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Classifications

Harrison's Part

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Mappings

NCIT

NCIT:C3434 Uterine Corpus Leiomyoma

NCIT's uterine corpus leiomyoma concept matches this entry's MONDO anchor (MONDO:0007886, uterine corpus leiomyoma) term for term, and is the term the histopathology findings in this entry bind to.

ICD-10-CM

ICD10CM:D25 Leiomyoma of uterus

ICD10CM:D25 is the billing-code category for leiomyoma of uterus, coextensive with this entry. Its subcodes D25.0 (submucous), D25.1 (intramural) and D25.2 (subserosal) partition the same concept by location, so the parent category rather than any subcode is the exact match.

NCIT

NCIT:C3434 Uterine Corpus Leiomyoma

NCIT's uterine corpus leiomyoma concept matches this entry's MONDO anchor (MONDO:0007886, uterine corpus leiomyoma) term for term, and is the term the histopathology findings in this entry bind to.

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Subtypes

3

MED12-mutant leiomyoma

MED12 hgnc:11957

The dominant molecular subtype, defined by a recurrent somatic exon-2 point mutation in MED12 disrupting the CDK8/CDK19 kinase module of the Mediator complex. These tumors tend to be multiple rather than solitary, are found even at small size, are more frequent in Black women, and carry a distinctive ECM-organization and Wnt/beta-catenin transcriptional program. Reported frequency spans 50-80% of tumors depending on cohort and detection method.

Show evidence (1 reference)

PMID:37668348 SUPPORT Human Clinical

"Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs."

Establishes MED12-mutant tumors as the most common molecular subtype at 50-80%.

HMGA2-rearranged / HMGA2-overexpressing leiomyoma

HMGA2 hgnc:5009

The second subtype, defined by 12q14-15 rearrangement or overexpression of the architectural transcription factor HMGA2. Around 10% of fibroids overall, but markedly enriched in the cellular leiomyoma histologic variant, where HMGA2 overexpression was found in 36.5% and HMGA2 rearrangement in 13.2% of cases. Largely mutually exclusive with MED12 mutation.

Show evidence (2 references)

PMID:34626221 SUPPORT Human Clinical

"36.5% showed HMGA2 overexpression at the IHC level, associated with increased mRNA expression in 14/14 cases. The rearrangement of the HMGA2 gene was detected in 13.2%."

Quantifies HMGA2 overexpression and rearrangement in the cellular leiomyoma variant where this subtype concentrates.

PMID:38326302 SUPPORT Human Clinical

"Notably, the majority of these mutations are mutually exclusive, and integrative data analysis reveals mutation-specific distinct driver gene expression programs and biomarkers in UF"

Supplies the citation for the mutual-exclusivity claim in this subtype's description, and for the premise that each driver class has its own expression programme - which is what makes these molecular subtypes rather than co-occurring lesions.

FH-deficient leiomyoma

FH hgnc:3700

An uncommon but clinically consequential subtype defined by biallelic loss of fumarate hydratase, recognizable on routine histology by a cluster of features (staghorn vasculature, alveolar-pattern oedema, bizarre nuclei, eosinophilic nucleoli with perinucleolar haloes, eosinophilic intracytoplasmic globules) and confirmable by loss of FH or gain of 2SC staining. It matters out of proportion to its frequency because a large fraction of cases carry a germline FH variant - 31 of 80 tumors (39%) in the reference series, or 52% of those in which sequencing found a variant at all - which makes the patient and her relatives HLRCC kindred at risk of renal cell carcinoma.

Show evidence (1 reference)

PMID:37263921 SUPPORT Human Clinical

"More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients."

Establishes the recognizable histologic signature that defines this subtype in practice, present in 98.5% of the series.

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Discussions and Knowledge Gaps

3

If MED12 exon-2 mutation is a gain-of-function driver present in most fibroids, why do MED12 wild-type tumors grow faster than mutant ones?

CONTROVERSY OPEN med12_mutation_growth_paradox

Attached to

pathophysiology#Driver Mutation-Initiated Clonal Transformation genetic#MED12 somatic exon-2 mutation

The entry records MED12 mutation as a gain-of-function driver, which is what the review literature says, and that reading invites the inference that the mutation drives growth. A 44-tumor series reports the opposite for growth specifically: wild-type leiomyomas have higher growth potential and higher MED12-associated CDK8 kinase activity than mutant ones, and CDK8 inhibition suppresses wild-type cell growth in primary culture. One way to reconcile these is that the mutation is required for tumor initiation while wild-type tumors, once initiated by some other route, retain more intact Mediator-kinase output and therefore grow faster. That reconciliation is not established, and an entry that recorded only the gain-of-function label would hide the tension rather than resolve it.

Show evidence (2 references)

PMID:41493967 SUPPORT Human Clinical

"Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment."

The measurement behind the controversy: CDK8 activity is highest in untreated wild-type tumors, lower in mutant ones.

PMID:41493967 SUPPORT In Vitro

"Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis."

Shows the CDK8 activity is functionally load-bearing for growth in the wild-type tumors, which is what makes this a mechanistic question rather than a measurement artifact.

Which mechanism dominates fibroid-associated heavy menstrual bleeding: rupture of structurally deficient pseudocapsule neovessels, dilated venous lakes from mass effect, or TGF-beta-3-mediated endometrial hemostatic failure?

