FSHR

Summary

FSHR (follicle stimulating hormone receptor, HGNC:3969) is a protein-coding gene on chromosome 2p16.3, encoding Follicle-stimulating hormone receptor (P23945). G protein-coupled receptor for follitropin, the follicle-stimulating hormone.

The protein encoded by this gene belongs to family 1 of G-protein coupled receptors. It is the receptor for follicle stimulating hormone and functions in gonad development. Mutations in this gene cause ovarian dysgenesis type 1, and also ovarian hyperstimulation syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2492 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ovarian dysgenesis 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 251 total — 20 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 46
• Druggable target: yes
• MANE Select transcript: NM_000145

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3969
Approved symbol	FSHR
Name	follicle stimulating hormone receptor
Location	2p16.3
Locus type	gene with protein product
Status	Approved
Aliases	FSHRO, LGR1
Ensembl gene	ENSG00000170820
Ensembl biotype	protein_coding
OMIM	136435
Entrez	2492

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000304421, ENST00000406846, ENST00000419927, ENST00000454032, ENST00000469138

RefSeq mRNA: 2 — MANE Select: NM_000145 NM_000145, NM_181446

CCDS: CCDS1843, CCDS1844

Canonical transcript exons

ENST00000406846 — 10 exons

Exon	Start	End
ENSE00001163867	49017489	49017563
ENSE00001163875	49020086	49020160
ENSE00001163885	49068219	49068290
ENSE00001813294	48962157	48963966
ENSE00001869305	49154266	49154515
ENSE00003463668	48988977	48989054
ENSE00003576000	48990566	48990637
ENSE00003582348	48983098	48983166
ENSE00003622809	48982912	48982986
ENSE00003630136	48968698	48968883

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 81.41.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3953 / max 50.4064, expressed in 90 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28253	0.2484	67
28252	0.1470	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.41	gold quality
lower esophagus mucosa	UBERON:0035834	58.24	gold quality
apex of heart	UBERON:0002098	56.83	gold quality
left ovary	UBERON:0002119	56.78	gold quality
left testis	UBERON:0004533	56.07	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
testis	UBERON:0000473	55.75	gold quality
paraflocculus	UBERON:0005351	54.48	gold quality
right testis	UBERON:0004534	54.47	gold quality
ovary	UBERON:0000992	53.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	53.29	gold quality
lower esophagus	UBERON:0013473	53.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	53.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	52.68	gold quality
right ovary	UBERON:0002118	51.15	gold quality
gall bladder	UBERON:0002110	51.02	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
sigmoid colon	UBERON:0001159	50.40	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
thymus	UBERON:0002370	48.02	silver quality
right coronary artery	UBERON:0001625	47.51	gold quality
endometrium epithelium	UBERON:0004811	46.85	gold quality
descending thoracic aorta	UBERON:0002345	46.35	gold quality
urinary bladder	UBERON:0001255	45.93	gold quality
colonic epithelium	UBERON:0000397	45.91	gold quality
quadriceps femoris	UBERON:0001377	45.79	gold quality
right atrium auricular region	UBERON:0006631	45.62	gold quality
cardiac atrium	UBERON:0002081	45.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	50.67
E-ANND-3	yes	4.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, CREM, E2F1, E2F4, E2F5, GATA4, HDAC1, ID1, ID2, JUN, MTA2, NR0B1, NR2F1, NR5A1, PPARA, RREB1, SMAD3, USF1, USF2, ZNF202

miRNA regulators (miRDB)

37 targeting FSHR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-326	98.25	66.44	1565

Literature-anchored findings (GeneRIF, showing 40)

