Hypopituitarism

Summary

Hypopituitarism (MONDO:0005152) is a disease with 3 cohort genes (7 GWAS associations across 7 studies) and 37 clinical trials. Top therapeutic interventions include somatropin, liothyronine, and acipimox.

At a glance

• Cohort genes: 3
• GWAS associations: 7
• ClinVar variants: 3
• Clinical trials: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypopituitarism
Mondo ID	MONDO:0005152
EFO	EFO:0001380
MeSH	D007018
DOID	DOID:9406
ICD-10-CM	E23.0
ICD-11	768216194
NCIT	C62591
SNOMED CT	74728003
UMLS	C0020635
MedGen	9386
Is cancer (heuristic)	no

Also known as: pituitary insufficiency

Data availability: 3 ClinVar variants · 7 GWAS associations (7 studies).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › pituitary gland disorder › hypopituitarism

Related subtypes (8): necrosis of pituitary, pituitary hypoplasia, empty sella syndrome, inappropriate ADH syndrome, neurohypophyseal diabetes insipidus, pituitary tumor, hypophysitis, anterior pituitary gland disorder

Subtypes (3): combined pituitary hormone deficiencies, genetic form, acquired pituitary hormone deficiency, Kaplowitz-Bodurtha syndrome

Genetics & variants

GWAS landscape

7 GWAS associations across 7 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs59324344	4e-13	CORIN	G	3.01
rs565223029	1e-12	TEKT1	C	3.61
rs181407133	2e-12	LINC03108 - LINC01348	C	4.16
rs186677894	2e-11	FHIT	T	3.79
rs577717345	2e-11	LINC01182	G	2.69
rs532270112	2e-11	SWAP70	C	3.38
rs187098262	4e-11	SVIL2P	C	3.69

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477336	Verma A	2024	1,000	449,862	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479897	Verma A	2024	310	121,501	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481591	Verma A	2024	310	121,501	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435723	Zhou W	2018	262	405,386	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90043643	Jiang L	2021	161	456,187	A generalized linear mixed model association tool for biobank-scale data.
GCST90726891	Kim HI	2026	103	43,923	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90468137	Loya H	2025	0	0	A scalable variational inference approach for increased mixed-model association power.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	7
unknown	0

Functional consequences

Consequence	Count
intron_variant	6
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs59324344	4	47644071	G>T	0	intron_variant	CORIN	4e-13	Tier 4: intronic/intergenic
rs565223029	17	6814769	C>A,T	0	intron_variant	TEKT1	1e-12	Tier 4: intronic/intergenic
rs181407133	1	235030991	C>T	0	intergenic_variant	LINC03108 - LINC01348	2e-12	Tier 4: intronic/intergenic
rs186677894	3	60529927	T>A	0	intron_variant	FHIT	2e-11	Tier 4: intronic/intergenic
rs577717345	4	14035232	G>A	0	intron_variant	LINC01182	2e-11	Tier 4: intronic/intergenic
rs532270112	11	9685832	C>T	0	intron_variant	SWAP70	2e-11	Tier 4: intronic/intergenic
rs187098262	10	30681365	C>A,T	0	intron_variant	SVIL2P	4e-11	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500743	NM_152730.6(TBC1D32):c.2200C>T (p.Arg734Ter)	TBC1D32	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803978	NM_002070.4(GNAI2):c.544A>C (p.Thr182Pro)	GNAI2	Likely pathogenic	criteria provided, single submitter
1338794	NM_002941.4(ROBO1):c.1400C>T (p.Ala467Val)	ROBO1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROBO1	Orphanet:95496	Pituitary stalk interruption syndrome
TBC1D32	Orphanet:141007	Orofaciodigital syndrome type 9

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ROBO1	HGNC:10249	ENSG00000169855	Q9Y6N7	Roundabout homolog 1	clinvar
TBC1D32	HGNC:21485	ENSG00000146350	Q96NH3	Protein broad-minded	clinvar
GNAI2	HGNC:4385	ENSG00000114353	P04899	Guanine nucleotide-binding protein G(i) subunit alpha-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROBO1	Roundabout homolog 1	Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuro…
TBC1D32	Protein broad-minded	Required for high-level Shh responses in the developing neural tube.
GNAI2	Guanine nucleotide-binding protein G(i) subunit alpha-2	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ROBO1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
TBC1D32	Other/Unknown	no		BROMI_M, Rab-GAP_TBC_sf, PHAF1/BROMI
GNAI2	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
tibia	1
ventricular zone	1
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
granulocyte	1
monocyte	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROBO1	287	ubiquitous	marker	ventricular zone, ganglionic eminence, tibia
TBC1D32	208	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
GNAI2	291	ubiquitous	marker	granulocyte, monocyte, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAI2	3,311
ROBO1	2,359
TBC1D32	919