OPEN QUESTION OPEN hmb_dominant_mechanism

Attached to

pathophysiology#Aberrant Pseudocapsule Angiogenesis and Venous Ectasia pathophysiology#Endometrial Hemostatic Failure and Impaired Vessel Closure phenotypes#Heavy Menstrual Bleeding

All three mechanisms are separately evidenced and this entry curates all three, but their relative contribution is unsettled and the candidate explanations make different predictions. The pseudocapsule account predicts bleeding should track fibroid location, since only intramural fibroids develop a pseudocapsule. The venous-lake account was originally attributed to interstitial pressure and later reattributed to growth factors enlarging the veins. The endometrial account is location-independent and predicts bleeding even from fibroids that do not distort the cavity. Distinguishing them matters clinically, because tranexamic acid and the levonorgestrel system act on the endometrial arm while embolization and ablation act on the vascular one.

Show evidence (1 reference)

PMID:36303616 SUPPORT Human Clinical

"These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of..."

The source itself frames these as competing theories under review rather than as a settled mechanism, which is the state this discussion records.

Does a Tsc2-driven rat tumor tell us anything about how a MED12-, HMGA2- or FH-driven human fibroid starts?

HUMAN MODEL MISMATCH OPEN eker_rat_driver_mismatch

Attached to

pathophysiology#Driver Mutation-Initiated Clonal Transformation animal_models#Rat

The Eker rat is the workhorse spontaneous model and its tumors look and behave like human fibroids at the tissue and hormonal level, so results from it are routinely read as being about fibroid biology generally. But its lesion is a germline Tsc2 mutation acting through mTOR, and none of the recurrent human somatic drivers is present. The mismatch is therefore not that evidence is missing but that evidence exists in a system whose initiating genotype is wrong, which is the distinction between a knowledge gap and a model mismatch. The practical consequence is that the developmental-exposure and vitamin D results obtained in this strain support the environmental records in this entry at the level of myometrial stem cell DNA repair, and do not support any claim about the human driver mutations themselves.

Show evidence (1 reference)

PMID:41810407 SUPPORT Model Organism

"Current uterine fibroid animal models cannot fully reproduce the complex pathological process of human ULs, so optimization of current pathological models is needed."

The review's own statement that no current animal model fully reproduces human fibroid pathology, which is the general form of this specific mismatch.

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Pathophysiology

9

Driver Mutation-Initiated Clonal Transformation

Uterine leiomyomas (fibroids) originate as monoclonal tumors from a single myometrial smooth muscle cell (or a myometrial stem cell acquiring tumor-initiating features) that acquires a recurrent somatic driver mutation. The most common driver is a MED12 exon-2 mutation (~70-77%), followed by HMGA2/HMGA1 overexpression or chromosomal rearrangement (~10%, 12q14-15), biallelic FH (fumarate hydratase) loss defining the FH-deficient subtype (also seen in hereditary leiomyomatosis and renal cell cancer, HLRCC), with rarer collagen IV (COL4A5/COL4A6) deletions also reported. Heterozygous MED12 mutations disrupt the CDK8/CDK19 kinase module of the Mediator complex, altering the chromatin landscape, enhancer engagement, genomic stability, and progesterone responsiveness. Scoping decision, recorded so it is not mistaken for an oversight: COL4A5/COL4A6 deletion and the SRCAP-complex class are named here but are deliberately not given has_subtypes entries. Both are recurrent but rare relative to the three modelled classes, neither has a distinct pathophysiology arm this entry could populate beyond the shared ECM output, and neither changes management. A curator with a collagen-IV-specific mechanism or frequency source should add the subtype then.

myometrial smooth muscle cell CL:0002366

MED12 hgnc:11957 HMGA2 hgnc:5009 FH hgnc:3700

Genetic context variant_origin: SOMATIC functional_impact_category: GAIN_OF_FUNCTION

This block describes the MED12 arm only, which is the majority route and the one the node's evidence characterizes. It does not describe FH, whose lesion is biallelic loss of a tumor suppressor (LOSS_OF_FUNCTION) and is germline in roughly half of FH-deficient tumors - see the separate FH node and the FH-deficient subtype. It does not describe HMGA2 rearrangement either, which is a structural event rather than a point-mutation gain of function. The slots are single-valued, so restricting them to one arm and saying so is more accurate than picking a value that is wrong for two of the three genes.

Wnt/beta-catenin signaling dysregulation GO:0016055 ↑ INCREASED

Animal models

Eker rat (germline Tsc2 mutation) Rat fails to recapitulate The model does not reproduce the human initiating lesion. Its tumors start from a germline Tsc2 mutation present in every cell, where human fibroids start from a somatic driver acquired by one myometrial cell, so the monoclonal-origin and driver-genotype claims of this node are outside what the model can support.

Downstream

Hormone-Driven Myometrial Smooth Muscle Proliferation The transformed clonal cell becomes dependent on estrogen and progesterone: progesterone (via PGR) drives paracrine WNT ligand secretion that stimulates tumor stem cell proliferation.

Fumarate Accumulation in FH-Deficient Leiomyoma In the FH-deficient subtype the driver lesion is biallelic loss of the tricarboxylic-acid-cycle enzyme fumarate hydratase, so the initiating event is metabolic rather than transcriptional: fumarate accumulates and succinates cysteine residues, which is the branch this edge names.

