Details of Disease

General Information of Disease (ID: DISICMNI)

• Disease Name: Hypogonadism
• Synonyms: hypogonadotropism; gonadotropin deficiency
• Disease Class: 5A60-5A61: Pituitary gland disorder
• Definition: A disorder characterized by decreased function of the gonads. Clinical manifestations in both males and females include poor libido, infertility, and osteoporosis. Additional signs in males include erectile dysfunction, muscle atrophy, gynecomastia and increased abdominal fat. In females, additional signs include shrinking of the breasts and loss of, or failure to develop menstruation.
• Disease Hierarchy:
  DIS4HEW4: Gonadal disorder
  DISICMNI: Hypogonadism
• ICD Code:
  ICD-11: ICD-11: 5A61.0
  ICD-9: ICD-9: 257.2
  Expand ICD-9: 257.2
• Disease Identifiers:
  MONDO ID: MONDO_0002146
  MESH ID: D007006
  UMLS CUI: C0020619
  MedGen ID: 5711
  HPO ID: HP:0000135
  SNOMED CT ID: 48130008

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 4 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Estropipate	DMRMDWA	Approved	Small molecular drug	[1]
Methyltestosterone	DMWLFGO	Approved	Small molecular drug	[2]
Testosterone	DM7HUNW	Approved	Small molecular drug	[3]
Testosterone undecanoate	DMZO10Y	Approved	Small molecular drug	[1]

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Testogen TDS	DMMK6IT	Phase 2	NA	[4]

This Disease is Treated as An Indication in 1 Discontinued Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Testosterone glucoside	DM5O6HM	Discontinued in Phase 2	NA	[5]

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
FOXO4-DRI	DMBZVYG	Preclinical	Peptide	[6]

This Disease is Treated as An Indication in 1 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Testetrol	DMQDVNZ	Investigative	NA	[7]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 31 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
LEPR	TT0HD6V	Limited	Biomarker	[8]
PRL	TTJ2TSA	Limited	Altered Expression	[9]
DMPK	TTZQTY2	Disputed	Altered Expression	[10]
STS	TTHM0R1	Disputed	Genetic Variation	[11]
CGB3	TTUH273	moderate	Therapeutic	[12]
CTNS	TT1W2ZS	moderate	Genetic Variation	[13]
CYP19A1	TTSZLWK	moderate	Biomarker	[14]
GH1	TTT3YKH	moderate	Biomarker	[15]
GNRH1	TT0ID4A	moderate	Biomarker	[16]
SGPL1	TT618Q2	moderate	Biomarker	[17]
CYP11A1	TTSYVO6	Strong	Biomarker	[18]
CYP17A1	TTRA5BZ	Strong	Biomarker	[19]
EDN1	TTJR60Z	Strong	Biomarker	[18]
EPHB6	TTZEMUY	Strong	Genetic Variation	[20]
FGF8	TTIUF3J	Strong	Biomarker	[21]
FSHB	TT13GFV	Strong	Therapeutic	[22]
FSHR	TTZFDBT	Strong	Biomarker	[23]
GABRG3	TTEX6LM	Strong	Biomarker	[24]
GNRHR	TT8R70G	Strong	Genetic Variation	[25]
HAMP	TTRV5YJ	Strong	Genetic Variation	[26]
KISS1R	TT3KBZY	Strong	Biomarker	[27]
LEP	TTBJEZ5	Strong	Biomarker	[28]
NR0B1	TTTK36V	Strong	Biomarker	[29]
OTC	TT5KIO9	Strong	Biomarker	[30]
PNPLA6	TTWAQU2	Strong	Genetic Variation	[31]
POLA1	TTGPJ0U	Strong	Genetic Variation	[32]
PRKG1	TT7IZSA	Strong	Biomarker	[33]
PROKR2	TTM67AX	Strong	Genetic Variation	[34]
STAR	TTEI40H	Strong	Biomarker	[18]
TACR3	TTBPGLU	Strong	Genetic Variation	[25]
BRD2	TTDP48B	Definitive	Biomarker	[35]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC20A1	DTMULXV	Strong	Biomarker	[36]
SLC29A3	DTZAWTH	Strong	Genetic Variation	[37]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
HSD3B1	DERDQWN	Strong	Biomarker	[18]

