Details of Disease

Disease Name

Hypogonadotropic hypogonadism

hypogonadotropism; isolated hypogonadotropic hypogonadism; isolated congenital gonadotropin deficiency; congenital idiopathic hypogonadotropic hypogonadism; central hypogonadism; normosmic congenital hypogonadotropic hypogonadism; secondary hypogonadism; hypogonadotropic hypogonadism; hypogonadism, hypogonadotropic; hypogonadotropic hypogonadism with or without anosmia; Normosmic idiopathic hypogonadotropic hypogonadism; low gonadotropins (secondary hypogonadism); nIHH; gonadotropic deficiency

Definition

Abnormal ovarian or testicular function due to insufficient hormonal stimulation from the hypothalamic-pituitary axis.

Disease Hierarchy

DISYKSRF: Genetic disease

DISICMNI: Hypogonadism

DIS8JSKR: Hypogonadotropic hypogonadism

Disease Identifiers

MONDO ID

MONDO_0018555

UMLS CUI

C0271623

MedGen ID

82883

HPO ID

HP:0000044

Orphanet ID

432

SNOMED CT ID

33927004

General Information of Disease (ID: DIS8JSKR)

Drug-Interaction Atlas (DIA) of This Disease

Drug-Interaction Atlas (DIA)

This Disease is Treated as An Indication in 3 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Clomifene	DMKI7RB	Approved	Small molecular drug	[1]
Methyltestosterone	DMWLFGO	Approved	Small molecular drug	[2]
Testosterone	DM7HUNW	Approved	Small molecular drug	[3]
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Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 32 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
WDR11	OT5CY5UR	Supportive	Autosomal dominant	[4]
ANOS1	OTZJT4KN	Limited	Biomarker	[38]
CCDC141	OTQ9HA3I	Limited	Autosomal dominant	[39]
CHD7	OTHNIZWZ	Supportive	Autosomal dominant	[40]
DUSP6	OT4H6RKW	Supportive	Autosomal dominant	[41]
FGF17	OTAQSFZ2	Supportive	Autosomal dominant	[41]
FGF8	OTFU0IUW	Supportive	Autosomal dominant	[9]
FGFR1	OT4GLCXW	Supportive	Autosomal dominant	[10]
GNRH1	OTH8A44K	Supportive	Autosomal dominant	[11]
GNRHR	OTLE25K3	Supportive	Autosomal dominant	[12]
HS6ST1	OTABV7D2	Supportive	Autosomal dominant	[42]
KISS1	OT6IE3K2	Supportive	Autosomal dominant	[13]
KISS1R	OTQA3J6G	Supportive	Autosomal dominant	[14]
NSMF	OTLTA24A	Supportive	Autosomal dominant	[43]
PROK2	OT70IFEZ	Supportive	Autosomal dominant	[44]
PROKR2	OT51C69M	Supportive	Autosomal dominant	[15]
SPRY4	OT2VK9N0	Supportive	Autosomal dominant	[41]
TAC3	OTOJGM38	Supportive	Autosomal dominant	[16]
TACR3	OT7Q68XE	Supportive	Autosomal dominant	[16]
PROP1	OT8GF6N8	moderate	Genetic Variation	[45]
CSHL1	OTQKU2F5	Strong	Biomarker	[46]
GGN	OTKPYNWP	Strong	Biomarker	[5]
GHRH	OT94U6MO	Strong	Biomarker	[47]
GK	OTK2YRA0	Strong	Genetic Variation	[48]
IGSF10	OTB9QOGO	Strong	Genetic Variation	[49]
NDN	OTYBYJ82	Strong	Biomarker	[50]
NEUROG3	OT6DIPWC	Strong	Biomarker	[51]
NR5A1	OTOULYR4	Strong	Altered Expression	[52]
POLD1	OTWO4UCJ	Strong	Biomarker	[53]
RNF216	OTR1XEZ3	Strong	Biomarker	[54]
SERPINA4	OTBK0GG7	Strong	Genetic Variation	[55]
SRY	OT516T6D	Strong	Biomarker	[56]
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⏷ Show the Full List of 32 DOT(s)

