KEGG   DISEASE: Hypogonadotropic hypogonadismHelp
Entry
H00255                      Disease                                

Name
Hypogonadotropic hypogonadism
  Subgroup
Kallmann syndrome (KAL)
Fertile eunuch syndrome (FEUNS) [DS:H01973]
  Supergrp
Male hypogonadism [DS:H02027]
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 IHH, 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
BRITE hierarchy
Pathway
hsa04912  GnRH signaling pathway
hsa04080  Neuroactive ligand-receptor interaction
hsa04810  Regulation of actin cytoskeleton
Gene
(HH1/KAL1) KAL1 [HSA:3730]
(HH2/KAL2) FGFR1 [HSA:2260] [KO:K04362]
(HH3/KAL3) PROKR2 [HSA:128674] [KO:K08380]
(HH4/KAL4) PROK2 [HSA:60675]
(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]
(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]
(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]
(HH23/FEUNS) LHB [HSA:3972] [KO:K08521]
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
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
Dode C, Hardelin JP
  Title
Kallmann syndrome.
  Journal
Eur J Hum Genet 17:139-46 (2009)
DOI:10.1038/ejhg.2008.206
Reference
  Authors
Trarbach EB, Silveira LG, Latronico AC
  Title
Genetic insights into human isolated gonadotropin deficiency.
  Journal
Pituitary 10:381-91 (2007)
DOI:10.1007/s11102-007-0061-7
Reference
  Authors
Karges B, de Roux N
  Title
Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome.
  Journal
Endocr Dev 8:67-80 (2005)
DOI:10.1159/000084094
Reference
PMID:11397842 (FEUNS)
  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
  Authors
Beate K, Joseph N, Nicolas de R, Wolfram K
  Title
Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes.
  Journal
Int J Endocrinol 2012:147893 (2012)
DOI:10.1155/2012/147893
Reference
  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
  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
  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
  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
  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
  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
  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
  Authors
Silveira LF, Latronico AC
  Title
Approach to the patient with hypogonadotropic hypogonadism.
  Journal
J Clin Endocrinol Metab 98:1781-8 (2013)
DOI:10.1210/jc.2012-3550
Reference
  Authors
Fraietta R, Zylberstejn DS, Esteves SC
  Title
Hypogonadotropic hypogonadism revisited.
  Journal
Clinics (Sao Paulo) 68 Suppl 1:81-8 (2013)
DOI:10.6061/clinics/2013(Sup01)09

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