Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function

  • Livio Casarini
  • Elisa Pignatti
  • Manuela Simoni


Gonadotropins, the action of which is mediated at the level of their gonadal receptors, play a key role in sexual development, reproductive functions and in metabolism. The involvement of the gonadotropins and their receptor genotypes on reproductive function are widely studied. A large number of gonadotropins and their receptors gene polymorphisms are known, but the only one considerable as a clear, absolute genetic marker of reproductive features or disfunctions is the FSHR Asn680Ser polymorphism, since it modulates ovarian response to FSH. The aim of these studies would to be the prediction of the genetic causes of sex-related diseases to enable a customized clinical setting based on individual response of patients undergoing gonadotropin stimulation. In this review we discuss the latest information about the effects of polymorphisms of the gonadotropins and their receptor genes on reproductive functions of both male and female, and discuss their patho-physiological implications.


Gonadotropin Gonadotropin receptor Polymorphism SNP FSHR LHCGR 



This work was supported by Fondazione Cassa di Risparmio di Modena and by a grant of the Italian Ministry of University and Research (FIRB IDEAS 2008 RBID08777T).


  1. 1.
    Simoni M, Gromoll J, Nieschlag E. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev. 1997;18(6):739–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;23(2):141–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev. 2000;21(5):551–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Dias JA, Van Roey P. Structural biology of human follitropin and its receptor. Arch Med Res. 2001;32(6):510–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Szkudlinski MW, Fremont V, Ronin C, Weintraub BD. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev. 2002;82(2):473–502.PubMedGoogle Scholar
  6. 6.
    Maston G, Ruvolo M. Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection. Mol Biol Evol. 2002;19(3):320–35.PubMedGoogle Scholar
  7. 7.
    Henke A, Gromoll J. New insights into the evolution of chorionic gonadotrophin. Mol Cell Endocrinol. 2008;291(1–2):11–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Nagirnaja L, Rull K, Uusküla L, Hallast P, Grigorova M, Laan M. Genomics and genetics of gonadotropin beta-subunit genes: unique FSHB and duplicated LHB/CGB loci. Mol Cell Endocrinol. 2010;329(1–2):4–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Talmadge K, Vamvakopoulos NC, Fiddes JC. Evolution of the genes for the beta subunits of human chorionic gonadotropin and luteinizing hormone. Nature. 1984;5(5946):37–40.CrossRefGoogle Scholar
  10. 10.
    Fredriksson R, Lagerström MC, Lundin L, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63(6):1256–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Gromoll J, Pekel E, Nieschlag E. The structure and organization of the human follicle-stimulating hormone receptor (FSHR) gene. Genomics. 1996;35(2):308–11.PubMedCrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    Nordhoff V, Gromoll J, Simoni M. Constitutively active mutations of G protein-coupled receptors: the case of the human luteinizing hormone and follicle-stimulating hormone receptors. Arch Med Res. 1999;30(6):501–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Simoni M, Tempfer CB, Destenaves B, Fauser BCJM. Functional genetic polymorphisms and female reproductive disorders: Part I: polycystic ovary syndrome and ovarian response. Hum Reprod Update. 2008;14(5):459–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576):2225–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Barrett JC. Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc. 2009 Ott;2009(10):pdb.ip71.Google Scholar
  18. 18.
    Simoni M, Gromoll J, Höppner W, Kamischke A, Krafft T, Stähle 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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Gromoll J, Simoni M. Follicle-stimulating-hormone receptor and twinning. Lancet. 2001;20(9251):230. author reply 231–232.CrossRefGoogle Scholar
  21. 21.
    Hodgen GD. The dominant ovarian follicle. Fertil Steril. 1982;38(3):281–300.PubMedGoogle Scholar
  22. 22.
    Baird DT. A model for follicular selection and ovulation: lessons from superovulation. J Steroid Biochem. 1987;27(1–3):15–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Brown JB. Pituitary control of ovarian function—concepts derived from gonadotrophin therapy. Aust N Z J Obstet Gynaecol. 1978;18(1):46–54.PubMedCrossRefGoogle Scholar
  24. 24.
    Schipper I, Hop WCJ, Fauser BCJM. The Follicle-Stimulating Hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J Clin Endocrinol Metab. 1998;83(4):1292–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Zheng W, Magid M, Kramer E, Chen Y. Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube. Am J Pathol. 1996;148(1):47–53.PubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends Endocrinol Metab. 2005;16(8):368–73.PubMedCrossRefGoogle Scholar
  28. 28.
    Nordhoff V, Sonntag B, von Tils D, Götte M, Schüring AN, Gromoll J, et al. Effects of the FSH receptor gene polymorphism p.N680S on cAMP and steroid production in cultured primary human granulosa cells. Reprod Biomed Online [Internet]. 2011 Mag 12 [citato 2011 Lug 29]; Available from:
  29. 29.
    Loutradis D, Vlismas A, Drakakis P, Antsaklis A. Pharmacogenetics in ovarian stimulation—current concepts. Ann N Y Acad Sci. 2008;1127:10–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Meyer JM, Eaves LJ, Heath AC, Martin NG. Estimating genetic influences on the age-at-menarche: a survival analysis approach. Am J Med Genet. 1991;39(2):148–54.PubMedCrossRefGoogle Scholar
  31. 31.
    Kaprio J, Rimpelä A, Winter T, Viken RJ, Rimpelä M, Rose RJ. Common genetic influences on BMI and age at menarche. Hum Biol. 1995;67(5):739–53.PubMedGoogle Scholar
  32. 32.
