LHB

Summary

LHB (luteinizing hormone subunit beta, HGNC:6584) is a protein-coding gene on chromosome 19q13.33, encoding Lutropin subunit beta (P01229). Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.

This gene is a member of the glycoprotein hormone beta chain family and encodes the beta subunit of luteinizing hormone (LH). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. LH is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids. The genes for the beta chains of chorionic gonadotropin and for luteinizing hormone are contiguous on chromosome 19q13.3. Mutations in this gene are associated with hypogonadism which is characterized by infertility and pseudohermaphroditism.

Source: NCBI Gene 3972 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 23 with or without anosmia (Strong, GenCC)
• Clinical variants (ClinVar): 94 total — 6 pathogenic
• Phenotypes (HPO): 22
• MANE Select transcript: NM_000894

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6584
Approved symbol	LHB
Name	luteinizing hormone subunit beta
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	LSH-B, CGB4, hLHB
Ensembl gene	ENSG00000104826
Ensembl biotype	protein_coding
OMIM	152780
Entrez	3972

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000649238, ENST00000649284

RefSeq mRNA: 1 — MANE Select: NM_000894 NM_000894

CCDS: CCDS12748

Canonical transcript exons

ENST00000649238 — 3 exons

Exon	Start	End
ENSE00001129751	49015980	49016310
ENSE00002495450	49016547	49016714
ENSE00003836811	49017067	49017091

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 99.81.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2726 / max 399.6614, expressed in 7 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181980	0.2347	5
181979	0.0378	5

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	99.81	gold quality
pituitary gland	UBERON:0000007	99.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.70	gold quality
pancreatic ductal cell	CL:0002079	89.36	silver quality
triceps brachii	UBERON:0001509	85.48	gold quality
gluteal muscle	UBERON:0002000	84.44	gold quality
parotid gland	UBERON:0001831	83.00	gold quality
buccal mucosa cell	CL:0002336	82.85	silver quality
body of pancreas	UBERON:0001150	78.94	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.72	gold quality
heart right ventricle	UBERON:0002080	77.66	gold quality
inferior olivary complex	UBERON:0002127	77.15	gold quality
endothelial cell	CL:0000115	76.91	silver quality
tendon of biceps brachii	UBERON:0008188	76.77	gold quality
tongue squamous epithelium	UBERON:0006919	75.10	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	74.27	gold quality
type B pancreatic cell	CL:0000169	72.19	gold quality
nasal cavity epithelium	UBERON:0005384	71.90	gold quality
left testis	UBERON:0004533	71.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	71.71	gold quality
cervix squamous epithelium	UBERON:0006922	71.36	gold quality
placenta	UBERON:0001987	71.30	gold quality
right testis	UBERON:0004534	71.20	gold quality
biceps brachii	UBERON:0001507	71.12	gold quality
olfactory bulb	UBERON:0002264	71.12	gold quality
deltoid	UBERON:0001476	70.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	70.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.27	gold quality
layer of synovial tissue	UBERON:0007616	69.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AR, CREBBP, CREM, DNMT1, EGR1, ESR1, FOS, FOXO1, HESX1, ISL1, JUN, KLF13, LHX3, MSX1, NR0B1, NR2F1, NR2F2, NR4A1, NR5A1, NR5A2, PGR, PITX1, PITX2, POU1F1, PRDM2, PROP1, SF1, SMAD3, SP1, SP3, TXK, YBX3

Literature-anchored findings (GeneRIF, showing 39)