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAI2	P04899	34
ROBO1	Q9Y6N7	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D32	Q96NH3	80.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SLIT2:ROBO1 increases RHOA activity	1	1427.5×	0.008	ROBO1
Regulation of cortical dendrite branching	1	1142.0×	0.008	ROBO1
Inactivation of CDC42 and RAC1	1	713.8×	0.008	ROBO1
Role of ABL in ROBO-SLIT signaling	1	634.4×	0.008	ROBO1
Regulation of commissural axon pathfinding by SLIT and ROBO	1	475.8×	0.008	ROBO1
Activation of RAC1	1	407.9×	0.008	ROBO1
Adenylate cyclase inhibitory pathway	1	380.7×	0.008	GNAI2
ADP signalling through P2Y purinoceptor 12	1	248.3×	0.011	GNAI2
Netrin-1 signaling	1	219.6×	0.011	ROBO1
Adrenaline,noradrenaline inhibits insulin secretion	1	196.9×	0.011	GNAI2
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.014	GNAI2
GPER1 signaling	1	124.1×	0.014	GNAI2
G alpha (z) signalling events	1	116.5×	0.014	GNAI2
Regulation of insulin secretion	1	109.8×	0.014	GNAI2
Extra-nuclear estrogen signaling	1	85.2×	0.017	GNAI2
Signaling by ROBO receptors	1	62.1×	0.022	ROBO1
G alpha (s) signalling events	1	36.6×	0.035	GNAI2
Regulation of expression of SLITs and ROBOs	1	34.6×	0.035	ROBO1
Axon guidance	1	22.6×	0.051	ROBO1
Nervous system development	1	21.5×	0.051	ROBO1
G alpha (i) signalling events	1	19.5×	0.053	GNAI2
Developmental Biology	1	7.2×	0.134	ROBO1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chemorepulsion involved in postnatal olfactory bulb interneuron migration	1	2808.7×	0.008	ROBO1
negative regulation of negative chemotaxis	1	1872.4×	0.008	ROBO1
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	1404.3×	0.008	TBC1D32
axon midline choice point recognition	1	1123.5×	0.008	ROBO1
negative regulation of mammary gland epithelial cell proliferation	1	1123.5×	0.008	ROBO1
Roundabout signaling pathway	1	936.2×	0.008	ROBO1
G protein-coupled adenosine receptor signaling pathway	1	802.5×	0.008	GNAI2
negative regulation of chemokine-mediated signaling pathway	1	802.5×	0.008	ROBO1
negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway	1	802.5×	0.008	GNAI2
heart induction	1	702.2×	0.008	ROBO1
negative regulation of calcium ion-dependent exocytosis	1	624.1×	0.008	GNAI2
retinal pigment epithelium development	1	561.7×	0.008	TBC1D32
negative regulation of synaptic transmission	1	561.7×	0.008	GNAI2
endocardial cushion formation	1	468.1×	0.008	ROBO1
negative regulation of adenylate cyclase activity	1	468.1×	0.008	GNAI2
positive regulation of urine volume	1	432.1×	0.009	GNAI2
positive regulation of vascular endothelial growth factor signaling pathway	1	374.5×	0.009	ROBO1
G protein-coupled acetylcholine receptor signaling pathway	1	351.1×	0.009	GNAI2
positive regulation of vascular endothelial growth factor receptor signaling pathway	1	351.1×	0.009	ROBO1
pulmonary valve morphogenesis	1	312.1×	0.009	ROBO1
positive regulation of superoxide anion generation	1	295.6×	0.009	GNAI2
regulation of calcium ion transport	1	267.5×	0.010	GNAI2
positive regulation of neural precursor cell proliferation	1	255.3×	0.010	GNAI2
cell migration involved in sprouting angiogenesis	1	216.1×	0.011	ROBO1
outflow tract septum morphogenesis	1	216.1×	0.011	ROBO1
positive regulation of Rho protein signal transduction	1	193.7×	0.011	ROBO1
positive regulation of axonogenesis	1	193.7×	0.011	ROBO1
aorta development	1	187.2×	0.011	ROBO1
negative regulation of apoptotic signaling pathway	1	187.2×	0.011	GNAI2
gamma-aminobutyric acid signaling pathway	1	181.2×	0.011	GNAI2

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Somatropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Anastrozole.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNAI2	2	3
ROBO1	0	0
TBC1D32	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALISERTIB	3	GNAI2
MOLIBRESIB	2	GNAI2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GNAI2	9	Binding:9

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ALISERTIB	3	GNAI2
MOLIBRESIB	2	GNAI2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GNAI2
C	Druggable family + PDB, no drug	1	ROBO1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TBC1D32