Show evidence (4 references)

PMID:40214304 SUPPORT Human Clinical

"The most common somatic mutations in fibroids affect the Mediator complex subunit 12 (MED12; 77%) and high-mobility group AT-hook 2/1 (HMGA2/1; 10%) genes."

Establishes MED12 (77%) and HMGA2/1 (10%) as the dominant recurrent somatic drivers initiating fibroid tumors.

PMID:40214304 SUPPORT Human Clinical

"Heterozygous mutations in MED12, a chromatin-associated protein, disrupt the attached CDK8 kinase module in the Mediator complex. MED12 mutations are associated with increased genomic instability, altered chromatin landscape and enhancer engagement, and increased responsiveness to progesterone."

Describes the molecular consequence of MED12 driver mutations on the Mediator kinase module and progesterone responsiveness.

PMID:37668348 SUPPORT Human Clinical

"Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs."

Independent review confirming MED12 as the most common driver, present in 50-80% of fibroids.

+ 1 more reference

Hormone-Driven Myometrial Smooth Muscle Proliferation

Estradiol and progesterone are essential for fibroid growth. During each ovulatory cycle the myometrium proliferates under ovarian steroid stimulation. Progesterone, acting through its nuclear receptor (PGR) in differentiated fibroid cells, activates paracrine secretion of WNT ligands, cytokines, and growth factors that drive a small stem cell population to proliferate. Fibroids rarely arise before menarche and frequently regress after menopause, underscoring steroid hormone dependence. The excessive matrix these proliferating cells and the adjacent tumor-associated fibroblasts lay down is modelled as the separate downstream node "Excessive Extracellular Matrix Deposition and Tissue Stiffening"; this node is the cell-population expansion alone.

myometrial smooth muscle cell CL:0002366 tumor-associated fibroblast CL:0000057

smooth muscle cell proliferation GO:0048661 ↑ INCREASED progesterone receptor signaling GO:0050847 ↑ INCREASED

Animal models

Eker rat (germline Tsc2 mutation) Rat partially recapitulates Reproduces spontaneous, hormone-dependent uterine smooth muscle tumorigenesis in an intact animal, which is what makes it usable for gene-environment and chemoprevention work no in vitro system can do.

Downstream

Excessive Extracellular Matrix Deposition and Tissue Stiffening The expanded clone and the tumor-associated fibroblasts recruited alongside it secrete the collagen-rich matrix that gives the tumor its bulk and its name.

Aberrant Pseudocapsule Angiogenesis and Venous Ectasia The growing clone induces its own blood supply, organized as a vascularized pseudocapsule rather than by the hypoxia-driven route used by malignant tumors.

Show evidence (5 references)

PMID:40214304 SUPPORT Other

"Progesterone, via its receptors in differentiated fibroid cell populations, activates the production of Wingless-type MMTV integration site family (WNT) ligands, cytokines, and other growth substances to act on adjacent stem cells in a paracrine fashion to support tumor growth."

Defines the progesterone-driven paracrine WNT mechanism supporting fibroid stem cell proliferation.

PMID:40214304 SUPPORT Other

"Both the mutated smooth muscle cells and the adjacent tumor-associated fibroblasts lay down excessive quantities of extracellular matrix, providing a unique feature that led to naming these tumors "fibroids.""

Establishes that mutated smooth muscle cells and tumor-associated fibroblasts deposit the excessive ECM characteristic of fibroids.

PMID:37668348 SUPPORT Human Clinical

"Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs."

Links MED12 mutation to upregulated ECM-organization/collagen genes and Wnt/beta-catenin dysregulation.

+ 2 more references

Fumarate Accumulation in FH-Deficient Leiomyoma

In the fumarate-hydratase-deficient subtype, biallelic FH loss blocks the tricarboxylic-acid cycle at the fumarate-to-malate step, so fumarate accumulates and non-enzymatically succinates protein cysteine residues, forming the S-(2-succino)-cysteine adduct that immunohistochemistry detects. This node is the accumulation step alone; what the accumulated fumarate then does is the downstream pseudohypoxia node, matching the way the module it conforms to separates the two. The subtype is defined by the same chemistry whether the first FH hit is germline or somatic, and the germline case is hereditary leiomyomatosis and renal cell cancer, curated separately as Hereditary_Leiomyomatosis_and_Renal_Cell_Cancer.

myometrial smooth muscle cell CL:0002366

FH hgnc:3700

tricarboxylic acid cycle GO:0006099 ↓ DECREASED

fumarate hydratase activity GO:0004333 ↓ DECREASED

Downstream

Pseudohypoxic HIF Stabilization in FH-Deficient Leiomyoma Accumulated fumarate competitively inhibits the 2-oxoglutarate-dependent HIF prolyl hydroxylases, which is the step from oncometabolite to pseudohypoxia.

Show evidence (2 references)

PMID:37263921 SUPPORT Human Clinical

"Based on the Sanger sequencing results, the cases were divided into germline variant group (31 cases), somatic variant group (29 cases) and no variant group (20 cases)."

An 80-case FH-deficient leiomyoma series in which the FH lesion is germline in roughly as many tumors as it is somatic, supporting the claim that the subtype is defined by FH loss rather than by how the first hit was acquired.

PMID:36981015 SUPPORT In Vitro

"Loss of function variant of FH gene inactivates the Kreb's cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC."

Establishes that the pathogenic mechanism of an FH variant in uterine leiomyoma is loss of the Krebs-cycle enzyme activity, which is the lesion this node describes.