• relationship between endometriosis and a variant of the beta-subunit of luteinizing hormone (PMID:12042273)
• findings demonstrate that Gly(102)Ser mutation of the LHbeta gene does not affect receptor binding and bioactivity of the hormone, when tested in vitro (PMID:12356936)
• Results suggest that a single nucleotide polymorphism alters the post-translational modification of luteinizing hormone beta and hence its structural phenotype. (PMID:12683946)
• MIP-2A (MBP-1 interacting protein-2A) preferentially expresses in certain tissues, including the pituitary gland, and negatively regulates the LHbeta gene transcription (PMID:12700240)
• genetically determined variation in LH function might affect susceptibility to prostate cancer via altered testosterone secretion. (PMID:12746844)
• pituitary exit of LH and FSH occur via different secretion pathways, and are released spatially from the pituitary via different circulatory routes. (PMID:14585810)
• LH modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition (PMID:14871891)
• LHbeta-null mice are viable but demonstrate postnatal defects in gonadal growth and function resulting in infertility. (PMID:15569941)
• The tight linkage between the two missense substitutions in the coding region and the eight nucleotide substitutions in the promoter region of LHB appears to be common to various ethnic groups. (PMID:16410673)
• homozygous mutation of a 5’ splice site in LHB: IVS2+1G–>C disrupts the splicing of messenger RNA, generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone (PMID:17761593)
• GnRH stimulation of signaling pathway for annexin A5 mRNA expression is distinct from that of LHbeta mRNA and dependent more on MAPK. (PMID:18703851)
• Progesterone feedback at the level of the pituitary gonadotrope is likely to play a key role in differential production of the gonadotropin genes. (PMID:19106225)
• Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. (PMID:19129711)
• v-betaLH is more frequent in women with ovarian resistance to rhFSH. (PMID:19146763)
• Variant LH remains longer in circulation than wild type during GnRH receptor blockade in heterozygous women, in accord with its higher content of sialic acid. (PMID:19890021)
• Both normal-weight and overweight women with classic PCOS phenotypes present higher LH levels and LH-to-FSH ratios than women with similar BMI but the newer phenotypes. (PMID:21353371)
• A dileucine determinant in the carboxyl terminal sequence of the luteinizing hormone beta subunit is implicated in the regulated secretion of lutropin (PMID:21458524)
• the presence of LHbeta G1502A and ERbeta G+1730A polymorphisms is associated with infertility and endometriosis associated infertility.When two polymorphisms are present it does not appear to increase the chance of developing endometriosis or infertility. (PMID:21764500)
• Polymorphisms of Trp8Arg and Ile15Thr in the LH-beta subunit gene occur in infertile women. (PMID:22108961)
• We identified seven SNPs in the LH beta gene; one SNP in exon 3 (rs#1056917) exhibited significant difference in the allele frequency between the PCOS cases and controls (PMID:22209983)
• Results suggested LH G1052A mutation might influence polycystic ovary syndrome susceptibility and phenotypes. (PMID:22546001)
• FOXO1 transcription factor inhibits luteinizing hormone beta gene expression in pituitary gonadotrope cells (PMID:22865884)
• Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. (PMID:23015653)
• Both estradiol and progesterone uniquely modulate basal and GnRH-stimulated gonadotropin promoters without affecting cell growth. (PMID:23160221)
• the frequency of v-betaLH in Denmark is similar to a number of European countries (PMID:23725475)
• LH, progesterone, and TSH can stimulate aldosterone. (PMID:24297486)
• No association was found between poor ovarian response to ovarian stimulation and variant-betaLH. (PMID:24625195)
• Data indicate a modulatory effect of luteinizing hormone beta-subunit (LHB) gene polymorphisms on hyperandrogenemia phenotype of Polycystic Ovary Syndrome (PCOS) was observed. (PMID:25111116)
• This paper shows a conclusive contribution of Variant-Luteinizing hormone to the natural variance in male serum Luteinizing hormone levels (PMID:25820123)
• The Trp8Arg/Ile15Thr polymorphism within the LHB gene was not associated with endometriosis and infertility. (PMID:25935136)
• LHbeta G1052A and LHCGR G935A genes polymorphisms are associated with increased risk of polycystic ovary syndrome in Egyptian women especially in obese cases. (PMID:26662070)
• In girls with central precocious puberty, increased body mass index (BMI) was associated with slightly lower peak stimulated luteinizing hormone (LH) levels at early pubertal stages (Tanner stages 2 and 3). (PMID:27215137)
• A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. (PMID:27656125)
• Homozygous nonsense mutation Trp28X in the LHB gene causes LH deficiency. (PMID:29476300)
• The rs34349826 and rs6521 loci of the LHB gene were not related to male infertility, which can be further confirmed by larger-sample studies. The GG genotype combination is a protective factor against male infertility. (PMID:30173455)
• A genome-wide association study identifies FSHR rs2300441 associated with follicle-stimulating hormone levels. (PMID:32185793)
• Elevated circulating luteinizing hormone levels are associated with diabetic macroalbuminuria in Chinese men and postmenopausal women: A cross-sectional study. (PMID:32475064)
• Proliferating primary pituitary cells as a model for studying regulation of gonadotrope chromatin and gene expression. (PMID:34090968)
• Single molecule characterization of the binding kinetics of a transcription factor and its modulation by DNA sequence and methylation. (PMID:34606618)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Gpb5	FBGN0063368