This Disease Is Related to 31 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
SOHLH1	OT3RBLSK	Limited	Autosomal recessive	[38]
HJV	OT4235J2	Disputed	Biomarker	[26]
CHD7	OTHNIZWZ	Strong	Genetic Variation	[39]
CRYM	OTRGSR6B	Strong	Biomarker	[40]
DCAF17	OTFNVJLN	Strong	Genetic Variation	[41]
EFNB1	OT7JJW8P	Strong	Genetic Variation	[20]
EFNB3	OT12WTXQ	Strong	Genetic Variation	[20]
EIF2S3	OTARRES9	Strong	Biomarker	[42]
GK	OTK2YRA0	Strong	Biomarker	[30]
INHA	OT7HWCO3	Strong	Biomarker	[43]
INHBB	OT2QLD11	Strong	Biomarker	[43]
INSL3	OT7KUNTE	Strong	Biomarker	[44]
MMACHC	OTX0TT3W	Strong	Genetic Variation	[45]
NHLH2	OT88N84O	Strong	Biomarker	[46]
NMT2	OTLNA39Z	Strong	Genetic Variation	[47]
NSMF	OTLTA24A	Strong	Genetic Variation	[48]
OTUD4	OT7U62SW	Strong	Biomarker	[49]
POLD1	OTWO4UCJ	Strong	Biomarker	[50]
POU1F1	OTXT8A5C	Strong	Biomarker	[36]
PROK2	OT70IFEZ	Strong	Genetic Variation	[51]
PROP1	OT8GF6N8	Strong	Genetic Variation	[52]
RAB3GAP1	OT4DQ8F2	Strong	Biomarker	[40]
SERPINA4	OTBK0GG7	Strong	Genetic Variation	[53]
SETX	OTG3JNOQ	Strong	Biomarker	[54]
SIX6	OTD1RD9D	Strong	Genetic Variation	[55]
STUB1	OTSUYI9A	Strong	Genetic Variation	[56]
TAC3	OTOJGM38	Strong	Biomarker	[57]
TSPY1	OTPY57X4	Strong	Biomarker	[24]
AMH	OT5FH4BD	Definitive	Biomarker	[58]
ANOS1	OTZJT4KN	Definitive	Genetic Variation	[48]
LHB	OT5GBOVJ	Definitive	Genetic Variation	[59]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] Methyltestosterone FDA Label
• [3] Testosterone FDA Label
• [4] ClinicalTrials.gov (NCT01894308) A Dose Ranging Study to Examine Testagen TDS-Testosterone 5%. U.S. National Institutes of Health.
• [5] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018266)
• [6] FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY). 2020 Jan 20;12(2):1272-1284.
• [7] Estetrol review: profile and potential clinical applications. Climacteric. 2008;11 Suppl 1:47-58.
• [8] Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.N Engl J Med. 2007 Jan 18;356(3):237-47. doi: 10.1056/NEJMoa063988.
• [9] Rare case of meningococcal sepsis-induced testicular failure, primary hypothyroidism and hypoadrenalism: Is there a link?.BMJ Case Rep. 2018 Sep 15;2018:bcr2018224437. doi: 10.1136/bcr-2018-224437.
• [10] The pleiotropic expression of the myotonic dystrophy protein kinase gene illustrates the complex relationships between genetic, biological and clinical covariates of male aging.Aging Male. 2002 Dec;5(4):223-32.
• [11] Ichthyosis and hypogonadism in two brothers with deletion of the short arm of the X chromosome.Horm Res. 1988;30(4-5):173-6; discussion 177. doi: 10.1159/000181056.
• [12] 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.
• [13] Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy.Ann Intern Med. 2007 Aug 21;147(4):242-50. doi: 10.7326/0003-4819-147-4-200708210-00006.
• [14] Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?.Andrology. 2020 Nov;8(6):1590-1597. doi: 10.1111/andr.12725. Epub 2019 Dec 2.
• [15] Frontiers in hormone therapy for male infertility.Transl Androl Urol. 2018 Jul;7(Suppl 3):S353-S366. doi: 10.21037/tau.2018.04.03.
• [16] Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome.Front Cell Dev Biol. 2019 Jul 11;7:121. doi: 10.3389/fcell.2019.00121. eCollection 2019.
