{"paper_id":"d168251e-fb2f-4ab4-94f8-16e0772a2cac","body_text":"Abstract\nPurpose\nThe pro-inflammatory advanced glycation end products (AGEs) and their anti-inflammatory soluble receptors, sRAGE, play a role in the pathogenesis of PCOS. There is a correlation between vitamin D (vit D) and sRAGE in the serum, whereby vit D replacement increases serum sRAGE levels in women with PCOS, thus incurring a protective anti-inflammatory role.\nObjective\nThis study aims to compare levels of sRAGE, N-carboxymethyl-lysine (CML; one of the AGEs), and 25-hydroxy-vit D in the follicular fluid (FF) of women with or without PCOS, and to evaluate the correlation between sRAGE and 25-hydroxy-vit D in the FF.\nMaterial and methods\nWomen with (n = 12) or without (n = 13) PCOS who underwent IVF were prospectively enrolled.\nResults\nWomen with PCOS had significantly higher anti-Mullerian hormone levels, higher number of total retrieved and mature oocytes, and higher number of day 3 and day 5 embryos formed. Compared to women without PCOS, women with PCOS had significantly lower FF sRAGE levels. In women with PCOS, in women without PCOS, and in all participants together, there was a significant positive correlation between sRAGE and 25-hydroxy-vit D. sRAGE positively correlated with CML in women without PCOS but not in women with PCOS.\nConclusions\nIn women with PCOS, the low ovarian levels of the anti-inflammatory sRAGE suggest that sRAGE could represent a biomarker and a potential therapeutic target for ovarian dysfunction in PCOS. Whether there is a direct causal relationship between sRAGE and vit D in the ovaries remains to be determined.\nSimilar content being viewed by others\nAbbreviations\n- AGEs:\n-\nAdvanced glycation end products\n- sRAGE:\n-\nSoluble receptor for advanced glycation end products\nReferences\nGoodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7:219–31.\nAzziz 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.\nWang JX, Davies MJ, Norman RJ. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod. 2001;16:2606–9.\nHeijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:13–21.\nRajani S, Chattopadhyay R, Goswami SK, Ghosh S, Sharma S, Chakravarty B. Assessment of oocyte quality in polycystic ovarian syndrome and endometriosis by spindle imaging and reactive oxygen species levels in follicular fluid and its relationship with IVF-ET outcome. J Hum Reprod Sci. 2012;5:187–93.\nPiperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E, Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol Metab. 2012;97:2231–42.\nGarg D, Merhi Z. Advanced glycation end products: link between diet and ovulatory dysfunction in PCOS? Nutrients. 2015;7:10,129–44.\nDiamanti-Kandarakis E, Piperi C, Korkolopoulou P, Kandaraki E, Levidou G, Papalois A, et al. Accumulation of dietary glycotoxins in the reproductive system of normal female rats. J Mol Med (Berl). 2007;85:1413–20.\nYamagishi S, Nakamura K, Imaizumi T. Advanced glycation end products (AGEs) and diabetic vascular complications. Curr Diabetes Rev. 2005;1:93–106.\nUribarri J, del Castillo MD, de la Maza MP, Filip R, Gugliucci A, Luevano-Contreras C, et al. Dietary advanced glycation end products and their role in health and disease. Adv Nutr. 2015;6:461–73.\nRutkowska AZ, Diamanti-Kandarakis E. Do advanced glycation end products (AGEs) contribute to the comorbidities of polycystic ovary syndrome (PCOS)? Curr Pharm Des. 2016;22:5558–71.\nDiamanti-Kandarakis E, Piouka A, Livadas S, Piperi C, Katsikis I, Papavassiliou AG, et al. Anti-Mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome. Eur J Endocrinol. 2009;160:847–53.\nDiamanti-Kandarakis E, Piperi C, Patsouris E, Korkolopoulou P, Panidis D, Pawelczyk L, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol. 2007;127:581–9.\nGarg D, Merhi Z. Relationship between advanced glycation end products and steroidogenesis in PCOS. Reprod Biol Endocrinol. 2016;14:71.\nKalea AZ, Schmidt AM, Hudson BI. RAGE: a novel biological and genetic marker for vascular disease. Clin Sci (Lond). 2009;116:621–37.\nDiamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G. Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol. 2005;62:37–43.\nWang B, Hao M, Yang Q, Li J, Guo Y. Follicular fluid soluble receptor for advanced glycation end products (sRAGE): a potential protective role in polycystic ovary syndrome. J Assist Reprod Genet. 2016;33:959–65.\nSchmidt AM. Soluble RAGEs—prospects for treating & tracking metabolic and inflammatory disease. Vasc Pharmacol. 2015;72:1–8.\nWang B, Li J, Yang Q, Zhang F, Hao M, Guo Y. Decreased levels of sRAGE in follicular fluid from patients with PCOS. Reproduction. 2017;153:285–92.\nLiao Y, Huang R, Sun Y, Yue J, Zheng J, Wang L, et al. An inverse association between serum soluble receptor of advanced glycation end products and hyperandrogenism and potential implication in polycystic ovary syndrome patients. Reprod Biol Endocrinol. 