Journal of Assisted Reproduction and Genetics

, Volume 34, Issue 2, pp 263–273 | Cite as

The carriers of the A/G-G/G allelic combination of the c.2039 A>G and c.-29 G>A FSH receptor polymorphisms retrieve the highest number of oocytes in IVF/ICSI cycles

  • Adolfo AllegraEmail author
  • Angelo Marino
  • Stefania Raimondo
  • Antonio Maiorana
  • Salvatore Gullo
  • Piero Scaglione
  • Aldo Volpes
  • Riccardo Alessandro



The objective of this study was the elucidation of the possible role of the single-nucleotide polymorphisms (SNP) at position -29 and 2039 of the FSH receptor gene (FSHR) as independent predictive markers of ovarian response. Indeed, the tailoring of reproductive treatments is crucial for both maximizing the success of IVF patients and obtaining a reduction in hypo- or hyper-response rates.


This prospective, observational study analyzed the association of -29 and 2039 FSHR polymorphisms with the number of retrieved oocytes in 140 patients attending an IVF/ICSI cycle for severe male factors (≤5,000,000 spermatozoa/mL) or tubal factors at the ANDROS Day Surgery Clinic, Palermo, Italy.


The results of this study demonstrate that the genetic combination of A/G for polymorphism c.2039 A>G with G/G for polymorphism c.-29 G>A is significantly associated with the highest number of collected oocytes (p = 0.03). This association was significant even after controlling for the effect of other clinical variables.


The A/G-G/G allelic variant, identified as an independent variable, if confirmed in a larger number of patients, could be considered as a new genetic biomarker, which could increase the efficacy of prediction models for ovarian stimulation.


FSH receptor polymorphisms Treatment personalization COH IVF/ICSI 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector; the funds were provided directly by Centro Andros S.r.l., Palermo, Italy.


