Laboratory Studies

Along with the above-described clinical manifestations, most patients have low serum levels of basal gonadotropins, estrogen/testosterone, and poor response to gonadotropin-releasing hormone (GnRH) stimulation. The difficulty arises when trying to differentiate between healthy prepubertal males and those with idiopathic hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS).

Patients with KS can be distinguished from prepubertal males aged 12.5 years or older by determining the level of luteinizing hormone (LH) in pooled serum samples collected every 20 minutes for 6 hours commencing 1 hour after sleep onset.

The GnRH stimulation test using a synthetic GnRH analog, such as buserelin, has been used to differentiate males with gonadotropin deficiency from those with delayed puberty. In a study by Wilson et al, a total 31 prepubertal males were given 100 µcg of buserelin subcutaneously, and blood samples for LH and follicle-stimulating hormone (FSH) were obtained at 0 and 4 hours after treatment.^{[47, 48]}Participants were then followed for a mean duration of 4.2 years to determine if they progressed through puberty. Twenty-six percent of individuals failed to undergo puberty and were diagnosed with gonadotropin deficiency. None of these men had had a buserelin-stimulated serum LH level higher than 5 U/L. In fact, the LH response was significantly lower when compared with those males who ultimately developed puberty. The stimulated FSH levels were comparable in both groups, and thus are not useful when distinguishing delayed puberty from IHH or KS.

Imaging Studies

MRI appears to be the single best study for the diagnosis of KS and exclusion of other CNS disorders associated with hypogonadotropic hypogonadism.

T1-weighted MRI of the inferior frontal region in the coronal plane appears most helpful in examining the olfactory sulci, bulbs, and rhinencephalon.

Because of the lack of production of sex steroids, men and women with KS and IHH can experience abnormal bone development. The prudent use of a dual-energy x-ray absorptiometry (DEXA) scan to monitor bone mineral density in these individuals is appropriate.

Other Tests

Many affected individuals are unaware of their loss of olfaction, especially those with partial defects. Testing with graded dilutions of pure scents is often necessary to identify the impaired olfaction. The magnitude of GnRH deficiency appears to correlate with the severity of anosmia.

Along with the anosmia, another interesting neurological finding is that of mirror movements related to the cerebellar defects. Mirroring, involuntary movements of a limb that mirror voluntary movements of the contralateral limb, is present in as many as 85% of patients.

