KEGG   DISEASE: Hypogonadotropic hypogonadism
Entry
H00255                      Disease                                
Name
Hypogonadotropic hypogonadism
  Subgroup
Kallmann syndrome (KAL)
Fertile eunuch syndrome (FEUNS) [DS:H01973]
Isolated follicle-stimulating hormone deficiency (HH24/IFSHD)
  Supergrp
Hypopituitarism [DS:H01700]
Description
Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic gonadotropin releasing hormone (GnRH) secretion or failure of pituitary gonadotropin secretion. HH can be congenital or acquired. Congenital HH is clinically and genetically heterogeneous. Clinically, the disorder is characterized by an absence of puberty and infertility. The genetic condition is classically divided in 2 groups based on the presence or absence of olfaction dysfunction. Around 50-60% of the affected individuals exhibit anosmia or hyposmia in association with idiopathic HH, defining Kallmann syndrome. Acquired HH can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X.
Category
Endocrine disease
Brite
Human diseases [BR:br08402]
 Endocrine and metabolic diseases
  Hypothalamus and pituitary gland diseases
   H00255  Hypogonadotropic hypogonadism
Human diseases in ICD-11 classification [BR:br08403]
 05 Endocrine, nutritional or metabolic diseases
  Endocrine diseases
   Disorders of the pituitary hormone system
    5A61  Hypofunction or certain specified disorders of pituitary gland
     H00255  Hypogonadotropic hypogonadism
Related
pathway
hsa04929  GnRH secretion
hsa04912  GnRH signaling pathway
hsa04080  Neuroactive ligand-receptor interaction
hsa04810  Regulation of actin cytoskeleton
Network
nt06323  KISS1-GnRH-LH/FSH-E2 signaling
nt06361  Hypogonadotropic hypogonadism
Gene
(HH1/KAL1) ANOS1 [HSA:3730] [KO:K23413]
(HH2/KAL2) FGFR1 [HSA:2260] [KO:K04362]
(HH3/KAL3) PROKR2 [HSA:128674] [KO:K08380]
(HH4/KAL4) PROK2 [HSA:60675] [KO:K24191]
(HH5/KAL5) CHD7 [HSA:55636] [KO:K14437]
(HH6/KAL6) FGF8 [HSA:2253] [KO:K04358]
(HH7/FEUNS) GNRHR [HSA:2798] [KO:K04280]
(HH8) KISS1R [HSA:84634] [KO:K08374]
(HH9) NSMF [HSA:26012] [KO:K23844]
(HH10) TAC3 [HSA:6866] [KO:K05240]
(HH11) TACR3 [HSA:6870] [KO:K04224]
(HH12) GNRH1 [HSA:2796] [KO:K05252]
(HH13) KISS1 [HSA:3814] [KO:K23140]
(HH14) WDR11 [HSA:55717] [KO:K24260]
(HH15) HS6ST1 [HSA:9394] [KO:K02514]
(HH16) SEMA3A [HSA:10371] [KO:K06840]
(HH17) SPRY4 [HSA:81848] [KO:K17385]
(HH18) IL17RD [HSA:54756] [KO:K05167]
(HH19) DUSP6 [HSA:1848] [KO:K21946]
(HH20) FGF17 [HSA:8822] [KO:K04358]
(HH21) FLRT3 [HSA:23767] [KO:K16362]
(HH22) FEZF1 [HSA:389549] [KO:K24502]
(HH23/FEUNS) LHB [HSA:3972] [KO:K08521]
(HH24/IFSHD) FSHB [HSA:2488] [KO:K05250]
(HH25) NDNF [HSA:79625] [KO:K25687]
(HH26) TCF12 [HSA:6938] [KO:K15603]
(HH27) NHLH2 [HSA:4808] [KO:K09075]
Drug
Fluoxymesterone [DR:D00327]
Methyltestosterone [DR:D00408]
Testosterone [DR:D00075]
Testosterone cypionate [DR:D00957]
Testosterone enanthate [DR:D00958]
Testosterone undecanoate [DR:D06087]
Other DBs
ICD-11: 5A61.2
ICD-10: E23.0
MeSH: D007006 D017436 C537919
OMIM: 308700 147950 244200 610628 612370 612702 146110 614837 614838 614839 614840 614841 614842 228300 614858 614880 614897 615266 615267 615269 615270 615271 616030 618841 619718 619755
Reference
  Authors
Dode C, Hardelin JP
  Title
Kallmann syndrome.
  Journal
Eur J Hum Genet 17:139-46 (2009)
DOI:10.1038/ejhg.2008.206
Reference
  Authors
Hardelin JP, Dode C
  Title
The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.
  Journal
Sex Dev 2:181-93 (2008)
DOI:10.1159/000152034
Reference
  Authors
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J
  Title
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
  Journal
Nat Rev Endocrinol 11:547-64 (2015)
DOI:10.1038/nrendo.2015.112
Reference
PMID:1594017 (ANOS1)
  Authors
Bick D, Franco B, Sherins RJ, Heye B, Pike L, Crawford J, Maddalena A, Incerti B, Pragliola A, Meitinger T, Ballabio A
  Title
Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.
  Journal
N Engl J Med 326:1752-5 (1992)
DOI:10.1056/NEJM199206253262606
Reference
PMID:12627230 (FGFR1)
  Authors
Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP
  Title
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.
  Journal
Nat Genet 33:463-5 (2003)
DOI:10.1038/ng1122
Reference
PMID:17054399 (PROKR2 PROK2)
  Authors
Dode C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP
  Title
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.
  Journal
PLoS Genet 2:e175 (2006)
DOI:10.1371/journal.pgen.0020175
Reference
PMID:18834967 (CHD7)
  Authors
Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC
  Title
Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
  Journal
Am J Hum Genet 83:511-9 (2008)
DOI:10.1016/j.ajhg.2008.09.005
Reference
PMID:18596921 (FGF8)
  Authors
Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N
  Title
Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.
  Journal
J Clin Invest 118:2822-31 (2008)
DOI:10.1172/JCI34538
Reference
PMID:11397842 (GNRHR)
  Authors
Pitteloud N, Boepple PA, DeCruz S, Valkenburgh SB, Crowley WF Jr, Hayes FJ
  Title
The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor.
  Journal
J Clin Endocrinol Metab 86:2470-5 (2001)
DOI:10.1210/jcem.86.6.7542
Reference
PMID:14573733 (KISS1R)
  Authors
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH
  Title
The GPR54 gene as a regulator of puberty.
  Journal
N Engl J Med 349:1614-27 (2003)
DOI:10.1056/NEJMoa035322
Reference
PMID:15362570 (NSMF)
  Authors
Miura K, Acierno JS Jr, Seminara SB
  Title
Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH).
  Journal
J Hum Genet 49:265-8 (2004)
DOI:10.1007/s10038-004-0137-4
Reference
PMID:19079066 (TAC3 TACR3)
  Authors
Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK
  Title
TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.
  Journal
Nat Genet 41:354-8 (2009)
DOI:10.1038/ng.306
Reference
PMID:19535795 (GNRH1)
  Authors
Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombes M, Millar RP, Guiochon-Mantel A, Young J
  Title
Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.
  Journal
N Engl J Med 360:2742-8 (2009)
DOI:10.1056/NEJMoa0900136
Reference
PMID:22335740 (KISS1)
  Authors
Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B
  Title
Inactivating KISS1 mutation and hypogonadotropic hypogonadism.
