Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)

Nelly Pitteloud, MD
William F Crowley, Jr, MD
Section Editors
Peter J Snyder, MD
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD


Isolated gonadotropin-releasing hormone (GnRH) deficiency (or idiopathic hypogonadotropic hypogonadism [IHH] with normal smell [normosmic IHH (nIHH)] or anosmia [Kallmann syndrome (KS)]) is associated with defects in the production or action of hypothalamic GnRH. The pathogenesis, genetics, clinical presentation, and management of isolated GnRH deficiency will be discussed here. Other causes of hypogonadotropic hypogonadism (HH) are reviewed separately. (See "Causes of secondary hypogonadism in males" and "Evaluation and management of secondary amenorrhea".)


Often this condition has evidence of being present from birth (eg, cryptorchidism and microphallus, or low gonadotropins and sex steroids during the "mini-puberty" of the neonatal period) and can therefore be viewed as congenital. However, more often, its age of onset cannot be determined and thus the term "idiopathic" is also used. By either terminology, this defect results in hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is differentiated from primary gonadal failure by the demonstration of low serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of castrate levels of gonadal steroids. The diagnosis is presumptive, however, and can only be confirmed by normal radiologic studies of the hypothalamic-pituitary region. Testing of other anterior pituitary endocrine function should also be undertaken to assure that the defect in gonadotropin secretion is isolated. The major diagnostic problem is distinguishing this disorder from constitutional delay of puberty prior to age 18 years.


The lack of endogenous GnRH secretion in patients with congenital GnRH deficiency cannot be proven by direct assay but can be reasonably inferred by two findings:

The complete lack of any endogenous GnRH-induced luteinizing hormone (LH) pulses during frequent blood sampling (figure 1) [1].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: May 2017. | This topic last updated: Jan 11, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Spratt DI, Carr DB, Merriam GR, et al. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab 1987; 64:283.
  2. Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med 1982; 307:1237.
  3. Caron P, Chauvin S, Christin-Maitre S, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab 1999; 84:990.
  4. Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007; 117:457.
  5. Sykiotis GP, Plummer L, Hughes VA, et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A 2010; 107:15140.
  6. Prager O, Braunstein GD. X-chromosome-linked Kallmann's syndrome: pathology at the molecular level. J Clin Endocrinol Metab 1993; 76:824.
  7. 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.
  8. Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989; 338:161.
  9. Soussi-Yanicostas N, de Castro F, Julliard AK, et al. Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons. Cell 2002; 109:217.
  10. Legouis R, Hardelin JP, Levilliers J, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 1991; 67:423.
  11. Franco B, Guioli S, Pragliola A, et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991; 353:529.
  12. Hardelin JP, Levilliers J, Blanchard S, et al. Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 1993; 2:373.
  13. Georgopoulos NA, Pralong FP, Seidman CE, et al. Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency. J Clin Endocrinol Metab 1997; 82:213.
  14. Oliveira LM, Seminara SB, Beranova M, et al. The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 2001; 86:1532.
  15. Pitteloud N, Hayes FJ, Boepple PA, et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87:152.
  16. Salenave S, Chanson P, Bry H, et al. Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab 2008; 93:758.
  17. Pitteloud N, Hayes FJ, Dwyer A, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87:4128.
  18. Dodé C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003; 33:463.
  19. González-Martínez D, Kim SH, Hu Y, 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.
  20. Pitteloud N, Acierno JS Jr, Meysing A, et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A 2006; 103:6281.
  21. Falardeau, J, Chung, W, Beenken, W, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice J Clin Invest 2008; 118: 2822.
  22. Falardeau J, Chung WC, Beenken A, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 2008; 118:2822.
  23. Trarbach EB, Abreu AP, Silveira LF, et al. Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. J Clin Endocrinol Metab 2010; 95:3491.
  24. Dodé, C, Teixeira, L, Levilliers, J, et al. Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2. Plos Genetics 2006; 2:175.
  25. Cole LW, Sidis Y, Zhang C, 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.
  26. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349:1614.
  27. de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100:10972.
  28. Miele ME, Robertson G, Lee JH, et al. Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6. Mol Carcinog 1996; 15:284.
  29. Lee, JH, Welch, DR. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res 1997; 15:57.
  30. Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88:1731.
  31. Navarro VM, Fernández-Fernández R, Castellano JM, 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.
  32. Castellano JM, Navarro VM, Fernández-Fernández R, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 2005; 146:3917.
  33. Silveira LG, Noel SD, Silveira-Neto AP, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010; 95:2276.
  34. Teles MG, Bianco SD, Brito VN, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358:709.
  35. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012; 366:629.
  36. de Roux N, Young J, Misrahi M, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997; 337:1597.
  37. Pralong FP, Gomez F, Castillo E, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 1999; 84:3811.
  38. Beranova M, Oliveira LM, Bédécarrats GY, 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.
  39. Seminara SB, Beranova M, Oliveira LM, et al. Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. J Clin Endocrinol Metab 2000; 85:556.
  40. Bouligand J, Ghervan C, Tello JA, et al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009; 360:2742.
  41. Chan YM, de Guillebon A, Lang-Muritano M, et al. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A 2009; 106:11703.
  42. Topaloglu AK, Reimann F, Guclu M, 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.
  43. Young J, Bouligand J, Francou B, et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010; 95:2287.
  44. Gianetti E, Tusset C, Noel SD, et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95:2857.
  45. Bergman JE, de Ronde W, Jongmans MC, et al. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. J Clin Endocrinol Metab 2012; 97:E858.
  46. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, et al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet 2009; 75:65.
  47. Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet 2006; 43:306.
  48. Hanchate NK, Giacobini P, Lhuillier P, et al. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet 2012; 8:e1002896.
  49. Young J, Metay C, Bouligand J, et al. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod 2012; 27:1460.
  50. Tornberg J, Sykiotis GP, Keefe K, 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 U S A 2011; 108:11524.
  51. Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 2013; 92:725.
  52. Kim HG, Ahn JW, Kurth I, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2010; 87:465.
  53. Salian-Mehta S, Xu M, Knox AJ, et al. Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2014; 99:1452.
  54. Pingault V, Bodereau V, Baral V, et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet 2013; 92:707.
  55. 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.
  56. El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, et al. Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 2011; 20:38.
  57. Faiman C, Hoffman DL, Ryan RJ, Albert A. The "fertile eunuch" syndrome: demonstration of isolated luteinizing hormone deficiency by radioimmunoassay technique. Mayo Clin Proc 1968; 43:661.
  58. Pitteloud N, Boepple PA, DeCruz S, et al. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 2001; 86:2470.
  59. Pitteloud, N, Acierno, JS, Meysing, A, et al. Mutations in Fibroblast Growth Factor Receptor 1 cause both Kallmann Syndrome and normosmic idiopathic hypogonadotropic hypogonadism, Proceedings of the National Academy of Science 2006; 103:6281.
  60. Kallmann, FJ, Schoenfeld, WA, Barrera, SE. The genetic aspects of primary eunuchoidism. Am J Mental Defic 1944; 48:203.
  61. Quinton R, Duke VM, Robertson A, et al. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 2001; 55:163.
  62. Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev 1998; 19:521.
  63. Ankarberg-Lindgren C, Elfving M, Wikland KA, Norjavaara E. Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab 2001; 86:3039.
  64. Martin KA, Hall JE, Adams JM, Crowley WF Jr. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1993; 77:125.
  65. Whitcomb RW, Crowley WF Jr. Clinical review 4: Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. J Clin Endocrinol Metab 1990; 70:3.
  66. Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 1994; 131:347.
  67. Liu L, Banks SM, Barnes KM, Sherins RJ. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1988; 67:1140.
  68. Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 1998; 139:298.
  69. Liu PY, Baker HW, Jayadev V, et al. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94:801.
  70. Sykiotis GP, Hoang XH, Avbelj M, et al. Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 2010; 95:3019.
  71. Quinton R, Cheow HK, Tymms DJ, et al. Kallmann's syndrome: is it always for life? Clin Endocrinol (Oxf) 1999; 50:481.
  72. Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357:863.