Pseudohypoxic HIF Stabilization in FH-Deficient Leiomyoma

With the HIF prolyl hydroxylases inhibited by fumarate, HIF-alpha escapes degradation and a hypoxia transcriptional programme runs in a normoxic cell. This is the FH subtype's distinctive route to the tumor's distorted, staghorn vasculature. Read this alongside the angiogenesis node, which records HIF-1-alpha as absent from uterine fibroids. The two are not in conflict but the boundary matters: that observation comes from unselected fibroids, which are overwhelmingly MED12- or HMGA2-driven, and it is what establishes that the common fibroid does NOT use the hypoxia/VEGF route. Pseudohypoxia is specific to the uncommon FH-deficient subtype, where it is driven by a metabolite rather than by low oxygen. A reader who took the pseudohypoxia claim to apply to fibroids generally would have it backwards.

myometrial smooth muscle cell CL:0002366

Downstream

Excessive Extracellular Matrix Deposition and Tissue Stiffening The FH-deficient route converges on the same fibrotic output as the transcriptional drivers, producing a tumor with the characteristic distorted staghorn vasculature and alveolar-pattern oedema.

Show evidence (1 reference)

PMID:36981015 SUPPORT Human Clinical

"This increases the levels of intracellular fumarate which inhibits the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, contributing to the accumulation of HIF-"

The mechanism of this node: fumarate inhibits the prolyl hydroxylases, so HIF-alpha accumulates without hypoxia.

Excessive Extracellular Matrix Deposition and Tissue Stiffening

The defining feature of a fibroid is not its cell count but its matrix: the mutated smooth muscle cells and the adjacent tumor-associated fibroblasts deposit disproportionate quantities of collagen, fibronectin and proteoglycans, which constitute a substantial fraction of tumor volume. The accumulated matrix is not inert. It stiffens the tissue, and it binds and prolongs the activity of the growth factors (TGF-beta chief among them) that drove its own deposition, so the matrix becomes a self-reinforcing feed-forward arm of the mechanism rather than the end of it. Matrix metalloproteinase activity is dysregulated in parallel, so remodeling as well as deposition is abnormal. This is the node on which the disease's name rests and the one that distinguishes a fibroid from a simple hyperplasia.

leiomyoma smooth muscle cell CL:0000192 tumor-associated fibroblast CL:0000057

excessive extracellular matrix deposition GO:0030198 ↑ INCREASED collagen fibril organization GO:0030199 ↑ INCREASED TGF-beta receptor signaling GO:0007179 ↑ INCREASED

Animal models

Eker rat (germline Tsc2 mutation) Rat rescues The Eker rat is the system in which vitamin D3 was shown to restore the MRN complex/ATM DNA-repair axis in myometrial stem cells after developmental DES exposure, which is the experimental basis for the vitamin D environmental record in this entry.

Human leiomyoma tissue xenograft in immunodeficient mouse Mouse recapitulates The graft retains the histopathological morphology of the source tumor, matrix included, which is exactly the property that makes it the translational bridge.

Downstream

Tumor Growth and Clinical Manifestations Sustained proliferation plus excessive matrix deposition produce a growing, space-occupying smooth muscle tumor that distorts the uterine architecture and generates the clinical phenotype.

Show evidence (3 references)

PMID:36982852 SUPPORT Human Clinical

"Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs."

Names excessive ECM deposition and aberrant remodeling as the central characteristic of uterine fibroids, which is exactly what this node asserts.

PMID:36982852 SUPPORT Human Clinical

"An increased stiffness characterizes the fibrotic microenvironment, and this rigidity is associated with disease progression."

Supports the tissue-stiffening half of this node and its link to progression, which is why the node is tagged at the TISSUE scale rather than the cellular one.

PMID:41514933 SUPPORT Human Clinical

"They are benign tumors consisting of disorganized myofibroblasts embedded within significant amounts of extracellular matrix, which constitute a considerable portion of the tumor volume"

Quantifies the matrix as a considerable portion of tumor volume, supporting the claim that the matrix rather than the cell mass is the defining component.

Aberrant Pseudocapsule Angiogenesis and Venous Ectasia

Fibroid vasculature is organized differently from that of a malignant solid tumor. The fibroid mass itself is poorly vascularized and is instead supplied by a highly vascularized pseudocapsule that develops in response to its growth and appears as a peripheral "ring of fire" on Doppler ultrasound. The angiogenic drive is attributed principally to the insulin-like growth factor system rather than to the HIF-1-alpha/VEGF axis of hypoxic tumors, and HIF-1-alpha has been reported absent from fibroids where it is readily demonstrable in leiomyosarcoma - which is what establishes that the common fibroid does not use the hypoxia route, and is not contradicted by the pseudohypoxia node, whose HIF stabilization is metabolite-driven and confined to the uncommon FH-deficient subtype. Separately, the growing mass raises interstitial pressure and obstructs venous drainage, enlarging the endometrial and myometrial venous lakes. Both the structurally deficient pseudocapsule vessels and the dilated venous lakes are proposed sources of the heavy bleeding, and which of them dominates is unsettled. One correction the source makes about its own history is worth keeping: the interstitial-pressure explanation for the enlarged venous lakes was later challenged, with growth factors rather than mechanical pressure held largely responsible for enlarging the veins. The pressure account is recorded here because the microradiographic observation of enlarged lakes stands; its mechanical explanation does not.

endothelial cell CL:0000115

angiogenesis GO:0001525 ↑ INCREASED

Downstream

Endometrial Hemostatic Failure and Impaired Vessel Closure Vessels of increased diameter, whether pseudocapsule neovessels or dilated venous lakes, are the substrate that the endometrial hemostatic mechanism then fails to close.