• A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. (PMID:11889179)
• review of the mechanism of desensitization to FSH mediated by extensive clustering and internalization of the FSH hormone-receptor complex (PMID:11988313)
• The GCT had high expression of FSHR compared with normal ovaries (PMID:11994539)
• study indicates that the intracellular loop of the follicle-stimulating hormone receptor possesses amino acid residues that are important for both coupling the receptor to the G(s) protein and maintaining the receptor molecule in an inactive conformation. (PMID:12039074)
• Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor. Ala189Val mutation of the FSH receptor gene results in a complete block of FSH action in vivo. (PMID:12095499)
• differences in hydrophobic interactions between transmembrane domains 6 and 7 of the rat and human FSH receptors (PMID:12145341)
• FSH receptor polymorphisms have no discernible effect on FSH receptor function in vitro, there are associations between the genotype and some aspects of patient status. (PMID:12356937)
• Follicle-stimulating hormone interacts with exoloop 3 of the receptor. (PMID:12374801)
• Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. (review) (PMID:12398222)
• stimulates FSH-like activity in gonadotropin-deficient transgenic mice (PMID:12403847)
• Importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations. (PMID:12571157)
• association of arrestin-3 with the FSHR is dependent on receptor phosphorylation, however phosphorylation of the third intracellular loop residues is not needed for arrestin-3 association. (PMID:12850288)
• mutagenesis of FSH-R beta-strand 6 appeared to allow the interaction of hCG/hLH with the hFSH-R; ability of FSH-R to interact with hCG/hLH depends primarily on Asn104 and Lys179 situated on the C-terminal ends of beta-strands 3 and 6, respectively (PMID:12869592)
• downregulation of FSH-FSHR (PMID:12907758)
• After treatment with proteasome inhibitors, HEK293 cells stably transfected with an hFSHR expression plasmid showed an increase in follitropin binding. Role for ubiquitination in the regulation of hFSHR cell surface residency. (PMID:12960054)
• Role for FSHR gene in controlled ovarian stimulation outcome. Weight of this factor is probably low. Ser680 allele may act in concert with other environmental and genetic factors that contribute to FSH efficacy. (PMID:12969700)
• Normogonadotropic anovulatory infertile patients have different FSH receptor genotype than do normo-ovulatory controls. Increased baseline FSH serum levels. (PMID:14556822)
• A 1.5kb 5’-region of the human FSH receptor drives mRNA expression of the transgene in the testis but leads to ectopic expression in germ cells and in the brain (PMID:14695976)
• trans-activation in mutant receptors is selective and limited in signal generation (PMID:14726491)
• Mutations in FSH receptor gene display an increased sensitivity to hCG and are responsible for development of spontaneous ovarian hyperstimulation syndrome (OHSS). Molecular basis for physiopathology of spontaneous OHSS. Review. (PMID:14998941)
• None of the markers showed evidence in favor of linkage with overall age at natural menopause or early age at natural menopause. (PMID:15037410)
• APPL1 is a potential interactor with FSHR (PMID:15070827)
• specificity is exerted both by the ectodomain and the serpentine portion (PMID:15166252)
• FSH receptor interacts with 14-3-3tau. (PMID:15196694)
• Genotype in position 680 of the FSHr cannot predict which patients will develop ovarian hyperstimulation syndrome(OHSS), but could be a predictor of severity of symptoms among OHSS patients. (PMID:15579795)
• results indicate that E-box 3 and the initiator element(Inr) are important elements of the human follicle-stimulating hormone receptor(FSH-R) promoter/ enhancer (PMID:15625767)
• 2.9-A-resolution structure of a partially deglycosylated complex of human FSH bound to the extracellular hormone-binding domain of its receptor (PMID:15662415)
• OCT-1 binds within DHS3 to silence Fshr transcription, an activity that involves members of the GATA family (PMID:15817654)
• The FSH receptor Ser680/Ser680 genotype is associated with higher ovarian threshold to FSH, decreased negative feedback of luteal secretion to the pituitary during the intercycle transition, and longer menstrual cycles. (PMID:15886248)
• FSH receptors form dimers exhibiting allosterism. (PMID:15889138)
• human follitropin (FSH) receptor association with splicing variant of human lutropin/choriogonadotropin receptor negatively controls the expression of human FSH receptor (PMID:15890674)
• regions 285-300 and 327-341 hFSHR appear to be the chief FSH-binding sites (PMID:15948771)
• The FSH receptor genotype does not play a significant role in the risk of iatrogenic ovarian hyperstimulation syndrome after ovulation induction for in vitro fertilization. (PMID:15950638)
• FSH receptor polymorphism are associated with infertily of women. (PMID:16026410)
• Newly identified promoter single-nucleotide polymorphisms do not seem to influence clinical parameters in women undergoing controlled ovarian stimulation for IVF, but modulate expression of the FSHR via changes in transcription factor binding sites. (PMID:16084888)
• In this review, the key to carcinogenic process of sporadic epithelial ovarian cancer involves deregulated expression and signalling of FSHR by nerve growth factor (PMID:16168216)
• None of the 54 azoospermic patients showed a C566T FSH receptor mutation. (PMID:16338864)
• FSHR*D567G activity enhances Sertoli and spermatogenic development in normal testes but has limited ability to maintain spermatogenesis during gonadotropin deficiency. (PMID:16452461)
• FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IN VITRO FERTILIZATION PROGRAM. (PMID:16758348)
• The SNP in the 5’-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women. (PMID:16864747)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fshr	ENSDARG00000071494
mus_musculus	Fshr	ENSMUSG00000032937
rattus_norvegicus	Fshr	ENSRNOG00000016783
drosophila_melanogaster	Lgr1	FBGN0016650
caenorhabditis_elegans		WBGENE00008239

Paralogs (2): LHCGR (ENSG00000138039), TSHR (ENSG00000165409)

Protein

Protein identifiers

Follicle-stimulating hormone receptor — P23945 (reviewed: P23945)

Alternative names: Follitropin receptor

All UniProt accessions (3): P23945, C9JDA1, F8WBM4

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor for follitropin, the follicle-stimulating hormone. Through cAMP production activates the downstream PI3K-AKT and ERK1/ERK2 signaling pathways.

Subunit / interactions. Homotrimer. Functions as a homotrimer binding the FSH hormone heterodimer composed of CGA and FSHB. Interacts with ARRB2. Interacts with APPL2; interaction is independent of follicle stimulating hormone stimulation.

Subcellular location. Cell membrane.

Tissue specificity. Sertoli cells and ovarian granulosa cells.

Post-translational modifications. Sulfated. N-glycosylated; indirectly required for FSH-binding, possibly via a conformational change that allows high affinity binding of hormone.

Disease relevance. Ovarian dysgenesis 1 (ODG1) [MIM:233300] An autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, poorly developed streak ovaries, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The disease is caused by variants affecting the gene represented in this entry. Ovarian hyperstimulation syndrome (OHSS) [MIM:608115] Disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P23945-1	Long, R1	yes
P23945-2	Short, E9Del
P23945-3	3, E6Del
P23945-4	4, E8’Inc

RefSeq proteins (2): NP_000136, NP_852111 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000372	LRRNT	Domain
IPR002131	Gphrmn_rcpt_fam	Family
IPR002272	FSH_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR024635	GnHR_TM	Domain
IPR026906	LRR_5	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF00001, PF01462, PF12369, PF13306

UniProt features (113 total): sequence variant 21, strand 19, helix 15, turn 10, repeat 9, topological domain 8, transmembrane region 7, disulfide bond 7, glycosylation site 4, sequence conflict 4, splice variant 3, mutagenesis site 2, signal peptide 1, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4AY9	X-RAY DIFFRACTION	2.5
8I2G	ELECTRON MICROSCOPY	2.8
4MQW	X-RAY DIFFRACTION	2.9
1XWD	X-RAY DIFFRACTION	2.92
8I2H	ELECTRON MICROSCOPY	6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23945-F1	81.87	0.53

Antibody-complex structures (SAbDab): 1 — 8I2G

Functional residue map

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

Post-translational modifications (1): 335

Disulfide bonds (7): 18–25, 23–32, 275–346, 276–356, 276–292, 292–338, 442–517

Glycosylation sites (4): 191, 199, 293, 318

Mutagenesis-validated functional residues (2):

Position	Phenotype
330	no change in intracellular camp accumulation.
335	reduces intracellular camp accumulation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 324 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, MORF_MSH3, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_SERTOLI_CELL_DEVELOPMENT, GOBP_GROWTH, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE

GO Biological Process (41): primary ovarian follicle growth (GO:0001545), regulation of systemic arterial blood pressure (GO:0003073), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), spermatogenesis (GO:0007283), female gamete generation (GO:0007292), locomotory behavior (GO:0007626), gonad development (GO:0008406), male gonad development (GO:0008584), female gonad development (GO:0008585), hormone-mediated signaling pathway (GO:0009755), intracellular water homeostasis (GO:0009992), regulation of platelet-derived growth factor receptor signaling pathway (GO:0010640), obsolete regulation of protein kinase A signaling (GO:0010738), neuron projection development (GO:0031175), regulation of hormone metabolic process (GO:0032350), regulation of chromosome organization (GO:0033044), positive regulation of intracellular estrogen receptor signaling pathway (GO:0033148), sperm DNA condensation (GO:0035092), follicle-stimulating hormone signaling pathway (GO:0042699), transcytosis (GO:0045056), regulation of osteoclast differentiation (GO:0045670), negative regulation of bone resorption (GO:0045779), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), Sertoli cell development (GO:0060009), Sertoli cell proliferation (GO:0060011), uterus development (GO:0060065), regulation of acetylcholine metabolic process (GO:0060408), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to follicle-stimulating hormone stimulus (GO:0071372), basement membrane organization (GO:0071711), ovarian follicle development (GO:0001541), signal transduction (GO:0007165), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), spermatid development (GO:0007286), response to hormone (GO:0009725), ovulation cycle process (GO:0022602), regulation of intracellular estrogen receptor signaling pathway (GO:0033146)

GO Molecular Function (7): follicle-stimulating hormone receptor activity (GO:0004963), G protein-coupled peptide receptor activity (GO:0008528), peptide hormone binding (GO:0017046), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515), protein-hormone receptor activity (GO:0016500), signaling receptor activity (GO:0038023)

GO Cellular Component (5): endosome (GO:0005768), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	2
signal transduction	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
G protein-coupled receptor signaling pathway	2
gonad development	2
cellular anatomical structure	2
ovarian follicle development	1
ovulation cycle process	1
developmental growth	1
regulation of blood pressure	1
adenylate cyclase activator activity	1
adenylate cyclase inhibitor activity	1
phospholipase C activator activity	1
developmental process involved in reproduction	1
male gamete generation	1
gamete generation	1
behavior	1
development of primary sexual characteristics	1
animal organ development	1
reproductive structure development	1
development of primary male sexual characteristics	1
development of primary female sexual characteristics	1
cellular response to hormone stimulus	1
cell volume homeostasis	1
intracellular chemical homeostasis	1
regulation of signal transduction	1
platelet-derived growth factor receptor signaling pathway	1
neuron development	1
plasma membrane bounded cell projection organization	1
regulation of hormone levels	1
regulation of metabolic process	1
hormone metabolic process	1
regulation of organelle organization	1
chromosome organization	1
estrogen receptor signaling pathway	1
positive regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
protein-hormone receptor activity	1
follicle-stimulating hormone signaling pathway	1
peptide receptor activity	1

Protein interactions and networks

STRING

1599 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSHR	FSHB	P01225	984
FSHR	BMP15	O95972	930
FSHR	GDF9	O60383	906
FSHR	AMH	P03971	882
FSHR	GPHB5	Q86YW7	819
FSHR	CYP19A1	P11511	813
FSHR	CYP17A1	P05093	810
FSHR	CYP11A1	P05108	809
FSHR	CGA	P01215	808
FSHR	GNRH1	P01148	779
FSHR	TSHB	P01222	766
FSHR	AMHR2	Q16671	755
FSHR	HSD3B1	P14060	734
FSHR	STAR	P49675	723
FSHR	ESR1	P03372	718

IntAct

20 interactions, top by confidence:

A	B	Type	Score
FSHB	CGA	psi-mi:“MI:0915”(physical association)	0.760
YWHAQ	FSHR	psi-mi:“MI:0915”(physical association)	0.630
FSHR	YWHAQ	psi-mi:“MI:0915”(physical association)	0.630
FSHR	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
FSHR	GPER1	psi-mi:“MI:2364”(proximity)	0.520
GPER1	FSHR	psi-mi:“MI:0403”(colocalization)	0.520
GPER1	FSHR	psi-mi:“MI:2364”(proximity)	0.520
FSHR	GPER1	psi-mi:“MI:0403”(colocalization)	0.520
RAMP1	FSHR	psi-mi:“MI:0915”(physical association)	0.400
FSHR	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
FSHR	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
FCN1	FSHR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (48): TOP1 (Two-hybrid), DNAJC18 (Affinity Capture-MS), DAD1 (Affinity Capture-MS), EDA (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), UPK3BL (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), NAGPA (Affinity Capture-MS), FAM189B (Affinity Capture-MS), BMPR1A (Affinity Capture-MS), ABHD6 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), SNX14 (Affinity Capture-MS), C10orf35 (Affinity Capture-MS), PPP1R15B (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2IDB4, A0A8B7HA97, A4ZYQ5, A6NK97, G1SZD9, O35956, O57379, O88909, P22732, P23945, P43427, Q0IHM1, Q2KIV1, Q3ZAV1, Q4U2R8, Q4W8A2, Q4W8A3, Q5R9C4, Q5RC45, Q5RCH6, Q5RET7, Q63ZE4, Q66J52, Q6DFR1, Q6NUB3, Q6NYN7, Q6PXP3, Q6T423, Q70BM6, Q76M72, Q76M99, Q80UJ1, Q863Y9, Q864Z3, Q8CFZ5, Q8HY24, Q8IVM8, Q8MK48, Q8N4F4, Q8R0S9

Diamond homologs: O02721, P14763, P16235, P16473, P16582, P20395, P21463, P22888, P23945, P30549, P30730, P32212, P35376, P35378, P35379, P35409, P46023, P47750, P47799, P49059, P56495, P79763, Q27987, Q28005, Q28585, Q5GJ04, Q6QMG1, Q6R6L8, Q6YNB6, Q7ZTV5, Q8R428, Q8SPP9, Q90674, Q95179, Q9BGN4, Q9EQD2, B0BLW3, O42328, O42451, O42466

