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Elevated circulating levels of secreted frizzled-related protein 4 in relation to insulin resistance and androgens in women with polycystic ovary syndrome

  • M. Bicer
  • P. Alarslan
  • A. Guler
  • I. Demir
  • B. Aslanipour
  • M. CalanEmail author
Original Article
  • 51 Downloads

Abstract

Purpose

Secreted frizzled-related protein 4 (SFRP4) is an adipokine involving in apoptotic process during ovulation and energy metabolism. Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder associated with insulin resistance and impaired oocyte maturation as well as apoptotic dysfunctions through oocyte development. Our aim was to determine whether there was an alteration in levels of SFRP4 and if there was an association between metabolic or hormonal parameters and SFRP4 in women with PCOS.

Methods

We enrolled 80 subjects with PCOS and 80 age- and body mass index (BMI)-matched subjects with normal menstrual cycle into current case–control study. Metabolic and hormonal parameters of enrolled subjects were determined. Circulating SFRP4 levels were measured with ELISA method.

Results

We found that circulating SFRP4 levels were elevated in women with PCOS with respect to controls (5.87 ± 1.91 vs. 3.72 ± 1.29 ng/ml, P < 0.001). We also found a positive association between SFRP4 and insulin resistance, androgens, ovarian follicular number or ovarian volume in women with PCOS. Binary logistic regression analysis revealed that subjects with the highest tertile of SFPR4 levels displayed increased possibility of having PCOS risk compared to those subjects with the lowest tertile of SFRP4 levels.

Conclusions

Increased SFRP4 levels were not only associated with higher possibility of having PCOS but also related to insulin resistance, hyperandrogenism, ovarian follicular number and ovarian volume, suggesting that SFPR4 could be a player in different pathophysiologic pathways of PCOS.

Keywords

Polycystic ovary syndrome Secreted frizzled-related protein 4 Insulin resistance Hyperandrogenism Ovarian follicular number 

Abbreviations

AMH

Anti-müllerian hormone

BMI

Body mass index

CI

Confidence interval

CV

Coefficient of variability

DBP

Diastolic blood pressure

DHEA-S

Dehydroepiandrosterone sulfate

FAI

Free androgen index

FBG

Fasting blood glucose

FG

Ferriman-Gallwey

HDL-C

High density lipoprotein cholesterol

HOMA-IR

Homeostasis model assessment of insulin resistance

hs-CRP

High sensitivity C-reactive protein

LDL-C

Low density lipoprotein cholesterol

OR

Odds ratio

PCOS

Polycystic ovary syndrome

ROC

Receiver Operator Characteristic

SFRP4

Secreted frizzled-related protein 4

SBP

Systolic blood pressure

T2DM

Type 2 diabetes mellitus

VIF

Variance inflation factor

Notes

Author contributions

M.B., M.C., I.D., A.G, and P.A. participated in study design and B.A. and M.C. performed ELISA. M.B., M.C., I.D., A.G, P.A. and B.A. participated in study design, analyzed the data, wrote, reviewed and edited the manuscript. M.C., I.D., A.G. and P.A. provided serum samples and contributed to discussions of data interpretation. All authors reviewed and edited the manuscript. M.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This study has not been funded by any organizations.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study adhered strictly to the principles of the Declaration of Helsinki as revised in 2008.

Informed consent

The subjects gave their oral and written informed consent before their inclusion in the study.

