Familial hyperprolactinemia

Summary

Familial hyperprolactinemia (MONDO:0014250) is a disease with 1 cohort gene and 26 clinical trials. Top therapeutic interventions include aripiprazole, ropinirole, and bromocriptine.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 8
• Phenotypes (HPO): 9
• Clinical trials: 26

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000876	Oligomenorrhea	Very frequent (80-99%)
HP:0100829	Galactorrhea	Very frequent (80-99%)
HP:0000141	Amenorrhea	Frequent (30-79%)
HP:0000789	Infertility	Frequent (30-79%)
HP:0012886	Hemorrhagic ovarian cyst	Frequent (30-79%)
HP:0000132	Menorrhagia	Occasional (5-29%)
HP:0000134	Female hypogonadism	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperprolactinemia
Mondo ID	MONDO:0014250
OMIM	615555
Orphanet	397685
SNOMED CT	763715007
UMLS	C4706551
MedGen	1645317
GARD	0017634
Is cancer (heuristic)	no

Also known as: familial hyperprolactinemia · familial isolated prolactin receptor deficiency · hereditary hyperprolactinemia (disease) · HPRL · hyperprolactinemia

Data availability: 8 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › pituitary gland disorder › anterior pituitary gland disorder › hyperpituitarism › hyperprolactinemia › familial hyperprolactinemia

Related subtypes (1): acquired hyperprolactinemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

8 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
599315	NM_000949.7(PRLR):c.511C>T (p.Arg171Ter)	PRLR	Pathogenic	no assertion criteria provided
599316	NM_000949.7(PRLR):c.806C>T (p.Pro269Leu)	PRLR	Pathogenic	no assertion criteria provided
89027	NM_000949.7(PRLR):c.635A>G (p.His212Arg)	PRLR	Pathogenic	no assertion criteria provided
1526078	NM_000949.7(PRLR):c.1483C>T (p.Pro495Ser)	PRLR	Uncertain significance	criteria provided, single submitter
3310228	NM_000949.7(PRLR):c.235A>G (p.Ile79Val)	PRLR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3783429	NM_000949.7(PRLR):c.1469C>T (p.Thr490Met)	PRLR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892187	NM_000949.7(PRLR):c.119A>G (p.Asn40Ser)	PRLR	Uncertain significance	criteria provided, single submitter
4294053	NM_000949.7(PRLR):c.842C>T (p.Ala281Val)	PRLR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PRLR	Supportive	Autosomal dominant	familial hyperprolactinemia	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRLR	Orphanet:397685	Familial hyperprolactinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRLR	HGNC:9446	ENSG00000113494	P16471	Prolactin receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRLR	Prolactin receptor	This is a receptor for the anterior pituitary hormone prolactin (PRL).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRLR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
placenta	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRLR	200	broad	marker	placenta, choroid plexus epithelium, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRLR	985