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ROBO1	0	—
TBC1D32	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 37.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE4	8
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT00360074	PHASE4	COMPLETED	Phase 4 Study in Secondary Hypothyroidism: Body Weight Adapted Thyroxin Treatment and Triiodothyronine Supplementation
NCT00490191	PHASE4	COMPLETED	Comparison of Two Growth Hormone Dosing Methods in Adults With Growth Hormone Deficiency
NCT00851942	PHASE4	COMPLETED	Determination of Method-specific Normal Cortisol and Adrenal Hormone Responses to the Short Synacthen Test
NCT04897802	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (GLP1 Study)
NCT04902235	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (CRH Study)
NCT05188131	PHASE4	COMPLETED	Acute Neuroendocrine Response to Intravenous Infusion of Diclofenac Sodium
NCT05206149	PHASE4	COMPLETED	Stimulation Test With Intranasal Glucagon for Corticotroph, Somatotroph and Antidiuretic Axes
NCT00133354	PHASE2/PHASE3	COMPLETED	Arimidex Multicenter Trial in Growth Hormone (GH) Deficient Boys
NCT01007071	PHASE3	COMPLETED	Effects of Growth Hormone on Cognition and Cerebral Metabolism in Adults With Growth Hormone Deficiency
NCT04121780	PHASE2	RECRUITING	Growth Hormone Replacement Therapy for Retried Professional Football Players
NCT00080483	PHASE2	COMPLETED	Testosterone and Growth Hormone for Bone Loss in Men
NCT07568509	EARLY_PHASE1	RECRUITING	Identifying Oxytocin Deficiency in Pediatric Patients With Pituitary Disease
NCT05990491	Not specified	RECRUITING	Pituitary Function After Recovery From Septic Shock Among ICU Survivors
NCT06326853	Not specified	NOT_YET_RECRUITING	Neuroendocrine Mechanisms in Adiposity: An Integrated Approach to the Characterization of Potential Pharmacological Novel Targets Based on Experimental and Clinical Models
NCT07143266	Not specified	RECRUITING	Sleep Disorders in Hypothalamic and Pituitary Damage
NCT00027430	Not specified	COMPLETED	Androgen Replacement Therapy in Women With Hypopituitarism
NCT00139945	Not specified	COMPLETED	Ghrelin, Growth Hormone and Cortisol Interaction in Growth Hormone Deficient Patients
NCT00462475	Not specified	COMPLETED	Effect of 5 Years of GH Replacement on Atherosclerosis
NCT00504218	Not specified	TERMINATED	Detection and Treatment of Endocrine Abnormalities in Childhood Cancer Survivors and Hematopoietic Stem Cell Transplant Recipients
NCT00507104	Not specified	COMPLETED	Pituitary Functions After Traumatic Brain Injury (TBI) and/or Subarachnoid Hemorrhage (SAH)
NCT00572390	Not specified	COMPLETED	Oestrogen Withdrawal in Hypopituitary Women
NCT00666068	Not specified	COMPLETED	Effects of Corticotropin Releasing Hormone (CRH) on the Sleep in Patients With Hypopituitarism
NCT00962559	Not specified	COMPLETED	Hypopituitarism After Aneurismal Subarachnoid Hemorrhage
NCT01009905	Not specified	COMPLETED	An Observational Study (Registry) Assessing Treatment Outcomes and Safety for Children and Adults Who Are Prescribed Norditropin® (Human Growth Hormone)
NCT01028742	Not specified	COMPLETED	Posttraumatic Hypopituitarism - Incidence, Predictors and Test Validity
NCT01088399	Not specified	COMPLETED	A Prospective Observational Study of Effect of Somatropin on Growth Hormone Deficient Adults
NCT01209416	Not specified	COMPLETED	The Effect of Pharmacological Antilipolysis on the Metabolic Effects of Ghrelin
NCT01574859	Not specified	COMPLETED	Central Hypothyroidism and Cardiovascular Risk
NCT01666964	Not specified	UNKNOWN	Hormone Deficiency After Brain Injury During Combat
NCT02360046	Not specified	TERMINATED	The Influence of Different Hydrocortisone Replacement Doses on the Partitioning and Flexibility of Ectopic Lipids in Patients With Corticotropic Hypopituitarism
NCT02782208	Not specified	COMPLETED	Lipolytic Effects of GH in Hypopituitary Patients in Vivo
NCT02871986	Not specified	UNKNOWN	Pubertal Induction in Individuals With Hypogonadism
NCT03708523	Not specified	UNKNOWN	Next Day Growth Hormone Predicting Pituitary Function After Adenomectomy
NCT05319301	Not specified	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (Melatonin Study)
NCT06014398	Not specified	UNKNOWN	Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours
NCT07015645	Not specified	COMPLETED	Long-Term Outcomes of Hypopituitarism Following Gamma Knife Radiosurgery for Pituitary Adenomas

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOMATROPIN	4	6
LIOTHYRONINE	4	3
ACIPIMOX	4	2
ANASTROZOLE	4	1
COSYNTROPIN	4	1
LEVOTHYROXINE	4	1
TESTOSTERONE	4	1
GHRELIN	3	1
RATHYRONINE	2	1
CHEMBL4746472	0	1
CHEMBL425281	0	1
CHEMBL5410324	0	1