    Zerbetto I, Gromoll J, Luisi S, Reis FM, Nieschlag E, Simoni M, et al. Follicle-stimulating hormone receptor and DAZL gene polymorphisms do not affect the age of menopause. Fertil Steril. 2008;90(6):2264–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Achrekar SK, Modi DN, Meherji PK, Patel ZM, Mahale SD. Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea. J Assist Reprod Genet. 2010;27(6):317–26.PubMedCrossRefGoogle Scholar
  34. 34.
    Sowers MR, Jannausch ML, McConnell DS, Kardia SR, Randolph JF. Menstrual cycle markers of ovarian aging and sex steroid hormone genotypes. Am J Med. 2006;119(9 Suppl 1):S31–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Grigorova M, Punab M, Ausmees K, Laan M. FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men. Hum Reprod. 2008;23(9):2160–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Fauser BCJM, Diedrich K, Devroey P. Predictors of ovarian response: progress towards individualized treatment in ovulation induction and ovarian stimulation. Hum Reprod Update. 2008;14(1):1–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Sudo S, Kudo M, Wada S, Sato O, Hsueh AJW, Fujimoto S. Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod. 2002;8(10):893–9.PubMedCrossRefGoogle Scholar
  38. 38.
    de Castro F, Ruiz R, Montoro L, Pérez-Hernández D, Sánchez-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
  39. 39.
    de Castro F, Morón FJ, Montoro L, Galán JJ, Hernández DP, Padilla ES, et al. Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics. 2004;14(5):285–93.PubMedCrossRefGoogle Scholar
  40. 40.
    Jun JK, Yoon JS, Ku S, 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.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    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
  43. 43.
    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
  44. 44.
    Klinkert ER, te Velde ER, Weima S, van Zandvoort PM, Hanssen RGJM, 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.PubMedCrossRefGoogle Scholar
  45. 45.
    Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Poor ovarian response to gonadotrophin stimulation is associated with FSH receptor polymorphism. Reprod Biomed Online. 2009;18(4):509–15.PubMedCrossRefGoogle Scholar
  46. 46.
    Ochsenkühn R, von Schönfeldt V, Simoni M. FSH receptor polymorphisms and ovarian function. Texte intégral de l’article Printable version FSH receptor polymorphisms and ovarian function. MT/médecine de la reproduction, gynécologie et endocrinologie. 2009;11(4):265–70.Google Scholar
  47. 47.
    Richter-Unruh A, Martens JWM, Verhoef-Post M, Wessels HT, Kors WA, Sinnecker GHG, et al. Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene. Clin Endocrinol (Oxf). 2002;56(1):103–12.CrossRefGoogle Scholar
  48. 48.
    Powell BL, Piersma D, Kevenaar ME, van Staveren IL, Themmen APN, 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
  49. 49.
    Themmen APN. An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms. Reproduction. 2005;130(3):263–74.PubMedCrossRefGoogle Scholar
  50. 50.
    Rull K, Laan M. Expression of beta-subunit of HCG genes during normal and failed pregnancy. Hum Reprod. 2005;20(12):3360–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Rull K, Nagirnaja L, Ulander V, Kelgo P, Margus T, Kaare M, et al. Chorionic gonadotropin beta-gene variants are associated with recurrent miscarriage in two European populations. J Clin Endocrinol Metab. 2008;93(12):4697–706.PubMedCrossRefGoogle Scholar
  52. 52.
    Uusküla L, Rull K, Nagirnaja L, Laan M. Methylation allelic polymorphism (MAP) in chorionic gonadotropin beta5 (CGB5) and its association with pregnancy success. J Clin Endocrinol Metab. 2011;96(1):E199–207.PubMedCrossRefGoogle Scholar
  53. 53.
    Nastri CO, Ferriani RA, Rocha IA, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology and prevention. J Assist Reprod Genet. 2010;27(2–3):121–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update. 2002;8(6):559–77.PubMedCrossRefGoogle Scholar
  55. 55.
    Vlahos NF, Gregoriou O. Prevention and management of ovarian hyperstimulation syndrome. Ann N Y Acad Sci. 2006;1092:247–64.PubMedCrossRefGoogle Scholar
  56. 56.
    Nappi RG, Di Naro E, D’Aries AP, Nappi L. Natural pregnancy in hypothyroid woman complicated by spontaneous ovarian hyperstimulation syndrome. Am J Obstet Gynecol. 1998;178(3):610–1.PubMedCrossRefGoogle Scholar
  57. 57.
    Michaelson-Cohen R, Altarescu G, Beller U, Reens R, Halevy-Shalem T, Eldar-Geva T. Does elevated human chorionic gonadotropin alone trigger spontaneous ovarian hyperstimulation syndrome? Fertil Steril. 2008;90(5):1869–74.PubMedCrossRefGoogle Scholar
  58. 58.
    Dieterich M, Bolz M, Reimer T, Costagliola S, Gerber B. Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation. Reprod Biomed Online. 2010;20(6):751–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Rodien P, Beau I, Vasseur C. Ovarian hyperstimulation syndrome (OHSS) due to mutations in the follicle-stimulating hormone receptor. Ann Endocrinol (Paris). 2010;71(3):206–9.CrossRefGoogle Scholar
  60. 60.
    Kerkelä E, Skottman H, Friden B, Bjuresten K, Kere J, Hovatta O. Exclusion of coding-region mutations in luteinizing hormone and follicle-stimulating hormone receptor genes as the cause of ovarian hyperstimulation syndrome. Fertil Steril. 2007;87(3):603–6.PubMedCrossRefGoogle Scholar
  61. 61.
    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(12):6310–5.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Chen S, Chou C, Lin C, Lee H, Wu J, Lu H, et al. Signal mechanisms of vascular endothelial growth factor and interleukin-8 in ovarian hyperstimulation syndrome: dopamine targets their common pathways. Hum Reprod. 2010;25(3):757–67.PubMedCrossRefGoogle Scholar
  64. 64.
