Association between Biomarkers of Low-grade Inflammation and Sex Hormones in Women with Polycystic Ovary Syndrome

Abstract

Objective Women with polycystic ovary syndrome (PCOS) have higher circulating levels of C-reactive protein, but the relationship between inflammation and endocrine function in PCOS remains poorly understood. Thus, this study aimed to investigate the association between low-grade inflammation and sex hormones in women with PCOS.

Design and Patients A comprehensive panel of biomarkers of inflammation was measured in serum of 63 women with PCOS using proximity extension assay technology. Associations of 65 biomarkers with sex hormones were assessed without and with adjustment for age and body mass index (BMI).

Results In the unadjusted analysis, 20 biomarkers were positively correlated with 17-OH-progesterone (17-OH-P), 14 with prolactin and 6 with free testosterone, whereas inverse associations were found for 16 biomarkers with sex hormone-binding globulin (SHBG), 6 with luteinizing hormone (LH) and 6 with estrogen (all p<0.05). Among the positive associations, correlations were mainly found for five chemokines (CXCL11, CCL4, MCP-4/CCL13, CXCL5, CXCL6) and for VEGF-A, LAP-TGFβ1, TNFSF14 and MMP-1. Inverse associations with sex hormones were mainly present for two chemokines (CXCL1, MCP-2/CCL8), CDCP1, CST5 and CSF-1. Adjustment for age and BMI reduced the number of biomarker associations for SHBG and estrogen, but had hardly any impact on associations with 17-OH-P, prolactin, free testosterone and LH.

Conclusion Women with PCOS feature BMI-independent associations between biomarkers of inflammation and certain sex steroid and hypophyseal hormones. Most of these inflammation-related biomarkers were chemokines, which may be relevant as potential mediators of the increased cardiometabolic risk of women with PCOS.

Key words

inflammation - chemokines - sex hormones - polycystic ovary syndrome - cardiometabolic risk