Show evidence (2 references)

PMID:36303616 SUPPORT Human Clinical

"These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular."

Establishes both halves of this node's angiogenic claim: the IGF-driven rather than VEGF-driven route, and the irregular vasculature that results.

PMID:36303616 SUPPORT Human Clinical

"Microradiographic studies in the 1970's supported the notion that HMB resulted not from the fibroid vasculature itself but rather from venous lakes dilated and enlarged by virtue of increased interstitial pressure from the growing tumors"

Supports the venous-ectasia arm of this node, in which the mass effect of the tumor rather than its own vessels enlarges the draining veins.

Endometrial Hemostatic Failure and Impaired Vessel Closure

Fibroids do not bleed only by mechanics. Fibroid tissue secretes TGF-beta-3 in response to ovarian steroids, and TGF-beta-3 acts on the overlying endometrium to downregulate BMP receptor 2 (which the source says is likely to cause defective decidualization) and to reduce expression of plasminogen activator inhibitor 1, antithrombin III and thrombomodulin, which the source says likely contributes to the bleeding. Both steps are hedged in the source and are hedged here. Note also that two of those three regulators are anticoagulants, so the net direction is an interpretation of the hemostatic outcome the source draws rather than a reading of each protein in isolation - the DECREASED modifier on the blood-coagulation process below records that net outcome, not a per-protein reading. The endometrium is therefore both less able to decidualize and less able to form and hold a hemostatic plug. This node is where the reproductive and the bleeding phenotypes share a mechanism. Scope note: the purely physical contributions to the bleeding - increased endometrial surface area, disordered myometrial contractility, and venous ectasia from compression - are real and are cited below, but they are properties of the tumor mass and belong to the Tumor Growth and Bulk Compression nodes. This node is the endometrial signalling arm, which is why it is tagged TISSUE.

endometrial stromal cell CL:0002255

endometrial hemostatic plug formation GO:0007596 ↓ DECREASED endometrial decidualization GO:0046697 ↓ DECREASED

Downstream

Heavy Menstrual Bleeding The hemostatic and vascular failure described by this node is what makes the menstrual loss heavy.

Infertility and Reproductive Morbidity Defective decidualization is the shared step by which the same TGF-beta-3 signal that impairs hemostasis also impairs implantation.

Show evidence (3 references)

PMID:36303616 SUPPORT Human Clinical

"TGF-β3 secreted by fibroids has been shown to induce BMP-2 resistance in endometrium by down-regulation of BMPR-2, likely causing defective endometrial decidualization"

Supports the decidualization arm: fibroid-derived TGF-beta-3 downregulates BMPR-2 in the endometrium and impairs decidualization.

PMID:36303616 SUPPORT Human Clinical

"TGF-β3 also reduces expression of plasminogen activator inhibitor-1 (PAI-1), Antithrombin III (ATIII), and thrombomodulin in endometrium, likely contributing to bleeding"

Supports the hemostatic arm: the same fibroid-derived TGF-beta-3 lowers three endometrial coagulation regulators, which the source links to the bleeding.

PMID:36303616 SUPPORT Human Clinical

"Fibroids may cause HMB merely physically, i.e., through an increase in endometrial surface due to underlying fibroid growth; through an influence on normal myometrial contractility patterns; through an ulcerated or degenerating fibroid, or through uterine venous ectasia due to compression from..."

Enumerates the mechanical contributions this node records alongside the TGF-beta-3-mediated ones, and is the reason the node is not described as purely biochemical.

Tumor Growth and Clinical Manifestations

Progressive growth of the leiomyoma produces a benign smooth muscle tumor of the uterus. Submucosal and intramural tumors distort the endometrial cavity and impair hemostasis, causing heavy menstrual bleeding and consequent iron deficiency anemia. Bulk from larger tumors compresses adjacent pelvic organs (bladder, rectum), causing pressure symptoms, while distortion of the cavity and tubal ostia contributes to reproductive morbidity. Most affected women are asymptomatic: fibroids cause clinically significant disease in roughly a quarter of reproductive-age women overall, and affect quality of life in approximately 30% of cases.

leiomyoma smooth muscle cell CL:0000192

Downstream

Bulk Compression of Adjacent Pelvic Organs Once the tumor is large enough, its mass alone displaces the neighbouring bladder and rectum; this arm of the mechanism is purely mechanical and is independent of the bleeding arm.

Pelvic Mass A tumor large enough to enlarge the uterus becomes palpable.

Pelvic Pain Bulk and pressure from the growing tumor produce pelvic pain and discomfort.

Dysmenorrhea Disordered myometrial contractility around the tumor makes menstruation painful.

Dyspareunia The enlarged, deformed uterus makes intercourse painful, position-dependently.

Endometrial Hemostatic Failure and Impaired Vessel Closure A cavity-distorting tumor is the precondition for the endometrial signalling and hemostatic changes that produce the bleeding.

Show evidence (2 references)

PMID:40214304 SUPPORT Human Clinical

"Uterine fibroids (leiomyomas), the most common tumors in women and those assigned female at birth, originate from myometrial smooth muscle cells and cause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction of labor in approximately a quarter of reproductive-age women."