    Peitsidis P, Agrawal R. Role of vascular endothelial growth factor in women with PCO and PCOS: a systematic review. Reprod Biomed Online. 2010;20(4):444–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–97.PubMedCrossRefGoogle Scholar
  66. 66.
    Du J, Zhang W, Guo L, Zhang Z, Shi H, Wang J, et al. Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome. Mol Genet Metab. 2010;100(3):292–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Tong Y, Liao WX, Roy AC, Ng SC. Absence of mutations in the coding regions of follicle-stimulating hormone receptor gene in Singapore Chinese women with premature ovarian failure and polycystic ovary syndrome. Horm Metab Res. 2001;33(4):221–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Laven JSE, Mulders AGMGJ, Suryandari DA, Gromoll J, Nieschlag E, Fauser BCJM, et al. Follicle-stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility. Fertil Steril. 2003;80(4):986–92.PubMedCrossRefGoogle Scholar
  69. 69.
    Orio F, Ferrarini E, Cascella T, Dimida A, Palomba S, Gianetti E, et al. Genetic analysis of the follicle stimulating hormone receptor gene in women with polycystic ovary syndrome. J Endocrinol Invest. 2006;29(11):975–82.PubMedGoogle Scholar
  70. 70.
    Unsal T, Konac E, Yesilkaya E, Yilmaz A, Bideci A, Ilke Onen H, et al. Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome. J Assist Reprod Genet. 2009;26(4):205–16.PubMedCrossRefGoogle Scholar
  71. 71.
    Valkenburg O, Uitterlinden AG, Piersma D, Hofman A, Themmen APN, de Jong FH, et al. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum Reprod. 2009;24(8):2014–22.PubMedCrossRefGoogle Scholar
  72. 72.
    Gu B, Park J, Baek K. Genetic variations of follicle stimulating hormone receptor are associated with polycystic ovary syndrome. Int J Mol Med. 2010;26(1):107–12.PubMedGoogle Scholar
  73. 73.
    Overbeek A, Kuijper EAM, Hendriks ML, Blankenstein MA, Ketel IJG, Twisk JWR, et al. Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome. Hum Reprod. 2009;24(8):2007–13.PubMedCrossRefGoogle Scholar
  74. 74.
    Tong Y, Liao WX, Roy AC, Ng SC. Association of AccI polymorphism in the follicle-stimulating hormone beta gene with polycystic ovary syndrome. Fertil Steril. 2000;74(6):1233–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Lamminen T, Jokinen P, Jiang M, Pakarinen P, Simonsen H, Huhtaniemi I. Human FSH beta subunit gene is highly conserved. Mol Hum Reprod. 2005;11(8):601–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Nilsson C, Jiang M, Pettersson K, Iitiä A, Mäkelä M, Simonsen H, et al. Determination of a common genetic variant of luteinizing hormone using DNA hybridization and immunoassays. Clin Endocrinol (Oxf). 1998;49(3):369–76.CrossRefGoogle Scholar
  77. 77.
    Pettersson K, Ding YQ, Huhtaniemi I. An immunologically anomalous luteinizing hormone variant in a healthy woman. J Clin Endocrinol Metab. 1992;74(1):164–71.PubMedCrossRefGoogle Scholar
  78. 78.
    Suganuma N, Furui K, Kikkawa F, Tomoda Y, Furuhashi M. Effects of the mutations (Trp8→Arg and Ile15→Thr) in human luteinizing hormone (LH) beta-subunit on LH bioactivity in vitro and in vivo. Endocrinology. 1996;137(3):831–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Jiang M, Pakarinen P, Zhang FP, El-Hefnawy T, Koskimies P, Pettersson K, et al. A common polymorphic allele of the human luteinizing hormone beta-subunit gene: additional mutations and differential function of the promoter sequence. Hum Mol Genet. 1999;8(11):2037–46.PubMedCrossRefGoogle Scholar
  80. 80.
    Cramer DW, Petterson KS, Barbieri RL, Huhtaniemi IT. Reproductive hormones, cancers, and conditions in relation to a common genetic variant of luteinizing hormone. Hum Reprod. 2000;15(10):2103–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Tapanainen JS, Koivunen R, Fauser BCJM, 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.PubMedCrossRefGoogle Scholar
  82. 82.
    Kevenaar ME, Laven JSE, Fong SL, Uitterlinden AG, de Jong FH, Themmen APN, et al. A functional anti-mullerian hormone gene polymorphism is associated with follicle number and androgen levels in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2008;93(4):1310–6.PubMedCrossRefGoogle Scholar
  83. 83.
    van Houten ELAF, Themmen APN, Visser JA. Anti-Müllerian hormone (AMH): regulator and marker of ovarian function. Ann Endocrinol (Paris). 2010;71(3):191–7.CrossRefGoogle Scholar
  84. 84.
    Xita N, Lazaros L, Georgiou I, Tsatsoulis A. CYP19 gene: a genetic modifier of polycystic ovary syndrome phenotype. Fertil Steril. 2010;94(1):250–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev U, Peters M, Karro H, et al. Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand. 2010;89(12):1557–63.PubMedCrossRefGoogle Scholar
  86. 86.
    Ke L, Che Y, Cao Y, Wu X, Hu Y, Sun H, et al. Polymorphisms of the HSD17B6 and HSD17B5 genes in Chinese women with polycystic ovary syndrome. J Womens Health (Larchmt). 2010;19(12):2227–32.CrossRefGoogle Scholar
  87. 87.
