Journal of Endocrinological Investigation

, Volume 42, Issue 1, pp 91–96 | Cite as

Increased fibulin-1 plasma levels in polycystic ovary syndrome (PCOS) patients: possible contribution to the link between PCOS and cardiovascular risk

  • E. ScarinciEmail author
  • A. Tropea
  • G. Russo
  • G. Notaristefano
  • C. Messana
  • O. Alesiani
  • S. M. Fabozzi
  • A. Lanzone
  • R. Apa
Original Article



To investigate a possible relation between fibulin-1 plasma levels and PCOS.


ELISA quantitative determination of human fibulin-1.


50 women with PCOS and 40 control patients who attended the Unit of Human Reproductive Pathophysiology, Università Cattolica del Sacro Cuore, Rome, were enrolled. Ultrasonographic pelvic examinations, hormonal profile assays, oral tolerance test OGTT, lipid profile and ELISA quantitative determination of human fibulin-1 were performed.


Fibulin-1 levels were found to be statistically significantly higher in PCOS patients than in matched control women. No statistically significant positive correlation was found between fibulin-1 and AUCi, HOMA-IR, total cholesterol, LDL, AMH, androstenedione and FAI, whereas a statistically significant positive correlation was found between fibulin-1 and 17OHP (p = 0.016) in the PCOS group. However, multivariable linear regression analysis showed that 17 OH P did not independently predict fibulin-1 levels (p = 0.089).


Our data could contribute to explain the hypothesized increased cardiovascular risk and vascular damage in patients with PCOS. A better understanding of the cellular and molecular mechanisms involved in cardiometabolic disorders associated with PCOS is mandatory to identify new therapeutic strategies to eventually prevent the progression of cardiovascular diseases in these patients.


PCOS Fibulin-1 Cardiovascular risk Hormonal assay 



This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Compliance with ethical standards