Connects the smooth muscle tumor to its core clinical manifestations: heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction of labor.

PMID:38723935 SUPPORT Human Clinical

"in approximately 30% of cases, UFs affect the quality of life and women's health, with abnormal uterine bleeding and heavy menstrual bleeding being the most common complaints, along with iron deficiency (ID) and ID anemia."

Quantifies the symptomatic fraction and identifies AUB/HMB and iron deficiency anemia as the dominant complaints.

Bulk Compression of Adjacent Pelvic Organs

A fibroid large enough to enlarge and deform the uterus displaces the structures around it. Anterior and fundal tumors press on the bladder, producing urinary frequency and, when the ureters are involved, hydronephrosis; posterior tumors press on the rectum, producing constipation; a large fibroid can go further and cause urinary obstruction or, rarely, hydronephrosis. This is the one arm of the mechanism that is purely a consequence of volume and position: severity correlates with fibroid size, number and anatomical placement rather than with driver genotype, and the treatments that shrink or remove the tumor relieve it while the treatments that only control bleeding do not.

Downstream

Urinary Frequency Anterior and fundal tumors press on the bladder, reducing its capacity.

Constipation from Bulk Compression Posterior tumors press on the rectum.

Show evidence (4 references)

PMID:36303616 SUPPORT Human Clinical

"The bulk growth of this extremely dense tissue leads an enlarged and deformed uterus and to some of the key symptoms associated with uterine fibroids in addition to HMB such as pressure symptoms, abdominal pain, and infertility"

Attributes the pressure symptoms specifically to the bulk of the dense tumor enlarging and deforming the uterus, which is the mechanical claim of this node.

PMID:40970558 SUPPORT Human Clinical

"Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."

States the compression mechanism and both of its outputs directly, which is the whole content of this node.

PMID:40970558 SUPPORT Human Clinical

"In severe cases, particularly large fibroids may lead to urinary obstruction or rare hydronephrosis"

Supplies the severe end of the compression spectrum named in this node's description, including the hydronephrosis that would otherwise be uncited.

+ 1 more reference

✶

Histopathology

3

Whorled fascicles of spindle smooth muscle cells in collagenous stroma

The conventional leiomyoma is a well-circumscribed nodule of bland spindle smooth muscle cells arranged in interlacing whorled fascicles, separated from the surrounding myometrium by a cleft, and set in an abundant collagen-rich stroma that accounts for much of the tumor's volume. Histology is confirmatory rather than diagnostic in routine practice, because fibroids are diagnosed on imaging and tissue is normally examined only after resection.

Show evidence (2 references)

PMID:36303616 SUPPORT Human Clinical

"Despite the name, fibroids largely comprise of myocytes rather than fibroblasts and are characterized by the excessive deposition of extracellular matrix substances, mainly collagen, within the tumor"

Establishes the two components of this finding: a tumor made of smooth muscle cells rather than fibroblasts, in an excess of mainly collagenous matrix.

PMID:36303616 SUPPORT Human Clinical

"it is separated from the myometrium by a clear cleft, as observed in histological images"

Supports the circumscription and the cleft that separate the nodule from the adjacent myometrium on histology.

FH-deficient histologic signature VERY_FREQUENT

A recognizable constellation rather than a single feature: staghorn vasculature, alveolar-pattern oedema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes, and eosinophilic intracytoplasmic globules. More than four of these were present in 98.5% of an 80-case series. Confirmation is immunohistochemical: loss of FH staining (97.3% sensitive) or gain of S-(2-succino)-cysteine staining (100% in the five cases tested). Finding this pattern is what prompts germline FH testing, so it is the histology with the largest downstream consequence in this disease.

Show evidence (2 references)

PMID:37263921 SUPPORT Human Clinical

"More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients."

Lists the exact constellation and its frequency within the FH-deficient series.

PMID:37263921 SUPPORT Human Clinical

"FH immunohistochemistry were performed in 74 cases; S-(2-succino)-cysteine (2SC) were also detected by immunohistochemistry in five cases."

Documents the immunohistochemical confirmation step, and the small number of 2SC cases behind its reported 100% sensitivity.

Cellular leiomyoma variant

A histologic variant with markedly increased cellularity and correspondingly less stroma, which raises the differential with endometrial stromal tumors and leiomyosarcoma. Molecularly it is enriched for HMGA2 aberration, then chromosome 1p deletion, then MED12 mutation, so the variant is not just a morphologic curiosity but tracks a different driver distribution from conventional leiomyoma.

Show evidence (1 reference)

PMID:34626221 SUPPORT Human Clinical

"36.5% showed HMGA2 overexpression at the IHC level, associated with increased mRNA expression in 14/14 cases."

Supports the enrichment of HMGA2 aberration in this histologic variant.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

12

Blood 2

Heavy Menstrual Bleeding Menorrhagia HP:0000132

Sequelae: Iron Deficiency Anemia

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"abnormal uterine bleeding and heavy menstrual bleeding being the most common complaints"

Identifies heavy menstrual bleeding as the most common fibroid complaint.