    Mu Y, Liu J, Wang B, Wen Q, Wang J, Yan J, et al. Interleukin 1 beta (IL-1β) promoter C [−511] T polymorphism but not C [+3953] T polymorphism is associated with polycystic ovary syndrome. Endocrine. 2010;37(1):71–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Yang Y, Qiao J, Li M. Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in Chinese population. Reprod Biol Endocrinol. 2010;8:125.PubMedCrossRefGoogle Scholar
  89. 89.
    Vural P, Küskü-Kiraz Z, Doğru-Abbasoğlu S, Cil E, Karadağ B, Akgül C, et al. Vascular endothelial growth factor −2578 A/C, −460 T/C and +405 G/C polymorphisms in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2009;147(1):57–60.PubMedCrossRefGoogle Scholar
  90. 90.
    Sproul K, Jones MR, Mathur R, Azziz R, Goodarzi MO. Association study of four key folliculogenesis genes in polycystic ovary syndrome. BJOG. 2010;117(6):756–60.PubMedCrossRefGoogle Scholar
  91. 91.
    Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986;67(4):604–6.PubMedGoogle Scholar
  92. 92.
    Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril. 1990;53(5):804–10.PubMedGoogle Scholar
  93. 93.
    Conway GS. Premature ovarian failure. Br Med Bull. 2000;56(3):643–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf). 2008;68(4):499–509.CrossRefGoogle Scholar
  95. 95.
    De Vos M, Devroey P, Fauser BCJM. Primary ovarian insufficiency. Lancet. 2010;376(9744):911–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Woad KJ, Watkins WJ, Prendergast D, Shelling AN. The genetic basis of premature ovarian failure. Aust N Z J Obstet Gynaecol. 2006;46(3):242–4.PubMedCrossRefGoogle Scholar
  97. 97.
    Persani L, Rossetti R, Cacciatore C, Bonomi M. Primary ovarian insufficiency: X chromosome defects and autoimmunity. J Autoimmun. 2009;33(1):35–41.PubMedCrossRefGoogle Scholar
  98. 98.
    van Dooren MF, Bertoli-Avellab AM, Oldenburg RA. Premature ovarian failure and gene polymorphisms. Curr Opin Obstet Gynecol. 2009;21(4):313–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Christin-Maitre S, Tachdjian G. Genome-wide association study and premature ovarian failure. Ann Endocrinol (Paris). 2010;71(3):218–21.CrossRefGoogle Scholar
  100. 100.
    Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–68.PubMedCrossRefGoogle Scholar
  101. 101.
    Ghadami M, El-Demerdash E, Salama SA, Binhazim AA, Archibong AE, Chen X, et al. Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(−/−) FORKO mice. Mol Hum Reprod. 2010;16(4):241–50.PubMedCrossRefGoogle Scholar
  102. 102.
    Shelling AN, Burton KA, Chand AL, van Ee CC, France JT, Farquhar CM, et al. Inhibin: a candidate gene for premature ovarian failure. Hum Reprod. 2000;15(12):2644–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Rannikko A, Pakarinen P, Manna PR, Beau I, Misrahi M, Aittomäki K, et al. Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation. Mol Hum Reprod. 2002;8(4):311–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Conway GS, Conway E, Walker C, Hoppner W, Gromoll J, Simoni M. Mutation screening and isoform prevalence of the follicle stimulating hormone receptor gene in women with premature ovarian failure, resistant ovary syndrome and polycystic ovary syndrome. Clin Endocrinol (Oxf). 1999;51(1):97–9.CrossRefGoogle Scholar
  105. 105.
    Vilodre LC, Kohek MBF, Spritzer PM. Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations with phenotype. J Endocrinol Invest. 2008;31(6):552–7.PubMedGoogle Scholar
  106. 106.
    Doherty E, Pakarinen P, Tiitinen A, Kiilavuori A, Huhtaniemi I, Forrest S, et al. A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J Clin Endocrinol Metab. 2002;87(3):1151–5.PubMedCrossRefGoogle Scholar
  107. 107.
    Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.PubMedCrossRefGoogle Scholar
  108. 108.
    Falconer H, D’Hooghe T, Fried G. Endometriosis and genetic polymorphisms. Obstet Gynecol Surv. 2007;62(9):616–28.PubMedCrossRefGoogle Scholar
  109. 109.
    Tempfer CB, Simoni M, Destenaves B, Fauser BCJM. Functional genetic polymorphisms and female reproductive disorders: part II—endometriosis. Hum Reprod Update. 2009;15(1):97–118.PubMedCrossRefGoogle Scholar
  110. 110.
    Liao WX, Roy AC, Chan C, Arulkumaran S, Ratnam SS. A new molecular variant of luteinizing hormone associated with female infertility. Fertil Steril. 1998;69(1):102–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Mafra FA, Bianco B, Christofolini DM, Souza AMB, Zulli K, Barbosa CP. Luteinizing hormone beta-subunit gene (LHbeta) polymorphism in infertility and endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol. 2010;151(1):66–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Wang H, Cheng B, Wu H, Yen C, Liu C, Chao A, et al. A mutant single nucleotide polymorphism of follicle-stimulating hormone receptor is associated with a lower risk of endometriosis. Fertil Steril [Internet]. 2010 Set 2 [citato 2010 Dic 9];Available from:
  113. 113.
    Layman LC, McDonough PG. Mutations of follicle stimulating hormone-beta and its receptor in human and mouse: genotype/phenotype. Mol Cell Endocrinol. 2000;161(1–2):9–17.PubMedCrossRefGoogle Scholar
  114. 114.
    Wunsch A, Ahda Y, Banaz-Yaşar 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(2):446–53.PubMedCrossRefGoogle Scholar
  115. 115.
