: a significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices. Mol Genet Metab 2005; 85 (1) 61-69
94 Bideci A, Camurdan MO, Yeşilkaya E, Demirel F, Cinaz P. Serum ghrelin, leptin and resistin levels in adolescent girls with polycystic ovary syndrome. J Obstet Gynaecol Res 2008; 34 (4) 578-584
95 Wang Q, Kim JY, Xue K, Liu JY, Leader A, Tsang BK. Chemerin, a novel regulator of follicular steroidogenesis and its potential involvement in polycystic ovarian syndrome. Endocrinology 2012; 153 (11) 5600-5611
96 Kort DH, Kostolias A, Sullivan C, Lobo RA. Chemerin as a marker of body fat and insulin resistance in women with polycystic ovary syndrome. Gynecol Endocrinol 2015; 31 (2) 152-155
97 Olszanecka-Glinianowicz M, Madej P, Zdun D , et al. Are plasma levels of visfatin and retinol-binding protein 4 (RBP4) associated with body mass, metabolic and hormonal disturbances in women with polycystic ovary syndrome?. Eur J Obstet Gynecol Reprod Biol 2012; 162 (1) 55-61
98 Aigner E, Bachofner N, Klein K , et al. Retinol-binding protein 4 in polycystic ovary syndrome—association with steroid hormones and response to pioglitazone treatment. J Clin Endocrinol Metab 2009; 94 (4) 1229-1235
99 Hutchison SK, Harrison C, Stepto N, Meyer C, Teede HJ. Retinol-binding protein 4 and insulin resistance in polycystic ovary syndrome. Diabetes Care 2008; 31 (7) 1427-1432
100 Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural activation in visceral obesity. Circulation 2002; 106 (20) 2533-2536
101 Lambert E, Straznicky N, Schlaich M , et al. Differing pattern of sympathoexcitation in normal-weight and obesity-related hypertension. Hypertension 2007; 50 (5) 862-868
102 Dechend R, Fiebler A, Lindschau C , et al. Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition. Am J Hypertens 2001; 14 (6, Pt 2) 55S-61S
103 Jänig W. Sympathetic nervous system and inflammation: a conceptual view. Auton Neurosci 2014; 182: 4-14
104 Iwen KA, Wenzel ET, Ott V , et al. Cold-induced alteration of adipokine profile in humans. Metabolism 2011; 60 (3) 430-437
105 Imai J, Katagiri H, Yamada T , et al. Cold exposure suppresses serum adiponectin levels through sympathetic nerve activation in mice. Obesity (Silver Spring) 2006; 14 (7) 1132-1141
106 Marketou ME, Zacharis EA, Koukouraki S , et al. Effect of angiotensin-converting enzyme inhibitors on systemic inflammation and myocardial sympathetic innervation in normotensive patients with type 2 diabetes mellitus. J Hum Hypertens 2008; 22 (3) 191-196
107 Ram CVS. Angiotensin blockade with eprosartan: vascular and functional implications. Curr Med Res Opin 2007; 23 (Suppl. 05) S5-S11
108 Lansdown A, Rees DA. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target?. Clin Endocrinol (Oxf) 2012; 77 (6) 791-801
109 Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ. Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab 2005; 90 (11) 5998-6005
110 Minamino T, Orimo M, Shimizu I , et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009; 15 (9) 1082-1087
111 Shimizu I, Yoshida Y, Katsuno T , et al. p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. [Erratum appears in Cell Metab. 2012 May 2;15(5):787] Cell Metab 2012; 15 (1) 51-64
112 Hopkins DF, Williams G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med 1997; 14 (12) 1044-1050
113 Dampney RA. Arcuate nucleus - a gateway for insulin's action on sympathetic activity. J Physiol 2011; 589 (Pt 9) 2109-2110
114 Pausova Z. From big fat cells to high blood pressure: a pathway to obesity-associated hypertension. Curr Opin Nephrol Hypertens 2006; 15 (2) 173-178
115 Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril 2001; 75 (6) 1141-1147
116 Lara HE, Ferruz JL, Luza S, Bustamante DA, Borges Y, Ojeda SR. Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology 1993; 133 (6) 2690-2695
117 Sverrisdóttir YB, Mogren T, Kataoka J, Janson PO, Stener-Victorin E. Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth?. Am J Physiol Endocrinol Metab 2008; 294 (3) E576-E581
118 Lambert EA, Teede H, Sari CI , et al. Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance. Clin Endocrinol (Oxf) 2015; doi: 10.1111/cen.12803. (Epub ahead of print)
119 Stener-Victorin E, Lundeberg T, Waldenström U , et al. Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries. Biol Reprod 2000; 63 (5) 1497-1503
120 Stener-Victorin E, Jedel E, Janson PO, Sverrisdottir YB. Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Am J Physiol Regul Integr Comp Physiol 2009; 297 (2) R387-R395
