Skip to main content
SpringerLink
Log in

Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study is to evaluate the influence of follicle-stimulating hormone receptor (FSHR) Asn680Ser polymorphism on the ovarian response to exogenous follicle-stimulating hormone (FSH) and clinical outcomes in women undergoing controlled ovarian hyperstimulation (COH).

Methods

A database search was conducted to identify the eligible studies that investigated the effect of FSHR Asn680Ser polymorphism on ovarian response and clinical outcomes. A pooled analysis was performed with the odds ratio (OR) or weighted mean difference (WMD) and their respective 95 % confidence interval (CI) by the STATA software with random effects model.

Results

Sixteen cohort studies comprising a total of 4287 subjects were included. The number of retrieved oocytes was significantly fewer in subjects with the SS genotype at position 680, compared to subjects with the NN or NS genotype (WMD = −1.36, 95 % CI = −1.85 to −0.87). Lack of association was detected between the genotypes (SS genotype vs. NN or NS genotype) and clinical outcomes such as exogenous FSH dose (WMD = 98.96 IU, 95 % CI = −22.33 to 220.24), poor response (OR = 1.08, 95 % CI = 0.71–1.64), ovarian hyperstimulation syndrome (OHSS) (OR = 1.58, 95 % CI = 0.41–6.07), and clinical pregnancy rate (OR = 1.10, 95 % CI = 0.86–1.40). However, poor ovarian response and number of retrieved oocytes were significantly influenced by the Asn680Ser polymorphism in the Asian subjects. In addition, no publication bias was detected.

Conclusion

FSHR Asn680Ser polymorphism might be a significant biomarker for predicting the number of retrieved oocytes and poor response, especially in Asian subjects. Other outcomes such as exogenous FSH dose, OHSS, and pregnancy rate were not influenced by FSHR Asn680Ser polymorphism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Altmae S, Hovatta O, Stavreus-Evers A, Salumets A. Genetic predictors of controlled ovarian hyperstimulation: where do we stand today? Hum Reprod Update. 2011;17(6):813–28.

    Article  CAS  PubMed  Google Scholar 

  2. Gearhart J, Coutifaris C. In vitro fertilization, the Nobel Prize, and human embryonic stem cells. Cell Stem Cell. 2011;8(1):12–5.

    Article  CAS  PubMed  Google Scholar 

  3. de Castro F, Moron FJ, Montoro L, Real LM, Ruiz A. Pharmacogenetics of controlled ovarian hyperstimulation. Pharmacogenomics. 2005;6(6):629–37.

    Article  PubMed  Google Scholar 

  4. Enskog A, Henriksson M, Unander M, Nilsson L, Brannstrom M. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 1999;71(5):808–14.

    Article  CAS  PubMed  Google Scholar 

  5. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20(1):124–40.

    Article  PubMed  Google Scholar 

  6. Simoni M, Gromoll J, Nieschlag E. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev. 1997;18(6):739–73.

    CAS  PubMed  Google Scholar 

  7. Aittomaki K, Herva R, Stenman UH, Juntunen K, Ylostalo P, Hovatta O, et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab. 1996;81(10):3722–6.

    CAS  PubMed  Google Scholar 

  8. Simoni M, Nieschlag E, Gromoll J. Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. Hum Reprod Update. 2002;8(5):413–21.

    Article  CAS  PubMed  Google Scholar 

  9. Simoni M, Tempfer CB, Destenaves B, Fauser BC. Functional genetic polymorphisms and female reproductive disorders: part I: polycystic ovary syndrome and ovarian response. Hum Reprod Update. 2008;14(5):459–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Yao Y, Ma CH, Tang HL, Hu YF. Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis. Mol Genet Metab. 2011;103(4):388–93.

    Article  CAS  PubMed  Google Scholar 

  11. Moron FJ, Ruiz A. Pharmacogenetics of controlled ovarian hyperstimulation: time to corroborate the clinical utility of FSH receptor genetic markers. Pharmacogenomics. 2010;11(11):1613–8.

    Article  CAS  PubMed  Google Scholar 

  12. Perez Mayorga M, Gromoll J, Behre HM, Gassner C, Nieschlag E, Simoni M. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab. 2000;85(9):3365–9.

    CAS  PubMed  Google Scholar 

  13. Sudo S, Kudo M, Wada S, Sato O, Hsueh AJ, Fujimoto S. Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod. 2002;8(10):893–9.

    Article  CAS  PubMed  Google Scholar 

  14. de Castro F, Ruiz R, Montoro L, Perez-Hernandez D, Sanchez-Casas Padilla E, Real LM, et al. Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone. Fertil Steril. 2003;80(3):571–6.

    Article  PubMed  Google Scholar 

  15. Behre HM, Greb RR, Mempel A, Sonntag B, Kiesel L, Kaltwasser P, et al. Significance of a common single nucleotide polymorphism in exon 10 of the follicle-stimulating hormone (FSH) receptor gene for the ovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation. Pharmacogenet Genomics. 2005;15(7):451–6.

    Article  CAS  PubMed  Google Scholar 

  16. Jun JK, Yoon JS, Ku SY, Choi YM, Hwang KR, Park SY, et al. Follicle-stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET. J Hum Genet. 2006;51(8):665–70.

    Article  CAS  PubMed  Google Scholar 

  17. Klinkert ER, te Velde ER, Weima S, van Zandvoort PM, Hanssen RG, Nilsson PR, et al. FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF. Reprod Biomed Online. 2006;13(5):687–95.

