Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 4 , Pages 561-576 , December 2006

Gonadotrophin resistance

  • Ilpo Huhtaniemi, MD, PhD (Professor of Reproductive Biology)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +44 20 75942104; Fax: +44 20 75942184.

References 

  1. Aittomaki K, Lucena JL, Pakarinen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–968
  2. Kremer H, Kraaij R, Toledo SP, et al. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Nature Genetics. 1995;9(2):160–164
  3. Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocrine Reviews. 2000;21(5):551–583
  4. Huhtaniemi IT, Themmen AP. Mutations in human gonadotropin and gonadotropin-receptor genes. Endocrine. 2005;26(3):207–217
  5. Alevizaki M, Huhtaniemi I. Structure-function repationships of glycoprotein horemones; lessons form mutations and polymorphisms of the thyrotrophin and gonadotrophin subunit genes. Hormones. 2002;1:224–232
  6. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocrine Reviews. 2002;23(2):141–174
  7. Dias JA, Van Roey P. Structural biology of human follitropin and its receptor. Archives of Medical Research. 2001;32(6):510–519
  8. Szkudlinski MW, Fremont V, Ronin C, et al. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiological Reviews. 2002;82(2):473–502
  9. Braun T, Schofield PR, Sprengel R. Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. The EMBO Journal. 1991;10(7):1885–1890
  10. Cornelis S, Uttenweiler-Joseph S, Panneels V, et al. Purification and characterization of a soluble bioactive amino-terminal extracellular domain of the human thyrotropin receptor. Biochemistry. 2001;40(33):9860–9869
  11. Remy JJ, Nespoulous C, Grosclaude J, et al. Purification and structural analysis of a soluble human chorionogonadotropin hormone-receptor complex. The Journal of Biological Chemistry. 2001;276(3):1681–1687
  12. Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science. 2000;289(5480):739–745
  13. Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature. 2005;433(7023):269–277
  14. Ji I, Lee C, Song Y, et al. Cis- and trans-activation of hormone receptors: the LH receptor. Molecular Endocrinology. 2002;16(6):1299–1308
  15. Osuga Y, Hayashi M, Kudo M, et al. Co-expression of defective luteinizing hormone receptor fragments partially reconstitutes ligand-induced signal generation. The Journal of Biological Chemistry. 1997;272(40):25006–25012
  16. Urizar E, Montanelli L, Loy T, et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. The EMBO Journal. 2005;24(11):1954–1964
  17. Filicori M, Fazleabas AT, Huhtaniemi I, et al. Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility. Fertility and Sterility. 2005;84(2):275–284
  18. Pakarainen T, Zhang FP, Poutanen M, et al. Fertility in luteinizing hormone receptor-knockout mice after wild-type ovary transplantation demonstrates redundancy of extragonadal luteinizing hormone action. The Journal of Clinical Investigation. 2005;115(7):1862–1868
  19. Huhtaniemi I. Fetal testis–a very special endocrine organ. European Journal of Endocrinology. 1994;130(1):25–31
  20. Berthezene F, Forest MG, Grimaud JA, et al. Leydig-cell agenesis: a cause of male pseudohermaphroditism. The New England Journal of Medicine. 1976;295(18):969–972
  21. Brown DM, Markland C, Dehner LP. Leydig-cell hypoplasia: a cause of male pseudohermaphroditism. The Journal of Clinical Endocrinology and Metabolism. 1978;46(1):1–7
  22. Lee PA, Rock JA, Brown TR, et al. Leydig cell hypofunction resulting in male pseudohermaphroditism. Fertility and Sterility. 1982;37(5):675–679
  23. Wu RH, Rosenfeld R, Fukushima D. Hypogonadism and Leydig-cell hypoplasia unresponsive to human luteinizing hormone (hLH). The American Journal of the Medical Sciences. 1984;287(3):23–25
  24. Eil C, Austin RM, Sesterhenn I, et al. Leydig-cell hypoplasia causing male pseudohermaphroditism: diagnosis 13 years after prepubertal castration. The Journal of Clinical Endocrinology and Metabolism. 1984;58(3):441–448