Treatment & Management

Kallman FJ, Schoenfeld WA. The genetic aspects of primary eunuchoidism. Am J Ment Def. 1944. 158:203-236.
Cariboni A, André V, Chauvet S, Cassatella D, Davidson K, Caramello A, et al. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J Clin Invest. 2015 Jun. 125 (6):2413-28. [QxMD MEDLINE Link].
deMorsier G. Etudes sur les dysraphies cranio-encephaliques. Agenesie des lobes olfactifs (telencephaloschizis lateral) et des comissures calleuse et anterieure (telencephaloschizis median). La dysplasie olfacto-genitale. Schweiz Arch Neurol Neurochir Psychiatr. 1954. 74:309.
Choi JH, Balasubramanian R, Lee PH, Shaw ND, Hall JE, Plummer L, et al. Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab. 2015 Oct. 100 (10):E1378-85. [QxMD MEDLINE Link].
Wildt L, Schwilden H, Wesner G. The pulsatile pattern of gonadotropin secretion and follicular development during the menstrual cycle and in women with hypothalamic and hypoandrogenic amenorrhea. Leyendecker G, et al, eds. Brain and Pituitary Peptides. New York, NY: Karger Publishers; 1983. 11-27.
Plant TM. Hypothalamic control of the pituitary-gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol. 2008 Jun. 20(6):719-26. [QxMD MEDLINE Link].
Foster DL, Karsch FJ. Development of the mechanism regulating the preovulatory surge of luteinizing hormone in sheep. Endocrinology. 1975 Nov. 97(5):1205-9. [QxMD MEDLINE Link].
Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978 Nov 10. 202(4368):631-3. [QxMD MEDLINE Link].
Suter KJ, Song WJ, Sampson TL, et al. Genetic targeting of green fluorescent protein to gonadotropin-releasing hormone neurons: characterization of whole-cell electrophysiological properties and morphology. Endocrinology. 2000 Jan. 141(1):412-9. [QxMD MEDLINE Link].
Waldstreicher J, Seminara SB, Jameson JL, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. 1996 Dec. 81(12):4388-95. [QxMD MEDLINE Link].
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 Oct 10. 353(6344):529-36. [QxMD MEDLINE Link].
Topaloglu AK, Kotan LD. Molecular causes of hypogonadotropic hypogonadism. Curr Opin Obstet Gynecol. 2010 Aug. 22(4):264-70. [QxMD MEDLINE Link].
Pitteloud N, Meysing A, Quinton R, et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006 Jul 25. 254-255:60-9. [QxMD MEDLINE Link].
Massin N, Pecheux C, Eloit C, 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 May. 88(5):2003-8. [QxMD MEDLINE Link].
Cadman SM, Kim SH, Hu Y, et al. Molecular pathogenesis of Kallmann's syndrome. Horm Res. 2007. 67(5):231-42. [QxMD MEDLINE Link].
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 Jul. 25(2):108-30. [QxMD MEDLINE Link].
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 Jul. 95(7):3491-6. [QxMD MEDLINE Link].
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 Aug. 118(8):2822-31. [QxMD MEDLINE Link].
Ng KL, Li JD, Cheng MY, et al. Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science. 2005 Jun 24. 308(5730):1923-7. [QxMD MEDLINE Link].
Prosser HM, Bradley A, Caldwell MA. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. Eur J Neurosci. 2007 Dec. 26(12):3339-44. [QxMD MEDLINE Link].
Dode C, Teixeira L, Levilliers J, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20. 2(10):e175. [QxMD MEDLINE Link].
Pitteloud N, Zhang C, Pignatelli D, et al. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007 Oct 30. 104(44):17447-52. [QxMD MEDLINE Link].
Dode C, Teixeira L, Levilliers J, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20. 2(10):e175. [QxMD MEDLINE Link].
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 Oct. 19(5):521-39. [QxMD MEDLINE Link].
Navarro VM, Fernandez-Fernandez 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 Dec 1. 561:379-86. [QxMD MEDLINE Link].
Kauffman AS, Park JH, McPhie-Lalmansingh AA, et al. The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci. 2007 Aug 15. 27(33):8826-35. [QxMD MEDLINE Link].
Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009 Jun 25. 360(26):2742-8. [QxMD MEDLINE Link].