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HDAC1	“down-regulates quantity by repression”	FSHR	“transcriptional regulation”
MTA2	“down-regulates quantity by repression”	FSHR	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	20
Uncertain significance	137
Likely benign	29
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1256023	NM_000145.4(FSHR):c.349C>T (p.Gln117Ter)	Pathogenic
1256040	NM_000145.4(FSHR):c.1679_1685del (p.Asn560fs)	Pathogenic
154949	GRCh38/hg38 2p16.3(chr2:48929614-50839499)x1	Pathogenic
16243	NM_000145.4(FSHR):c.566C>T (p.Ala189Val)	Pathogenic
16245	NM_000145.4(FSHR):c.1717C>T (p.Arg573Cys)	Pathogenic
16248	NM_000145.4(FSHR):c.1255G>A (p.Ala419Thr)	Pathogenic
16249	NM_000145.4(FSHR):c.1346C>T (p.Thr449Ile)	Pathogenic
16250	NM_000145.4(FSHR):c.1699G>A (p.Asp567Asn)	Pathogenic
16251	NM_000145.4(FSHR):c.1555C>A (p.Pro519Thr)	Pathogenic
16252	NM_000145.4(FSHR):c.1345A>G (p.Thr449Ala)	Pathogenic
16253	NM_000145.4(FSHR):c.1634T>C (p.Ile545Thr)	Pathogenic
16254	NM_000145.4(FSHR):c.383C>A (p.Ser128Tyr)	Pathogenic
2071906	NM_000145.4(FSHR):c.396dup (p.Lys133Ter)	Pathogenic
3381984	NM_000145.4(FSHR):c.564_565del (p.Ala189fs)	Pathogenic
4076030	GRCh37/hg19 2p16.3(chr2:49195037-50625932)x1	Pathogenic
4279494	GRCh37/hg19 2p16.3(chr2:49183378-49245850)x1	Pathogenic
523337	NM_000145.4(FSHR):c.2T>C (p.Met1Thr)	Pathogenic
685315	GRCh37/hg19 2p16.3(chr2:49016672-49229962)x1	Pathogenic
686634	GRCh37/hg19 2p16.3(chr2:49158272-49209034)x1	Pathogenic
689110	GRCh37/hg19 2p16.3(chr2:49113632-49255072)x1	Pathogenic
1256019	NM_000145.4(FSHR):c.1396G>A (p.Glu466Lys)	Likely pathogenic
1256032	NM_000145.4(FSHR):c.884C>T (p.Ser295Phe)	Likely pathogenic
1256038	NM_000145.4(FSHR):c.1763T>C (p.Ile588Thr)	Likely pathogenic
1256039	NM_000145.4(FSHR):c.683C>T (p.Thr228Ile)	Likely pathogenic
1256041	NM_000145.4(FSHR):c.374T>G (p.Leu125Arg)	Likely pathogenic
3381987	NM_000145.4(FSHR):c.1255G>C (p.Ala419Pro)	Likely pathogenic
3779679	NM_000145.4(FSHR):c.507del (p.Phe170fs)	Likely pathogenic
3892624	NM_000145.4(FSHR):c.1109G>A (p.Trp370Ter)	Likely pathogenic
3901829	NM_000145.4(FSHR):c.445C>T (p.Leu149Phe)	Likely pathogenic
4081405	NM_000145.4(FSHR):c.940_941del (p.Leu314fs)	Likely pathogenic

SpliceAI

2433 predictions. Top by Δscore:

Variant	Effect	Δscore
2:48982910:A:AC	donor_gain	1.0000
2:48982911:C:CC	donor_gain	1.0000
2:48983096:A:AC	donor_gain	1.0000
2:48983097:C:CC	donor_gain	1.0000
2:48983097:CAG:C	donor_gain	1.0000
2:48983097:CAGCT:C	donor_gain	1.0000
2:48988975:A:AC	donor_gain	1.0000
2:48988976:C:CC	donor_gain	1.0000
2:48990564:A:AC	donor_gain	1.0000
2:48990565:C:CC	donor_gain	1.0000
2:49017487:A:AC	donor_gain	1.0000
2:49017488:C:CC	donor_gain	1.0000
2:49017488:CAG:C	donor_gain	1.0000
2:49017488:CAGAT:C	donor_gain	1.0000
2:49017559:TTCTA:T	acceptor_gain	1.0000
2:49017561:CTA:C	acceptor_gain	1.0000
2:49017562:TA:T	acceptor_gain	1.0000
2:49017564:C:CC	acceptor_gain	1.0000
2:49020084:A:AC	donor_gain	1.0000
2:49020085:C:CC	donor_gain	1.0000
2:49020085:CATTT:C	donor_gain	1.0000
2:49066947:C:CA	donor_gain	1.0000
2:49154264:A:AC	donor_gain	1.0000
2:49154265:C:CC	donor_gain	1.0000
2:49154265:CA:C	donor_gain	1.0000
2:48963962:CAGAG:C	acceptor_gain	0.9900
2:48963967:C:CC	acceptor_gain	0.9900
2:48982903:GCTAC:G	donor_loss	0.9900
2:48982904:CTACT:C	donor_loss	0.9900
2:48982905:TAC:T	donor_loss	0.9900

AlphaMissense

4622 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:48983098:A:G	L198P	0.997
2:49017489:A:G	L125P	0.996
2:48963785:A:G	C346R	0.995
2:48989039:G:C	N154K	0.995
2:48989039:G:T	N154K	0.995
2:48982981:A:G	L200P	0.994
2:48963784:C:G	C346S	0.993
2:48963785:A:T	C346S	0.993
2:48968727:G:C	C275W	0.993
2:48990632:A:T	I127K	0.993
2:49020145:A:C	N80K	0.993
2:49020145:A:T	N80K	0.993
2:48963783:G:C	C346W	0.992
2:48968728:C:G	C275S	0.992
2:48968729:A:G	C275R	0.992
2:48968729:A:T	C275S	0.992
2:48968821:A:G	L244P	0.992
2:48963784:C:T	C346Y	0.991
2:48968728:C:T	C275Y	0.991
2:48982912:A:G	L223P	0.991
2:49154323:C:G	C32S	0.991
2:49154324:A:T	C32S	0.991
2:49020113:A:G	F91S	0.990
2:49154266:A:G	L51P	0.990
2:48983122:A:G	F190S	0.989
2:48983161:A:G	L177P	0.988
2:48983151:A:C	N180K	0.987
2:48983151:A:T	N180K	0.987
2:48990632:A:C	I127R	0.987
2:49017498:A:G	L122P	0.987

