Skip to main content
Download PDF

Les hypogonadismes hypogonadotrophiques congénitaux masculins, quelles données récentes ?

Male congenital hypogonadotropic hypogonadisms, any new recent data?

Basic and Clinical Andrology volume 21, pages 68–74 (2011)Cite this article

Résumé

Les hypogonadismes hypogonadotrophiques congénitaux (HHC) sont un ensemble très hétérogène d’affections résultant d’un défaut de sécrétion des gonadotrophines hypophysaires en rapport avec un défaut de migration des neurones à GnRH ou secondaires à des anomalies organiques ou fonctionnelles de la commande hypothalamohypophysaire. Le déficit gonadotrope reste une cause rare d’hypogonadisme avec une prévalence mal précisée estimée à 1/5 000, il est responsable de manifestations cliniques en rapport avec la baisse de testostérone circulante variable en fonction de l’âge de leur expression. La classification des HHC, basée sur l’existence ou non d’anosmie, s’est enrichie ces deux dernières décennies par la découverte de nombreux gènes impliqués dans le développement et le fonctionnement de l’axe gonadotrope; cela a permis de mieux préciser les HHC et de proposer le conseil génétique dans les formes dominantes. Le but de ce travail est de faire le point sur les nouvelles connaissances qui ont permis de mieux préciser la physiopathologie et le cadre nosologique des HHC.

Abstract

Congenital hypogonadotropic hypogonadism (CHH) is a very heterogeneous group of disorders resulting from a deficiency of pituitary gonadotropin secretion that is related to defective migration of GnRH neurons or dysfunction of pituitary or hypothalamic system. Gonadotropin deficiency remains a rare cause of hypogonadism; its prevalence is not definitely established and is thought to be about 1/5,000. It is responsible for clinical symptoms that are related to low testosterone levels. The classification of CHH which was previously based on presence of or lack of anosmia has been enriched in the last two decades by the discovery of many genes involved. This allowed a better understanding of CHH and led to new approaches regarding genetic counselling.

Références

  1. Young J, Shaison G (1998) Hypogonadisme hypogonadotrophique: données récentes. Rev Fr Endocrinol Clin Nutr Metab 39:15–33

    Google Scholar 

  2. Sedlemeyer IL, Palmer MR (2002) Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 87:1613–1620

    Article  Google Scholar 

  3. Salenave S, Chanson P, Bry H, et al (2008) Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab 93:758–763

    Article  PubMed  CAS  Google Scholar 

  4. Crowley WF Jr, Filicori M, Spratt DI, et al (1985) The physiology of gonadotropin-releasing hormone secretion in men and women. Recent Prog Horm Res 41:473–531

    PubMed  CAS  Google Scholar 

  5. Chabbert Buffet N, Bouchard P (1999) Physiologie de l’axe gonadotrope. Rev Pract 49:1270–1276

    CAS  Google Scholar 

  6. Main KM, Schmidt IM, Skakkebaek NE (2000) A possible role for reproductive hormones in newborn boys: progressive hypogonadism without the postnatal testosterone peak. J Clin Endocrinol Metab 85: 4905–4907

    Article  PubMed  CAS  Google Scholar 

  7. Delamarre van de Wall HA (2004) Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism diagnostic and therapeutic aspects. Eur J Endocrinol 151:89–94

    Article  Google Scholar 

  8. Kallmann FJ, Schoenfeld WA, Barrera SE (1944) The genetic aspects of primary eunuchoidism. Am J Mental Deficiency XLVIII: 203–236

    Google Scholar 

  9. Dodé C, Hardelin JP (2010) Syndrome de Kallmann-De Morsier: génétique clinique. Ann Endocrinol 71:149–157

    Article  Google Scholar 

  10. Sato N, Katsumata N, Kagami M, et al (2004). Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast gowth factor receptor 1 (FGFR1 or KAL 2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 89: 1079–1088

    Article  PubMed  CAS  Google Scholar 

  11. Klingmuller D, Dewes W, Krahe T, et al (1987) Magnetic resonance imaging of the brain in patients with anosmia and hypothalamic hypogonadism (Kallmann syndrome). J Clin Endocrinol Metab 65:581–584

    Article  PubMed  CAS  Google Scholar 

  12. Aiba T, Inoue Y, Matsumoto K, et al (2004) Magnetic resonance imaging for diagnosis of congenital anosmia. Acta Otolaryngol Suppl 554:50–54