Paralogs (9): CGB2 (ENSG00000104818), CGB3 (ENSG00000104827), FSHB (ENSG00000131808), TSHB (ENSG00000134200), GPHB5 (ENSG00000179600), CGB5 (ENSG00000189052), CGB7 (ENSG00000196337), CGB8 (ENSG00000213030), CGB1 (ENSG00000267631)

Protein

Protein identifiers

Lutropin subunit beta — P01229 (reviewed: P01229)

Alternative names: Luteinizing hormone subunit beta

All UniProt accessions (2): A0A0F7RQE6, P01229

UniProt curated annotations — full annotation on UniProt →

Function. Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.

Subunit / interactions. Heterodimer of a common alpha chain and a unique beta chain which confers biological specificity to thyrotropin, lutropin, follitropin and gonadotropin.

Subcellular location. Secreted.

Tissue specificity. Pituitary gland.

Disease relevance. Hypogonadotropic hypogonadism 23 with or without anosmia (HH23) [MIM:228300] A form of hypogonadotropic hypogonadism, a group of disorders characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. HH23 male patients have normal sexual differentiation, reduced or absent Leydig cells, reduced or absent spermatogenesis, and absence of spontaneous puberty. Female patients exhibit normal pubertal development and menarche, followed by oligomenorrhea and anovulatory secondary amenorrhea. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glycoprotein hormones subunit beta family.

RefSeq proteins (1): NP_000885* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001545	Gonadotropin_bsu	Family
IPR006208	Glyco_hormone_CN	Domain
IPR018245	Gonadotropin_bsu_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (18 total): sequence variant 6, disulfide bond 6, sequence conflict 3, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01229-F1	84.33	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (6): 29–77, 43–92, 46–130, 54–108, 58–110, 113–120

Glycosylation sites (1): 50

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-193048	Androgen biosynthesis
R-HSA-193993	Mineralocorticoid biosynthesis
R-HSA-209822	Glycoprotein hormones
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events
R-HSA-975578	Reactions specific to the complex N-glycan synthesis pathway
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-196071	Metabolism of steroid hormones
R-HSA-209952	Peptide hormone biosynthesis
R-HSA-2980736	Peptide hormone metabolism
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-500792	GPCR ligand binding
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification
R-HSA-8957322	Metabolism of steroids
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-975576	N-glycan antennae elongation in the medial/trans-Golgi

MSigDB gene sets: 183 (showing top): MODULE_92, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_KETONE_METABOLIC_PROCESS, KORKOLA_CHORIOCARCINOMA, GOBP_CELL_CELL_SIGNALING, MODULE_66, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_OVARIAN_FOLLICLE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, MODULE_206, GOBP_HORMONE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): progesterone biosynthetic process (GO:0006701), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), male gonad development (GO:0008584), hormone-mediated signaling pathway (GO:0009755)