    Asatiani K, Gromoll J, Eckardstein SV, Zitzmann M, Nieschlag E, Simoni M. Distribution and function of FSH receptor genetic variants in normal men. Andrologia. 2002;34(3):172–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Ahda Y, Gromoll J, Wunsch A, Asatiani K, Zitzmann M, Nieschlag E, et al. Follicle-stimulating hormone receptor gene haplotype distribution in normozoospermic and azoospermic men. J Androl. 2005;26(4):494–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Lend AK, Belousova A, Haller-Kikkatalo K, Punab M, Poolamets O, Peters M, et al. Follicle-stimulating hormone receptor gene haplotypes and male infertility in estonian population and meta-analysis. Syst Biol Reprod Med. 2010;56(1):84–90.PubMedCrossRefGoogle Scholar
  118. 118.
    Balkan M, Gedik A, Akkoc H, Izci Ay O, Erdal ME, Isi H, et al. FSHR single nucleotide polymorphism frequencies in proven fathers and infertile men in Southeast Turkey. J Biomed Biotechnol. 2010;2010:640318.PubMedCrossRefGoogle Scholar
  119. 119.
    Nakayama T, Kuroi N, Sano M, Tabara Y, Katsuya T, Ogihara T, et al. Mutation of the follicle-stimulating hormone receptor gene 5′-untranslated region associated with female hypertension. Hypertension. 2006;48(3):512–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Plant TM, Marshall GR. The functional significance of FSH in spermatogenesis and the control of its secretion in male primates. Endocr Rev. 2001;22(6):764–86.PubMedCrossRefGoogle Scholar
  121. 121.
    Grigorova M, Rull K, Laan M. Haplotype structure of FSHB, the beta-subunit gene for fertility-associated follicle-stimulating hormone: possible influence of balancing selection. Ann Hum Genet. 2007;71(Pt 1):18–28.PubMedCrossRefGoogle Scholar
  122. 122.
    Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, et al. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993;5(1):83–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Layman L, Lee E, Peak D, Namnoum A, Vu K, Van Lingen B, et al. Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone β-subunit gene. N Engl J Med. 1997;337(9):607–11.PubMedCrossRefGoogle Scholar
  124. 124.
    Lindstedt G, Nyström E, Matthews C, Ernest I, Janson PO, Chatterjee K. Follitropin (FSH) deficiency in an infertile male due to FSHβ gene mutation. A syndrome of normal puberty and virilization but under-developed testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clin Chem Lab Med. 1998;36(8):663–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Phillip M, Arbelle JE, Segev Y, Parvari R. Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med. 1998;338(24):1729–32.PubMedCrossRefGoogle Scholar
  126. 126.
    Clark AD, Layman LC. Analysis of the Cys82Arg mutation in follicle-stimulating hormone beta (FSHbeta) using a novel FSH expression vector. Fertil Steril. 2003;79(2):379–85.PubMedCrossRefGoogle Scholar
  127. 127.
    Huhtaniemi I. Mutations affecting gonadotropin secretion and action. Horm Res. 2003;60 Suppl 3:21–30.PubMedCrossRefGoogle Scholar
  128. 128.
    Giltay JC, Deege M, Blankenstein RA, Kastrop PMM, Wijmenga C, Lock TTWT. Apparent primary follicle-stimulating hormone deficiency is a rare cause of treatable male infertility. Fertil Steril. 2004;81(3):693–6.PubMedCrossRefGoogle Scholar
  129. 129.
    Berger K, Souza H, Brito VN, d’Alva CB, Mendonca BB, Latronico AC. Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes. Fertil Steril. 2005;83(2):466–70.PubMedCrossRefGoogle Scholar
  130. 130.
    Lofrano-Porto A, Casulari LA, Nascimento PP, Giacomini L, Naves LA, da Motta LDC, et al. Effects of follicle-stimulating hormone and human chorionic gonadotropin on gonadal steroidogenesis in two siblings with a follicle-stimulating hormone beta subunit mutation. Fertil Steril. 2008;90(4):1169–74.PubMedCrossRefGoogle Scholar
  131. 131.
    Ciccone NA, Xu S, Lacza CT, Carroll RS, Kaiser UB. Frequency-dependent regulation of follicle-stimulating hormone beta by pulsatile gonadotropin-releasing hormone is mediated by functional antagonism of bZIP transcription factors. Mol Cell Biol. 2010;30(4):1028–40.PubMedCrossRefGoogle Scholar
  132. 132.
    Kottler M, Chou Y, Chabre O, Richard N, Polge C, Brailly-Tabard S, et al. A new FSHbeta mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH. Eur J Endocrinol. 2010;162(3):633–41.PubMedCrossRefGoogle Scholar
  133. 133.
    Grigorova M, Punab M, Poolamets O, Kelgo P, Ausmees K, Korrovits P, et al. Increased prevalance of the −211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men. J Clin Endocrinol Metab. 2010;95(1):100–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Miller WL, Shafiee-Kermani F, Strahl BD, Huang H. The nature of FSH induction by GnRH. Trends Endocrinol Metab. 2002;13(6):257–63.PubMedCrossRefGoogle Scholar
  135. 135.
    Hoogendoorn B, Coleman SL, Guy CA, Smith K, Bowen T, Buckland PR, et al. Functional analysis of human promoter polymorphisms. Hum Mol Genet. 2003;12(18):2249–54.PubMedCrossRefGoogle Scholar
  136. 136.
    Knobil E, Neill JD. Knobil and Neill’s physiology of reproduction. Gulf Professional Publishing; 2006.Google Scholar
  137. 137.