    Article  PubMed  Google Scholar 

  13. Quinton R, Duke VM, De Zoysa PA, et al (1996) The neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 81:3010–3017

    PubMed  CAS  Google Scholar 

  14. Mayston MJ, Harrison LM, Stephens JA, et al (2001) Physiological tremor in human subjects with X-linked Kallmann’s syndrome and mirror movements. J Physiol 530:551–563

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Sukthar S, Watson AR (2000) Unilateral multicystic dysplasic kidney disease, defining the natural history. Acta Pediatr 89: 811–813

    Article  Google Scholar 

  16. El Ansari N (2008) Le syndrome de Kallmann-De Morsier, aspect génétique. Andrologie 18:127–130

    Article  Google Scholar 

  17. Hardelin JP, Levilliers J, Blanchard S, et al (1993) Heterogeneity in the mutations resposible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 2:373–377

    Article  PubMed  CAS  Google Scholar 

  18. Dodé C, Hardelin JP (2004) Syndrome de Kallmann-De Morsier, insuffisance de signalisation par les FGF. Med Sci 20:8–9

    Google Scholar 

  19. Hébert JM, Lin M, Partanen J, et al (2003) FGF signaling through FGFR1 is required for olfactory bulb morphogenesis. Development 130:1101–1111

    Article  PubMed  Google Scholar 

  20. Pitteloud N, James S, Astrid U, et al (2005) Reversible Kallmann Syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 90:1317–1322

    Article  PubMed  CAS  Google Scholar 

  21. Dodé C, Teixeira L, Levilliers J, et al (2006) Kallmann syndrome: mutation in the genes encoding prokineticin-2 and prokineticin receptor-2. PloS Genet 10:1648–1652

    Google Scholar 

  22. Abreu A, Trarbach EB, de Castro M, et al (2008) Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab 10:4113–4118

    Article  Google Scholar 

  23. Sarfati J, Guiochon-Mantel A, Rondard P, et al (2010) A Comparative phenotypic study of Kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin-2 or prokineticin receptor-2 genes. J Clin Endocrinol Metab 95:659–669

    Article  PubMed  CAS  Google Scholar 

  24. Xu N, Bhagavath B, Kim HG, et al (2010) NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration. Mol Cell Endocrinol 19:47–55

    Article  Google Scholar 

  25. Miura K, Acierno Jr JS, Seminara SB, et al (2004) Characterization of the human nasal embryonic LHRH factor gene NELF and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet 49:265–268

    Article  PubMed  CAS  Google Scholar 

  26. Falardeau J, Chung CJ, Beenken A, et al (2008) Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 118:2822–2831

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Trarbach EB, Abreu AP, Silveira LF, et al (2010) Nonsensemutations in FGF8 gene causing different degrees of human gonadotropinreleasing deficiency. J Clin Endocrinol Metab 95:3491–3496

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Kim HG, Ahn JW, Kurth I, et al (2010) WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 87:465–479

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Semple RK, Topaloglu AK (2010) The recent genetics of hypogonadotrophic hypogonadism-novel insights and new questions. Clin Endocrinol 72:427–435

    Article  CAS  Google Scholar 

  30. Ribeiro RS, Vieira T, Abucham J (2007) Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol 156:285–290

    Article  PubMed  CAS  Google Scholar 

  31. Burman P, Ritzen EM, Lindgren AC, et al (2001) Endocrine dysfonction in Prader-Willi syndrome: a review with special reference to GH. Endoc Rev 22:787–799

    Article  CAS  Google Scholar 

  32. Janssen S, Ramaswami G, Davis EE, et al (2011) Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. Hum Genet 129:79–90

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Zentner GE, Layman WS, Martin DM, et al (2010) Molecular and phenotypic aspects of CHD7 mutation in Charge syndrome. Am J Med Genet 152A:674–686

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Jogmans MC, Van Ravenswaaij-Arts CMA, Pitteloud N, et al (2009) CHD7 mutations in patients initially diagnosed with Kallmann syndrome — the clinical overlap with Charge syndrome. Clin Genet 75:65–71

    Article  Google Scholar 

  35. Quinton R, Barnett P, Coskeran P, et al (1999) Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin-releasing hormone. Clin Endocrinol 51:525–529