Conflict of interest

All authors have nothing to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Scholze A, Bladbjerg EM, Sidelmann JJ, Diederichsen AC, Mickley H, Nybo M, Argraves WS, Marckmann P, Rasmussen LM (2013) Plasma concentrations of extracellular matrix protein fibulin-1 are related to cardiovascular risk markers in chronic kidney disease and diabetes. Cardiovasc diabetol 12:6CrossRefGoogle Scholar
  2. 2.
    Hungerford JE, Hoeffler JP, Bowers CW, Dahm LM, Falchetto R, Shabanowitz J, Hunt DF, Little CD (1997) Identification of a novel marker for primordial smooth muscle and its differential expression pattern in contractile vs noncontractile cells. J Cell Biol 137(4):925–937CrossRefGoogle Scholar
  3. 3.
    Roark EF, Keene DR, Haudenschild CC, Godyna S, Little CD, Argraves WS (1995) The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and RNA study. J Histochem Cytochem 43(4):401–411CrossRefGoogle Scholar
  4. 4.
    Cangemi C, Skov V, Poulsen MK, Funder J, Twal WO, Gall MA, Hjortdal V, Jespersen ML, Kruse TA, Aagard J, Parving HH, Knudsen S, Høilund-Carlsen PF, Rossing P, Henriksen JE, Argraves WS, Rasmussen LM (2011) Fibulin-1 is a marker for arterial extracellular matrix alterations in type 2 diabetes. Clin Chem 57(11):1556–1565CrossRefGoogle Scholar
  5. 5.
    Kaur P, Rizk NM, Ibrahim S, Younes N, Uppal A, Dennis K, Karve T, Blakeslee K, Kwagyan J, Zirie M, Ressom HW, Cheema AK (2012) iTRAQ-based quantitative protein expression profiling and MRM verification of markers in type 2 diabetes. J Proteome Res 11(11):5527–5539CrossRefGoogle Scholar
  6. 6.
    Kruger R, Rasmussen LM, Argraves WS, Eugen-Olsen J, Nielsen OW, Blyme A, Willenheimer R, Wachtell K, Olsen MH (2014) Extracellular matrix biomarker, fibulin-1, is closely related to NT-proBNP and soluble urokinase plasminogen activator receptor in patients with aortic valve stenosis (the SEAS study). PLoS One 9(7):e101522CrossRefGoogle Scholar
  7. 7.
    Kruger R, Schutte R, Huisman HW, Argraves WS, Rasmussen LM, Olsen MH, Schutte AE (2012) NT-proBNP is associated with fibulin-1 in Africans: the SAfrEIC study. Atherosclerosis 222(1):216–221CrossRefGoogle Scholar
  8. 8.
    Paapstel K, Zilmer M, Eha J, Tootsi K, Piir A, Kals J (2016) Association between fibulin-1 and aortic augmentation index in male patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 51(1):76–82CrossRefGoogle Scholar
  9. 9.
    Godyna S, Diaz-Ricart M, Argraves WS (1996) Fibulin-1 mediates platelet adhesion via a bridge of fibrinogen. Blood 88(7):2569–2577PubMedGoogle Scholar
  10. 10.
    Argraves WS, Tanaka A, Smith EP, Twal WO, Argraves KM, Fan D, Haudenschild CC (2009) Fibulin-1 and fibrinogen in human atherosclerotic lesions. Histochem Cell Biol 132(5):559–565CrossRefGoogle Scholar
  11. 11.
    Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L (1995) Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 15(7):821–826CrossRefGoogle Scholar
  12. 12.
    Cibula D, Cífková R, Fanta M, Poledne R, Zivny J, Skibová J (2000) Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum Reprod 15(4):785–789CrossRefGoogle Scholar
  13. 13.
    Moran LJ, Cameron JD, Strauss BJ, Teede HJ (2011) Vascular function in the diagnostic categories of polycystic ovary syndrome. Hum Reprod 26(8):2192–2199CrossRefGoogle Scholar
  14. 14.
    Pasquali R, Gambineri A (2018) New perspectives on the definition and management of polycystic ovary syndrome. J Endocrinol Invest (e-pub ahead of print) Google Scholar
  15. 15.
    Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81(1):19–25CrossRefGoogle Scholar
  16. 16.
    Legro RS (2001) Diabetes prevalence and risk factors in polycystic ovary syndrome. Obstet Gynecol Clin North Am 28(1):99–109CrossRefGoogle Scholar
  17. 17.
    Dunaif A, Segal KR, Futterweit W, Dobrjansky A (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38(9):1165–1174CrossRefGoogle Scholar
  18. 18.
    Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N (2001) Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 86(6):2453–2455CrossRefGoogle Scholar
  19. 19.
    Schachter M, Raziel A, Friedler S, Strassburger D, Bern O, Ron-El R (2003) Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine. Hum Reprod 18(4):721–727CrossRefGoogle Scholar
  20. 20.
    Legro RS, Kunselman AR, Dodson WC, Dunaif A (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84(1):165–169PubMedGoogle Scholar
  21. 21.
    Apridonidze T, Essah PA, Iuorno MJ, Nestler JE (2005) Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90(4):1929–1935CrossRefGoogle Scholar
  22. 22.
    Kelly CJ, Speirs A, Gould GW, Petrie JR, Lyall H, Connell JM (2002) Altered vascular function in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 87(2):742–746CrossRefGoogle Scholar
  23. 23.
    Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, Kuller LH (2000) Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 20(11):2414–2421CrossRefGoogle Scholar
  24. 24.
    Battaglia C, Mancini F, Cianciosi A, Busacchi P, Persico N, Paradisi R, Facchinetti F, de Aloysio D (2009) Cardiovascular risk in normal weight, eumenorrheic, nonhirsute daughters of patients with polycystic ovary syndrome: a pilot study. Fertil Steril 92(1):240–249CrossRefGoogle Scholar
  25. 25.