  1. 1.
    Sunkara SK, Rittenberg V, Raine-Ferring N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400.135 treatment cycles. Hum Reprod. 2011;26:1768–74.CrossRefPubMedGoogle Scholar
  2. 2.
    Genro VK, Grynberg M, Scheffer JB, Roux I, Frydman R, Fanchin R. Serum anti-Müllerian hormone levels are negatively related to Follicular Output RaTe (FORT) in norm-cycling women undergoing controlled ovarian hyperstimulation. Hum Reprod. 2011;26:671–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Aittomaki K, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82:959–68.CrossRefPubMedGoogle Scholar
  4. 4.
    Wunsch A, Ahda Y, Banaz-Yasar F, Sonntag B, Nieschlag E, Simoni M, et al. Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor. Fertil Steril. 2005;84:446–53.CrossRefPubMedGoogle Scholar
  5. 5.
    Perez-Mayorga M, Gromoll J, Behere 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;85:3365–9.Google Scholar
  6. 6.
    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;8:893–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Jun JK, Yoon JS, Ku S-Y, 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;51:665–70.CrossRefPubMedGoogle Scholar
  8. 8.
    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;23:177–84.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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;103:388–93.CrossRefPubMedGoogle Scholar
  10. 10.
    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, e38700.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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. 2015;82:577–83.CrossRefGoogle Scholar
  12. 12.
    Falconer H, Andersson E, Aanesen A, Fried G. Follicle-stimulating hormone receptor polymorphisms in a population of infertile women. Acta Obstet Gynecol Scand. 2005;84:806–11.CrossRefPubMedGoogle Scholar
  13. 13.
    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;13:687–95.CrossRefPubMedGoogle Scholar
  14. 14.
    Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Follicle-stimulating hormone receptor polymorphism (Thr(307)Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women. Fertil Steril. 2008;91:432–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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;4:86–90.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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;97:677–81.CrossRefPubMedGoogle Scholar
  17. 17.
    La Marca A, Papaleo E, Alviggi C, Ruvolo G, De Placido G, Candiani M, et al. The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age. Hum Reprod. 2013;28:1369–74.CrossRefPubMedGoogle Scholar
  18. 18.
    Mohiyiddeen L, Nardo LG. Single-nucleotide polymorphisms in the FSH receptor gene and ovarian performance: future role in IVF. Hum Fertil. 2010;13:72–8.CrossRefGoogle Scholar
  19. 19.
    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;15:451–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Alviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I, et al. In estimated good prognosis patients could unexpected “hyporesponse” to controlled ovarian stimulation be related to genetic polymorphisms of FSH receptor? Reprod Sci. 2016;23:1103–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Daelemans C, Smits G, de Maertelaer V, Costagliola S, Englert Y, Vassart G, et al. Prediction of severity of symptoms in iatrogenic ovarian hyperstimulation syndrome by follicle-stimulating hormone receptor Ser680Asn polymorphism. J Clin Endocrinol Metab. 2004;89:6310–5.CrossRefPubMedGoogle Scholar
  22. 22.
    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;99:149–55.CrossRefPubMedGoogle Scholar
  23. 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;29:657–63.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lindgren I, Bååth M, Uvebrant K, Dejmek A, Kjaer L, Henic E, et al. Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod. 2016;31:672–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Tang H, Yan Y, Wang T, Zhang T, Shi W, Fan R, 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. 2015;32:1801–10.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moròn FJ, Ruiz A. Pharmacogenetics of controlled ovarian hyperstimulation: time to corroborate the clinical utility of FSH receptor genetic markers. Pharmacogenomics. 2010;11:1613–8.CrossRefPubMedGoogle Scholar
  27. 27.
    La Marca A, Sighinolfi G, Argento C, Grisendi V, Casarini L, Volpe A, et al. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization. Fertil Steril. 2013;99:970–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Tohlob D, Abo Hashem E, Ghareeb N, Ghanem M, Elfarahaty R, Byers H, et al. Association of a promoter polymorphism in FSHR with ovarian reserve and response to ovarian stimulation in women undergoing assisted reproductive treatment. Reprod Biomed Online. 2016;33:391–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Poor ovarian response to gonadotropin stimulation is associated with FSH receptor polymorphism. Reprod Biomed Online. 2009;18:509–15.CrossRefPubMedGoogle Scholar
  30. 30.
    Desai SS, Achrekar SK, Pathak BR, Desai SK, Mangoli VS, Mangoli RV, et al. Follicle-stimulating hormone receptor polymorphism (G-29A) is associated with altered level of receptor expression in Granulosa cells. J Clin Endocrinol Metab. 2011;96:2805–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Desai SS, Achrekar SK, Paranjape SR, Desai SK, Mangoli VS, Mahale SD. Association of allelic combinations of FSHR gene polymorphisms with ovarian response. Reprod Biomed Online. 2013;27:400–6.CrossRefPubMedGoogle Scholar
  32. 32.
    American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21.CrossRefGoogle Scholar
  33. 33.
    Volpes A, Sammartano F, Coffaro F, Mistretta V, Scaglione P, Allegra A. Number of good quality embryos on day 3 is predictive for both pregnancy and implantation rates in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2004;82:1330–6.CrossRefPubMedGoogle Scholar
  34. 34.
    La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20:124–40.CrossRefPubMedGoogle Scholar
  35. 35.
    Deb S, Batcha M, Campbell BK, Jayaprakasan K, Clewes JS, Hopkisson JF, et al. The predictive value of the automated quantification of the number and size of small antral follicles in women undergoing ART. Hum Reprod. 2009;24:2124–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Nelson S. Biomarkers of ovarian stimulation: current and future applications. Fertil Steril. 2013;99:963–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Pinborg A, Gaarsley C, Hougaard CO, Nyboe Andersen A, Andersen PK, Boivin J, et al. Influence of female bodyweight on IVF outcome: a longitudinal multicentre cohort study of 487 infertile couples. Reprod Biomed Online. 2011;23:490–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T. Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis. Reprod Biomed Online. 2011;23:421–39.CrossRefPubMedGoogle Scholar
  39. 39.
    Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, teVelde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotropins in IVF treatment: a randomized controlled trial. Hum Reprod. 2005;20:611–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Berkkanoglu M, Ozgur K. What is the optimum maximal gonadotropin dosage used in microdose flare-up cycles in poor responders? Fertil Steril. 2010;94:662–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, et al. Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009;24:867–75.CrossRefPubMedGoogle Scholar
  42. 42.
    Yates AP, Rustamov O, Roberts SA, Lim HY, Pemberton PW, Smith A, et al. Anti-Mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF. Hum Reprod. 2011;26:2353–62.CrossRefPubMedGoogle Scholar
  43. 43.
    Stimpfel M, Vrtačnik-Bokal E, Pozlep B, Kmecl J, Virant-Klun I. Gonadotropin-releasing hormone agonist protocol of controlled ovarian hyperstimulation as an efficient treatment in Bologna-defined poor ovarian responders. Syst Biol Reprod Med. 2016;62:290–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Pandian Z, McTavish AR, Aucott L, Hamilton MP, Bhattacharya S. Interventions for ‘poor responders’ to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. 2010;1, CD004379.Google Scholar
  45. 45.
    Pu D, Wu J, Liu J. Comparisons of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF. Hum Reprod. 2011;26:2742–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Adolfo Allegra
    • 1
    Email author
  • Angelo Marino
    • 1
  • Stefania Raimondo
    • 2
  • Antonio Maiorana
    • 3
  • Salvatore Gullo
    • 4
  • Piero Scaglione
    • 1
  • Aldo Volpes
    • 1
  • Riccardo Alessandro
    • 2
  1. 1.Reproductive Medicine UnitANDROS Day Surgery ClinicPalermoItaly
  2. 2.Dipartimento di Biopatologia e Biotecnologie MedicheUniversità di PalermoPalermoItaly
  3. 3.Unità Operativa Complessa di Ginecologia ed OstetriciaA.R.N.A.S. Ospedale CivicoPalermoItaly
  4. 4.Medical Statistics UnitANDROS Day Surgery ClinicPalermoItaly

Personalised recommendations