References

  1. 1.
    Piltonen TT, Chen J, Erikson DW, Spitzer TLB, Barragan F, Rabban JT, Huddleston H, Irwin JC, Giudice LC (2013) Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display ınflammatory and oncogenic potential. J Clin Endocrinol Metab 98:3765–3775CrossRefGoogle Scholar
  2. 2.
    Mahdi T, Hänzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, Axelsson AS, Zhou Y, Jing X, Almgren P, Krus U, Taneera J, Blom AM, Lyssenko V, Esguerra JLS, Hansson O, Eliasson L, Derry J, Zhang E, Wollheim CB, Groop L, Renström E, Rosengren AH (2012) Secreted frizzled-related protein 4 reduces ınsulin secretion and ıs overexpressed in type 2 diabetes. Cell Metab 16:625–633CrossRefGoogle Scholar
  3. 3.
    Garufi G, Seyhan AA, Pasarica M (2015) Elevated secreted frizzled-related protein 4 in obesity: a potential role in adipose tissue dysfunction. Obesity (Silver Spring) 23:24–27CrossRefGoogle Scholar
  4. 4.
    Surendran K, Schiavi S, Hruska KA (2005) Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol 16:2373–2384CrossRefGoogle Scholar
  5. 5.
    Berndt T, Kumar R (2007) Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 69:341–359CrossRefGoogle Scholar
  6. 6.
    Muley A, Majumder S, Kolluru GK, Parkinson S, Viola H, Hool L, Arfuso F, Ganss R, Dharmarajan A, Chatterjee S (2010) Secreted frizzled-related protein 4. Am J Pathol 176:1505–1516CrossRefGoogle Scholar
  7. 7.
    Pohl S, Scott R, Arfuso F, Perumal V, Dharmarajan A (2015) Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumor Biol 36:143–152CrossRefGoogle Scholar
  8. 8.
    Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Sokol SY, Kocher O (1999) Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Lab Invest 79:439–447Google Scholar
  9. 9.
    Maman E, Yung Y, Cohen B, Konopnicki S, Dal Canto M, Fadini R, Kanety H, Kedem A, Dor J, Hourvitz A (2011) Expression and regulation of sFRP family members in human granulosa cells. Mol Hum Reprod 17:399–404CrossRefGoogle Scholar
  10. 10.
    Drake JM, Friis RR, Dharmarajan AM (2003) The role of sFRP4, a secreted frizzled-related protein, in ovulation. Apoptosis 8:389–397CrossRefGoogle Scholar
  11. 11.
    Anand K, Vidyasagar S, Lasrado I, Pandey GK, Amutha A, Ranjani H, Mohan Anjana R, Mohan V, Gokulakrishnan K (2016) Secreted frizzled-related protein 4 (SFRP4): a novel biomarker of β-cell dysfunction and ınsulin resistance in ındividuals with prediabetes and type 2 diabetes. Diabetes Care 39:e147–e148CrossRefGoogle Scholar
  12. 12.
    Baldane S, Ipekci SH, Ekin A, Abusoglu S, Unlu A, Kebapcilar L (2018) Evaluation of fractalkine (FKN) and secreted frizzled-related protein 4 (SFRP-4) serum levels in patients with prediabetes and type 2 diabetes. Bratisl Lek Listy 119:112–115Google Scholar
  13. 13.
    Baldane S, Ipekci SH, Kebapcilar AG, Abusoglu A, Beyhekim H, Ilhan TT, Unlu A, Kebapcilar A (2018) Prorenin and secreted frizzled-related protein 4 levels in women with gestational diabetes mellitus. Bratisl Lek Listy 119:450–453Google Scholar
  14. 14.
    Yuan X-S, Zhang M, Wang H-Y, Jiang J, Yu B (2018) Increased secreted frizzled-related protein 4 and ficolin-3 levels in gestational diabetes mellitus women. Endocr J 65:499–508CrossRefGoogle Scholar
  15. 15.
    Chang RJ, Cook-Andersen H (2013) Disordered follicle development. Mol Cell Endocrinol 373:51–60CrossRefGoogle Scholar
  16. 16.
    Das M, Djahanbakhch O, Hacihanefioglu B, Saridogan E, Ikram M, Ghali L, Raveendran M, Storey A (2008) Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. J Clin Endocrinol Metab 93:881–887CrossRefGoogle Scholar
  17. 17.
    Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236CrossRefGoogle Scholar
  18. 18.
    Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ (2013) Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod 28:777–784CrossRefGoogle Scholar
  19. 19.
    Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800Google Scholar
  20. 20.
    Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749CrossRefGoogle Scholar
  21. 21.
    March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ (2010) The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 25:544–551CrossRefGoogle Scholar
  22. 22.
    Pasquali R, Gambineri A (2018) New perspectives on the definition and management of polycystic ovary syndrome. J Endocrinol Invest 41:1123–1135CrossRefGoogle Scholar
  23. 23.
    Balen AH, Laven JSE, Tan S-L, Dewailly D (2003) Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 9:505–514CrossRefGoogle Scholar
  24. 24.
    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 (PCOS). Hum Reprod 19:41–47CrossRefGoogle Scholar
  25. 25.
    Ferriman D, Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447CrossRefGoogle Scholar
  26. 26.
    Al Kindi MK, Al Essry FS, Al Essry FS, Mula-Abed W-AS (2012) Validity of serum testosterone, free androgen index, and calculated free testosterone in women with suspected hyperandrogenism. Oman Med J 27:471–474CrossRefGoogle Scholar
  27. 27.
    Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502Google Scholar
  28. 28.
    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 28:412–419CrossRefGoogle Scholar
  29. 29.
    Reverchon M, Ramé C, Bertoldo M, Dupont J (2014) Adipokines and the female reproductive tract. Int J Endocrinol 2014:1–10CrossRefGoogle Scholar
  30. 30.
    Guo K, Wolf V, Dharmarajan AM, Feng Z, Bielke W, Saurer S, Friis R (1998) Apoptosis-associated gene expression in the corpus luteum of the rat1. Biol Reprod 58:739–746CrossRefGoogle Scholar
  31. 31.
    Hsieh M, Mulders SM, Friis RR, Dharmarajan A, Richards JS (2003) Expression and localization of secreted frizzled-related protein-4 in the rodent ovary: evidence for selective up-regulation in luteinized granulosa cells. Endocrinology 144:4597–4606CrossRefGoogle Scholar
  32. 32.
    Liu F, Qu H, Li Y, Tang Q, Yang Z, Wang H, Deng H (2015) Relationship between serum secreted frizzled-related protein 4 levels and the first-phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance. Endocr J 62:733–740CrossRefGoogle Scholar
  33. 33.
    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) 2019

Authors and Affiliations

  • M. Bicer
    • 1
  • P. Alarslan
    • 2
  • A. Guler
    • 3
  • I. Demir
    • 4
  • B. Aslanipour
    • 5
  • M. Calan
    • 2
    Email author
  1. 1.Department of Obstetrics and GynecologyMedical Park HospitalIzmirTurkey
  2. 2.Division of Endocrinology and Metabolism, Department of Internal MedicineIzmir Bozyaka Training and Research HospitalIzmirTurkey
  3. 3.Department of Family PhysicianIzmir Bozyaka Training and Research HospitalIzmirTurkey
  4. 4.Department of Internal MedicineIzmir Bozyaka Training and Research HospitalIzmirTurkey
  5. 5.Department of Bioengineering, Faculty of EngineeringEge UniversityIzmirTurkey

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