    Toppari J, Kaleva M, Virtanen HE, Main KM, Skakkebaek NE. Luteinizing hormone in testicular descent. Mol Cell Endocrinol. 2007;269(1–2):34–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Simoni M, Tüttelmann F, Michel C, Böckenfeld Y, Nieschlag E, Gromoll J. Polymorphisms of the luteinizing hormone/chorionic gonadotropin receptor gene: association with maldescended testes and male infertility. Pharmacogenet Genomics. 2008;18(3):193–200.PubMedCrossRefGoogle Scholar
  139. 139.
    Catena R, Argentini M, Martianov I, Parello C, Brancorsini S, Parvinen M, et al. Proteolytic cleavage of ALF into alpha- and beta-subunits that form homologous and heterologous complexes with somatic TFIIA and TRF2 in male germ cells. FEBS Lett. 2005;579(16):3401–10.PubMedCrossRefGoogle Scholar
  140. 140.
    Huang M, Wang H, Li J, Zhou Z, Du Y, Lin M, et al. Involvement of ALF in human spermatogenesis and male infertility. Int J Mol Med. 2006;17(4):599–604.PubMedGoogle Scholar
  141. 141.
    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
  142. 142.
    Kaleva M, Virtanen H, Haavisto A, Main K, Skakkebaek NE, Huhtaniemi I, et al. Does variant luteinizing hormone (V-LH) predispose to improper testicular position in late pregnancy? Pediatr Res. 2005;58(3):447–50.PubMedCrossRefGoogle Scholar
  143. 143.
    Martin AC. Osteoporosis in men: a review of endogenous sex hormones and testosterone replacement therapy. J Pharm Pract. 2011;24(3):307–15.PubMedCrossRefGoogle Scholar
  144. 144.
    Zaidi M, Alam AS, Shankar VS, Bax BE, Bax CM, Moonga BS, et al. Cellular biology of bone resorption. Biol Rev Camb Philos Soc. 1993;68(2):197–264.PubMedCrossRefGoogle Scholar
  145. 145.
    Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995;332(5):305–11.PubMedCrossRefGoogle Scholar
  146. 146.
    Lindsay R. Hormones and bone health in postmenopausal women. Endocrine. 2004;24(3):223–30.PubMedCrossRefGoogle Scholar
  147. 147.
    Roggia C, Gao Y, Cenci S, Weitzmann M, Toraldo G, Isaia G, et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci USA. 2001;98(24):13960–5.PubMedCrossRefGoogle Scholar
  148. 148.
    Cenci S, Toraldo G, Weitzmann M, Roggia C, Gao Y, Qian W, et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator. Proc Natl Acad Sci USA. 2003;100(18):10405–10.PubMedCrossRefGoogle Scholar
  149. 149.
    Shevde N, Bendixen A, Dienger K, Pike J. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA. 2000;97(14):7829–34.PubMedCrossRefGoogle Scholar
  150. 150.
    Srivastava S, Toraldo G, Weitzmann M, Cenci S, Ross F, Pacifici R. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-κB ligand (RANKL)-induced JNK activation. J Biol Chem. 2001;276(12):8836–40.PubMedCrossRefGoogle Scholar
  151. 151.
    McCauley L, Tözüm T, Rosol T. Estrogen receptors in skeletal metabolism: Lessons from genetically modified models of receptor function. Crit Rev Eukaryot Gene Expr. 2002;12(2):89–100.PubMedCrossRefGoogle Scholar
  152. 152.
    Windahl S, Andersson G, Gustafsson J. Elucidation of estrogen receptor function in bone with the use of mouse models. Trends Endocrinol Metab. 2002;13(5):195–200.PubMedCrossRefGoogle Scholar
  153. 153.
    Lindberg M, Alatalo S, Halleen J, Mohan S, Gustafsson J, Ohlsson C. Estrogen receptor specificity in the regulation of the skeleton in female mice. J Endocrinol. 2001;171(2):229–36.PubMedCrossRefGoogle Scholar
  154. 154.
    Yeh J, Chen M, Aloia J. Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats. Bone. 1996;18(5):443–50.PubMedCrossRefGoogle Scholar
  155. 155.
    Yeh J, Chen M, Aloia J. Effects of 17β-estradiol administration on cortical and cancellous bone of ovariectomized rats with and without hypophysectomy. Bone. 1997;20(5):413–20.PubMedCrossRefGoogle Scholar
  156. 156.
    Sowers M, Greendale G, Bondarenko I, Finkelstein J, Cauley J, Neer R, et al. Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN. Osteoporos Int. 2003;14(3):191–7.PubMedGoogle Scholar
  157. 157.
    Devleta B, Adem B, Senada S. Hypergonadotropic amenorrhea and bone density: new approach to an old problem. J Bone Miner Metab. 2004;22(4):360–4.PubMedCrossRefGoogle Scholar
  158. 158.
    Iqbal J, Sun L, Kumar TR, Blair HC, Zaidi M. Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci USA. 2006;103(40):14925–30.PubMedCrossRefGoogle Scholar
  159. 159.
    Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, et al. FSH directly regulates bone mass. Cell. 2006;125(2):247–60.PubMedCrossRefGoogle Scholar
  160. 160.
    Baron R. FSH versus estrogen: who’s guilty of breaking bones? Cell Metab. 2006;3(5):302–5.PubMedCrossRefGoogle Scholar
  161. 161.
    Gao J, Tiwari-Pandey R, Samadfam R, Yang Y, Miao D, Karaplis AC, et al. Altered ovarian function affects skeletal homeostasis independent of the action of follicle-stimulating hormone. Endocrinology. 2007;148(6):2613–21.PubMedCrossRefGoogle Scholar
  162. 162.