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRLR	P16471	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Prolactin receptor signaling	1	761.3×	0.002	PRLR
Growth hormone receptor signaling	1	475.8×	0.002	PRLR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
activation of transmembrane receptor protein tyrosine kinase activity	1	5617.3×	0.002	PRLR
activation of Janus kinase activity	1	4213.0×	0.002	PRLR
prostate gland growth	1	2106.5×	0.002	PRLR
regulation of epithelial cell differentiation	1	1872.4×	0.002	PRLR
cellular response to granulocyte macrophage colony-stimulating factor stimulus	1	1296.3×	0.002	PRLR
mammary gland epithelial cell differentiation	1	1203.7×	0.002	PRLR
mammary gland alveolus development	1	991.3×	0.003	PRLR
steroid biosynthetic process	1	601.9×	0.004	PRLR
lactation	1	421.3×	0.005	PRLR
embryo implantation	1	351.1×	0.005	PRLR
positive regulation of B cell proliferation	1	343.9×	0.005	PRLR
regulation of cell adhesion	1	306.4×	0.005	PRLR
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.005	PRLR
response to bacterium	1	193.7×	0.007	PRLR
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	PRLR
cytokine-mediated signaling pathway	1	130.6×	0.009	PRLR
negative regulation of apoptotic process	1	34.8×	0.030	PRLR
positive regulation of cell population proliferation	1	33.6×	0.030	PRLR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRLR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRLR	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	1	PRLR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRLR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 26.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE4	5
PHASE2	3
PHASE3	2
PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00541554	PHASE4	UNKNOWN	Reversal of Antipsychotic-Induced Hyperprolactinemia, Weight Gain, Hyperglycemia and Dyslipidemia
NCT00625950	PHASE4	COMPLETED	Endometriosis Patients Undergoing Quinagolide Treatment
NCT00889512	PHASE4	TERMINATED	The Luveris In Vitro Fertilization Trial
NCT01085383	PHASE4	COMPLETED	Aripiprazole and Prolactin Study
NCT01742390	PHASE4	UNKNOWN	A Multicenter Study to Evaluate the Effects of Switching to Aripiprazole 12 Weeks on the Sexual Dysfunction From Risperidone or Paliperidone in Patients With Schizophrenia Spectrum Disorders or Bipolar Spectrum Disorders
NCT07124221	PHASE3	RECRUITING	A Phase III Clinical Study of Cabergoline Tablets Compared With Bromocriptine Mesylate Tablets
NCT00315081	PHASE3	UNKNOWN	Risperidone-Induced Hyperprolactinemia Treated With Bromocriptine
NCT01852331	PHASE2	COMPLETED	Peony-Glycyrrhiza Decoction (PGD) for Antipsychotic-induced Hyperprolactinemia in Patients With Schizophrenia
NCT02956447	PHASE2	COMPLETED	Administration of Kisspeptin in Patients With Hyperprolactinemia
NCT03038308	PHASE1/PHASE2	COMPLETED	Treatment of Hyperprolactinemia With the Non-ergoline Dopamine Agonist Ropinirole
NCT03709849	PHASE2	UNKNOWN	Effectiveness and Safety of Bushen Culuan Decoction for Anovulatory Infertility
NCT07008417	PHASE1	ACTIVE_NOT_RECRUITING	A Study on Bioequivalence of Cabergoline Tablets in Human Body
NCT00914823	PHASE1	COMPLETED	Kisspeptin Administration in the Adult
NCT00436111	Not specified	COMPLETED	Characterization of Macroprolactinemia
NCT00699530	Not specified	WITHDRAWN	Substrate Metabolism and Insulin Sensitivity in Patients With Hyperprolactinemia Before and After Treatment
NCT01052948	Not specified	COMPLETED	The Association Between Dopamine Agonists and Cardiac Valvulopathy, Fibrosis and Other Cardiopulmonary Events
NCT01270711	Not specified	COMPLETED	Study On Utilization Of Cabergoline For Compliance With Risk Minimization Activities (SUCRE)
NCT01338298	Not specified	COMPLETED	Double-Blind Placebo Controlled Study of Adjunctive Aripiprazole for Symptomatic Hyperprolactinemia In Premenopausal Women With Schizophrenia
NCT02098668	Not specified	COMPLETED	Mathematical Model for the Human Menstrual Cycle, Endocrinological Diseases and Fertility Treatment-PAEON
NCT02603549	Not specified	SUSPENDED	Pituitary Function and Spontaneous Intracranial Hypotension
NCT03569787	Not specified	COMPLETED	Hyperprolactinaemia Management in Reproductive Services at University Hospital of Coventry and Warwickshire
NCT04146389	Not specified	TERMINATED	Hyperprolactinemia and Adrenal Steroidogenesis
NCT04439747	Not specified	UNKNOWN	Develop and Implement Methods for Diagnostic and Treatment of Hormonal Disorders in Patients With Chronic Kidney Disease
NCT04746313	Not specified	COMPLETED	Prevalence of Hyperprolactinemia in Systemic Scleroderma
NCT05033119	Not specified	COMPLETED	PROSA: Prolactin, Sex Hormones, Growth and Metabolic Biomarkers in Children and Adolescents on Antipsychotics
NCT06326840	Not specified	COMPLETED	Clinical Efficacy and Adverse Reactions of Antipsychotic Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ARIPIPRAZOLE	4	4
ROPINIROLE	4	3
BROMOCRIPTINE	4	2
CABERGOLINE	4	2
GONADORELIN ACETATE	4	2
KISSPEPTIN	2	2
CHEMBL4593105	0	2
CHEMBL5192470	0	2
CHEMBL2370644	0	2