LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility

  • Carla Regina Schmitz
  • Carlos Augusto Bastos de Souza
  • Vanessa Krebs Genro
  • Ursula Matte
  • Emily de Conto
  • João Sabino Cunha-Filho



To verify if polymorphisms of LH (Trp8Arg/Ile15Thr), LH receptor (insLQ), and FSH receptor (Asn680Ser) are associated with endometriosis and infertility.


This is a prospective case–control study. Sixty-seven patients with endometriosis and infertility (study group) and 65 healthy fertile patients (control group) were enrolled in the study between July 2010 and July 2013. All patients had their endometriosis diagnosis made or excluded by laparoscopic surgery; study group was submitted to the surgery for infertility investigation and control group for tubal ligation. Day-3 serum hormones were collected from all patients. Analysis of nucleotide mutations for LH polymorphisms (Trp8Arg and Ile15Thr), LHR polymorphism (insLQ), and FSHR polymorphism (Asn680Ser) were performed by PCR.


Day-3 FSH, estradiol and LH serum levels were not different between the groups, while CA-125 was higher in patients with endometriosis and infertility. All polymorphisms studied were in Hardy-Weinberg equilibrium. The prevalence of insLQ was significantly higher in patients with endometriosis and infertility (P = 0.005). Allele occurrence in control group was 0.10 versus 0.25 in infertile endometriosis group (P = 0.001). There was no difference regarding Trp8Arg/Ile15Thr (P > 0.05) and Asn680Ser (P > 0.05) prevalence between groups.


This is the first time that prevalence of insLQ was shown to be higher in patients with endometriosis and infertility than in healthy fertile patients. There was no difference in LH and FSHR polymorphisms’ prevalence between groups.


Endometriosis Infertility Hormones Polymorphisms 



This study was supported by grants from the CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and from the Fundo de Incentivo a Pesquisa (FIPE) of Hospital de Clínicas de Porto Alegre, RS – Brazil.

Supplementary material

10815_2015_477_MOESM1_ESM.doc (216 kb)
Supplemental Figure 1 (DOC 216 kb)