Iron Deficiency Anemia HP:0001891

Fatigue is the expected sequela of this anemia and was drafted as its own phenotype (HP:0012378), then removed: no source cited anywhere in this entry names fatigue as a fibroid symptom, and a targeted PubMed search for one (fibroid + iron deficiency + fatigue in title/abstract) returned nothing usable. The claim is clinically obvious and bibliographically unsupported here, so it is recorded as this note rather than as an ontology-bound phenotype resting on an inference.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"along with iron deficiency (ID) and ID anemia"

Documents iron deficiency anemia as a consequence of fibroid-related bleeding.

Digestive 2

Constipation from Bulk Compression HP:0002019

Show evidence (1 reference)

PMID:40970558 SUPPORT Human Clinical

"Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."

Names constipation directly and attributes it to rectal compression by a posteriorly placed fibroid, which is both this phenotype and its mechanism.

Pelvic Mass HP:0031501

Show evidence (2 references)

PMID:40970558 SUPPORT Human Clinical

"Interestingly, fibroids are not reliably diagnosed on physical examination, nor can their impact be predicted through palpation."

Supports the description's caveat about the limited diagnostic value of the palpable mass, which is the clinically important point about this phenotype.

PMID:38929485 SUPPORT Human Clinical

"the most common benign gynecological condition in patients presenting with abnormal uterine bleeding, pelvic masses causing pressure or pain"

Names pelvic masses as a presenting finding of uterine fibroids.

Genitourinary 4

Uterine Leiomyoma HP:0000131

Show evidence (1 reference)

PMID:40214304 SUPPORT Human Clinical

"Uterine fibroids (leiomyomas), the most common tumors in women and those assigned female at birth, originate from myometrial smooth muscle cells"

Documents uterine leiomyoma as a myometrial smooth muscle tumor.

Infertility and Reproductive Morbidity HP:0000789

Sequelae: Recurrent Pregnancy Loss Preterm Birth

Show evidence (2 references)

PMID:40214304 SUPPORT Human Clinical

"cause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction of labor"

Documents pregnancy loss and obstruction of labor among fibroid-associated reproductive complications.

PMID:38929485 SUPPORT Human Clinical

"pelvic masses causing pressure or pain, infertility and obstetric complications"

Directly lists infertility and obstetric complications among the presentations of uterine fibroids, supporting the infertility phenotype term.

Urinary Frequency Pollakisuria HP:0100515

Show evidence (2 references)

PMID:40970558 SUPPORT Human Clinical

"Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."

Names urinary frequency as a consequence of bladder compression by an anteriorly placed fibroid, which is this phenotype and its mechanism.

PMID:40970558 SUPPORT INDIRECT Human Clinical

"Furthermore, when symptoms occur, they may not be related to the fibroids since abnormal uterine bleeding (AUB), infertility, recurrent pregnancy loss, pressure, pain, urinary frequency, or gastrointestinal dysfunction may be present with a variety of otherwise unrelated conditions."

Kept deliberately as the source's own counter-caution: urinary frequency is not specific to fibroids and may belong to an unrelated condition in the same patient. Quoted in full including the "may not be related to the fibroids" clause so it cannot be read as attributing the symptom.

Dyspareunia HP:0030016

Show evidence (1 reference)

PMID:35106750 SUPPORT Human Clinical

"Uterine leyomyomas are benign, monoclonal tumors that can cause abnormal uterine bleeding, pelvic pain, dyspareunia and/or obstruction of bladder or rectum."

Names dyspareunia outright among the symptoms fibroids cause, which is a direct attestation of the term bound here. (The source's own spelling of "leyomyomas" is preserved, as a snippet never corrects the text it quotes.)

Prenatal and Birth 1

Preterm Birth Premature birth HP:0001622

Show evidence (1 reference)

PMID:38710995 SUPPORT Human Clinical

"However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia."

Preterm birth is first in the list of associations that remain significant after adjustment, which is the stronger claim this phenotype rests on.

Constitutional 2

Pelvic Pain HP:0034267

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"the most common benign gynecological condition in patients presenting with abnormal uterine bleeding, pelvic masses causing pressure or pain"

Documents pelvic masses causing pressure or pain as a fibroid presentation.

Dysmenorrhea HP:0100607

Show evidence (2 references)

PMID:41514933 SUPPORT Human Clinical

"Several symptoms exist in women with UFs: a heavy and irregular menstrual cycle, dysmenorrhea, pelvic pressure, and infertility"

Names dysmenorrhea directly among the symptoms of uterine fibroids, which is a direct attestation of the term bound here.

PMID:39335725 SUPPORT Human Clinical

"mifepristone demonstrated its efficacy in reducing abnormal uterine bleedings (AUBs) and fibroid-related dysmenorrhea"

Second, independent attestation: the phrase "fibroid-related dysmenorrhea" treats this phenotype as an established consequence of fibroids, and its reducibility by antiprogestin therapy supports the hormone-dependent mechanism it is attached to.

Other 1

Recurrent Pregnancy Loss

Show evidence (2 references)

PMID:38710995 SUPPORT Human Clinical

"The pooled results showed that fibroids elevated the risk of adverse outcomes, including preterm birth, cesarean delivery, placenta previa, miscarriage, preterm premature rupture of membranes (PPROM), placental abruption, postpartum hemorrhage (PPH), fetal distress, malposition, intrauterine..."

The pooled unadjusted meta-analysis result includes miscarriage among the fibroid-associated adverse outcomes.

PMID:38710995 REFUTE Human Clinical

"However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia."