    Allan CM, Kalak R, Dunstan CR, McTavish KJ, Zhou H, Handelsman DJ, et al. Follicle-stimulating hormone increases bone mass in female mice. Proc Natl Acad Sci USA. 2010;107(52):22629–34.PubMedCrossRefGoogle Scholar
  163. 163.
    Rendina D, Gianfrancesco F, De Filippo G, Merlotti D, Esposito T, Mingione A, et al. FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. Eur J Endocrinol. 2010;163(1):165–72.PubMedCrossRefGoogle Scholar
  164. 164.
    Seibel MJ, Dunstan CR, Zhou H, Allan CM, Handelsman DJ. Sex steroids, not FSH, influence bone mass. Cell. 2006;127(6):1079. author reply 1080–1081.PubMedCrossRefGoogle Scholar
  165. 165.
    Castelo-Branco C, León M, Durán M, Balasch J. Follicle-stimulating hormone does not directly regulate bone mass in human beings: evidence from nature. Fertil Steril. 2008;90(6):2211–6.PubMedCrossRefGoogle Scholar
  166. 166.
    Rouach V, Katzburg S, Koch Y, Stern N, Somjen D. Bone loss in ovariectomized rats: dominant role for estrogen but apparently not for FSH. J Cell Biochem. 2011;112(1):128–37.PubMedCrossRefGoogle Scholar
  167. 167.
    Krum SA. Direct transcriptional targets of sex steroid hormones in bone. J Cell Biochem. 2011;112(2):401–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Rauhio A, Uusi-Rasi K, Kunnas T, Nikkari ST, Kannus P, Sievänen H. Estrogen receptor-1 genotype is associated with bone structure in premenopausal obese women. Maturitas [Internet]. 2011 Gen 7 [citato 2011 Gen 28]; Available from:
  169. 169.
    Zhang X, Dai J, Long Y, Wu H, Li X, Ding Y. Correlation of estrogen receptor alpha gene polymorphisms and bone mineral density in Chinese women with chronic periodontitis. Chin Med J. 2010;123(22):3262–7.PubMedGoogle Scholar
  170. 170.
    Erdogan MO, Yıldız H, Artan S, Solak M, Taşcıoğlu F, Dündar U, et al. Association of estrogen receptor alpha and collagen type I alpha 1 gene polymorphisms with bone mineral density in postmenopausal women. Osteoporos Int [Internet]. 2010 Giu 8 [citato 2011 Gen 28]; Available from:
  171. 171.
    Harsløf T, Husted LB, Carstens M, Stenkjaer L, Langdahl BL. Genotypes and haplotypes of the estrogen receptor genes, but not the retinoblastoma-interacting zinc finger protein 1 gene, are associated with osteoporosis. Calcif Tissue Int. 2010;87(1):25–35.PubMedCrossRefGoogle Scholar
  172. 172.
    Kim SY, Kim HH, Nam CM, Kim HC, Suh I, Kang BY. Association of estrogen receptor-alpha gene polymorphism with pathogenesis of osteoporosis in Korean vegetarian men. Med Princ Pract. 2010;19(3):200–5.PubMedCrossRefGoogle Scholar
  173. 173.
    Ichikawa S, Koller DL, Padgett LR, Lai D, Hui SL, Peacock M, et al. Replication of previous genome-wide association studies of bone mineral density in premenopausal American women. J Bone Miner Res. 2010;25(8):1821–9.PubMedCrossRefGoogle Scholar
  174. 174.
    Jeedigunta Y, Bhoomi Reddy PR, Kolla VK, Munshi A, Ananthapur V, Narasimulu G, et al. Association of estrogen receptor alpha gene polymorphisms with BMD and their affect on estradiol levels in pre- and postmenopausal women in south Indian population from Andhra Pradesh. Clin Chim Acta. 2010;411(7–8):597–600.PubMedCrossRefGoogle Scholar
  175. 175.
    Elfassihi L, Giroux S, Bureau A, Laflamme N, Cole DE, Rousseau F. Association with replication between estrogen-related receptor gamma (ESRRgamma) polymorphisms and bone phenotypes in women of European ancestry. J Bone Miner Res. 2010;25(4):901–11.PubMedGoogle Scholar
  176. 176.
    Drake MT, McCready LK, Hoey KA, Atkinson EJ, Khosla S. Effects of suppression of follicle-stimulating hormone secretion on bone resorption markers in postmenopausal women. J Clin Endocrinol Metab. 2010;95(11):5063–8.PubMedCrossRefGoogle Scholar
  177. 177.
    D’Andrilli G, Giordano A, Bovicelli A. Epithelial ovarian cancer: the role of cell cycle genes in the different histotypes. Open Clin Cancer J. 2008;2:7–12.PubMedCrossRefGoogle Scholar
  178. 178.
    Yamano T, Morii E, Arai I, Takada T, Kubota K, Sato M, et al. Diagnosis of primary versus metastatic ovarian adenocarcinoma using p53 gene mutation analysis. Int J Clin Oncol. 2010;15(6):621–5.PubMedCrossRefGoogle Scholar
  179. 179.
    Zagouri F, Dimopoulos MA, Bournakis E, Papadimitriou CA. Molecular markers in epithelial ovarian cancer: their role in prognosis and therapy. Eur J Gynaecol Oncol. 2010;31(3):268–77.PubMedGoogle Scholar
  180. 180.
    Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst. 1998;90(23):1774–86.PubMedCrossRefGoogle Scholar
  181. 181.
    Ji Q, Liu PI, Chen PK, Aoyama C. Follicle stimulating hormone-induced growth promotion and gene expression profiles on ovarian surface epithelial cells. Int J Cancer. 2004;112(5):803–14.PubMedCrossRefGoogle Scholar
  182. 182.