    Article  CAS  Google Scholar 

  36. Kelberman D, Rizzoti K, Avilion A, et al (2006) Mutations within SOX2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 116:2442–2455

    PubMed  CAS  PubMed Central  Google Scholar 

  37. Strobel A, Issad T, Camoin L, et al (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18:213–215

    Article  PubMed  CAS  Google Scholar 

  38. Chehab FF, Lim ME, Lu R (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12:318–320

    Article  PubMed  CAS  Google Scholar 

  39. Farooqi IS, Wangensteen T, Collins S, et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356:237–247

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Jackson RS, Creemrs JW, Ohagi S, et al (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303–306

    Article  PubMed  CAS  Google Scholar 

  41. Lalli E, Bardoni B, Zazopoulos E, et al (1997) Transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenital. Mol Endocrinol 11:1950–1960

    Article  PubMed  CAS  Google Scholar 

  42. Mantovani G, Ozisik G, Achermann JC, et al (2002) Hypogonadotropic hypogonadism as a presenting feature of late onset X linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 87:44–48

    Article  PubMed  CAS  Google Scholar 

  43. Reynaud R, Barlier A, Valette Kasic S, et al (2005) An uncommun phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain. J Clin Endocrinol Metab 90:4880–4887

    Article  PubMed  CAS  Google Scholar 

  44. Tajima T, Hattori T, Nakajima T, et al (2007) A novel missense mutation (P366T) of the LHX4 causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr J 54:637–641

    Article  PubMed  CAS  Google Scholar 

  45. Reynaud R, Guedan M, Saveanu A, et al (2006) Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J Clin Endocrinol Metab 91:3329–3336

    Article  PubMed  CAS  Google Scholar 

  46. Mason AJ, Pitts SL, Nikolics K, et al (1986) The hypogonadal mouse: reproductive functions restored by gene therapy. Science 234:1372–1378

    Article  PubMed  CAS  Google Scholar 

  47. Bouligand J, Ghervan C, Tello J, et al (2008) Isolated familial hypogonadotropic hypogonadism and a GNRH1 Mutation. J Clin Invest 118: 2822–2822

    Article  Google Scholar 

  48. Chana YM, De Guillebona A, Lang-Muritanoc M (2009) GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci 106:11703–11708

    Article  Google Scholar 

  49. De Roux N, Young J, Misrahi M, et al (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropinreleasing hormone receptor. N Engl J Med 337:1597

    Article  PubMed  Google Scholar 

  50. Bhagavath B, Ozata M, Ozdemir IC, et al (2005) The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertil Steril 84:951–957

    Article  PubMed  CAS  Google Scholar 

  51. Lafranco F, Gromoll J, von Eckardstein S, et al (2005) Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 153:845–852

    Article  Google Scholar 

  52. Lofrano-Porto A, Barra GB, Giacomini LA, et al (2007) Luteinizing hormone beta mutation and hypogonadism in men and women. N Engl J Med 357:897–904

    Article  PubMed  CAS  Google Scholar 

  53. Achard C, Courtillot C, Lahuna O, et al (2009) Normal spermatogenesis in a man with mutant luteinizing hormone. N Engl J Med 361:1856–1863

    Article  PubMed  CAS  Google Scholar 

  54. Layman LC, McDonough PG (2000) Mutations of follicle stimulating hormone-beta and its receptor in human and mouse: genotype/phenotype. Mol Cell Endocrinol 161:9–17

    Article  PubMed  CAS  Google Scholar 

  55. Tapanainen JS, Aittomäki K, Min J, et al (1997) Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 15:205–206

    Article  PubMed  CAS  Google Scholar 

  56. Topaloglu AK, Reimann F, Guclu M, et al (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41:269–270

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hôpital Ibn-Tofail, CHU Mohammed-VI, Marrakech, Maroc

    N. El Ansari

  2. Faculté de médecine et de pharmacie de Marrakech, université Caddi-Ayad de Marrakech, Marrakech, Maroc

    N. El Ansari

Authors
  1. N. El Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. El Ansari.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

El Ansari, N. Les hypogonadismes hypogonadotrophiques congénitaux masculins, quelles données récentes ?. Basic Clin. Androl. 21, 68–74 (2011). https://doi.org/10.1007/s12610-011-0127-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12610-011-0127-2

Mots clés

Keywords

Basic and Clinical Andrology

ISSN: 2051-4190