dbSNP variants (sampled 300 via entrez): RS1000000997 (2:49134954 T>C), RS1000009122 (2:49125076 G>C), RS1000013074 (2:49099551 C>A), RS1000031721 (2:48977333 C>A), RS1000045982 (2:48995573 A>G), RS1000065809 (2:49154719 A>G,T), RS1000072219 (2:49052354 G>C), RS1000074864 (2:48977942 G>A,C,T), RS1000115240 (2:49094289 T>G), RS1000115601 (2:49120132 A>G), RS1000121352 (2:48996453 C>G,T), RS1000133630 (2:49063363 G>A), RS1000142254 (2:49053325 C>A,T), RS1000145501 (2:48978427 T>C), RS1000157620 (2:49106730 G>A,T)

Disease associations

OMIM: gene MIM:136435 | disease phenotypes: MIM:608115, MIM:233300, MIM:614325, MIM:278300

GenCC curated gene-disease

Disease	Classification	Inheritance
ovarian dysgenesis 1	Strong	Autosomal recessive
ovarian hyperstimulation syndrome	Strong	Autosomal dominant
46 XX gonadal dysgenesis	Supportive	Autosomal dominant

Mondo (7): ovarian hyperstimulation syndrome (MONDO:0011972), ovarian dysgenesis 1 (MONDO:0024463), Pitt-Hopkins-like syndrome 2 (MONDO:0013690), gonadal dysgenesis (MONDO:0001967), amenorrhea (MONDO:0001836), xanthinuria type I (MONDO:0010209), 46 XX gonadal dysgenesis (MONDO:0009299)

Orphanet (7): Rare genetic premature ovarian failure (Orphanet:485382), 46,XX gonadal dysgenesis (Orphanet:243), Ovarian hyperstimulation syndrome (Orphanet:64739), OBSOLETE: Pitt-Hopkins-like syndrome (Orphanet:221150), NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance (Orphanet:600663), Hereditary xanthinuria (Orphanet:3467), Xanthinuria type I (Orphanet:93601)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000062	Ambiguous genitalia
HP:0000119	Abnormality of the genitourinary system
HP:0000133	Gonadal dysgenesis
HP:0000138	Ovarian cyst
HP:0000144	Decreased fertility
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000837	Increased circulating gonadotropin level
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001007	Hirsutism
HP:0001166	Arachnodactyly
HP:0001251	Ataxia
HP:0001541	Ascites
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002017	Nausea and vomiting
HP:0002018	Nausea
HP:0002027	Abdominal pain
HP:0002202	Pleural effusion
HP:0002206	Pulmonary fibrosis
HP:0002225	Sparse pubic hair
HP:0002750	Delayed skeletal maturation
HP:0003270	Abdominal distention
HP:0003621	Juvenile onset
HP:0004322	Short stature

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000823_4	Radiation response	5.000000e-06
GCST000824_14	Erectile dysfunction and prostate cancer treatment	5.000000e-08
GCST000914_4	Polycystic ovary syndrome	8.000000e-21
GCST001634_4	Polycystic ovary syndrome	1.000000e-12
GCST002000_2	Adverse response to chemotherapy (neutropenia/leucopenia) (etoposide)	7.000000e-06
GCST002363_12	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	5.000000e-07
GCST002755_6	Depressive symptoms (SSRI exposure interaction)	2.000000e-06
GCST004749_92	Lung cancer in ever smokers	7.000000e-06
GCST004813_1	Laterality in neovascular age-related macular degeneration	3.000000e-08
GCST007002_1	Cerebrospinal fluid t-tau levels in normal cognition	5.000000e-07
GCST007204_6	Low density lipoprotein cholesterol levels	1.000000e-06
GCST007565_27	Morning person	5.000000e-14
GCST007576_367	Chronotype	2.000000e-08
GCST007576_368	Chronotype	5.000000e-14
GCST007851_10	Anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TgAb) levels in Hashimoto’s thyroiditis	8.000000e-06
GCST008153_31	Lean body mass	6.000000e-06
GCST008369_13	Plasma anti-thyroglobulin levels	5.000000e-06
GCST009391_878	Metabolite levels	3.000000e-06
GCST011494_10	Daytime nap	2.000000e-15
GCST011743_12	HDL cholesterol levels in HIV infection	8.000000e-06
GCST012302_6	Recurrent major depressive disorder	4.000000e-06

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0007006	depressive symptom measurement
EFO:0007010	drug use measurement
EFO:0007011	SSRI use measurement
EFO:0008372	laterality measurement
EFO:0004760	t-tau measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0008328	chronotype measurement
EFO:0004995	lean body mass
EFO:0010437	triacylglycerol 58:10 measurement
EFO:0007828	daytime rest measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D006059	Gonadal Dysgenesis	C12.050.351.875.253.309; C12.200.706.316.309; C12.800.316.309; C16.131.939.316.309; C19.391.119.309
D023961	Gonadal Dysgenesis, 46,XX	C12.050.351.875.253.064.249; C12.050.351.875.253.309.193; C12.200.706.316.064.249; C12.200.706.316.309.193; C12.800.316.064.249; C12.800.316.309.193; C16.131.939.316.064.249; C16.131.939.316.309.193; C19.391.119.064.249; C19.391.119.309.193
D016471	Ovarian Hyperstimulation Syndrome	C12.050.351.500.056.630.642; C12.100.250.056.630.642; C19.391.630.642
C562584	Xanthinuria, Type I (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2024 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

6 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6166	Efficacy	3	follitropin beta;thyrotropin alfa;urofollitropin	Infertility;Female;Ovarian hyperstimulation syndrome
rs6166	Efficacy	3	follitropin beta;menotropins;thyrotropin alfa;urofollitropin	Infertility disorder
rs6166	Dosage	3	follitropin beta;menotropins;thyrotropin alfa;urofollitropin	Infertility disorder
rs6166	Dosage	3	follitropin beta;urofollitropin
rs6166	Dosage	3	menotropins
rs6166	Dosage	3	chorionic gonadotropin