This Disease Is Related to 31 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
BRD2	TTDP48B	Limited	Biomarker	[5]
GH1	TTT3YKH	Limited	Biomarker	[6]
PROKR2	TTM67AX	Limited	Genetic Variation	[7]
SOX2	TTCNOT6	Limited	Biomarker	[8]
FGF8	TTIUF3J	Supportive	Autosomal dominant	[9]
FGFR1	TTRLW2X	Supportive	Autosomal dominant	[10]
GNRH1	TT0ID4A	Supportive	Autosomal dominant	[11]
GNRHR	TT8R70G	Supportive	Autosomal dominant	[12]
KISS1	TTU2O6T	Supportive	Autosomal dominant	[13]
KISS1R	TT3KBZY	Supportive	Autosomal dominant	[14]
PROKR2	TTM67AX	Supportive	Autosomal dominant	[15]
TACR3	TTBPGLU	Supportive	Autosomal dominant	[16]
CGB3	TTUH273	moderate	Therapeutic	[17]
FGF8	TTIUF3J	moderate	Biomarker	[18]
TACR3	TTBPGLU	moderate	Biomarker	[19]
AXL	TTZPY6J	Strong	Genetic Variation	[20]
CPE	TTXPWO6	Strong	Genetic Variation	[21]
CYP17A1	TTRA5BZ	Strong	Biomarker	[22]
CYP19A1	TTSZLWK	Strong	Altered Expression	[23]
ESRRB	TTKF0XS	Strong	Genetic Variation	[24]
FGF10	TTNPEFX	Strong	Altered Expression	[25]
FSHB	TT13GFV	Strong	Therapeutic	[26]
GJB2	TTRGZX3	Strong	Genetic Variation	[27]
GNRH1	TT0ID4A	Strong	Biomarker	[28]
KISS1	TTU2O6T	Strong	Genetic Variation	[29]
LEP	TTBJEZ5	Strong	Altered Expression	[30]
LEPR	TT0HD6V	Strong	Genetic Variation	[31]
PNPLA6	TTWAQU2	Strong	Genetic Variation	[32]
SEMA3A	TTVKD3S	Strong	Altered Expression	[33]
TYMP	TTO0IB8	Strong	Genetic Variation	[34]
PRL	TTJ2TSA	Definitive	Altered Expression	[35]
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⏷ Show the Full List of 31 DTT(s)

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC29A3	DTZAWTH	moderate	Biomarker	[36]
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This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
ADH5	DEIOH6A	Strong	Biomarker	[37]
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References