Santhakumar A, Balasubramaniam R, Miller M, Quinton R. Reversal of Isolated Hypogonadotropic Hypogonadism: long-term integrity of hypothalamo-pituitary-testicular axis in two men is dependent on intermittent androgen exposure. Clin Endocrinol (Oxf). 2013 Oct 7. [QxMD MEDLINE Link].
Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999 Sep 16. 341(12):879-84. [QxMD MEDLINE Link].
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 Mar. 41(3):354-8. [QxMD MEDLINE Link].
Nagae M, Uenoyama Y, Okamoto S, et al. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. Proc Natl Acad Sci U S A. 2021 Feb 2. 118 (5):[QxMD MEDLINE Link]. [Full Text].
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(5):265-8. [QxMD MEDLINE Link].
Cariboni A, Davidson K, Rakic S, et al. Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Hum Mol Genet. 2011 Jan 15. 20(2):336-44. [QxMD MEDLINE Link].
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 Oct 8. 87(4):465-79. [QxMD MEDLINE Link]. [Full Text].
Pitteloud N, Durrani S, Raivio T, Sykiotis GP. Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res. 2010. 39:142-53. [QxMD MEDLINE Link].
Sykiotis GP, Plummer L, Hughes VA, et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A. 2010 Aug 24. 107(34):15140-4. [QxMD MEDLINE Link]. [Full Text].
Stamou MI, Varnavas P, Kentrou M, Adamidou F, Voutetakis A, Jing J, et al. Isolated GnRH Deficiency: Genotypic and Phenotypic Characteristics of the Genetically Heterogeneous Greek Population. Eur J Endocrinol. 2016 Nov 24. [QxMD MEDLINE Link].
Filippi G. Klinefelter's syndrome in Sardinia. Clinical report of 265 hypogonadic males detected at the time of military check-up. Clin Genet. 1986 Oct. 30(4):276-84. [QxMD MEDLINE Link].
Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 May. 98(5):1781-8. [QxMD MEDLINE Link].
Colquhoun-Kerr JS, Gu WX, Jameson JL, Withers S, Bode HH. X-linked Kallmann syndrome and renal agenesis occurring together and independently in a large Australian family. Am J Med Genet. 1999 Mar 5. 83(1):23-7. [QxMD MEDLINE Link].
Jongmans MC, van Ravenswaaij-Arts CM, et al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. 2009 Jan. 75(1):65-71. [QxMD MEDLINE Link]. [Full Text].
Teixeira L, Guimiot F, Dode C, et al. Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions. J Clin Invest. 2010 Oct 1. 120(10):3668-72. [QxMD MEDLINE Link]. [Full Text].
Shiraishi K, Naito K. Fertile eunuch syndrome with the mutations (Trp8Arg and Ile15Thr) in the beta subunit of luteinizing hormone. Endocr J. 2003 Dec. 50(6):733-7. [QxMD MEDLINE Link].
Makler A, Glezerman M, Lunenfeld B. The fertile eunuch syndrome. An isolated leydig-cell failure?. Andrologia. 1977 Apr-Jun. 9(2):163-70. [QxMD MEDLINE Link].
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 Jun. 86(6):2470-5. [QxMD MEDLINE Link].
Roth MY, Lin K, Bay K, Amory JK, Anawalt BD, Matsumoto AM, et al. Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial. Fertil Steril. 2013 Jan. 99(1):132-9. [QxMD MEDLINE Link]. [Full Text].
Wilson DA, Hofman PL, Miles HL, et al. Evaluation of the buserelin stimulation test in diagnosing gonadotropin deficiency in males with delayed puberty. J Pediatr. 2006 Jan. 148(1):89-94. [QxMD MEDLINE Link].
Sun QH, Zheng Y, Zhang XL, Mu YM. Role of Gonadotropin-releasing Hormone Stimulation Test in Diagnosing Gonadotropin Deficiency in Both Males and Females with Delayed Puberty. Chin Med J (Engl). 2015 20th Sep. 128 (18):2439-2443. [QxMD MEDLINE Link].
Mishell DR Jr, Nakamura RM, Crosignani PG, et al. Serum gonadotropin and steroid patterns during the normal menstrual cycle. Am J Obstet Gynecol. 1971 Sep. 111(1):60-5. [QxMD MEDLINE Link].
Stevenson JC. Metabolic effects of the menopause and oestrogen replacement. Baillieres Clin Obstet Gynaecol. 1996 Sep. 10(3):449-67. [QxMD MEDLINE Link].
Jewelewicz R. New developments in topical estrogen therapy. Fertil Steril. 1997 Jan. 67(1):1-12. [QxMD MEDLINE Link].
Quinton R, Cheow HK, Tymms DJ, et al. Kallmann's syndrome: is it always for life?. Clin Endocrinol (Oxf). 1999 Apr. 50(4):481-5. [QxMD MEDLINE Link].
Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 Aug 30. 357(9):863-73. [QxMD MEDLINE Link].