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6166	FSHR	3	2.50	6	menotropins;follitropin beta;thyrotropin alfa;urofollitropin;follitropin beta;menotropins;thyrotropin alfa;urofollitropin;follitropin beta;urofollitropin;chorionic gonadotropin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Glycoprotein hormone receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
FSH deglycosylated α/β	Antagonist	10.0	pKd

ChEMBL bioactivities

111 potent at pChembl≥5 of 118 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	EC50	1	nM	CHEMBL2216803
8.92	EC50	1.2	nM	CHEMBL295895
8.77	EC50	1.7	nM	CHEMBL45770
8.74	EC50	1.8	nM	CHEMBL47953
8.57	EC50	2.7	nM	CHEMBL433263
8.52	EC50	3	nM	CHEMBL300022
8.44	EC50	3.6	nM	CHEMBL48030
8.40	IC50	4	nM	CHEMBL192135
8.30	IC50	5	nM	CHEMBL360981
8.30	IC50	5	nM	CHEMBL436481
8.15	IC50	7	nM	CHEMBL361847
8.14	EC50	7.2	nM	CHEMBL49608
8.10	EC50	7.9	nM	CHEMBL295895
8.05	IC50	9	nM	CHEMBL365545
8.05	EC50	8.9	nM	CHEMBL48375
8.02	EC50	9.5	nM	CHEMBL49608
8.01	EC50	9.7	nM	CHEMBL46216
8.00	IC50	10	nM	CHEMBL192135
7.89	EC50	13	nM	CHEMBL49624
7.85	EC50	14	nM	CHEMBL47059
7.77	IC50	17	nM	CHEMBL5281228
7.77	IC50	17	nM	CHEMBL5618086
7.60	IC50	25	nM	CHEMBL195469
7.60	EC50	25	nM	CHEMBL279759
7.57	IC50	27	nM	CHEMBL361167
7.55	IC50	28	nM	CHEMBL192135
7.52	IC50	30	nM	CHEMBL192868
7.51	IC50	31	nM	CHEMBL178980
7.51	EC50	31	nM	CHEMBL433263
7.50	EC50	32	nM	CHEMBL279759
7.50	EC50	32	nM	CHEMBL49624
7.46	EC50	35	nM	CHEMBL47059
7.41	IC50	39	nM	CHEMBL1651722
7.32	EC50	48	nM	CHEMBL48375
7.30	EC50	50	nM	CHEMBL2216804
7.30	IC50	50	nM	CHEMBL195347
7.27	IC50	54	nM	CHEMBL192334
7.23	EC50	59	nM	CHEMBL48375
7.19	IC50	64	nM	CHEMBL5285685
7.17	EC50	68	nM	CHEMBL296449
7.12	IC50	76	nM	CHEMBL179505
7.10	EC50	80	nM	CHEMBL2216804
7.00	EC50	100	nM	CHEMBL3809148
7.00	EC50	100	nM	CHEMBL3263667
7.00	EC50	100	nM	CHEMBL3263691
7.00	EC50	100	nM	CHEMBL47500
6.92	EC50	120	nM	CHEMBL49308
6.90	EC50	126	nM	CHEMBL1651721
6.82	EC50	150	nM	CHEMBL44663
6.81	IC50	156	nM	CHEMBL5267043