1	[Stimulation of spermatogenesis: For whom? Why? How?]. Gynecol Obstet Fertil. 2016 Sep;44(9):505-16.
2	Methyltestosterone FDA Label
3	Testosterone FDA Label
4	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. doi: 10.1016/j.ajhg.2010.08.018.
5	Possible role of androgen receptor gene in therapeutic response of infertile men with hypogonadotropic hypogonadism.Syst Biol Reprod Med. 2019 Aug;65(4):326-332. doi: 10.1080/19396368.2019.1590478. Epub 2019 Apr 28.
6	The paradox of marrow adipose tissue in anorexia nervosa.Bone. 2019 Jan;118:47-52. doi: 10.1016/j.bone.2018.02.013. Epub 2018 Feb 16.
7	Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways.J Clin Endocrinol Metab. 2014 Mar;99(3):E458-63. doi: 10.1210/jc.2013-2431. Epub 2013 Nov 25.
8	SOX 2 Expression in Human Pituitary Adenomas-Correlations With Pituitary Function.In Vivo. 2019 Jan-Feb;33(1):79-83. doi: 10.21873/invivo.11442.
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12	Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure. Mol Endocrinol. 2012 Nov;26(11):1847-56. doi: 10.1210/me.2012-1072. Epub 2012 Aug 23.
13	Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012 Feb 16;366(7):629-35. doi: 10.1056/NEJMoa1111184.
14	A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab. 2011 Mar;96(3):E536-45. doi: 10.1210/jc.2010-1676. Epub 2010 Dec 30.
15	Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008 Oct;93(10):4113-8. doi: 10.1210/jc.2008-0958. Epub 2008 Aug 5.
16	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):354-358. doi: 10.1038/ng.306. Epub 2008 Dec 11.
17	Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy.J Urol. 1997 Nov;158(5):1764-7. doi: 10.1016/s0022-5347(01)64123-5.
18	Genotypic and phenotypic spectra of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.Fertil Steril. 2020 Jan;113(1):158-166. doi: 10.1016/j.fertnstert.2019.08.069. Epub 2019 Nov 17.
19	Genetics of Hypogonadotropic Hypogonadism.Endocr Dev. 2016;29:36-49. doi: 10.1159/000438841. Epub 2015 Dec 17.
20	Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism.J Clin Endocrinol Metab. 2014 Apr;99(4):1452-60. doi: 10.1210/jc.2013-3426. Epub 2014 Jan 29.
21	Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.PLoS One. 2015 Jun 29;10(6):e0131417. doi: 10.1371/journal.pone.0131417. eCollection 2015.
22	Partial 17alpha-hydroxylase/17,20-lyase deficiency-clinical report of five Chinese 46,XX cases. Gynecol Endocrinol. 2008 Jul;24(7):362-7. doi: 10.1080/09513590802194051.
23	Adult-onset hypogonadotropic hypogonadism caused by aberrant expression of aromatase in an adrenocortical adenocarcinoma.Endocr J. 2010;57(7):651-6. doi: 10.1507/endocrj.k10e-046. Epub 2010 May 13.
24	Partial defects in transcriptional activity of two novel DAX-1 mutations in childhood-onset adrenal hypoplasia congenita.Clin Endocrinol (Oxf). 2006 Nov;65(5):681-6. doi: 10.1111/j.1365-2265.2006.02649.x.
25	Molecular pathology of the fibroblast growth factor family.Hum Mutat. 2009 Sep;30(9):1245-55. doi: 10.1002/humu.21067.
26	Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2.FASEB J. 2014 Aug;28(8):3396-410. doi: 10.1096/fj.14-249532. Epub 2014 Apr 16.
27	Hypogonadotrophic hypogonadism associated with prelingual deafness due to a connexin 26 gene mutation.J Pediatr Endocrinol Metab. 2002 Feb;15(2):219-23. doi: 10.1515/jpem.2002.15.2.219.
28	GnRH-1 Neural Migration From the Nose to the Brain Is Independent From Slit2, Robo3 and NELL2 Signaling.Front Cell Neurosci. 2019 Mar 1;13:70. doi: 10.3389/fncel.2019.00070. eCollection 2019.
29	Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?.Cell Physiol Biochem. 2018;49(4):1259-1276. doi: 10.1159/000493406. Epub 2018 Sep 11.
30	Metabolic Disorders and Male Hypogonadotropic Hypogonadism.Front Endocrinol (Lausanne). 2019 Jul 25;10:345. doi: 10.3389/fendo.2019.00345. eCollection 2019.
31	Seven novel deleterious LEPR mutations found in early-onset obesity: a Exon6-8 shared by subjects from Reunion Island, France, suggests a founder effect.J Clin Endocrinol Metab. 2015 May;100(5):E757-66. doi: 10.1210/jc.2015-1036. Epub 2015 Mar 9.
32	A novel PNPLA6 compound heterozygous mutation identified in a Chinese patient with BoucherNeuhuser syndrome.Mol Med Rep. 2018 Jul;18(1):261-267. doi: 10.3892/mmr.2018.8955. Epub 2018 May 3.
33	Sema3a plays a role in the pathogenesis of CHARGE syndrome.Hum Mol Genet. 2018 Apr 15;27(8):1343-1352. doi: 10.1093/hmg/ddy045.
34	Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation.Eur J Neurol. 2007 May;14(5):581-5. doi: 10.1111/j.1468-1331.2007.01720.x.
35	Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism.Asian J Androl. 2019 Nov-Dec;21(6):623-627. doi: 10.4103/aja.aja_6_19.
36	Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease.PLoS Genet. 2010 Feb 5;6(2):e1000833. doi: 10.1371/journal.pgen.1000833.
37	S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism.J Sex Med. 2018 May;15(5):654-661. doi: 10.1016/j.jsxm.2018.03.002. Epub 2018 Mar 30.
38	Anosmin-1 over-expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb.Brain Struct Funct. 2016 Jan;221(1):239-60. doi: 10.1007/s00429-014-0904-8. Epub 2014 Oct 10.
39	Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
40	Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2008 Oct;83(4):511-9. doi: 10.1016/j.ajhg.2008.09.005. Epub 2008 Oct 2.
41	Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
42	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 Jul 12;108(28):11524-9. doi: 10.1073/pnas.1102284108. Epub 2011 Jun 23.
43	Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
44	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. doi: 10.1073/pnas.0707173104. Epub 2007 Oct 24.
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47	GH, but not GHRH, plays a role in the development of experimental autoimmune encephalomyelitis.Endocrinology. 2011 Oct;152(10):3803-10. doi: 10.1210/en.2011-1317. Epub 2011 Aug 16.
48	Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency.Eur J Pediatr. 1992 Mar;151(3):167-9. doi: 10.1007/BF01954375.
49	IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.EMBO Mol Med. 2016 Jun 1;8(6):626-42. doi: 10.15252/emmm.201606250. Print 2016 Jun.
50	Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism.Eur J Endocrinol. 2011 Jul;165(1):145-50. doi: 10.1530/EJE-11-0199. Epub 2011 May 4.
51	Hypogonadotropic Hypogonadism and Short Stature in Patients with Diabetes Due to Neurogenin 3 Deficiency.J Clin Endocrinol Metab. 2016 Oct;101(10):3555-3558. doi: 10.1210/jc.2016-2319. Epub 2016 Aug 17.
52	Identification of a pituitary ER-activated enhancer triggering the expression of Nr5a1, the earliest gonadotrope lineage-specific transcription factor.Epigenetics Chromatin. 2019 Aug 7;12(1):48. doi: 10.1186/s13072-019-0291-8.
53	An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet. 2013 Aug;45(8):947-50. doi: 10.1038/ng.2670. Epub 2013 Jun 16.
54	RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy.Front Endocrinol (Lausanne). 2019 Jan 24;10:12. doi: 10.3389/fendo.2019.00012. eCollection 2019.
55	Genetics of human hypogonadotropic hypogonadism.Am J Med Genet. 1999 Dec 29;89(4):240-8. doi: 10.1002/(sici)1096-8628(19991229)89:4<240::aid-ajmg8>3.0.co;2-7.
56	SOX2 regulates the hypothalamic-pituitary axis at multiple levels.J Clin Invest. 2012 Oct;122(10):3635-46. doi: 10.1172/JCI64311. Epub 2012 Sep 4.