• [17] Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat. 2017 Apr;38(4):365-372. doi: 10.1002/humu.23192. Epub 2017 Mar 6.
• [18] Strontium fructose 1,6-diphosphate rescues adenine-induced male hypogonadism and upregulates the testicular endothelin-1 system.Clin Exp Pharmacol Physiol. 2007 Nov;34(11):1131-7. doi: 10.1111/j.1440-1681.2007.04693.x.
• [19] 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.
• [20] Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism.Sci Rep. 2018 Sep 27;8(1):14497. doi: 10.1038/s41598-018-32836-x.
• [21] De novo frameshift mutation in fibroblast growth factor 8 in a male patient with gonadotropin deficiency.Horm Res Paediatr. 2014;81(2):139-44. doi: 10.1159/000355380. Epub 2013 Nov 20.
• [22] 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.
• [23] FSH directly regulates bone mass.Cell. 2006 Apr 21;125(2):247-60. doi: 10.1016/j.cell.2006.01.051.
• [24] Characterization of breakpoints in the GABRG3 and TSPY genes in a family with a t(Y;15)(p11.2;q12).Am J Med Genet A. 2004 Mar 1;125A(2):177-80. doi: 10.1002/ajmg.a.20482.
• [25] GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency.PLoS One. 2017 Nov 28;12(11):e0188750. doi: 10.1371/journal.pone.0188750. eCollection 2017.
• [26] Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease.Blood. 2018 Jul 5;132(1):101-110. doi: 10.1182/blood-2018-02-830562. Epub 2018 May 9.
• [27] Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype.Mol Cell Endocrinol. 2019 Dec 1;498:110559. doi: 10.1016/j.mce.2019.110559. Epub 2019 Aug 20.
• [28] Visceral Adipose Tissue and Leptin Hyperproduction Are Associated With Hypogonadism in Men With Chronic Kidney Disease.J Ren Nutr. 2017 Jul;27(4):243-248. doi: 10.1053/j.jrn.2017.01.023. Epub 2017 Mar 31.
• [29] Identification of a novel mutation of NR0B1 in a patient with X-linked adrenal hypoplasia and symptomatic treatment.J Pediatr Endocrinol Metab. 2017 Nov 27;30(12):1299-1304. doi: 10.1515/jpem-2017-0237.
• [30] Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.Am J Med Genet. 1988 Nov;31(3):603-16. doi: 10.1002/ajmg.1320310315.
• [31] Compound heterozygous PNPLA6 mutations cause Boucher-Neuhuser syndrome with late-onset ataxia.J Neurol. 2014 Dec;261(12):2411-23. doi: 10.1007/s00415-014-7516-3. Epub 2014 Sep 30.
• [32] Defective DNA Polymerase -Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism. Am J Hum Genet. 2019 May 2;104(5):957-967. doi: 10.1016/j.ajhg.2019.03.006. Epub 2019 Apr 18.
• [33] Testosterone-induced modulation of nitric oxide-cGMP signaling pathway and androgenesis in the rat Leydig cells.Biol Reprod. 2010 Sep;83(3):434-42. doi: 10.1095/biolreprod.110.083626. Epub 2010 May 12.
• [34] PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption.J Clin Endocrinol Metab. 2012 Jun;97(6):E1068-73. doi: 10.1210/jc.2011-3056. Epub 2012 Mar 30.
• [35] Approach to the infertile man.J Clin Endocrinol Metab. 2007 Jun;92(6):1995-2004. doi: 10.1210/jc.2007-0634.
• [36] Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.J Clin Endocrinol Metab. 1999 Jan;84(1):50-7. doi: 10.1210/jcem.84.1.5366.
• [37] 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.
• [38] 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.