2017;15:9.\nMerhi Z, Irani M, Doswell AD, Ambroggio J. Follicular fluid soluble receptor for advanced glycation end-products (sRAGE): a potential indicator of ovarian reserve. J Clin Endocrinol Metab. 2014;99:E226–33.\nBonetti TC, Borges E Jr, Braga DP, Iaconelli A Jr, Kleine JP, Silva ID. Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction. Reprod BioMed Online. 2013;26:62–7.\nThomson RL, Spedding S, Buckley JD. Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol. 2012;77:343–50.\nHahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114:577–83.\nYildizhan R, Kurdoglu M, Adali E, Kolusari A, Yildizhan B, Sahin HG, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet. 2009;280:559–63.\nPal L, Berry A, Coraluzzi L, Kustan E, Danton C, Shaw J, et al. Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome. Gynecol Endocrinol. 2012;28:965–8.\nSelimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, et al. The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Investig. 2010;33:234–8.\nIrani M, Minkoff H, Seifer DB, Merhi Z. Vitamin D increases serum levels of the soluble receptor for advanced glycation end products in women with PCOS. J Clin Endocrinol Metab. 2014;99:E886–90.\nRevised 2003 Consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004, 81:19–25.\nGonzalez 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;91:1508–12.\nPertynska-Marczewska M, Diamanti-Kandarakis E, Zhang J, Merhi Z. Advanced glycation end products: a link between metabolic and endothelial dysfunction in polycystic ovary syndrome? Metabolism. 2015;64:1564–73.\nMerhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29:135–45.\nDiamanti-Kandarakis E, Piperi C, Livadas S, Kandaraki EA, Papageorgiou E, Koutsilieris M: Interference of AGE-RAGE signaling with steroidogenic enzyme action in human ovarian cells. In Ovarian & Uterine Function I. SUN-556-SUN-556.\nHolick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.\nWang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–11.\nBalion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, et al. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology. 2012;79:1397–405.\nTalmor Y, Golan E, Benchetrit S, Bernheim J, Klein O, Green J, et al. Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells. Am J Physiol Renal Physiol. 2008;294:F1059–64.\nTalmor Y, Bernheim J, Klein O, Green J, Rashid G. Calcitriol blunts pro-atherosclerotic parameters through NFkappaB and p38 in vitro. Eur J Clin Investig. 2008;38:548–54.\nLee TW, Kao YH, Lee TI, Chang CJ, Lien GS, Chen YJ. Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts. Int J Cardiol. 2014;173:236–41.\nGuo YX, He LY, Zhang M, Wang F, Liu F, Peng WX. 1,25-Dihydroxyvitamin D3 regulates expression of LRP1 and RAGE in vitro and in vivo, enhancing Abeta1-40 brain-to-blood efflux and peripheral uptake transport. Neuroscience. 2016;322:28–38.\nSalum E, Kals J, Kampus P, Salum T, Zilmer K, Aunapuu M, et al. Vitamin D reduces deposition of advanced glycation end-products in the aortic wall and systemic oxidative stress in diabetic rats. Diabetes Res Clin Pract. 2013;100:243–9.\nSung JY, Chung W, Kim AJ, Kim HS, Ro H, Chang JH, et al. Calcitriol treatment increases serum levels of the soluble receptor of advanced glycation end products in hemodialysis patients with secondary hyperparathyroidism. Tohoku J Exp Med. 2013;230:59–66.\nSebekova K, Sturmer M, Fazeli G, Bahner U, Stab F, Heidland A. Is vitamin D deficiency related to accumulation of advanced glycation end products, markers of inflammation, and oxidative stress in diabetic subjects? Biomed Res Int. 2015;2015:958097.\nIrani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014;102:460–468.e463.\nWillemsen S, Hartog JW, van Veldhuisen DJ, van der Meer P, Roze JF, Jaarsma T, et al. The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction. Am Heart J. 2012;164:742–749.e743.\nKerkeni M, Saidi A, Bouzidi H, Ben Yahya S, Hammami M. Elevated serum levels of AGEs, sRAGE, and pentosidine in Tunisian patients with severity of diabetic retinopathy. Microvasc Res. 2012;84:378–83.\nAcknowledgements\nWe would like to thank Dr. Bharati Kalgi M.D., Grace Woo, and Dr. Rosine Rosanel M.D. in helping us collect the specimens for the study.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEthics declarations\nConflict of Interest\nThe authors declare that they have no conflict of interest.\nFunding\nGrant from Ferring Pharmaceuticals Inc. to Z.M and grant from Genesis Foundation to D.G.\nRights and permissions\nAbout this article\nCite this article\nGarg, D., Grazi, R., Lambert-Messerlian, G.M. et al. Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS. J Assist Reprod Genet 34, 1507–1513 (2017). https://doi.org/10.1007/s10815-017-1011-6\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s10815-017-1011-6","source_license":"CC0","license_restricted":false}