  25. Arnhold IJ, Mendonca BB, Bloise W, et al. Male pseudohermaphroditism resulting from Leydig-cell hypoplasia. The Journal of Pediatrics. 1985;106(6):1057
  26. Perez-Palacios G, Scaglia HE, Kofman-Alfaro S, et al. Inherited male pseudohermaphroditism due to gonadotrophin unresponsiveness. Acta Endocrinologica. 1981;98(1):148–155
  27. el-Awady MK, Temtamy SA, Salam MA, et al. Familial Leydig-cell hypoplasia as a cause of male pseudohermaphroditism. Human Heredity. 1987;37(1):36–40
  28. Saldanha PH, Arnhold IJ, Mendonca BB, et al. A clinico-genetic investigation of Leydig-cell hypoplasia. American Journal of Medical Genetics. 1987;26(2):337–344
  29. Schwartz M, Imperato-McGinley J, Peterson RE, et al. Male pseudohermaphroditism secondary to an abnormality in Leydig cell differentiation. The Journal of Clinical Endocrinology and Metabolism. 1981;53(1):123–127
  30. David R, Yoon DJ, Landin L, et al. A syndrome of gonadotropin resistance possibly due to a luteinizing hormone receptor defect. The Journal of Clinical Endocrinology and Metabolism. 1984;59(1):156–160
  31. Martinez-Mora J, Saez JM, Toran N, et al. Male pseudohermaphroditism due to Leydig cell agenesia and absence of testicular LH receptors. Clinical Endocrinology. 1991;34(6):485–491
  32. Toledo SP, Brunner HG, Kraaij R, et al. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. The Journal of Clinical Endocrinology and Metabolism. 1996;81(11):3850–3854
  33. Stavrou SS, Zhu YS, Cai LQ, et al. A novel mutation of the human luteinizing hormone receptor in 46XY and 46XX sisters. The Journal of Clinical Endocrinology and Metabolism. 1998;83(6):2091–2098
  34. Latronico AC, Anasti J, Arnhold IJ, et al. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. The New England Journal of Medicine. 1996;334(8):507–512
  35. Latronico AC, Chai Y, Arnhold IJ, et al. A homozygous microdeletion in helix 7 of the luteinizing hormone receptor associated with familial testicular and ovarian resistance is due to both decreased cell surface expression and impaired effector activation by the cell surface receptor. Molecular Endocrinology. 1998;12(3):442–450
  36. Toledo SP, Arnhold IJ, Luthold W, et al. Leydig-cell hypoplasia determining familial hypergonadotropic hypogonadism. Progress in Clinical and Biological Research. 1985;200:311–314
  37. Nef S, Parada LF. Hormones in male sexual development. Genes and Development. 2000;14(24):3075–3086
  38. Nef S, Verma-Kurvari S, Merenmies J, et al. Testis determination requires insulin receptor family function in mice. Nature. 2003;426(6964):291–295
  39. Martens JW, Lumbroso S, Verhoef-Post M, et al. Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig-cell hypoplasia: abnormal processing causes signaling deficiency. The Journal of Clinical Endocrinology and Metabolism. 2002;87(6):2506–2513
  40. Martens JW, Verhoef-Post M, Abelin N, et al. A homozygous mutation in the luteinizing hormone receptor causes partial Leydig-cell hypoplasia: correlation between receptor activity and phenotype. Molecular Endocrinology. 1998;12(6):775–784
  41. Gromoll J, Eiholzer U, Nieschlag E, et al. Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. The Journal of Clinical Endocrinology and Metabolism. 2000;85(6):2281–2286
  42. da Fonte Kohek MB, Batista MC, Russell AJ, et al. No evidence of the inactivating mutation (C566T) in the follicle-stimulating hormone receptor gene in Brazilian women with premature ovarian failure. Fertility and Sterility. 1998;70(3):565–567
  43. Whitney EA, Layman LC, Chan PJ, et al. The follicle-stimulating hormone receptor gene is polymorphic in premature ovarian failure and normal controls. Fertility and Sterility. 1995;64(3):518–524
  44. Conway GS, Conway E, Walker C, et al. 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. Clinical Endocrinology. 1999;51(1):97–99