PubChem BioAssay actives

117 with measured affinity, of 244 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-chloro-4-[(2S,5R)-5-[2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl]-4-oxo-2-[4-(2-phenylethynyl)phenyl]-1,3-thiazolidin-3-yl]benzamide	719873: Allosteric activation of human FSH receptor	ec50	0.0010	uM
1-butyl-1-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]-3-methylurea	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0012	uM
2-[(3S)-3-[[4-[3-[[butyl(methylcarbamoyl)amino]methyl]phenyl]phenyl]methyl]-4-methyl-2,5-dioxopiperazin-1-yl]-N-pentylacetamide	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0017	uM
methyl N-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]-N-(methoxymethyl)carbamate	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0018	uM
methyl N-butyl-N-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]carbamate	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0027	uM
N-hexyl-2-[(3S)-4-methyl-2,5-dioxo-3-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazin-1-yl]acetamide	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0030	uM
1-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]-1-(methoxymethyl)-3-methylurea	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0036	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0040	uM
N-(1-acetyl-2,2,4,7-tetramethyl-4-phenyl-3H-quinolin-6-yl)-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0050	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-4-propylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0050	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-4-(trifluoromethyl)benzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0070	uM
1-butyl-1-[[3-[4-[[(2S,5S)-4-hexyl-1,5-dimethyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]-3-methylurea	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0072	uM
methyl N-butyl-N-[[3-[4-[[(2S,5S)-4-hexyl-1,5-dimethyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]carbamate	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0089	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-3-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0090	uM
N-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]-N-(methoxymethyl)acetamide	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0097	uM
(3S,6S)-1,3-dimethyl-4-octyl-6-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazine-2,5-dione	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0130	uM
N-butyl-N-[[3-[4-[[(2S,5S)-1,5-dimethyl-4-octyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]acetamide	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0140	uM
N-[(4S)-1-acetyl-4-methyl-4-phenyl-2,3-dihydroquinolin-6-yl]-3-[3-(trifluoromethyl)phenyl]propanamide	2130689: Inhibition of human FSH receptor	ic50	0.0170	uM
N-(1-acetyl-4-methyl-4-phenyl-2,3-dihydroquinolin-6-yl)-3-[3-(trifluoromethyl)phenyl]propanamide	1952508: Allosteric antagonist activity at human FSHR expressed in CHO cells assessed as inhibition of FSH-induced activity incubated for 4 hrs by CRE-luciferase assay	ic50	0.0170	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-2-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0250	uM
(3S,6S)-1-heptyl-4,6-dimethyl-3-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazine-2,5-dione	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0250	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)furan-2-carboxamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0270	uM
N-(1-acetyl-8-methoxy-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0300	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-4-chlorobenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0310	uM
N-[(4R)-1-acetyl-2,2,4-trimethyl-4-(4-prop-2-ynoxyphenyl)-3H-quinolin-6-yl]-4-phenylbenzamide	553586: Agonist activity at human FSHR receptor expressed in CHO-K1 cells assessed as inhibition of FSH-induced luciferase activity by CRE-driven luciferase reporter gene assay relative to control	ic50	0.0390	uM
N-[1-acetyl-2,2,4-trimethyl-4-(4-methylphenyl)-3H-quinolin-6-yl]-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0500	uM
N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]-2-[(2S,5R)-4-oxo-2-[4-(2-phenylethynyl)phenyl]-1,3-thiazolidin-5-yl]acetamide	719872: Agonist activity at human FSH receptor by aromatase-based assay	ec50	0.0500	uM
(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl) 4-phenylbenzoate	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0540	uM
(3-chlorophenyl)methyl N-(5’-acetyl-6’,6’-dimethylspiro[cyclohexane-1,7’-pyrrolo[3,2-d]pyrimidine]-2’-yl)carbamate	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.0640	uM
(3S,6R)-1,3-dimethyl-4-octyl-6-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazine-2,5-dione	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.0680	uM
N-(1-acetyl-2,2,4-trimethyl-4-phenyl-3H-quinolin-6-yl)-2-[(2-methylpropan-2-yl)oxy]acetamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.0760	uM
(3S,6S)-1-hexyl-4,6-dimethyl-3-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazine-2,5-dione	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.1000	uM
3-[(4-fluorobenzoyl)amino]-4-[4-(2-methylphenyl)piperazin-1-yl]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
N-[2-[4-(2-methylphenyl)piperazin-1-yl]-5-[3-(2-oxopyrrolidin-1-yl)propylcarbamoyl]phenyl]furan-2-carboxamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
2-cyclopropyl-N-[2-[4-(2-methylphenyl)piperazin-1-yl]-5-[3-(2-oxopyrrolidin-1-yl)propylcarbamoyl]phenyl]-1,3-oxazole-4-carboxamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
2-cyclopropyl-N-[2-[4-(2-methylphenyl)piperazin-1-yl]-5-[3-(2H-tetrazol-5-yl)propylcarbamoyl]phenyl]-1,3-oxazole-4-carboxamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
2-cyclopropyl-N-[5-[[(1S,3S)-3-hydroxycyclohexyl]carbamoyl]-2-[4-(2-methylphenyl)piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
N-[2-[4-(2-methylphenyl)piperazin-1-yl]-5-[3-(prop-2-enylcarbamoylamino)propylcarbamoyl]phenyl]furan-2-carboxamide	1303023: Positive allosteric modulation of FSHR (unknown origin) expressed in CHO cells assessed as FSH-induced cAMP accumulation incubated for 1 hr by HTRF assay	ec50	0.1000	uM
(3R,6S)-1,3-dimethyl-4-octyl-6-[[4-(3,4,5-trimethoxyphenyl)phenyl]methyl]piperazine-2,5-dione	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.1200	uM
5-amino-N-tert-butyl-2-methylsulfanyl-4-[3-[[2-oxo-2-(prop-2-ynylamino)ethyl]amino]phenyl]thieno[2,3-d]pyrimidine-6-carboxamide	553583: Agonist activity at human FSHR receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.1260	uM
N-butyl-N-[[3-[4-[[(2S,5S)-4-hexyl-1,5-dimethyl-3,6-dioxopiperazin-2-yl]methyl]phenyl]phenyl]methyl]acetamide	71210: Agonistic activity against human follicle stimulating hormone receptor in CHO-hFSHR-luciferase assay.	ec50	0.1500	uM
[1-(trifluoromethyl)cyclopropyl]methyl N-(5’-acetyl-4,4-difluoro-6’,6’-dimethylspiro[cyclohexane-1,7’-pyrrolo[3,2-d]pyrimidine]-2’-yl)carbamate	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.1560	uM
1-[2,2,4-trimethyl-4-phenyl-6-[(4-phenylphenyl)methoxy]-3H-quinolin-1-yl]ethanone	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.1660	uM
N-[1-acetyl-4-(2-methoxyphenyl)-2,2,4-trimethyl-3H-quinolin-6-yl]-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.1700	uM
benzyl N-(5’-acetyl-6’,6’-dimethylspiro[cyclohexane-1,7’-pyrrolo[3,2-d]pyrimidine]-2’-yl)carbamate	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.2140	uM
N-[1-acetyl-4-(4-hydroxyphenyl)-2,2,4-trimethyl-3H-quinolin-6-yl]-4-phenylbenzamide	248759: In vitro inhibition of maximum response on CHO-K1 cells expressing human Follicle stimulating hormone receptor	ic50	0.2400	uM
[(2S)-3,3-dimethylbutan-2-yl] N-(5’-acetyl-4,4-difluoro-6’,6’-dimethylspiro[cyclohexane-1,7’-pyrrolo[3,2-d]pyrimidine]-2’-yl)carbamate	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.2590	uM
4-[3-[[butyl(methylcarbamoyl)amino]methyl]phenyl]-N-[1-[2-[2-(4-chlorophenyl)ethylamino]-2-oxoethyl]-2-oxoazepan-3-yl]benzamide	71209: Agonistic activity against Follicle stimulating hormone receptor expressed in chinese hamster ovary cells(CHO)	ec50	0.2600	uM
[1-(trifluoromethyl)cyclopropyl]methyl N-(5’-acetyl-6’,6’-dimethylspiro[cyclohexane-1,7’-pyrrolo[3,2-d]pyrimidine]-2’-yl)carbamate	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.2700	uM
N-(1-acetyl-2-methylspiro[2H-indole-3,1’-cyclohexane]-5-yl)-3-(3-chlorophenyl)propanamide	1952478: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay	ic50	0.3220	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	decreases reaction, increases abundance, increases activity, affects methylation	2
bisphenol A	affects cotreatment, increases expression, increases reaction	1
alpha-naphthoflavone	decreases expression, decreases reaction	1
o,p’-DDT	increases abundance, increases activity, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cyanoginosin LR	decreases expression	1
CGP 52608	affects binding, increases reaction	1
FSH-BI protein, human	increases reaction, decreases reaction, increases expression	1
Org 41841	increases localization	1
Cyclic AMP	decreases reaction, increases abundance, increases activity, increases reaction	1
Cisplatin	decreases expression	1
Copper	affects expression, decreases reaction, increases expression, increases reaction	1
Dichlorodiphenyl Dichloroethylene	increases abundance, increases activity, increases reaction	1
DDT	increases abundance, increases activity, increases reaction	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Chorionic Gonadotropin	affects cotreatment, increases expression, increases reaction	1
Gonadotropins, Equine	affects cotreatment, increases expression, increases reaction	1
Lipopolysaccharides	decreases expression	1
Malathion	increases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1
Aflatoxin B1	decreases methylation	1
Paclitaxel	decreases expression	1

