Abstract
Purpose of review: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field.
Recent findings: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.
Conflict of interest statement
Authors’ contributions: A.K. Fathi drafted the article and X. Luo contributed to critical revision and final approval of the paper.
Funding: None.
Ethical approval: Not needed.
References
1. Plant TM. Hypothalamic control of the pituitary – gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol 2008;20:719–26.Search in Google Scholar
2. Sisk CL, Foster DL. The neural basis of puberty and adolescence. Nat Neurosci 2004;7:1040–7.Search in Google Scholar
3. Ojeda SR, Dubay C, Lomniczi A, Kaidar G, Matagne V, et al. Gene networks and the neuroendocrine regulation of puberty. Mol Cell Endocrinol 2010;324:3–11.Search in Google Scholar
4. Semple RK, Topaloglu AK. The recent genetics of hypogonadotrophic hypogonadism: novel insights and new questions. Clin Endocrinol (Oxf) 2010;72:427–35.Search in Google Scholar
5. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 2009;5:569–76.Search in Google Scholar
6. Seminara SB, Oliveira LM, Beranova M, Hayes FJ, Crowley Jr WF. Genetics of hypogonadotropic hypogonadism. J Endocrinol Invest 2000;23:560–5.Search in Google Scholar
7. Behre HM, Nieschlag E, Meschede D, Partsch CJ. Diseases of the hypothalamus and the pituitary gland. In: Behre HM and Nieschlag E, editors. Andrology. Male reproductive health and dysfunction, 2nd ed. Berlin, Heidelberg: Springer-Verlag, 2010:125–42. DOI: 10.1007/978-3-540-78355-8_12.Search in Google Scholar
8. Lovane A, Aumas C, de Roux N. New insights in the genetics of isolated hypogonadotropic hypogonadism. Eur J Endocrinol 2004;151:U83–8.Search in Google Scholar
9. Silveira LF, MacColl GS, Bouloux PM. Related hypogonadotropic hypogonadism. Semin Reprod Med 2002;20:327–38.Search in Google Scholar
10. Bouloux PM, Hu Y, MacColl G. Recent advances in the pathogenesis of Kallmann’s syndrome. Prog Brain Res 2002;141:79–83.Search in Google Scholar
11. 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.Search in Google Scholar
12. Beranova M, Oliveira LM, Bédécarrats GY, Schipani E, Vallejo M, et al. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86,1580–8.Search in Google Scholar
13. 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.Search in Google Scholar
14. Pralong FP, Gomez F, Castillo E, Giacomini M, Portmann L, et al. Idiopathic hypogonadotropic hypogonadism associated with a novel mutation in the GnRH receptor gene. Program of the 80th Annual Meeting of The Endocrine Society, New Orleans, LA. 1998. P2-505, p. 355.Search in Google Scholar
15. Conn PM, Crowley WF. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991;324:93–103.Search in Google Scholar
16. Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin releasing hormone receptors: structure and signal transduction pathways. Endocr Rev 1994;15:462–99.Search in Google Scholar
17. de Roux N. Isolated gonadotropic deficiency with and without anosmia: developmental defect or a neuroendocrine regulation abnormality of the gonadotropic axis. Horm Res 2005;64: 48–55.Search in Google Scholar
18. Hardelin JP. Kallmann syndrome: towards molecular pathogenesis. Mol Cell Endocrinol 2001;179:75–81.Search in Google Scholar
19. Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, 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.Search in Google Scholar
20. Bhagavath B, Layman LC. The genetics of hypogonadotropic hypogonadism. Semin Reprod Med 2007;25:272–86.Search in Google Scholar
21. Seminara SB. Kisspeptin in reproduction. Semin Reprod Med 2007;25:337–43.Search in Google Scholar
22. Kim HG, Bhagavath B, Layman LC. Clinical manifestations of impaired GnRH neuron development and function. Neuro-Signals 2008;16:165–82.Search in Google Scholar
23. 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.Search in Google Scholar
24. 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.Search in Google Scholar
25. Shahab M, Mastronarcli 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.Search in Google Scholar
26. Navarro VM, Fernández-Fernández R, Castellano JM, Roa J, Mayen A, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 2004;561:379–86.Search in Google Scholar
27. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, et al. The metastasis suppressor gene KiSS1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001;276:34631–6.Search in Google Scholar
28. 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.Search in Google Scholar
29. Wacker JL, Feller DB, Tang XB, Defino MC, Namkung Y, et al. Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. J Biol Chem 2008;283:31068–78.Search in Google Scholar
30. Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, et al. Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 2007;92:1137–44.Search in Google Scholar
31. Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, et al. Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005;90:1849–55.Search in Google Scholar
32. Caprio M, Fabbrini E, Isidori AM, Aversa A, Fabbri A. Leptin in reproduction. Trends Endocrinol Metab 2001;12:65–72.Search in Google Scholar
33. Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab 2008;294:e827–32.Search in Google Scholar
34. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, et al. A mutation in dysfunction the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.Search in Google Scholar
35. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213–5.Search in Google Scholar
36. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptindeficient adults. Proc Natl Acad Sci USA 2004;101:4531–6.Search in Google Scholar
37. Tena-Sempere M. KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 2006;83:275–81.Search in Google Scholar
38. 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.Search in Google Scholar
39. Guran T, Tolhurst G, Bereket A, Rocha N, Porter K, 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.Search in Google Scholar
40. Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, et al. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009;29: 11859–66.Search in Google Scholar
41. Young J, Bouligand J, Francou B, Raffin-Sanson ML, Gaillez S, et al. TAC3 and TACR3 defects cause congenital hypothalamic hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010;95:2287–95.Search in Google Scholar
42. O’Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, et al. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 1995;333:1386–90.Search in Google Scholar
43. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303–6.Search in Google Scholar
44. Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev 2006;27:710–8.Search in Google Scholar
45. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J. Clin Endocrinol Metab 2007;92:3369–73.Search in Google Scholar
46. Lloyd DJ, Bohan S, Gekakis N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 2006;15:1884–93.Search in Google Scholar
47. 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.Search in Google Scholar
48. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, et al. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. PNAS 2009;106:11703–8.Search in Google Scholar
49. Costa EM, Bedecarrats GY, Mendonca BB, Arnhold IJ, Kaiser UB, et al. Two novel mutations in the gonadotropinreleasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J Clin Endocrinol Metab 2001;86:2680–6.Search in Google Scholar
50. Ulloa-Aguirre A, Conn PM. G protein-coupled receptors and the G protein family. In: Conn PM, editor. Handbook of physiology (Section 7). Volume I, Cellular endocrinology. New York, USA: Oxford University Press, 1998:87–124.Search in Google Scholar
51. Kottler ML, Lorenzo F, Bergametti F, Commercon P, Souchier C, et al. Subregional mapping of the human gonadotropin-releasing hormone receptor (GnRH-R) gene to 4q between markers D4S392 and D4S409. Hum Genet 1995;96:477–80.Search in Google Scholar
52. Fan NC, Jeung E-B, Peng Ch, Olofsson JI, Krisinger J, et al. The human gonadotropin-releasing hormone (GnRH) receptor gene:cloning, genomic organization and chromosomal assignment. Mol Cell Endocrinol 1994;103:R1–6.Search in Google Scholar
53. Kakar SS. Molecular structure of the human gonadotropin-releasing hormone receptor gene. Eur J Endocrinol 1997;137:183–92.Search in Google Scholar
54. Layman LC, Cohen DP, Jin M, Xie J, Li Z, et al. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 1998;18:14–15.Search in Google Scholar
55. Maya-Nuñez G, Janovick JA, Ulloa-Aguirre A, Söderlund D, Conn PM, et al. Molecular basis of hypogonadotropic hypogonadism:restoration of mutant (E90K) GnRH receptor function by a deletion at a distant site. J Clin Endocrinol Metab 2002;87:2144–9.Search in Google Scholar
56. Bedecarrats GY, Linher KD, Kaiser U. Two common naturally occurring mutations in the human gonadotropin-releasing hormone (GnRH) receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction. J Clin Endocrinol Metab 2003;88:834–43.Search in Google Scholar
57. Caron P, Chauvin S, Christin-Maitre S, Bennet A, Lahlou N, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab 1999;84:990–6.Search in Google Scholar
58. Pralong FP, Gomez F, Castillo E, Cotecchia S, Abuin L, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 1999;84:3811–6.Search in Google Scholar
59. Karges B, Karges W, Mine M, Ludwig L, Kuhne R, et al. Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2003;88:1873–9.Search in Google Scholar
60. deRoux 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;84:567–72.Search in Google Scholar
61. Kottler ML, Chauvin S, Lahlou N, Harris CE, Johnston CJ, et al. A new compound heterozygous mutation of the gonadotropin releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. J Clin Endocrinol Metab 2000;85:3002–8.Search in Google Scholar
62. Meysing AU, Kanasaki H, Bedecarrats GY, Acierno Jr GW, Conn PM, et al. New GnRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight differential sensitivity of LH and FSH to GnRH. J Clin Endocrinol Metab 2004;89:3189–98.Search in Google Scholar
63. Söderlund D, Canto P, de la Chesnaye E, Ulloa-Aguirre A, Mendez JP. A novel homozygous mutation in the second transmembrane domain of the gonadotropin releasing hormone receptor gene. Clin Endocrinol 2001;54:493–8.Search in Google Scholar
64. Bhagavath B, Podolsky RH, Ozata M, Bolu E, Bick DP, et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 2006;85:706–13.Search in Google Scholar
65. Bhagavath B, Ozata M, Ozdemir IC, Bolu E, Bick DP, et al. The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertil Steril 2005;84:951–7.Search in Google Scholar
66. Pedersen-White JR, Chorich LP, Bick DP, Sherins RJ, Layman LC. The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Hum Reprod 2008;14: 367–70.Search in Google Scholar
67. Snyder J, Peachey H, Berlin JA, Hannoush P. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000;85:2670–7.Search in Google Scholar
68. Davidson JM, Camargo C, Smith ER. Effects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979;48:955–8.Search in Google Scholar
69. Bagatell CJ, Paulsen CA, Bremner WJ. Preservation of fertility despite subnormal gonadotropin and testosterone levels after cessation of pulsatile gonadotropin-releasing hormone therapy in a man with Kallmann’s syndrome. Fertil Steril 1994;61:392–4.Search in Google Scholar
70. Rowe RC, Schroeder ML, Faiman C. Testosterone-induced fertility in a patient with previously untreated Kallmann’s syndrome. Fertil Steril 1983;40:400–1.Search in Google Scholar
71. Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, et al. Kallmann’s syndrome: is it always for life? Clin Endocrinol 1999;50:481–5.Search in Google Scholar
72. 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.Search in Google Scholar
©2013 by Walter de Gruyter Berlin Boston