Ioannidou-Kadis S, Wright PJ, Neely RD, Quinton R. Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate. Fertil Steril. 2006 Nov. 86(5):1513.e5-9. [QxMD MEDLINE Link].
Adams JM, Taylor AE, Schoenfeld DA, Crowley WF Jr, Hall JE. The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency. J Clin Endocrinol Metab. 1994 Sep. 79(3):858-64. [QxMD MEDLINE Link].
Angelopoulos N, Goula A, Tolis G. The role of luteinizing hormone activity in controlled ovarian stimulation. J Endocrinol Invest. 2005 Jan. 28(1):79-88. [QxMD MEDLINE Link].
Apter D, Cacciatore B, Alfthan H, Stenman UH. Serum luteinizing hormone concentrations increase 100-fold in females from 7 years to adulthood, as measured by time-resolved immunofluorometric assay. J Clin Endocrinol Metab. 1989 Jan. 68(1):53-7. [QxMD MEDLINE Link].
Arimura A, Kastin AJ, Gonzalez-Barcena D, et al. Disappearance of LH-releasing hormone in man as determined by radioimmunoassay. Clin Endocrinol (Oxf). 1974 Oct. 3(4):421-5. [QxMD MEDLINE Link].
Backstrom CT, McNeilly AS, Leask RM, Baird DT. Pulsatile secretion of LH, FSH, prolactin, oestradiol and progesterone during the human menstrual cycle. Clin Endocrinol (Oxf). 1982 Jul 1. 17(1):29-42. [QxMD MEDLINE Link].
Baker HW, Santen RJ, Burger HG, et al. Rhythms in the secretion of gonadotropins and gonadal steroids. J Steroid Biochem. 1975 May. 6(5):793-801. [QxMD MEDLINE Link].
Bardin CW, Ross GT, Rifkind AB, Cargille CM, Lipsett MB. Studies of the pituitary-Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepuberal boys, and hypopituitary patients. J Clin Invest. 1969 Nov. 48(11):2046-56. [QxMD MEDLINE Link].
Barkan AL, Reame NE, Kelch RP, Marshall JC. Idiopathic hypogonadotropic hypogonadism in men: dependence of the hormone responses to gonadotropin-releasing hormone (GnRH) on the magnitude of the endogenous GnRH secretory defect. J Clin Endocrinol Metab. 1985 Dec. 61(6):1118-25. [QxMD MEDLINE Link].
Barnhart KM, Mellon PL. The orphan nuclear receptor, steroidogenic factor-1, regulates the glycoprotein hormone alpha-subunit gene in pituitary gonadotropes. Mol Endocrinol. 1994 Jul. 8(7):878-85. [QxMD MEDLINE Link].
Barron JL, Millar RP, Searle D. Metabolic clearance and plasma half-disappearance time of D-TRP6 and exogenous luteinizing hormone-releasing hormone. J Clin Endocrinol Metab. 1982 Jun. 54(6):1169-73. [QxMD MEDLINE Link].
Bartley JA, Miller DK, Hayford JT, McCabe ER. Concordance of X-linked glycerol kinase deficiency with X-linked congenital adrenal hypoplasia. Lancet. 1982 Oct 2. 2(8301):733-6. [QxMD MEDLINE Link].
Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 1997 Aug. 82(8):2386-90. [QxMD MEDLINE Link].
Beighle C, Karp LE, Hanson JW, Hall JG, Hoehn H. Small structural changes of chromosome 8. Two cases with evidence for deletion. Hum Genet. 1977 Aug 31. 38(1):113-21. [QxMD MEDLINE Link].
Bovet P, Reymond MJ, Rey F, Gomez F. Lack of gonadotropic response to pulsatile gonadotropin-releasing hormone in isolated hypogonadotropic hypogonadism associated to congenital adrenal hypoplasia. J Endocrinol Invest. 1988 Mar. 11(3):201-4. [QxMD MEDLINE Link].
Boyar R, Perlow M, Hellman L, Kapen S, Weitzman E. Twenty-four hour pattern of luteinizing hormone secretion in normal men with sleep stage recording. J Clin Endocrinol Metab. 1972 Jul. 35(1):73-81. [QxMD MEDLINE Link].
Boyar RM, Rosenfeld RS, Kapen S, et al. Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest. 1974 Sep. 54(3):609-18. [QxMD MEDLINE Link].
Boyar RM, Wu RH, Kapen S, Hellman L, Weitzman ED, Finkelstein JW. Clinical and laboratory heterogeneity in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1976 Dec. 43(6):1268-75. [QxMD MEDLINE Link].
Brandenberger AW, Haenggi W, von Fischer B, Birkhaeuser MH. Kallmann syndrome and associated malformation of the uterus. Fertil Steril. 1994 Feb. 61(2):395-7. [QxMD MEDLINE Link].
Bridges NA, Matthews DR, Hindmarsh PC, Brook CG. Changes in gonadotrophin secretion during childhood and puberty. J Endocrinol. 1994 Apr. 141(1):169-76. [QxMD MEDLINE Link].
Brown DC, Stirling HF, Butler GE, Kelnar CJ, Wu FC. Differentiation of normal male prepuberty and hypogonadotrophic hypogonadism using an ultrasensitive luteinizing hormone assay. Horm Res. 1996. 46(2):83-7. [QxMD MEDLINE Link].