    Polak K, Czyzyk A, Simoncini T, Meczekalski B (2017) New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest 40:1–8CrossRefGoogle Scholar
  26. 26.
    Legro RS, Castracane VD, Kauffman RP (2004) Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 59(2):141–154CrossRefGoogle Scholar
  27. 27.
    Orio F Jr, Palomba S, Cascella T, De Simone B, Manguso F, Savastano S, Russo T, Tolino A, Zullo F, Lombardi G (2005) Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6 month study. J Clin Endocrinol Metab 90(11):6072–6076CrossRefGoogle Scholar
  28. 28.
    Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P (1999) Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 48(4):437–441CrossRefGoogle Scholar
  29. 29.
    Niccoli G, Apa R, Lanzone A, Liuzzo G, Spaziani C, Sagnella F, Cosentino N, Moro F, Martinez D, Morciano A, Bacà M, Pazzano V, Gangale MF, Tropea A, Crea F (2011) CD4 + CD28 null T lymphocytes are expanded in young women with polycystic ovary syndrome. Fertil Steril 95(8):2651–2654CrossRefGoogle Scholar
  30. 30.
    Durmus U, Duran C, Ecirli S (2017) Visceral adiposity index levels in overweight and/or obese, and non-obese patients with polycystic ovary syndrome and its relationship with metabolic and inflammatory parameters. J Endocrinol Invest 40:487–497CrossRefGoogle Scholar
  31. 31.
    Romualdi D, Costantini B, Selvaggi L, Giuliani M, Cristello F, Macrì F, Bompiani A, Lanzone A, Guido M (2008) Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective. Hum Reprod 23(9):2127–2133CrossRefGoogle Scholar
  32. 32.
    Ciampelli M, Leoni F, Cucinelli F, Mancuso S, Panunzi S, De Gaetano A, Lanzone A (2005) Assessment of insulin sensitivity from measurements in the fasting state and during an oral glucose tolerance test in polycystic ovary syndrome and menopausal patients. J Clin Endocrinol Metab 90(3):1398–1406CrossRefGoogle Scholar
  33. 33.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419CrossRefGoogle Scholar
  34. 34.
    Laakso M (1993) How good a marker is insulin level for insulin resistance? Am J Epidemiol 137(9):959–965CrossRefGoogle Scholar
  35. 35.
    Skov V, Cangemi C, Gram J, Christensen MM, Grodum E, Sørensen D, Argraves WS, Henriksen JE, Rasmussen LM (2014) Metformin, but not rosiglitazone, attenuates the increasing plasma levels of a new cardiovascular marker, fibulin-1, in patients with type 2 diabetes. Diabetes Care 37(3):760–766CrossRefGoogle Scholar
  36. 36.
    De Jager J, Kooy A, Lehert P, Bets D, Wulffelé MG, Teerlink T, Scheffer PG, Schalkwijk CG, Donker AJ, Stehouwer CD (2005) Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo controlled trial. J Intern Med 257(1):100–109CrossRefGoogle Scholar
  37. 37.
    Tschakovsky ME, Pyke KE (2005) Counterpoint: flow-mediated dilation does not reflect nitric oxide-mediated endothelial function. J Appl Physiol 99(3):1235–1238CrossRefGoogle Scholar
  38. 38.
    Mohammadi A, Aghasi M, Jodeiry-Farshbaf L, Salary-Lac S, Ghasemi-Rad M (2011) Evaluation of early atherosclerotic findings in women with polycystic ovary syndrome. J Ovarian Res 4(1):19CrossRefGoogle Scholar
  39. 39.
    Sprung VS, Atkinson G, Cuthbertson DJ, Pugh CJ, Aziz N, Green DJ, Cable NT, Jones H (2013) Endothelial function measured using flow mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies. Clin Endocrinol (Oxf) 78(3):438–446CrossRefGoogle Scholar
  40. 40.
    Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Häring HU (2000) Endothelial dysfunction is detectable in young normotensive first degree relatives of subjects with type II diabetes in association with insulin resistance. Circulation 101(15):1780–1784CrossRefGoogle Scholar
  41. 41.
    Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC (2002) Insulin causes endothelial dysfunction in humans. Circulation 105(5):576–582CrossRefGoogle Scholar
  42. 42.
    Cakir E, Doğan M, Topaloglu O, Ozbek M, Cakal E, Vural MG, Yeter E, Delibasi T (2013) Subclinical atherosclerosis and hyperandrogenemia are independent risk factors for increased epicardial fat thickness in patients with PCOS and idiopathic hirsutism. Atherosclerosis 226(1):291–295CrossRefGoogle Scholar
  43. 43.
    Naka KK, Kalantaridou SN, Bechlioulis A, Kravariti M, Kazakos N, Katsouras CS, Tsatsoulis A, Michalis LK (2011) Effect of ethinylestradiol/cyproterone acetate on endothelial function in young non-obese women with polycystic ovary syndrome: a pilot study. Gynecol Endocrinol 27(9):615–621CrossRefGoogle Scholar
  44. 44.
    Livingstone C, Collison M (2002) Sex steroids and insulin resistance. Clin Sci (Lond) 102(2):151–166CrossRefGoogle Scholar
  45. 45.
    Condorelli RA, Calogero AE, Di Mauro M, Mongioi’ LM, Cannarella R, Rosta G, La Vignera S (2018) Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index. J Endocrinol Invest 41:383–388CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2018

Authors and Affiliations

  • E. Scarinci
    • 1
    Email author
  • A. Tropea
    • 1
  • G. Russo
    • 2
  • G. Notaristefano
    • 1
  • C. Messana
    • 1
  • O. Alesiani
    • 1
  • S. M. Fabozzi
    • 1
  • A. Lanzone
    • 1
  • R. Apa
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversità Cattolica del Sacro CuoreRomeItaly
  2. 2.Department of Cardiovascular SciencesUniversità Cattolica del Sacro CuoreRomeItaly

Personalised recommendations