GO Molecular Function (3): signaling receptor binding (GO:0005102), hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), Golgi lumen (GO:0005796), pituitary gonadotropin complex (GO:0061696)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Metabolism of steroid hormones	2
Metabolism of proteins	2
Signaling by GPCR	2
Peptide hormone biosynthesis	1
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
N-glycan antennae elongation in the medial/trans-Golgi	1
Metabolism of steroids	1
Peptide hormone metabolism	1
Signal Transduction	1
GPCR ligand binding	1
Post-translational protein modification	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
signal transduction	2
cellular anatomical structure	2
C21-steroid hormone biosynthetic process	1
ketone biosynthetic process	1
progesterone metabolic process	1
olefinic compound biosynthetic process	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
gonad development	1
development of primary male sexual characteristics	1
cellular response to hormone stimulus	1
protein binding	1
receptor ligand activity	1
binding	1
intracellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHB	GNRH1	P01148	682
LHB	GNRHR	P30968	649
LHB	NDNF	Q8TB73	608
LHB	KIAA0753	Q2KHM9	603
LHB	ATP1A4	Q13733	588
LHB	ATP1A1	P05023	588
LHB	AMY2B	P19961	584
LHB	FOS	P01100	566
LHB	CGA	P01215	557
LHB	ATP1A3	P13637	549
LHB	IL17RD	Q8NFM7	543
LHB	LHCGR	P22888	536
LHB	GNRH2	O43555	524
LHB	FSHR	P23945	503
LHB	S100A6	P06703	494

IntAct

12 interactions, top by confidence:

A	B	Type	Score
LHB	FHL3	psi-mi:“MI:0915”(physical association)	0.560
LHB	SGTB	psi-mi:“MI:0915”(physical association)	0.560
LHB	NTM	psi-mi:“MI:0915”(physical association)	0.560
LHB	GFAP	psi-mi:“MI:0915”(physical association)	0.400
LHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
LHB	FHL3	psi-mi:“MI:0915”(physical association)	0.000
LHB	SGTB	psi-mi:“MI:0915”(physical association)	0.000
NTM	LHB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): NTM (Two-hybrid), FHL3 (Two-hybrid), SGTB (Two-hybrid), GFAP (Affinity Capture-MS)

ESM2 similar proteins: A6NKQ9, B1AWI6, G7PWZ3, I6M4H4, O09108, O46482, O46483, O46641, O77805, O77835, P01229, P01230, P01231, P01232, P04651, P07434, P08751, P0DN86, P0DN87, P17490, P19794, P27767, P30984, P43021, P45646, P45657, P51500, Q04997, Q1L6U9, Q2Q1P0, Q2Q1P1, Q2Q1P2, Q3HRV3, Q3S2X5, Q6EV78, Q6HA10, Q6NT52, Q6PX77, Q7ZZV4, Q8CB67

Diamond homologs: A1BN60, A1BN61, A6NKQ9, O09108, O13050, O46430, O46482, O46483, O46641, O57340, O73824, O77805, O77835, P01222, P01223, P01224, P01225, P01226, P01227, P01228, P01229, P01230, P01231, P01232, P01235, P04651, P04652, P04837, P07434, P07732, P08751, P0DN86, P0DN87, P10256, P10257, P12656, P12837, P18427, P19794, P25330

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
LHB	up-regulates	LHCGR	binding
SF1	“up-regulates quantity by expression”	LHB	“transcriptional regulation”
EGR1	“up-regulates quantity by expression”	LHB	“transcriptional regulation”
PITX1	“up-regulates quantity by expression”	LHB	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

94 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	32
Likely benign	25
Benign	27