Calof AL, Chikaraishi DM. Analysis of neurogenesis in a mammalian neuroepithelium: proliferation and differentiation of an olfactory neuron precursor in vitro. Neuron. 1989 Jul. 3(1):115-27. [QxMD MEDLINE Link].
Cariboni A, Pimpinelli F, Colamarino S, et al. The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet. 2004 Nov 15. 13(22):2781-91. [QxMD MEDLINE Link].
Castellano JM, Navarro VM, Fernandez-Fernandez R, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005 Sep. 146(9):3917-25. [QxMD MEDLINE Link].
Castillo RH, Matteri RL, Dumesic DA. Luteinizing hormone synthesis in cultured fetal human pituitary cells exposed to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 1992 Jul. 75(1):318-22. [QxMD MEDLINE Link].
Clark SJ, Hauffa BP, Rodens KP, Styne DL, Kaplan SL, Grumbach MM. Hormone ontogeny in the ovine fetus: XIX: The effect of a potent luteinizing hormone-releasing factor agonist on gonadotropin and testosterone release in the fetus and neonate. Pediatr Res. 1989 Apr. 25(4):347-52. [QxMD MEDLINE Link].
Clement K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998 Mar 26. 392(6674):398-401. [QxMD MEDLINE Link].
Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogs. Annu Rev Med. 1994. 45:391-405. [QxMD MEDLINE Link].
Cortez AB, Galindo A, Arensman FW, Van Dop C. Congenital heart disease associated with sporadic Kallmann syndrome. Am J Med Genet. 1993 Jun 15. 46(5):551-4. [QxMD MEDLINE Link].
Crowley WF Jr, Filicori M, Spratt DI, Santoro NF. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res. 1985. 41:473-531. [QxMD MEDLINE Link].
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 Nov 27. 337(22):1597-602. [QxMD MEDLINE Link].
de Roux N, Young J, Misrahi M, Schaison G, Milgrom E. Loss of function mutations of the GnRH receptor: a new cause of hypogonadotropic hypogonadism. J Pediatr Endocrinol Metab. 1999 Apr. 12 Suppl 1:267-75. [QxMD MEDLINE Link].
de Zegher F, Lagae L, Declerck D, Vinckier F. Kallmann syndrome and delayed puberty associated with agenesis of lateral maxillary incisors. J Craniofac Genet Dev Biol. 1995 Apr-Jun. 15(2):87-9. [QxMD MEDLINE Link].
Dean JC, Johnston AW, Klopper AI. Isolated hypogonadotrophic hypogonadism: a family with autosomal dominant inheritance. Clin Endocrinol (Oxf). 1990 Mar. 32(3):341-7. [QxMD MEDLINE Link].
Drenth J, Low BW, Richardson JS. The toxin-agglutinin fold. A new group of small protein structures organized around a four-disulfide core. J Biol Chem. 1980 Apr 10. 255(7):2652-5. [QxMD MEDLINE Link].
Duke VM, Winyard PJ, Thorogood P, Soothill P, Bouloux PM, Woolf AS. KAL, a gene mutated in Kallmann's syndrome, is expressed in the first trimester of human development. Mol Cell Endocrinol. 1995 Apr 28. 110(1-2):73-9. [QxMD MEDLINE Link].
Dungan HM, Clifton DK, Steiner RA. Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology. 2006 Mar. 147(3):1154-8. [QxMD MEDLINE Link].
Edelman GM, Crossin KL. Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem. 1991. 60:155-90. [QxMD MEDLINE Link].
Elmquist JK. Anatomic basis of leptin action in the hypothalamus. Front Horm Res. 2000. 26:21-41. [QxMD MEDLINE Link].
Evans WS, Sollenberger MJ, Booth RA Jr. Contemporary aspects of discrete peak-detection algorithms. II. The paradigm of the luteinizing hormone pulse signal in women. Endocr Rev. 1992 Feb. 13(1):81-104. [QxMD MEDLINE Link].
Fernald RD, White RB. Gonadotropin-releasing hormone genes: phylogeny, structure, and functions. Front Neuroendocrinol. 1999 Jul. 20(3):224-40. [QxMD MEDLINE Link].
Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 1984 Jun. 73(6):1638-47. [QxMD MEDLINE Link].
Finkelstein JS, Klibanski A, Neer RM. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med. 1987 Mar. 106(3):354-61. [QxMD MEDLINE Link].
Finkelstein JS, Klibanski A, Neer RM, et al. Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1989 Oct. 69(4):776-83. [QxMD MEDLINE Link].
Flanagan CA, Millar RP, Illing N. Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions. Rev Reprod. 1997 May. 2(2):113-20. [QxMD MEDLINE Link].