Publication History

Received: 18 October 2018
Received: 25 July 2019

Accepted: 07 August 2019

Article published online:
28 August 2019

• References

• 1 Ding T, Hardiman PJ, Petersen I. et al. The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: A systematic review and meta-analysis. Oncotarget 2017; 8: 96351-96358
• 2 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25
• 3 Chang RJ. The reproductive phenotype in polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2007; 3: 688-695
• 4 Teede HJ, Misso ML, Costello MF. et al. International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110: 364-379
• 5 Ding EL, Song Y, Malik VS. et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis. JAMA 2006; 295: 1288-1299
• 6 Ding EL, Song Y, Manson JE. et al. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: A prospective study. Diabetologia 2007; 50: 2076-2084
• 7 Zhao D, Guallar E, Ouyang P. et al. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J Am Coll Cardiol 2018; 71: 2555-2566
• 8 Subramanya V, Zhao D, Ouyang P. et al. Association of endogenous sex hormone levels with coronary artery calcium progression among post-menopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA). J Cardiovasc Comput Tomogr 2019; 13: 41-47
• 9 Gilbert EW, Tay CT, Hiam DS. et al. Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews. Clin Endocrinol (Oxf) 2018; 89: 683-699
• 10 Glintborg D, Rubin KH, Nybo M. et al. Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. Cardiovasc Diabetol 2018; 17: 37
• 11 Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences. Metabolism 2018; 86: 33-43
• 12 Norman RJ, Dewailly D, Legro RS. et al. Polycystic ovary syndrome. Lancet 2007; 370: 685-697
• 13 Sathyapalan T, Atkin SL. Mediators of inflammation in polycystic ovary syndrome in relation to adiposity. Mediators Inflamm 2010; 2010: 758656
• 14 Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol 2011; 335: 30-41
• 15 Skurk T, Alberti-Huber C, Herder C. et al. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-1033
• 16 Herder C, Dalmas E, Boni-Schnetzler M. et al. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab 2015; 26: 551-563
• 17 Herder C, Kannenberg JM, Huth C. et al. Proinflammatory cytokines predict the incidence and progression of distal sensorimotor polyneuropathy: KORA F4/FF4 Study. Diabetes Care 2017; 40: 569-576
• 18 Koliaki C, Szendroedi J, Kaul K. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015; 21: 739-746
• 19 Frasca D, Blomberg BB, Paganelli R. Aging, obesity, and inflammatory age-related diseases. Front Immunol 2017; 8: 1745
• 20 Herder C, de Las Heras Gala T, Carstensen-Kirberg M. et al. Circulating levels of interleukin 1-receptor antagonist and risk of cardiovascular disease: Meta-analysis of six population-based cohorts. Arterioscler Thromb Vasc Biol 2017; 37: 1222-1227
• 21 Wu H, Yu K, Yang Z. Associations between TNF-alpha and interleukin gene polymorphisms with polycystic ovary syndrome risk: A systematic review and meta-analysis. J Assist Reprod Genet 2015; 32: 625-634
• 22 de Alencar JB, Alves HV, Elpidio LN. et al. Polymorphisms of cytokine genes and polycystic ovary syndrome: A review. Metab Syndr Relat Disord 2016; 14: 468-474
• 23 González F. Inflammation in polycystic ovary syndrome: Underpinning of insulin resistance and ovarian dysfunction. Steroids 2012; 77: 300-305
• 24 Lind L, Arnlov J, Lindahl B. et al. Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis. Atherosclerosis 2015; 242: 205-210
• 25 Nowak C, Sundstrom J, Gustafsson S. et al. Protein biomarkers for insulin resistance and type 2 diabetes risk in two large community cohorts. Diabetes 2016; 65: 276-284
• 26 Herder C, Kannenberg JM, Carstensen-Kirberg M. et al. A systemic inflammatory signature reflecting cross talk between innate and adaptive immunity is associated with incident polyneuropathy: KORA F4/FF4 Study. Diabetes 2018; 67: 2434-2442
• 27 Nowak C, Carlsson AC, Östgren CJ. et al. Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes. Diabetologia 2018; 61: 1748-1757
• 28 Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
• 29 Schlesinger S, Herder C, Kannenberg JM. et al. General and abdominal obesity and incident distal sensorimotor polyneuropathy: Insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort. Diabetes Care 2019; 42: 240-247
• 30 Enroth S, Enroth SB, Johansson A. et al. Protein profiling reveals consequences of lifestyle choices on predicted biological aging. Sci Rep 2015; 5: 17282
• 31 Enroth S, Johansson A, Enroth SB. et al. Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs. Nat Commun 2014; 5: 4684
• 32 Kodama S, Horikawa C, Fujihara K. et al. Comparisons of the strength of associations with future type 2 diabetes risk among anthropometric obesity indicators, including waist-to-height ratio: A meta-analysis. Am J Epidemiol 2012; 176: 959-969
• 33 Glintborg D, Andersen M. An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome. Gynecol Endocrinol 2010; 26: 281-296
• 34 Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: A systematic review and metaanalysis. Fertil Steril 2011; 95: 1048-1058
• 35 Peng Z, Sun Y, Lv X. et al. Interleukin-6 levels in women with polycystic ovary syndrome: A systematic review and meta-analysis. PLoS One 2016; 11: e0148531
• 36 González F, Rote NS, Minium J. et al. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 2009; 58: 954-962
• 37 Atabekoglu CS, Sönmezer M, Özmen B. et al. Increased monocyte chemoattractant protein-1 levels indicating early vascular damage in lean young PCOS patients. Fertil Steril 2011; 95: 295-297
• 38 Hu W, Qiao J, Yang Y. et al. Elevated C-reactive protein and monocyte chemoattractant protein-1 in patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2011; 157: 53-56
• 39 Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals. Circulation 2000; 102: 185-190
• 40 Miyazono K, Olofsson A, Colosetti P. et al. A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J 1991; 10: 1091-1101
• 41 Shaikh RB, Santee S, Granger SW. et al. Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 2001; 167: 6330-6337
• 42 Wortmann A, He Y, Deryugina EI. et al. The cell surface glycoprotein CDCP1 in cancer—Insights, opportunities, and challenges. IUBMB Life 2009; 61: 723-730
• 43 Ferrer-Mayorga G, Alvarez-Diaz S, Valle N. et al. Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression. J Biol Chem 2015; 290: 26533-26548
• 44 Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 2012; 119: 1810-1820
• 45 Ojeda-Ojeda M, Murri M, Insenser M. et al. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Curr Pharm Des 2013; 19: 5775-5791
• 46 Shorakae S, Teede H, de Courten B. et al. The emerging role of chronic low-grade inflammation in the pathophysiology of polycystic ovary syndrome. Semin Reprod Med 2015; 33: 257-269
• 47 Herder C, Baumert J, Thorand B. et al. Chemokines as risk factors for type 2 diabetes: Results from the MONICA/KORA Augsburg study, 1984-2002. Diabetologia 2006; 49: 921-929
• 48 Herder C, Baumert J, Thorand B. et al. Chemokines and incident coronary heart disease: Results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Arterioscler Thromb Vasc Biol 2006; 26: 2147-2152
• 49 van der Vorst EP, Döring Y, Weber C. Chemokines. Arterioscler Thromb Vasc Biol 2015; 35: e52-e56
• 50 Dusi V, Ghidoni A, Ravera A. et al. Chemokines and heart disease: A network connecting cardiovascular biology to immune and autonomic nervous systems. Mediators Inflamm 2016; 2016: 5902947
• 51 Marchetti P. Islet inflammation in type 2 diabetes. Diabetologia 2016; 59: 668-672
• 52 Rudemiller NP, Crowley SD. The role of chemokines in hypertension and consequent target organ damage. Pharmacol Res 2017; 119: 404-411
• 53 Chang TT, Chen JW. Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: Friends or foes?. Cardiovasc Diabetol 2016; 15: 117
• 54 Yang Z, Zhang Z, Wen J. et al. Elevated serum chemokine CXC ligand 5 levels are associated with hypercholesterolemia but not a worsening of insulin resistance in Chinese people. J Clin Endocrinol Metab 2010; 95: 3926-3932
• 55 Van Dyke AL, Lang Kuhs KA, Shiels MS. et al. Associations between self-reported diabetes and 78 circulating markers of inflammation, immunity, and metabolism among adults in the United States. PLoS One 2017; 12: e0182359
• 56 Choi SH, Ruggiero D, Sorice R. et al. Six novel loci associated with circulating VEGF levels identified by a meta-analysis of genome-wide association studies. PLoS Genet 2016; 12: e1005874
• 57 Halvorsen B, Santilli F, Scholz H. et al. LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro. Diabetologia 2016; 59: 2134-2144