  45. Liu JY, Gromoll J, Cedars MI, et al. Identification of allelic variants in the follicle-stimulating hormone receptor genes of females with or without hypergonadotropic amenorrhea. Fertility and Sterility. 1998;70(2):326–331
  46. Kotlar T, Young RH, Albanese C, et al. Absence of mutations in the FSH receptor in ovarian granulosa cell tumors. The Journal of Clinical Endocrinology and Metabolism. 1998;83(8):3001
  47. Fuller PJ, Verity K, Shen Y, et al. No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors. The Journal of Clinical Endocrinology and Metabolism. 1998;83(1):274–279
  48. Ligtenberg MJ, Siers M, Themmen AP, et al. Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. The Journal of Clinical Endocrinology and Metabolism. 1999;84(6):2233–2234
  49. Tuerlings JH, Ligtenberg MJ, Kremer JA, et al. Screening male intracytoplasmic sperm injection candidates for mutations of the follicle stimulating hormone receptor gene. Human Reproduction. 1998;13(8):2098–2101
  50. Simoni M, Gromoll J, Hoppner W, 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. The Journal of Clinical Endocrinology and Metabolism. 1999;84(2):751–755
  51. Norio R. Finnish Disease Heritage I: characteristics, causes, background. Human Genetics. 2003;112(5-6):441–456
  52. Gromoll J, Schulz A, Borta H, et al. Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism. European Journal of Endocrinology. 2002;147(5):597–608
  53. Beau I, Touraine P, Meduri G, et al. A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. The Journal of Clinical Investigation. 1998;102(7):1352–1359
  54. Rannikko A, Pakarinen P, Manna PR, et al. Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation. Molecular Human Reproduction. 2002;8(4):311–317
  55. Gromoll J, Simoni M, Nordhoff V, et al. Functional and clinical consequences of mutations in the FSH receptor. Molecular and Cellular Endocrinology. 1996;125(1-2):177–182
  56. Aittomaki K, Herva R, Stenman UH, et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. The Journal of Clinical Endocrinology and Metabolism. 1996;81(10):3722–3726
  57. Touraine P, Beau I, Gougeon A, et al. New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype. Molecular Endocrinology. 1999;13(11):1844–1854
  58. Doherty E, Pakarinen P, Tiitinen A, et al. A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. The Journal of Clinical Endocrinology and Metabolism. 2002;87(3):1151–1155
  59. Allen LA, Achermann JC, Pakarinen P, et al. A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics. Human Reproduction. 2003;18(2):251–256
  60. Meduri G, Touraine P, Beau I, et al. Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies. The Journal of Clinical Endocrinology and Metabolism. 2003;88(8):3491–3498
  61. Jiang M, Aittomaki K, Nilsson C, et al. The frequency of an inactivating point mutation (566C–>T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry. The Journal of Clinical Endocrinology and Metabolism. 1998;83(12):4338–4343
  62. Loutradis D, Patsoula E, Stefanidis K, et al. Follicle-stimulating hormone receptor gene mutations are not evident in Greek women with premature ovarian failure and poor responders. Gynecologic and Obstetric Investigation. 2006;61(1):56–60
  63. Ishikawa T, Fujisawa M, Tapanainen J. Screening of FSH receptor gene mutation (C566T) in azoospermic men in Japan. Archives of Andrology. 2006;52(1):15–19
  64. Layman LC, Amde S, Cohen DP, et al. The Finnish follicle-stimulating hormone receptor gene mutation is rare in North American women with 46,XX ovarian failure. Fertility and Sterility. 1998;69(2):300–302
  65. Tapanainen JS, Aittomaki K, Min J, et al. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nature Genetics. 1997;15(2):205–206
  66. Vaskivuo TE, Aittomaki K, Anttonen M, et al. Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor. Fertility and Sterility. 2002;78(1):108–113
  67. Valdes-Socin H, Salvi R, Daly AF, et al. Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene. The New England Journal of Medicine. 2004;351(25):2619–2625