ChEMBL screening assays

43 unique, capped per target: 26 functional, 17 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614081	Functional	PUBCHEM_BIOASSAY: Counterscreen for Agonists of Thyroid Stimulating Hormone Receptor: HTRF Activity in a Follicle Stimulating Hormone Receptor Cell Line. (Class of assay: confirmatory) [Related pubchem assays: 926, 939, 933, 938, 953 ]	PubChem BioAssay data set
CHEMBL2217225	Binding	Allosteric activation of human FSH receptor	Recent developments and biological activities of thiazolidinone derivatives: a review. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 spontaneously immortalized cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0SM	ACTOne FSHR	Transformed cell line	Female
CVCL_E6QI	Genomeditech CHO-K1 H_FSHR Reporter	Spontaneously immortalized cell line	Female
CVCL_KV18	cAMP Hunter CHO-K1 FSHR Gs	Spontaneously immortalized cell line	Female
CVCL_KX07	PathHunter CHO-K1 FSHR beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_YK15	HEK293 FSHR HiTSeeker	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00349258	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger in the Prevention of OHSS
NCT00417144	PHASE4	UNKNOWN	Comparison Between GnRH Agonist and GnRH Antagonist Protocols of Ovarian Stimulation in PCOS Patients
NCT00627406	PHASE4	COMPLETED	Triggering of Final Oocyte Maturation With GnRHa (Buserelin) in GnRH Antagonist Cycles
NCT00756028	PHASE4	COMPLETED	Short Versus Long Protocol for IVF and IVF+ICSI
NCT01500863	PHASE4	COMPLETED	Endometrial Receptivity After GnRH Agonist Triggering
NCT01606709	PHASE4	TERMINATED	Gene Expression Profile After Gonadotropin Releasing Hormone (GnRH) Agonist Trigger of Oocyte Maturation
NCT01714648	PHASE4	TERMINATED	Can GnRH Agonist Trigger Prevent Ovarian Hyperstimulation Syndrome?
NCT01815138	PHASE4	COMPLETED	Co-administration of Low Dose hCG at the Time of GnRH Agonist Trigger or 35 Hours Later for the Prevention of OHSS
NCT02670304	PHASE4	COMPLETED	Preventive Application of Letrozole Decrease Incidence of Early Onset of OHSS
NCT03188471	PHASE4	UNKNOWN	Preventive Application of GnRH Antagonist on Early OHSS
NCT03996434	PHASE4	COMPLETED	Coasting Versus Antagonist Protocol in Patients at High Risk of OHSS
NCT04797338	PHASE4	UNKNOWN	Gonadotropin Releasing Hormone Agonist (GnRHa) Versus Estrogen and Progesterone for Luteal Support in High Responders
NCT05638529	PHASE4	UNKNOWN	Dual Trigger in IVF Patients at High Risk of Ovarian Hyper Stimulation Syndrome
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00440258	PHASE3	COMPLETED	Cabergoline Reduces OHSS
NCT01268761	PHASE3	COMPLETED	GnRH Antagonist for Treatment of Early Ovarian Hyperstimulation Syndrome
NCT01427335	PHASE3	COMPLETED	Calcium for Prevention of Ovarian Hyperstimulation Syndrome
NCT01535859	PHASE3	COMPLETED	Study of Cabergoline for Prevention of Ovarian Hyperstimulation Syndrome (OHSS) in In Vito Fertilization Cycles and Derivation of OHSS Biomarkers
NCT01709942	PHASE3	COMPLETED	Use of Degarelix in Controlled Ovarian Hyperstimulation (COH) Protocol for Women With PoliCystic Ovarian Syndrome (PCOS)
NCT02620605	PHASE3	UNKNOWN	The Influence of Timing of Cabergoline Initiation on Prevention of OHSS
NCT02686151	PHASE3	UNKNOWN	The Letrozole Administration During Luteal Phase
NCT03071172	PHASE3	UNKNOWN	Clinical Study of Recombinant Human Follitropin for Injection Assisted in COH Assisted IVF-ET
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00329693	PHASE2	COMPLETED	Study Assessing the Effect of 3-week Treatment With One of Three Oral Doses of Quinagolide
NCT00665041	PHASE2	COMPLETED	Tolerability of Quinagolide in a Dose-titration Regimen in Oocyte Donors at Risk of Developing Ovarian Hyperstimulation Syndrome
NCT02461875	PHASE2	UNKNOWN	Cabergoline Versus GnRH Antagonist Rescue and Cabergoline in the Prevention of Ovarian Hyperstimulation Syndrome
NCT02846493	PHASE2	UNKNOWN	Efficacy and Safety of Dexamethasone Prevention for Patients of Ovarian Hyperstimulation Syndrome
NCT02875587	PHASE2	COMPLETED	Cabergoline Versus Calcium Gluconate Infusion in the Prevention of Ovarian Hyperstimulation Syndrome
NCT03794037	PHASE2	SUSPENDED	Montelukast for Prevention & Treatment of OHSS
NCT04351126	PHASE2	COMPLETED	Management of Ovarian Hyperstimulation Syndrome as a State of Defective Mineralocorticoid Response
NCT00001221	PHASE2	COMPLETED	Effect of Biosynthetic Growth Hormone and/or Ethinyl Estradiol on Adult Height in Patients With Turner Syndrome
NCT00001253	PHASE2	COMPLETED	The Effects of Estrogen on Cognition in Girls With Turner Syndrome
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex