New understandings of the genetic basis of isolated idiopathic central hypogonadism

Asian Journal of Andrology

Volumn 14, Issue 1, 2012, Pages 49-56

  Bonomi, Marco ^a   Libri, Domenico Vladimiro ^a,b   Guizzardi, Fabiana ^a   Guarducci, Elena ^c   Maiolo, Elisabetta ^d   Pignatti, Elisa ^e   Asci, Roberta ^f   Persani, Luca ^a,b  

^a ISTITUTO AUXOLOGICO ITALIANO   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY OF FLORENCE   (Italy)

^d GALLIERA HOSPITAL   (Italy)

^e UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^f UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

central hypogonadism; congenital hypogonadism; GnRH; hypogonadotropic hypogonadism; hypothalamus pituitary gonadal axis; Kallmann syndrome; male infertility

Indexed keywords

FIBROBLAST GROWTH FACTOR 8; FIBROBLAST GROWTH FACTOR RECEPTOR 1; GONADORELIN; GONADORELIN RECEPTOR;

EPIGENETICS; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC VARIABILITY; HUMAN; HYPOGONADISM; IDIOPATHIC CENTRAL HYPOGONADISM; KALLMANN SYNDROME; NONHUMAN; PATHOGENESIS; PEDIGREE; REVIEW; SYNDROME CHARGE;

ANIMALS; HUMANS; HYPOGONADISM; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; INFERTILITY, MALE; ITALY; KALLMANN SYNDROME; MALE; MICE; MICE, KNOCKOUT; MODELS, ANIMAL;

EID: 84855458768     PISSN: 1008682X     EISSN: 17457262     Source Type: Journal    
DOI: 10.1038/aja.2011.68     Document Type: Review

References (94)

1. Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989; 338: 161-4. (Pubitemid 19074106)
2. Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci USA 1989; 86: 8132-6. (Pubitemid 19265333)
3. Gonzalez-Martinez D, Hu Y, Bouloux PM. Ontogeny of GnRH and olfactory neuronal systems in man: novel insights from the investigation of inherited forms of Kallmann's syndrome. Front Neuroendocrinol 2004; 25: 108-30. (Pubitemid 39572201)
4. Cadman SM, Kim SH, Hu Y, Gonzalez-Martinez D, Bouloux PM. Molecular pathogenesis of Kallmann's syndrome. Horm Res 2007; 67: 231-42. (Pubitemid 46558886)
5. Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab 2011; 22: 249-58.
6. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991; 353: 529-36. (Pubitemid 21912544)
7. Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 1991; 67: 423-35.
8. Hardelin JP, Levilliers J, del Castillo I, Cohen-Salmon M, Legouis R et al. X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc Natl Acad Sci USA 1992; 89: 8190-4.
9. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G et al. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 2001; 55: 163-74. (Pubitemid 32868580)
10. Hu Y, Gonzalez-Martinez D, Kim SH, Bouloux PM. Cross-talk of anosmin-1, the protein implicated in X-linked Kallmann's syndrome, with heparan sulphate and urokinase-type plasminogen activator. Biochem J 2004; 384: 495-505. (Pubitemid 40018963)
11. Soussi-Yanicostas N, Hardelin JP, Arroyo-Jimenez MM, Ardouin O, Legouis R et al. Initial characterization of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system. J Cell Sci 1996; 109(Pt 7): 1749-57. (Pubitemid 26248620)
12. Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C et al. Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome. Dev Dyn 1999; 215: 26-44. (Pubitemid 29215701)
13. Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res 1989; 6: 311-26. (Pubitemid 19283316)
14. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogon-adotropic hypogonadism. Nat Rev Endocrinol 2009; 5: 569-76.
15. Trarbach EB, Silveira LG, Latronico AC. Genetic insights into human isolated gonadotropin deficiency. Pituitary 2007; 10: 381-91. (Pubitemid 350130585)
16. Dode C, Hardelin JP. Kallmann syndrome: fibroblast growth factor signaling insufficiency? J Mol Med 2004; 82: 725-34. (Pubitemid 40022266)
17. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N et al. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 2004; 89: 1079-88. (Pubitemid 38368394)
18. Groth C, Lardelli M. The structure and function of vertebrate fibroblast growth factor receptor 1. Int J Dev Biol 2002; 46: 393-400. (Pubitemid 36841006)
19. Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 2005; 16: 107-37. (Pubitemid 40616111)
20. Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ. Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry 2004; 43: 4724-30. (Pubitemid 38509093)
21. González-Martínez D, Kim SH, Hu Y, Guimond S, Schofield J et al. Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism. J Neurosci 2004; 24: 10384-92. (Pubitemid 39552623)
22. Hebert JM, Lin M, Partanen J, Rossant J, McConnell SK. FGF signaling through FGFR1 is required for olfactory bulb morphogenesis. Development 2003; 130: 1101-11. (Pubitemid 36395692)
23. Tsai PS, Moenter SM, Postigo HR, el Majdoubi M, Pak TR et al. Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol Endocrinol 2005; 19: 225-36. (Pubitemid 40065972)
24. Chung WC, Moyle SS, Tsai PS. Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons. Endocrinology 2008; 149: 4997-5003.
25. Hu Y, Bouloux PM. Novel insights in FGFR1 regulation: lessons from Kallmann syndrome. Trends Endocrinol Metab 2010; 21: 385-93.
26. Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2006; 103: 6281-6.
27. Trarbach EB, Costa EM, Versiani B, de Castro M, Baptista MT et al. Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia. J Clin Endocrinol Metab 2006; 91: 4006-12. (Pubitemid 44536878)
28. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 2006; 254-255: 60-9. (Pubitemid 44056268)
29. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci USA 2010; 107: 15140-4.
30. Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and miceJ Clin Invest 2008: 118: 2822-31.
31. Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci USA 2011; 108: 11524-9.
32. Inatani M, Irie F, Plump AS, Tessier-Lavigne M, Yamaguchi Y. Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 2003; 302: 1044-6. (Pubitemid 37386197)
33. Hudson ML, Kinnunen T, Cinar HN, Chisholm AD. C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations. Dev Biol 2006; 294: 352-65. (Pubitemid 43866675)
34. Bulow HE, Berry KL, Topper LH, Peles E, Hobert O. Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1. Proc Natl Acad Sci USA 2002; 99: 6346-51. (Pubitemid 34493314)
35. Bulow HE, Hobert O. Differential sulfations and epimerization define heparan sulfate specificity in nervous system development. Neuron 2004; 41: 723-36. (Pubitemid 38326835)
36. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci USA 2006; 103: 4140-5.
37. Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol Pharmacol 2001; 59: 692-8. (Pubitemid 32273997)
38. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y et al. Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun 2002; 293: 396-402. (Pubitemid 34694220)
39. Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006; 2: e175.
40. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin- releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab 2008; 93: 3551-9.
41. Monnier C, Dodé C, Fabre L, Teixeira L, Labesse G et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum Mol Genet 2009; 18: 75-81.
42. Leroy C, Fouveaut C, Leclercq S, Jacquemont S, Boullay HD et al. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Eur J Hum Genet 2008; 16: 865-8. (Pubitemid 351865685)
43. Leroy C, Fouveaut C, Leclercq S, Jacquemont S, Boullay HD et al. Discovery of a receptor related to the galanin receptors. FEBS Lett 1999; 446: 103-7.
44. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276: 34631-6.
45. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 2001; 411: 613-7.
46. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001; 276: 28969-75.
47. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349: 1614-27. (Pubitemid 37303886)
48. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 2005; 102: 1761-6. (Pubitemid 40209241)
49. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004; 145: 4073-7. (Pubitemid 39120554)
50. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004; 320: 383-8. (Pubitemid 38798878)
51. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004; 80: 264-72. (Pubitemid 40187012)
52. Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 2005; 102: 2129-34. (Pubitemid 40262023)
53. Plant TM, Ramaswamy S, DiPietro MJ. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 2006; 147: 1007-13. (Pubitemid 43113020)
54. Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro ML, Roa J, Navarro VM et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 2004; 145: 4565-74. (Pubitemid 39281449)
55. Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90: 6609-15. (Pubitemid 41759323)
56. Navarro VM, Castellano JM, Fernández-Fernández R, Tovar S, Roa J et al. Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 2005; 146: 156-63. (Pubitemid 40051735)
57. Chan YM, Broder-Fingert S, Seminara SB. Reproductive functions of kisspeptin and Gpr54 across the life cycle of mice and men. Peptides 2009; 30: 42-8.
58. Rance NE. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 2009; 320: 111-22.
59. Clarkson J, d'Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE. Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 2009; 21: 673-82.
60. Clarkson J, Herbison AE. Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. J Neuroendocrinol 2009; 21: 305-11.
61. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100: 10972-6. (Pubitemid 37140137)
62. Semple RK, Topaloglu AK. The recent genetics of hypogonadotrophic hypogonadism-novel insights and new questions. Clin Endocrinol (Oxf) 2010; 72: 427-35.
63. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41: 354-8.
64. Guran T, Tolhurst G, Bereket A, Rocha N, Porter KT et al. Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. J Clin Endocrinol Metab 2009; 94: 3633-9.
65. Guran T, Tolhurst G, Bereket A, Rocha N, Porter K et al. mRNA expression of tachykinins and tachykinin receptors in different human tissues. Eur J Pharmacol 2004; 494: 233-9.
66. Maggi CA, Schwartz TW. The dual nature of the tachykinin NK1 receptor. Trends Pharmacol Sci 1997; 18: 351-55. (Pubitemid 27435057)
67. Sandoval-Guzman T, Rance NE. Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res 2004; 1026: 307-12. (Pubitemid 39361561)
68. Kung TT, Crawley Y, Jones H, Luo B, Gilchrest H et al. Tachykinin NK3-receptor deficiency does not inhibit pulmonary eosinophilia in allergic mice. Pharmacol Res 2004; 50: 611-5. (Pubitemid 39388972)
69. Chawla MK, Gutierrez GM, Young WS3rd, McMullen NT, Rance NE. Localization of neurons expressing substance P and neurokinin B gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 1997; 384: 429-42. (Pubitemid 27342585)
70. Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S et al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009; 360: 2742-8.
71. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F et al. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2009; 106: 11703-8.
72. Mason AJ, Pitts SL, Nikolics K, Szonyi E, Wilcox JN et al. The hypogonadal mouse: reproductive functions restored by gene therapy. Science 1986; 234: 1372-8. (Pubitemid 17210215)
73. Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G. Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism. Nature 1977; 269: 338-40. (Pubitemid 8178658)
74. Tiong J, Locastro T, Wray S. Gonadotropin-releasing hormone-1 (GnRH-1) is involved in tooth maturation and biomineralization. Dev Dyn 2007; 236: 2980-92. (Pubitemid 350174997)
75. de Roux N, Young J, Misrahi M, Genet R, Chanson P et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997; 337: 1597-602. (Pubitemid 27509763)
76. Wu S, Wilson MD, Busby ER, Isaac ER, Sherwood NM et al. Disruption of the single copy gonadotropin-releasing hormone receptor in mice by gene trap: severe reduction of reproductive organs and functions in developing and adult mice. Endocrinology 2010; 151: 1142-52.
77. Pask AJ, Kanasaki H, Kaiser UB, Conn PM, Janovick JA et al. A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Mol Endocrinol 2005; 19: 972-81. (Pubitemid 40397061)
78. Silveira LF, MacColl GS, Bouloux PM. Hypogonadotropic hypogonadism. Semin Reprod Med 2002; 20: 327-38. (Pubitemid 36043723)
79. Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2008; 83: 511-9.
80. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata T, Sato N et al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome-the clinical overlap with CHARGE syndrome. Clin Genet 2009; 75: 65-71.
81. Kramer PR, Wray S. Novel gene expressed in nasal region influences outgrowth of olfactory axons and migration of luteinizing hormone-releasing hormone (LHRH) neurons. Genes Dev 2000; 14: 1824-34. (Pubitemid 30603000)
82. Kramer PR, Wray S. Nasal embryonic LHRH factor (NELF) expression within the CNS and PNS of the rodent. Brain Res Gene Expr Patterns 2001; 1: 23-6. (Pubitemid 33634191)
83. Miura K, Acierno JS Jr, Seminara SB. 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 2004; 49: 265-8. (Pubitemid 38856018)
84. Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007; 117: 457-63. (Pubitemid 46203974)
85. Xu N, Kim HG, Bhagavath B, Cho SG, Lee JH et al. Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 2011; 95: 1613-20.
86. Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S et al. Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice. Development 2003; 130: 401-10. (Pubitemid 36175936)
87. Trarbach EB, Baptista MT, Garmes HM, Hackel C. Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients. J. Endocrinol 2005; 187: 361-8. (Pubitemid 43020257)
88. Dodé C, Levilliers J, Dupont JM, de Paepe A, le Dû N et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003; 33: 463-5. (Pubitemid 36390006)
89. de Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E et al. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 1999; 84: 567-572. (Pubitemid 29075685)
90. Massin N, Pêcheux C, Eloit C, Bensimon JL, Galey J et al. X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab 2003; 88: 2003-8. (Pubitemid 36549868)
91. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011; 364: 215-25.
92. Cerrato F, Shagoury J, Kralickova M, Dwyer A, Falardeau J et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism. Eur. J. Endocrinol 2006; 155Suppl 1: S3-10.
93. Nachtigall LB, Boepple PA, Pralong FP, Crowley WF Jr. Adult-onset idiopathic hypogonadotropic hypogonadism-a treatable form of male infertility. N Engl J Med 1997; 336: 410-15. (Pubitemid 27081904)
94. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357: 863-73. (Pubitemid 47347320)