Media Gallery

Human GPR54 receptor model. Mutations identified in patients with idiopathic hypogonadotropic hypogonadism are indicated.
KiSS-1 protein product model. Amino acids 1-19 are predicted to form a signal peptide. Proteolytic processing is predicted to produce kisspeptin-54, corresponding to amino acids 68-121. Shown is the C-terminal amidated decapeptide sequence, wherein biologic actively resides.

of 2

Author

Vaishali Popat, MD, MPH Clinical Investigator, Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Vaishali Popat, MD, MPH is a member of the following medical societies: American College of Physicians, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Karim Anton Calis, PharmD, MPH, FASHP, FCCP Clinical Professor, Medical College of Virginia, Virginia Commonwealth University School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy; Director of Clinical Research and Compliance, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Karim Anton Calis, PharmD, MPH, FASHP, FCCP is a member of the following medical societies: American College of Clinical Pharmacy, American Society of Health-System Pharmacists, Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Richard Scott Lucidi, MD, FACOG Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Richard Scott Lucidi, MD, FACOG is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Bruce A Meyer, MD, MBA Executive Vice President for Health System Affairs, Executive Director, Faculty Practice Plan, Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School

Bruce A Meyer, MD, MBA is a member of the following medical societies: Medical Group Management Association, American College of Obstetricians and Gynecologists, American Association for Physician Leadership, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Ziad Rafic Hubayter, MD, MPH, MBA Assistant Professor of Obstetrics and Gynecology, Division of Fertility and IVF, GW Medical Faculty Associates, George Washington University School of Medicine and Health Sciences

Ziad Rafic Hubayter, MD, MPH, MBA is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, American Society for Reproductive Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors James N Anasti, MD and Michael Cackovic, MD to the development and writing of this article.

Sections Gonadotropin-Releasing Hormone Deficiency in Adults
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