  68. Weiss J, Axelrod L, Whitcomb RW, et al. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. The New England Journal of Medicine. 1992;326(3):179–183
  69. Daly AF, Salvi R, Menage J-J, et al. Identification of a family harboring a novel LHbeta subunit mutation associated with hypogonadism. The Endocrine Society, 88th Annual Meeting 2006: OR52–OR55.
  70. Matthews CH, Borgato S, Beck-Peccoz P, et al. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nature Genetics. 1993;5(1):83–86
  71. Phillip M, Arbelle JE, Segev Y, et al. Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. The New England Journal of Medicine. 1998;338(24):1729–1732
  72. Layman LC, Lee EJ, Peak DB, et al. Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene. The New England Journal of Medicine. 1997;337(9):607–611
  73. Layman LC, Porto AL, Xie J, et al. FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. The Journal of Clinical Endocrinology and Metabolism. 2002;87(8):3702–3707
  74. Lindstedt G, Nystrom E, Matthews C, et al. Follitrophin (FSH) deficiency in an infertile male due to FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clinical Chemistry and Laboratory Medicine. 1998;36(8):663–665
  75. Rabinowitz D, Benveniste R, Linder J, et al. Isolated follicle-stimulating hormone deficiency revisited. Ovulation and conception in presence of circulating antibody to follicle-stimulating hormone. The New England Journal of Medicine. 1979;300(3):126–128
  76. Daly AF, Salvi R, Menage J-J, et al. Identification of a family harboring a novel LHbeta subunit mutation associated with hypogonadism. The Endocrine Society, 88th Annual Meeting 2006: OR52–OR55.
  77. Hovatta O, Soderstrom-Anttila V, Foudila T, et al. Pregnancies after oocyte donation in women with ovarian failure caused by an inactivating mutation in the follicle stimulating hormone receptor. Human Reproduction. 2002;17(1):124–127
  78. Danilovich N, Sairam MR. Targeting gonadotropin receptor genes: reproductive biology, aging, and related health implications. Endocrine. 2005;26(3):219–226
  79. Rao CV, Lei ZM. Consequences of targeted inactivation of LH receptors. Molecular and Cellular Endocrinology. 2002;187(1-2):57–67
  80. Hirst RC, Abel MH, Wilkins V, et al. Influence of mutations affecting gonadotropin production or responsiveness on expression of inhibin subunit mRNA and protein in the mouse ovary. Reproduction. 2004;128(1):43–52
  81. Zhang FP, Poutanen M, Wilbertz J, et al. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Molecular Endocrinology. 2001;15(1):172–183
  82. Lei ZM, Mishra S, Zou W, et al. Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Molecular Endocrinology. 2001;15(1):184–200
  83. Ma X, Dong Y, Matzuk MM, et al. Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility. Proceedings of the National Academy of Sciences of the USA. 2004;101(49):17294–17299
  84. El-Gehani F, Zhang FP, Pakarinen P, et al. Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis. Biology of Reproduction. 1998;58(1):116–123
  85. Dierich A, Sairam MR, Monaco L, et al. Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proceedings of the National Academy of Sciences of the USA. 1998;95(23):13612–13617
  86. Abel MH, Wootton AN, Wilkins V, et al. The effect of a null mutation in the follicle-stimulating hormone receptor gene on mouse reproduction. Endocrinology. 2000;141(5):1795–1803
  87. Kumar TR, Wang Y, Lu N, et al. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nature Genetics. 1997;15(2):201–204
  88. Richter-Unruh A, Verhoef-Post M, Hiort O, et al. 46,XY disorder of sex development (46,XY DSD) due to two new mutations of the luteinizing hormone receptor gene. The Endocrine Society, 88th Annual Meeting 2006:P2–701.

PII: S1521-690X(06)00074-1

doi: 10.1016/j.beem.2006.09.003

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 4 , Pages 561-576 , December 2006