    Brown TJ, Lioubin MN, Marquardt H. Purification and characterization of cytostatic lymphokines produced by activated human T lymphocytes. Synergistic antiproliferative activity of transforming growth factor beta 1, interferon-gamma, and oncostatin M for human melanoma cells. J Immunol. 1987;139(9):2977–83.PubMedGoogle Scholar
  183. 183.
    Horn D, Fitzpatrick WC, Gompper PT, Ochs V, Bolton-Hansen M, Zarling J, et al. Regulation of cell growth by recombinant oncostatin M. Growth Factors. 1990;2(2–3):157–65.PubMedCrossRefGoogle Scholar
  184. 184.
    Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS, et al. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem. 1996;271(51):32635–43.PubMedCrossRefGoogle Scholar
  185. 185.
    Douglas AM, Goss GA, Sutherland RL, Hilton DJ, Berndt MC, Nicola NA, et al. Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Oncogene. 1997;14(6):661–9.PubMedCrossRefGoogle Scholar
  186. 186.
    Yang CQ, Chan KYK, Ngan HYS, Khoo US, Chiu PM, Chan QKY, et al. Single nucleotide polymorphisms of follicle-stimulating hormone receptor are associated with ovarian cancer susceptibility. Carcinogenesis. 2006;27(7):1502–6.PubMedCrossRefGoogle Scholar
  187. 187.
    Heubner M, Riemann K, Otterbach F, Kimmig R, Kasimir-Bauer S, Siffert W, et al. The haplotype of two FSHR polymorphisms in ovarian cancer—a potential role of ethnology in risk modification. Gynecol Oncol. 2009;112(3):486–9.PubMedCrossRefGoogle Scholar
  188. 188.
    Ludwig AH, Murawska M, Panek G, Timorek A, Kupryjanczyk J. Androgen, progesterone, and FSH receptor polymorphisms in ovarian cancer risk and outcome. Endocr Relat Cancer. 2009;16(3):1005–16.PubMedCrossRefGoogle Scholar
  189. 189.
    The International HapMap Project. Nature. 2003;426(6968):789–96.CrossRefGoogle Scholar
  190. 190.
    Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer (1). N Engl J Med. 1992;327(5):319–28.PubMedCrossRefGoogle Scholar
  191. 191.
    Martin A, Weber BL. Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst. 2000;92(14):1126–35.PubMedCrossRefGoogle Scholar
  192. 192.
    Kuijper TM, Ruigrok-Ritstier K, Verhoef-Post M, Piersma D, Bruysters MWP, Berns EMJJ, et al. LH receptor gene expression is essentially absent in breast tumor tissue: implications for treatment. Mol Cell Endocrinol. 2009;302(1):58–64.PubMedCrossRefGoogle Scholar
  193. 193.
    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. Fertil Steril. 1997;67(6):998–1004.PubMedCrossRefGoogle Scholar
  194. 194.
    Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol. 2001;2(3):133–40.PubMedCrossRefGoogle Scholar
  195. 195.
    Piersma D, Berns E, Verhoef-Post M, Uitterlinden A, Braakman I, Pols H, 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
  196. 196.
    Müller T, Gromoll J, Simoni M. Absence of exon 10 of the human luteinizing hormone (LH) receptor impairs LH, but not human chorionic gonadotropin action. J Clin Endocrinol Metab. 2003;88(5):2242–9.PubMedCrossRefGoogle Scholar
  197. 197.
    Piersma D, Verhoef-Post M, Berns E, Themmen A. LH receptor gene mutations and polymorphisms: An overview. Mol Cell Endocrinol. 2007;260–262:282–6.PubMedCrossRefGoogle Scholar
  198. 198.
    Saito Y, Tetsuka M, Yue L, Kawamura Y, Maruyama K. Functional role of N-linked glycosylation on the rat melanin-concentrating hormone receptor 1. FEBS Lett. 2003;533(1–3):29–34.PubMedCrossRefGoogle Scholar
  199. 199.
    Piersma D, Verhoef-Post M, Look MP, Uitterlinden AG, Pols HAP, Berns EMJJ, et al. Polymorphic variations in exon 10 of the luteinizing hormone receptor: functional consequences and associations with breast cancer. Mol Cell Endocrinol. 2007;276(1–2):63–70.PubMedCrossRefGoogle Scholar
  200. 200.
    Rapley EA, Nathanson KL. Predisposition alleles for testicular germ cell tumour. Curr Opin Genet Dev. 2010;20(3):225–30.PubMedCrossRefGoogle Scholar
  201. 201.
    Horwich A, Shipley J, Huddart R. Testicular germ-cell cancer. Lancet. 2006;367(9512):754–65.PubMedCrossRefGoogle Scholar
  202. 202.
    Ferlin A, Pengo M, Selice R, Salmaso L, Garolla A, Foresta C. Analysis of single nucleotide polymorphisms of FSH receptor gene suggests association with testicular cancer susceptibility. Endocr Relat Cancer. 2008;15(2):429–37.PubMedCrossRefGoogle Scholar
  203. 203.
    Oosterhuis JW, Looijenga LHJ. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005;5(3):210–22.PubMedCrossRefGoogle Scholar
  204. 204.
    Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update. 2006;12(3):303–23.PubMedCrossRefGoogle Scholar
  205. 205.
    Garolla A, Ferlin A, Vinanzi C, Roverato A, Sotti G, Artibani W, et al. Molecular analysis of the androgen receptor gene in testicular cancer. Endocr Relat Cancer. 2005;12(3):645–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Livio Casarini
    • 1
  • Elisa Pignatti
    • 1
  • Manuela Simoni
    • 1
  1. 1.Department of Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio EmiliaModenaItaly

Personalised recommendations