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
14413	NM_000894.3(LHB):c.221A>G (p.Gln74Arg)	Pathogenic
14416	NM_000894.3(LHB):c.167G>A (p.Gly56Asp)	Pathogenic
189290	NM_000894.3(LHB):c.183+1G>C	Pathogenic
189291	NM_000894.3(LHB):c.88_96del (p.His30_Ile32del)	Pathogenic
189292	NM_000894.3(LHB):c.28_39del (p.Leu10_Leu13del)	Pathogenic
189293	NM_000894.3(LHB):c.183+1G>T	Pathogenic

SpliceAI

263 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49016541:GCTCA:G	donor_loss	0.9900
19:49016542:CTCA:C	donor_loss	0.9900
19:49016543:TCAC:T	donor_loss	0.9900
19:49016544:CACC:C	donor_loss	0.9900
19:49016545:A:AC	donor_gain	0.9900
19:49016545:AC:A	donor_gain	0.9900
19:49016546:C:CC	donor_gain	0.9900
19:49016546:CC:C	donor_gain	0.9900
19:49016546:CCATG:C	donor_gain	0.9900
19:49016711:GCCC:G	acceptor_gain	0.9900
19:49016712:CCCC:C	acceptor_gain	0.9900
19:49016713:CC:C	acceptor_gain	0.9900
19:49016714:CC:C	acceptor_gain	0.9900
19:49016714:CCT:C	acceptor_loss	0.9900
19:49016715:C:T	acceptor_gain	0.9900
19:49016716:T:A	acceptor_loss	0.9900
19:49016712:CCC:C	acceptor_gain	0.9800
19:49016713:CCC:C	acceptor_gain	0.9800
19:49016715:C:CC	acceptor_gain	0.9800
19:49016318:CCG:C	acceptor_gain	0.9700
19:49016319:CG:C	acceptor_gain	0.9700
19:49016320:G:C	acceptor_gain	0.9700
19:49016546:CCA:C	donor_gain	0.9700
19:49016546:CCAT:C	donor_gain	0.9700
19:49016539:CAGCT:C	donor_loss	0.9600
19:49016319:C:T	acceptor_gain	0.9500
19:49016540:AGCTC:A	donor_loss	0.9500
19:49016710:AGCCC:A	acceptor_gain	0.9500
19:49016320:G:GC	acceptor_gain	0.9400
19:49016946:A:AC	donor_gain	0.9400

AlphaMissense

900 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49016264:C:G	C77S	0.990
19:49016265:A:T	C77S	0.990
19:49016564:C:A	G56C	0.990
19:49016569:C:G	C54S	0.990
19:49016570:A:T	C54S	0.990
19:49016569:C:T	C54Y	0.988
19:49016263:G:C	C77W	0.987
19:49016264:C:T	C77Y	0.986
19:49016568:A:C	C54W	0.986
19:49016219:C:G	C92S	0.985
19:49016220:A:T	C92S	0.985
19:49016265:A:G	C77R	0.984
19:49016556:G:C	C58W	0.984
19:49016557:C:G	C58S	0.984
19:49016558:A:T	C58S	0.984
19:49016135:C:G	C120S	0.983
19:49016136:A:T	C120S	0.983
19:49016171:C:G	C108S	0.982
19:49016172:A:T	C108S	0.982
19:49016557:C:T	C58Y	0.982
19:49016170:A:C	C108W	0.981
19:49016570:A:G	C54R	0.981
19:49016171:C:T	C108Y	0.980
19:49016644:C:G	C29S	0.980
19:49016645:A:T	C29S	0.980
19:49016243:A:C	F84C	0.979
19:49016563:C:A	G56V	0.979
19:49016602:C:G	C43S	0.979
19:49016603:A:T	C43S	0.979
19:49016569:C:A	C54F	0.978

dbSNP variants (sampled 300 via entrez): RS1000208272 (19:49019680 T>C), RS1000577681 (19:49018504 C>T), RS1002657335 (19:49017706 A>T), RS1003134259 (19:49021200 C>A,T), RS1003435177 (19:49019989 C>G), RS1003465366 (19:49020196 C>T), RS1005107375 (19:49018971 C>G,T), RS1005138525 (19:49019159 C>T), RS1005458676 (19:49018077 G>T), RS1005491183 (19:49018233 G>A,C,T), RS1006951803 (19:49021268 C>A,T), RS1007165434 (19:49017489 TC>T), RS1007270557 (19:49020484 C>A,G,T), RS1007395722 (19:49021384 C>T), RS1007463920 (19:49016434 A>C)