• [39] Expanding the CHARGE Geno-Phenotype: A Girl with Novel CHD7 Deletion, Hypogonadotropic Hypogonadism, and Agenesis of Uterus and Ovaries.Horm Res Paediatr. 2016;85(4):288-90. doi: 10.1159/000443308. Epub 2016 Jan 8.
• [40] Gene screening facilitates diagnosis of complicated symptoms: A case report.Mol Med Rep. 2017 Dec;16(6):7915-7922. doi: 10.3892/mmr.2017.7590. Epub 2017 Sep 22.
• [41] A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature.J Pediatr Endocrinol Metab. 2019 Nov 26;32(11):1287-1293. doi: 10.1515/jpem-2019-0173.
• [42] EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. Hum Mutat. 2017 Apr;38(4):409-425. doi: 10.1002/humu.23170. Epub 2017 Jan 23.
• [43] Relationship of estradiol and inhibin to the follicle-stimulating hormone variability in hypergonadotropic hypogonadism or premature ovarian failure.J Clin Endocrinol Metab. 2005 Feb;90(2):826-30. doi: 10.1210/jc.2004-1319. Epub 2004 Nov 23.
• [44] Biology of insulin-like factor 3 in human reproduction.Hum Reprod Update. 2009 Jul-Aug;15(4):463-76. doi: 10.1093/humupd/dmp011. Epub 2009 Mar 28.
• [45] MMACHC gene mutation in familial hypogonadism with neurological symptoms.Gene. 2015 Dec 15;574(2):380-4. doi: 10.1016/j.gene.2015.08.029. Epub 2015 Aug 14.
• [46] Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome.J Clin Invest. 2017 Jan 3;127(1):293-305. doi: 10.1172/JCI88648. Epub 2016 Dec 12.
• [47] Is the disruption of an N-myristoyltransferase (NMT2) associated with hypoplastic testes?.Am J Med Genet A. 2007 Aug 1;143A(15):1796-8. doi: 10.1002/ajmg.a.31799.
• [48] The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.Mol Hum Reprod. 2008 Jun;14(6):367-70. doi: 10.1093/molehr/gan027. Epub 2008 May 7.
• [49] STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.Orphanet J Rare Dis. 2014 Sep 26;9:146. doi: 10.1186/s13023-014-0146-0.
• [50] 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.
• [51] 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 Sep;93(9):3551-9. doi: 10.1210/jc.2007-2654. Epub 2008 Jun 17.
• [52] An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.J Clin Endocrinol Metab. 2005 Aug;90(8):4880-7. doi: 10.1210/jc.2005-0119. Epub 2005 Jun 7.
• [53] Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene.Am J Med Genet. 1995 Jul 3;57(3):476-8. doi: 10.1002/ajmg.1320570323.
• [54] Germ cell arrest associated with aSETX mutation in ataxia oculomotor apraxia type 2.Reprod Biomed Online. 2019 Jun;38(6):961-965. doi: 10.1016/j.rbmo.2018.12.042. Epub 2019 Jan 9.
• [55] Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility.Endocrinology. 2019 Sep 1;160(9):2151-2164. doi: 10.1210/en.2019-00113.
• [56] STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.Orphanet J Rare Dis. 2017 Feb 13;12(1):31. doi: 10.1186/s13023-017-0580-x.
• [57] 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.
• [58] Correlation of anti-Mullerian hormone with humanchorionic gonadotropin test in the evaluation of testicular function of children with 46 XY male hypogonadism: Use of anti-Mullerian hormone as abiomarker.J Paediatr Child Health. 2020 Mar;56(3):411-419. doi: 10.1111/jpc.14643. Epub 2019 Oct 15.
• [59] Homozygous nonsense mutation Trp28X in the LHB gene causes male hypogonadism.J Assist Reprod Genet. 2018 May;35(5):913-919. doi: 10.1007/s10815-018-1133-5. Epub 2018 Feb 23.