  Journal
N Engl J Med 366:629-35 (2012)
DOI:10.1056/NEJMoa1111184
Reference
PMID:20887964 (WDR11)
  Authors
Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D, Rosenberger G, Ozata M, Bick DP, Sherins RJ, Nagase T, Tekin M, Kim SH, Kim CH, Ropers HH, Gusella JF, Kalscheuer V, Choi CY, Layman LC
  Title
WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
  Journal
Am J Hum Genet 87:465-79 (2010)
DOI:10.1016/j.ajhg.2010.08.018
Reference
PMID:21700882 (HS6ST1)
  Authors
Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, Van Uum S, Crowley WF, Habuchi H, Kimata K, Pitteloud N, Bulow HE
  Title
Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.
  Journal
Proc Natl Acad Sci U S A 108:11524-9 (2011)
DOI:10.1073/pnas.1102284108
Reference
PMID:22927827 (SEMA3A)
  Authors
Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, Collier F, Cruaud C, Meyer V, Garcia-Pinero A, Dewailly D, Cortet-Rudelli C, Gersak K, Metz C, Chabrier G, Pugeat M, Young J, Hardelin JP, Prevot V, Dode C
  Title
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
  Journal
PLoS Genet 8:e1002896 (2012)
DOI:10.1371/journal.pgen.1002896
Reference
PMID:23643382 (SPRY4 IL17RD DUSP6 FGF17 FLRT3)
  Authors
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N
  Title
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.
  Journal
Am J Hum Genet 92:725-43 (2013)
DOI:10.1016/j.ajhg.2013.04.008
Reference
PMID:25192046 (FEZF1)
  Authors
Kotan LD, Hutchins BI, Ozkan Y, Demirel F, Stoner H, Cheng PJ, Esen I, Gurbuz F, Bicakci YK, Mengen E, Yuksel B, Wray S, Topaloglu AK
  Title
Mutations in FEZF1 cause Kallmann syndrome.
  Journal
Am J Hum Genet 95:326-31 (2014)
DOI:10.1016/j.ajhg.2014.08.006
Reference
PMID:19129711 (LHB)
  Authors
Arnhold IJ, Lofrano-Porto A, Latronico AC
  Title
Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women.
  Journal
Horm Res 71:75-82 (2009)
DOI:10.1159/000183895
Reference
PMID:8220432 (FSHB)
  Authors
Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VK
  Title
Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone.
  Journal
Nat Genet 5:83-6 (1993)
DOI:10.1038/ng0993-83
Reference
PMID:31883645 (NDNF)
  Authors
Messina A, Pulli K, Santini S, Acierno J, Kansakoski J, Cassatella D, Xu C, Casoni F, Malone SA, Ternier G, Conte D, Sidis Y, Tommiska J, Vaaralahti K, Dwyer A, Gothilf Y, Merlo GR, Santoni F, Niederlander NJ, Giacobini P, Raivio T, Pitteloud N
  Title
Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.
  Journal
Am J Hum Genet 106:58-70 (2020)
DOI:10.1016/j.ajhg.2019.12.003
Reference
PMID:32620954 (TCF12)
  Authors
Davis EE, Balasubramanian R, Kupchinsky ZA, Keefe DL, Plummer L, Khan K, Meczekalski B, Heath KE, Lopez-Gonzalez V, Ballesta-Martinez MJ, Margabanthu G, Price S, Greening J, Brauner R, Valenzuela I, Cusco I, Fernandez-Alvarez P, Wierman ME, Li T, Lage K, Barroso PS, Chan YM, Crowley WF, Katsanis N
  Title
TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci.
  Journal
Hum Mol Genet 29:2435-2450 (2020)
DOI:10.1093/hmg/ddaa120
Reference
PMID:35066646 (NHLH2)
  Authors
Topaloglu AK, Simsek E, Kocher MA, Mammadova J, Bober E, Kotan LD, Turan I, Celiloglu C, Gurbuz F, Yuksel B, Good DJ
  Title
Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.
  Journal
Hum Genet 141:295-304 (2022)
DOI:10.1007/s00439-021-02422-9
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