    Article  CAS  PubMed  Google Scholar 

  18. Loutradis D, Patsoula E, Minas V, Koussidis GA, Antsaklis A, Michalas S, et al. FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. J Assist Reprod Genet. 2006;23(4):177–84.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women. Fertil Steril. 2009;91(2):432–9.

    Article  CAS  PubMed  Google Scholar 

  20. Huang SY, Yang J, Yin TL, Li X, Li J, Xu WM. Association of gene polymorphism of follicle stimulating hormone receptor with ovarian response in IVF cycles. Med J Wuhan Univ. 2010;31(3):334–8.

    CAS  Google Scholar 

  21. Sheikhha MH, Eftekhar M, Kalantar SM. Investigating the association between polymorphism of follicle-stimulating hormone receptor gene and ovarian response in controlled ovarian hyperstimulation. J Hum Reprod Sci. 2011;4(2):86–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Boudjenah R, Molina-Gomes D, Torre A, Bergere M, Bailly M, Boitrelle F, et al. Genetic polymorphisms influence the ovarian response to rFSH stimulation in patients undergoing in vitro fertilization programs with ICSI. PLoS One. 2012;7(6), e38700.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Genro VK, Matte U, De Conto E, Cunha-Filho JS, Fanchin R. Frequent polymorphisms of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT). J Assist Reprod Genet. 2012;29(7):657–63.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Mohiyiddeen L, Newman WG, Cerra C, Horne G, Mulugeta B, Byers H, et al. FSH receptor genotype does not predict metaphase-II oocyte output or fertilization rates in ICSI patients. Reprod Biomed Online. 2013;27(3):305–9.

    Article  CAS  PubMed  Google Scholar 

  25. Mohiyiddeen L, Newman WG, Cerra C, McBurney H, Mulugeta B, Roberts SA, et al. A common Asn680Ser polymorphism in the follicle-stimulating hormone receptor gene is not associated with ovarian response to gonadotropin stimulation in patients undergoing in vitro fertilization. Fertil Steril. 2013;99(1):149–55.

    Article  CAS  PubMed  Google Scholar 

  26. Yan Y, Gong Z, Zhang L, Li Y, Li X, Zhu L, et al. Association of follicle-stimulating hormone receptor polymorphisms with ovarian response in Chinese women: a prospective clinical study. PLoS One. 2013;8(10), e78138.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Huang X, Li L, Hong L, Zhou W, Shi H, Zhang H, et al. The Ser680Asn polymorphism in the follicle-stimulating hormone receptor gene is associated with the ovarian response in controlled ovarian hyperstimulation. Clin Endocrinol (Oxf). 2015;82(4):577–83.

    Article  CAS  Google Scholar 

  28. Mohiyiddeen L, Newman WG, McBurney H, Mulugeta B, Roberts SA, Nardo LG. Follicle-stimulating hormone receptor gene polymorphisms are not associated with ovarian reserve markers. Fertil Steril. 2012;97(3):677–81.

    Article  CAS  PubMed  Google Scholar 

  29. Lledo B, Guerrero J, Turienzo A, Ortiz JA, Morales R, Ten J, et al. Effect of follicle-stimulating hormone receptor N680S polymorphism on the efficacy of follicle-stimulating hormone stimulation on donor ovarian response. Pharmacogenet Genomics. 2013;23(5):262–8.

    Article  CAS  PubMed  Google Scholar 

  30. Pabalan N, Trevisan CM, Peluso C, Jarjanazi H, Christofolini DM, Barbosa CP, et al. Evaluating influence of the genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis. J Ovarian Res. 2014;7:285.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. www.cochrane-handbook.org. Accessed 3 Jun 2015.

  32. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement. PLoS Med. 2009;6(2), e22.

    Article  PubMed  Google Scholar 

  34. Zhou X, Qian W, Li J, Zhang P, Yang Z, Chen W, et al. Who are at risk for thromboembolism after arthroplasty? A systematic review and meta-analysis. Thromb Res. 2013;132(5):531–6.

    Article  CAS  PubMed  Google Scholar 

  35. Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA. DPYD IVS14 + 1G > A and 2846A > T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics. 2013;14(11):1255–72.

    Article  CAS  PubMed  Google Scholar 

  36. Dolfin E, Guani B, Lussiana C, Mari C, Restagno G, Revelli A. FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women. J Assist Reprod Genet. 2011;28(10):925–30.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are thankful to Prof. Hongguang Xie and Dr Shenyu Zhai, who provided valuable feedback about the manuscript

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China

      Huilin Tang, Yingying Yan, Ting Zhang, Weilong Shi, Rong Fan & Suodi Zhai

    2. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China

      Tiansheng Wang

    3. Pharmacy department of Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

      Yao Yao

    Authors
    1. Huilin Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yingying Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Tiansheng Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ting Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Weilong Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rong Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yao Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Suodi Zhai
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Suodi Zhai.

    Ethics declarations

    Compliance with ethical standards

    Formal institutional review board approval was not required because only published data were pooled.

    Conflict of interests

    The authors declare that they have no competing interests.

    Additional information

    Capsule The FSHR Asn680Ser polymorphism might be a significant biomarker for predicting the number of retrieved oocytes and poor response, especially in Asian subjects.

    Huilin Tang and Yingying Yan contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Tang, H., Yan, Y., Wang, T. et al. Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies. J Assist Reprod Genet 32, 1801–1810 (2015). https://doi.org/10.1007/s10815-015-0600-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10815-015-0600-5

    Keywords

    Search

    Navigation