121 Manni L, Lundeberg T, Holmäng A, Aloe L, Stener-Victorin E. Effect of electro-acupuncture on ovarian expression of alpha (1)- and beta (2)-adrenoceptors, and p75 neurotrophin receptors in rats with steroid-induced polycystic ovaries. Reprod Biol Endocrinol 2005; 3: 21
122 Stener-Victorin E, Waldenström U, Tägnfors U, Lundeberg T, Lindstedt G, Janson PO. Effects of electro-acupuncture on anovulation in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand 2000; 79 (3) 180-188
123 Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr 1998; 68 (4) 899-917
124 Teede HJ, Misso ML, Deeks AA , et al; Guideline Development Groups. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust 2011; 195 (6) S65-S112
125 Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011; (7) CD007506
126 Selvin E, Paynter NP, Erlinger TP. The effect of weight loss on C-reactive protein: a systematic review. Arch Intern Med 2007; 167 (1) 31-39
127 Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and the metabolic syndrome—causes, consequences and therapeutic implications. Pharmacol Ther 2010; 126 (2) 159-172
128 Lambert EA, Rice T, Eikelis N , et al. Sympathetic activity and markers of cardiovascular risk in nondiabetic severely obese patients: the effect of the initial 10% weight loss. Am J Hypertens 2014; 27 (10) 1308-1315
129 Moran LJ, Noakes M, Clifton PM, Wittert GA, Williams G, Norman RJ. Short-term meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr 2006; 84 (1) 77-87
130 Moran LJ, Noakes M, Wittert GA, Clifton PM, Norman RJ. Weight loss and vascular inflammatory markers in overweight women with and without polycystic ovary syndrome. Reprod Biomed Online 2012; 25 (5) 500-503
131 Thomson RL, Brinkworth GD, Noakes M, Clifton PM, Norman RJ, Buckley JD. The effect of diet and exercise on markers of endothelial function in overweight and obese women with polycystic ovary syndrome. Hum Reprod 2012; 27 (7) 2169-2176
132 Covington JD, Tam CS, Pasarica M, Redman LM. Higher circulating leukocytes in women with PCOS is reversed by aerobic exercise. Biochimie pii: S0300-9084(14)00330-7. doi: 10.1016/j.biochi.2014.10.028. (Epub ahead of print)
133 Giallauria F, Palomba S, Maresca L , et al. Exercise training improves autonomic function and inflammatory pattern in women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2008; 69 (5) 792-798
134 Rezvanfar MA, Saadat S, Shojaei Saadi HA , et al. Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary. Theriogenology 2015; 83 (6) 968-977
135 Kelly AC, Jewelewicz R. Alternate regimens for ovulation induction in polycystic ovarian disease. Fertil Steril 1990; 54 (2) 195-202
136 Garruti G, Depalo R, Vita MG , et al. Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment. Reprod Biomed Online 2009; 19 (4) 552-563
137 Naderpoor N, Shorakae S, de Courten B , et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update 2015; pii: dmv025. (Epub ahead of print)
138 Xu X, Du C, Zheng Q, Peng L, Sun Y. Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review. BMC Womens Health 2014; 14: 93
139 Luque-Ramírez M, Escobar-Morreale HF. Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations. Horm Metab Res 2010; 42 (11) 815-820
140 Irfan A, Mughal IA, Jalali S. Effect of metformin hydrochloride in correcting hyperinsulinemia and high leptin levels in treatment of infertile polycystic patients. J Ayub Med Coll Abbottabad 2013; 25 (1-2) 8-11
141 Tarkun I, Dikmen E, Cetinarslan B, Cantürk Z. Impact of treatment with metformin on adipokines in patients with polycystic ovary syndrome. Eur Cytokine Netw 2010; 21 (4) 272-277
142 Hamed HO. Role of adiponectin and its receptor in prediction of reproductive outcome of metformin treatment in patients with polycystic ovarian syndrome. J Obstet Gynaecol Res 2013; 39 (12) 1596-1603
143 Singh S, Akhtar N, Ahmad J. Plasma adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a case-control study. Diabetes Metab Syndr 2012; 6 (4) 207-211
144 Steiner CA, Janez A, Jensterle M, Reisinger K, Forst T, Pfützner A. Impact of treatment with rosiglitazone or metformin on biomarkers for insulin resistance and metabolic syndrome in patients with polycystic ovary syndrome. J Diabetes Sci Tech 2007; 1 (2) 211-217
145 Tan BK, Adya R, Farhatullah S, Chen J, Lehnert H, Randeva HS. Metformin treatment may increase omentin-1 levels in women with polycystic ovary syndrome. Diabetes 2010; 59 (12) 3023-3031
146 Kabiri N, Tabandeh MR, Tabatabaie SR. Beneficial effects of pioglitazone and metformin in murine model of polycystic ovaries via improvement of chemerin gene up-regulation. Daru: J Pharm Sci 2014; 22: 39