Disease associations

OMIM: gene MIM:152780 | disease phenotypes: MIM:228300, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 23 with or without anosmia	Strong	Autosomal recessive

Mondo (2): hypogonadotropic hypogonadism 23 with or without anosmia (MONDO:0009223), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (2): Leydig cell hypoplasia due to LHB deficiency (Orphanet:325448), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000138	Ovarian cyst
HP:0000771	Gynecomastia
HP:0000823	Delayed puberty
HP:0000869	Secondary amenorrhea
HP:0000876	Oligomenorrhea
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0004408	Abnormality of the sense of smell
HP:0008226	Androgen insufficiency
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008669	Abnormal spermatogenesis
HP:0010789	Abnormality of the Leydig cells
HP:0012215	Testicular microlithiasis
HP:0025708	Early young adult onset
HP:0030344	Decreased circulating luteinizing hormone level
HP:0033810	Decreased circulating dihydrotestosterone concentration
HP:0040171	Decreased serum testosterone concentration

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537919	Fertile eunuch syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Ethinyl Estradiol	affects expression, affects reaction, decreases expression, decreases activity, increases reaction (+1 more)	7
Testosterone	increases secretion, decreases secretion, affects cotreatment, increases abundance	7
Estradiol	decreases activity, decreases expression, decreases secretion, increases abundance, affects cotreatment (+1 more)	6
Progesterone	affects secretion, decreases abundance, increases abundance, increases reaction, decreases reaction (+1 more)	6
bisphenol A	affects expression, decreases activity, increases expression	3
MOPP protocol	increases expression, affects expression	3
Naloxone	increases expression, affects expression	3
Tamoxifen	affects secretion, decreases reaction, increases secretion, decreases expression	3
Levonorgestrel	affects cotreatment, affects expression, affects reaction, decreases expression, decreases secretion	3
ganirelix	decreases expression, decreases secretion	2
cetrorelix	decreases expression	2
Letrozole	increases expression	2
17 alpha-Hydroxyprogesterone Caproate	decreases expression	2
Cyclic AMP	decreases reaction, increases abundance, affects secretion, increases secretion, affects cotreatment	2
Atrazine	increases expression, affects reaction	2
Cisplatin	affects cotreatment, decreases expression, decreases response to substance	2
Clomiphene	increases reaction, increases secretion, decreases reaction, increases expression	2
Naltrexone	increases expression, increases secretion	2
Cyproterone Acetate	decreases expression, affects cotreatment	2
PF-06840003	decreases reaction, increases expression	1
tributyltin	affects cotreatment, decreases secretion, increases expression, increases secretion	1
nimesulide	decreases reaction, increases expression	1
dienogest	decreases expression	1
2-hydroxyestrone	decreases expression	1
ABVD protocol	increases expression	1
di-n-butyltin	affects cotreatment, decreases secretion, increases secretion	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases expression, increases secretion	1
LHRH, Ala(6)-Gly(10)-ethylamide-	affects cotreatment, decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction	1
U 0126	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

79 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism
NCT02733133	PHASE2	NOT_YET_RECRUITING	Product Transference Study of Testagen™ TDS®-Testosterone
NCT02908074	PHASE2	COMPLETED	A 6 Month Safety Extension Study of MBGS205
NCT03245827	PHASE2	TERMINATED	Hypogonadotropic Hypogonadism in Obese Young Males
NCT04189133	PHASE2	UNKNOWN	Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men