Levels of methylated arginines and L-arginine in patients with polycystic ovary syndrome: a promising approach in clinical evaluation

Abstract

Aim: Polycystic ovary syndrome (PCOS) is a prevalent disease in women. PCOS is related with metabolic syndrome and associated with cardiovascular disorders. Methylated arginine is involved in endothelial dysfunction, inflammation and atherosclerosis pathophysiology. Our aim is to determine the association between PCOS and methylated arginine metabolites in order to investigate the role of vascular factors in the etiopathogenesis of PCOS. Material and Method: This is a case-control study. The study group is consisted of 45 PCOS cases and 45 controls. The case group is patients who applied to Department of Gynecology and diagnosed with PCOS. Control group is consisted of healthy volunteers who applied to the outpatient clinics for other reasons. The study took place in Department of Gynecology in XX hospital. Data collection was held between 2018 October to 2019 June. Methylated arginine derivatives such as ADMA, SDMA, L-NMMA (L-NG-monomethyl Arginine Acetate) and also arginine and citrulline were determined. Results: ADMA, SDMA, L-NMMA, arginine, citrulline, Arginine/ADMA, SDMA/ADMA and total methylarginine parameters showed statistically significant differences between groups. Strong positive relation was determined between scoring of Ferriman-Gallway (FGS) and luteinizing hormone (LH), glucose, insulin, ADMA, citrulline, homoarginine, L-NMMA and total methylarginine levels. Conclusions: High levels of methylated arginine/NO pathway metabolites in PCOS patients may be related with cardiovascular outcomes of PCOS.

Keywords

• PCOS
• ADMA
• SDMA
• Methylated arginine

References

1. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet 2007; 370: 685-97.
2. Archer JS, Chang RJ. Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004; 18: 737-54.
3. Dokras A, Bochner M, Hollinrake E, Markham S, Vanvoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005; 106: 131-7.
4. van der Spuy ZM, Dyer SJ. The pathogenesis of infertility and early pregnancy loss in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004; 18: 755-71.
5. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod 2016; 31: 2841-55.
6. Schonfelder G, Friedrich K, Paul M, Chahoud I. Developmental effects of prenatal exposure to bisphenol a on the uterus of rat offspring. Neoplasia 2004; 6: 584-94.
7. Vagi SJ, Azziz-Baumgartner E, Sjodin A, et al. Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study. BMC Endocr Disord 2014; 14: 86.
8. Cheung AP, Cog F. Polycystic ovary syndrome: a contemporary view. J Obstet Gynaecol Can 2010; 32: 423-5.

9. Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25.
10. Ribeiro VB, Kogure GS, Lopes IP, et al. Effects of continuous and intermittent aerobic physical training on hormonal and metabolic profile, and body composition in women with polycystic ovary syndrome: A randomized controlled trial. Clin Endocrinol (Oxf) 2020; 93: 173-86.
11. Balen AH, Morley LC, Misso M, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 2016; 22: 687-708.
12. Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update 2006; 12: 351-61.
13. Willis DS, Watson H, Mason HD, Galea R, Brincat M, Franks S. Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation. J Clin Endocrinol Metab 1998; 83: 3984-91.
14. Hansen SL, Svendsen PF, Jeppesen JF, et al. Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean with polycystic ovary syndrome. J Clin Endocrinol Metab 2019; 104: 1841-54.
15. Ganie MA, Dhingra A, Nisar S, et al. Oral glucose tolerance test significantly impacts the prevalence of abnormal glucose tolerance among Indian women with polycystic ovary syndrome: lessons from a large database of two tertiary care centers on the Indian subcontinent. Fertil Steril 2016; 105: 194-201.
16. Forslund M, Landin-Wilhelmsen K, Trimpou P, Schmidt J, Brannstrom M, Dahlgren E. Type 2 diabetes mellitus in women with polycystic ovary syndrome during a 24-year period: importance of obesity and abdominal fat distribution. Hum Reprod Open 2020; 2020: hoz042.
17. Merz CN, Shaw LJ, Azziz R, et al. Cardiovascular Disease and 10-Year Mortality in Postmenopausal Women with Clinical Features of Polycystic Ovary Syndrome. J Womens Health (Larchmt) 2016; 25: 875-81.
18. Zhao L, Zhu Z, Lou H, et al. Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): a meta-analysis. Oncotarget 2016; 7: 33715-21.
19. Walch K, Kolbus A, Hefler-Frischmuth K. Polymorphisms of the endothelial nitric oxide synthase gene in premenopausal women with polycystic ovary syndrome. Maturitas 2008; 61: 256-9.
20. Sibal L, Agarwal SC, Home PD, Boger RH. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev 2010; 6: 82-90.
21. Mookerjee RP, Dalton RN, Davies NA, et al. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl 2007; 13: 400-5.
22. Notsu Y, Yano S, Shibata H, Nagai A, Nabika T. Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study. Atherosclerosis 2015; 239: 61-6.
23. Haghikia A, Yanchev GR, Kayacelebi AA, et al. The role of L-arginine/L-homoarginine/nitric oxide pathway for aortic distensibility and intima-media thickness in stroke patients. Amino Acids 2017; 49: 1111-21.
24. Surdacki A, Martens-Lobenhoffer J, Wloch A, et al. Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2007; 56: 809-19.
25. Di Gangi IM, Pirillo P, Carraro S, et al. Online trapping and enrichment ultra performance liquid chromatography-tandem mass spectrometry method for sensitive measurement of “arginine-asymmetric dimethylarginine cycle” biomarkers in human exhaled breath condensate. Anal Chim Acta 2012; 754: 67-74.
26. Perticone F, Sciacqua A, Maio R, et al. Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J Am Coll Cardiol 2005; 46: 518-23.
27. Krishna MB, Joseph A, Thomas PL, Dsilva B, Pillai SM, Laloraya M. Impaired arginine metabolism coupled to a defective redox conduit contributes to low plasma nitric oxide in polycystic ovary syndrome. Cell Physiol Biochem 2017; 43: 1880-92.
28. Elci E, Kaya C, Cim N, Yildizhan R, Elci GG. Evaluation of cardiac risk marker levels in obese and non-obese patients with polycystic ovaries. Gynecol Endocrinol 2017; 33: 43-7.
29. Burchall GF, Piva TJ, Linden MD, Gibson-Helm ME, Ranasinha S, Teede HJ. Comprehensive assessment of the hemostatic system in polycystic ovarian syndrome. Semin Thromb Hemost 2016; 42: 55-62.
30. Yavuz Taslipinar M, Kilic N, Bayraktar N, et al. Endothelial dysfunction and insulin resistance in young women with polycystic ovarian syndrome. Turk J Med Sci 2014; 44: 787-91.
31. Karakurt F, Carlioglu A, Kaygusuz I, Gumus, II, Uz B, Akdeniz D. Effect of ethinyl estradiol-cyproterone acetate treatment on asymmetric dimethyl-arginine levels in women with polycystic ovary syndrome. Arch Gynecol Obstet 2014; 289: 135-40.
32. 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: 500-3.
33. Atzler D, Schwedhelm E, Nauck M, Ittermann T, Boger RH, Friedrich N. Serum reference intervals of homoarginine, ADMA, and SDMA in the study of health in Pomerania. Clin Chem Lab Med 2014; 52: 1835-42.
34. Seppala I, Oksala N, Jula A, et al. The biomarker and causal roles of homoarginine in the development of cardiometabolic diseases: an observational and Mendelian randomization analysis. Sci Rep 2017; 7: 1130.
35. Loso J, Lund N, Avanesov M, et al. Serum biomarkers of endothelial dysfunction in fabry associated cardiomyopathy. Front Cardiovasc Med 2018; 5: 108.