  1. 1.
    Moghissi KS. Medical treatment of endometriosis. Clin Obstet Gynecol. 1999;42(3):620–32.PubMedCrossRefGoogle Scholar
  2. 2.
    Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril. 2006;86(6):1561–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol. 2009;16(5):540–50.PubMedCrossRefGoogle Scholar
  4. 4.
    ASRM. Endometriosis and infertility. Fertil Steril. 2006;86(5 Suppl 1):S156–60.Google Scholar
  5. 5.
    Dmowski WP, Gebel HM, Braun DP. The role of cell-mediated immunity in pathogenesis of endometriosis. Acta Obstet Gynecol Scand Suppl. 1994;159:7–14.PubMedGoogle Scholar
  6. 6.
    Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril. 2008;90(2):247–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Simpson JL, Elias S, Malinak LR, Buttram Jr VC. Heritable aspects of endometriosis. I. Genetic studies. Am J Obstet Gynecol. 1980;137(3):327–31.PubMedGoogle Scholar
  10. 10.
    Alviggi C, Clarizia R, Pettersson K, Mollo A, Humaidan P, Strina I, et al. Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism. Reprod Biomed Online. 2009;18(1):9–14.PubMedCrossRefGoogle Scholar
  11. 11.
    Cunha-Filho JS, Gross JL, Bastos de Souza CA, Lemos NA, Giugliani C, Freitas F, et al. Physiopathological aspects of corpus luteum defect in infertile patients with mild/minimal endometriosis. J Assist Reprod Genet. 2003;20(3):117–21.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Cunha-Filho JS, Gross JL, Lemos NA, Brandelli A, Castillos M, Passos EP. Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis. Horm Metab Res. 2001;33(4):216–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Lemos NA, Arbo E, Scalco R, Weiler E, Rosa V, Cunha-Filho JS. Decreased anti-Mullerian hormone and altered ovarian follicular cohort in infertile patients with mild/minimal endometriosis. Fertil Steril. 2008;89(5):1064–8.PubMedCrossRefGoogle Scholar
  14. 14.
    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(4):970–8.e1.PubMedCrossRefGoogle Scholar
  15. 15.
    Lamminen T, Huhtaniemi I. A common genetic variant of luteinizing hormone; relation to normal and aberrant pituitary-gonadal function. Eur J Pharmacol. 2001;414(1):1–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Rodini GP, Genro VK, Matte U, Pereira FS, Bilibio JP, Greggianin C, et al. There is no complete linkage between the polymorphisms N680S and T307A of the follicular stimulating hormone receptor gene in fertile women. J Assist Reprod Genet. 2011;28(3):221–4.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Hillier SG, Whitelaw PF, Smyth CD. Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited. Mol Cell Endocrinol. 1994;100(1–2):51–4.PubMedGoogle Scholar
  18. 18.
    Filicori M. The role of luteinizing hormone in folliculogenesis and ovulation induction. Fertil Steril. 1999;71(3):405–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Filicori M, Cognigni GE, Pocognoli P, Ciampaglia W, Bernardi S. Current concepts and novel applications of LH activity in ovarian stimulation. Trends Endocrinol Metab. 2003;14(6):267–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends Endocrinol Metab. 2005;16(8):368–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Haavisto AM, Pettersson K, Bergendahl M, Virkamaki A, Huhtaniemi I. Occurrence and biological properties of a common genetic variant of luteinizing hormone. J Clin Endocrinol Metab. 1995;80(4):1257–63.PubMedGoogle Scholar
  22. 22.
    Piersma D, Berns EM, Verhoef-Post M, Uitterlinden AG, Braakman I, Pols HA, et al. A common polymorphism renders the luteinizing hormone receptor protein more active by improving signal peptide function and predicts adverse outcome in breast cancer patients. J Clin Endocrinol Metab. 2006;91(4):1470–6.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Takahashi K, Kurioka H, Ozaki T, Kanasaki H, Kohsaka M, Miyazaki K, et al. Increased prevalence of luteinizing hormone beta-subunit variant in Japanese infertility patients. Hum Reprod. 1998;13(12):3338–44.PubMedCrossRefGoogle Scholar
  27. 27.
    Powell BL, Piersma D, Kevenaar ME, van Staveren IL, Themmen AP, Iacopetta BJ, et al. Luteinizing hormone signaling and breast cancer: polymorphisms and age of onset. J Clin Endocrinol Metab. 2003;88(4):1653–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Bischoff F, Simpson JL. Genetics of endometriosis: heritability and candidate genes. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):219–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Treloar S, Hadfield R, Montgomery G, Lambert A, Wicks J, Barlow DH, et al. The International Endogene Study: a collection of families for genetic research in endometriosis. Fertil Steril. 2002;78(4):679–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Vigano P, Somigliana E, Vignali M, Busacca M, Blasio AM. Genetics of endometriosis: current status and prospects. Front Biosci. 2007;12:3247–55.PubMedCrossRefGoogle Scholar
  31. 31.
    Montgomery GW, Nyholt DR, Zhao ZZ, Treloar SA, Painter JN, Missmer SA, et al. The search for genes contributing to endometriosis risk. Hum Reprod Update. 2008;14(5):447–57.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Tempfer CB, Simoni M, Destenaves B, Fauser BC. Functional genetic polymorphisms and female reproductive disorders: part II–endometriosis. Hum Reprod Update. 2009;15(1):97–118.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4(10):e296.CrossRefGoogle Scholar
  34. 34.
    ASRM. Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 2008;90(5 Suppl):S60.Google Scholar
  35. 35.
    ASRM. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–21.CrossRefGoogle Scholar
  36. 36.
    Elter K, Erel CT, Cine N, Ozbek U, Hacihanefioglu B, Ertungealp E. Role of the mutations Trp8 = > Arg and Ile15 = > Thr of the human luteinizing hormone beta-subunit in women with polycystic ovary syndrome. Fertil Steril. 1999;71(3):425–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Atger M, Misrahi M, Sar S, Le Flem L, Dessen P, Milgrom E. Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5′ non-coding regions. Mol Cell Endocrinol. 1995;111(2):113–23.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Nilsson C, Pettersson K, Millar RP, Coerver KA, Matzuk MM, Huhtaniemi IT. Worldwide frequency of a common genetic variant of luteinizing hormone: an international collaborative research. International Collaborative Research Group. Fertil Steril. 1997;67(6):998–1004.PubMedCrossRefGoogle Scholar
  40. 40.
    Rodien P, Cetani F, Costagliola S, Tonacchera M, Duprez L, Minegishi T, et al. Evidences for an allelic variant of the human LC/CG receptor rather than a gene duplication: functional comparison of wild-type and variant receptors. J Clin Endocrinol Metab. 1998;83(12):4431–4.PubMedGoogle Scholar
  41. 41.
    Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D, et al. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab. 1999;84(2):751–5.PubMedGoogle Scholar
  42. 42.
    Lambalk CB, de Koning CH, Flett A, Van Kasteren Y, Gosden R, Homburg R. Assessment of ovarian reserve. Ovarian biopsy is not a valid method for the prediction of ovarian reserve. Hum Reprod. 2004;19(5):1055–9.PubMedCrossRefGoogle Scholar
  43. 43.
    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 strengthening the reporting of observational studies in epidemiology (STROBE) statement. J Clin Epidemiol. 2009;62(6):581–98.CrossRefGoogle Scholar
  44. 44.
    Takahashi K, Ozaki T, Okada M, Kurioka H, Kanasaki H, Miyazaki K. Increased prevalence of luteinizing hormone beta-subunit variant in patients with premature ovarian failure. Fertil Steril. 1999;71(1):96–101.PubMedCrossRefGoogle Scholar
  45. 45.
    Raivio T, Huhtaniemi I, Anttila R, Siimes MA, Hagenas L, Nilsson C, et al. The role of luteinizing hormone-beta gene polymorphism in the onset and progression of puberty in healthy boys. J Clin Endocrinol Metab. 1996;81(9):3278–82.PubMedGoogle Scholar
  46. 46.
    Rajkhowa M, Talbot JA, Jones PW, Pettersson K, Haavisto AM, Huhtaniemi I, et al. Prevalence of an immunological LH beta-subunit variant in a UK population of healthy women and women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 1995;43(3):297–303.CrossRefGoogle Scholar
  47. 47.
    Tapanainen JS, Koivunen R, Fauser BC, Taylor AE, Clayton RN, Rajkowa M, et al. A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone. J Clin Endocrinol Metab. 1999;84(5):1711–5.PubMedGoogle Scholar
  48. 48.
    Gazvani R, Pakarinen P, Fowler P, Logan S, Huhtaniemi I. Lack of association of the common immunologically anomalous LH with endometriosis. Hum Reprod. 2002;17(6):1532–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Greb RR, Grieshaber K, Gromoll J, Sonntag B, Nieschlag E, Kiesel L, et al. A common single nucleotide polymorphism in exon 10 of the human follicle stimulating hormone receptor is a major determinant of length and hormonal dynamics of the menstrual cycle. J Clin Endocrinol Metab. 2005;90(8):4866–72.PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedGoogle Scholar
  51. 51.
    Grigorova M, Punab M, Poolamets O, Sober S, Vihljajev V, Zilaitiene B, et al. Study in 1790 Baltic men: FSHR Asn680Ser polymorphism affects total testes volume. Andrology. 2013;1(2):293–300.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Wang HS, Cheng BH, Wu HM, Yen CF, Liu CT, Chao A. A mutant single nucleotide polymorphism of follicle-stimulating hormone receptor is associated with a lower risk of endometriosis. Fertil Steril. 2011;95(1):455–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Ferrero S, Anserini P, Remorgida V, Ragni N. Body mass index in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005;121(1):94–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Maiorana A, Cicerone C, Niceta M, Alio L. Evaluation of serum CA 125 levels in patients with pelvic pain related to endometriosis. Int J Biol Markers. 2007;22(3):200–2.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Carla Regina Schmitz
    • 1
  • Carlos Augusto Bastos de Souza
    • 2
  • Vanessa Krebs Genro
    • 2
  • Ursula Matte
    • 3
  • Emily de Conto
    • 1
    • 3
  • João Sabino Cunha-Filho
    • 1
    • 2
  1. 1.Postgraduate Program in Medical Clinics of the Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Department of Obstetrics and GynecologyUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Terapia Genica Research UnitResearch Center of Hospital de Clinicas de Porto AlegrePorto AlegreBrazil

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