The same meta-analysis's adjusted analysis does not retain miscarriage, so this sentence contradicts the unadjusted association above. Recorded as a separate REFUTE item rather than folded into the first, because one evidence item cannot carry two opposite directions.

🧬

Genetic Associations

3

MED12 somatic exon-2 mutation

Gene: MED12 hgnc:11957 gene page variant_origin: SOMATIC

Show evidence (3 references)

PMID:36835153 SUPPORT Human Clinical

"Recent studies have demonstrated that somatic MED12 mutations in exon 2 occur at a frequency of up to 80% and have a functional role in leiomyoma pathogenesis."

Documents somatic MED12 exon-2 mutations at up to 80% frequency.

PMID:37668348 SUPPORT Human Clinical

"They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs."

Characterizes MED12 mutations as gain-of-function and more frequent in Black women.

PMID:41493967 REFUTE Human Clinical

"MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth."

Contradicts the reading of MED12 mutation as straightforwardly growth-promoting that a gain-of-function label invites: wild-type tumors grow faster. Recorded as REFUTE against that stronger claim rather than omitted, and followed up in the discussions section.

HMGA2 overexpression / rearrangement

Gene: HMGA2 hgnc:5009 gene page variant_origin: SOMATIC

Show evidence (1 reference)

PMID:34626221 SUPPORT Human Clinical

"36.5% showed HMGA2 overexpression at the IHC level, associated with increased mRNA expression in 14/14 cases. The rearrangement of the HMGA2 gene was detected in 13.2%."

Documents HMGA2 overexpression and rearrangement frequencies in cellular leiomyoma.

FH (fumarate hydratase) deficiency

Gene: FH hgnc:3700 gene page variant_origin: GERMLINE_AND_SOMATIC

Show evidence (4 references)

PMID:40862769 SUPPORT Human Clinical

"Driver mutations in genes such as MED12, HMGA2, and FH also play roles in the development and growth of fibroids."

Lists FH among recurrent fibroid driver genes.

PMID:36981015 SUPPORT Human Clinical

"HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC)."

Supplies the citation the previous version of this record said was missing: a heterozygous germline FH variant causes HLRCC, whose features include uterine leiomyoma alongside cutaneous leiomyoma and renal cell carcinoma.

PMID:37263921 SUPPORT Human Clinical

"Sixty-nine percent (20/29) of the patients with FH germline variation had clear family history."

Quantifies the family-history rate among germline-FH patients, supporting the claim that identifying this subtype has consequences beyond the index tumor.

+ 1 more reference

💊

Medical Actions

14

GnRH Agonist Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: leuprolide CHEBI:6427

Platform: Peptide

GnRH agonists (e.g., leuprolide) cause pituitary downregulation and hypoestrogenism, producing temporary fibroid shrinkage and bleeding control. Used as a preoperative bridge; limited by menopausal symptoms, bone loss, and rebound growth after stopping.

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"available medications (progestogens, combined oral contraceptives andgonadotropin-releasing hormone agonists and antagonists) are generally used for short-term treatment of fibroid-induced bleeding."

Documents GnRH agonists/antagonists for short-term fibroid bleeding control.

Oral GnRH Antagonist Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: elagolix NCIT:C153373 relugolix NCIT:C114498 linzagolix NCIT:C148479

Platform: Small molecule

Oral GnRH antagonists (elagolix, relugolix, linzagolix) directly block pituitary GnRH receptors to suppress ovarian steroid production, reducing heavy menstrual bleeding in a uterus-sparing, reversible regimen, usually with steroid add-back to avoid the hypoestrogenic effects that limit GnRH agonists. Linzagolix is the one agent with a lower-dose arm usable without mandatory add-back. The effect is suppressive, not curative: symptoms recur relatively quickly after the drug is stopped, which is the argument the PRIMROSE withdrawal study makes for long-term continuation.

Show evidence (4 references)

PMID:38723935 SUPPORT Human Clinical

"hormonal therapies, including combined oral contraceptives, gonadotropin-releasing hormone agonists or antagonists"

Documents GnRH antagonists among hormonal therapies for fibroid-related AUB.

PMID:33596357 SUPPORT Human Clinical

"A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons)."

The LIBERTY 1 and 2 phase-3 result quantifying the bleeding response to relugolix plus oestradiol and norethindrone against placebo, which is the trial evidence behind this treatment class.

PMID:33596357 SUPPORT Human Clinical

"Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects."

States the rationale for the add-back component this treatment record describes: the steroid add-back is what makes long-term GnRH-receptor blockade tolerable.

+ 1 more reference

Selective Progesterone Receptor Modulator Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: ulipristal acetate CHEBI:71025

Platform: Small molecule

Selective progesterone receptor modulators (SPRMs, e.g., ulipristal acetate) modulate PGR signaling to reduce bleeding and fibroid size; intermittent long-term use shows good results but is limited by hepatotoxicity concerns. Response may vary with MED12 mutation status.

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"it was shown that SPRMs could be administered intermittently long-term with good results on bleeding and fibroid size reduction."

Documents intermittent SPRM therapy reducing bleeding and fibroid size.

Mifepristone

Action: Pharmacotherapy NCIT:C15986

Agent: mifepristone CHEBI:50692

Platform: Small molecule

Antiprogestin studied for symptomatic fibroids, reducing abnormal uterine bleeding and fibroid-related dysmenorrhea. It acts on the same progesterone-receptor axis as the selective progesterone receptor modulators curated above, and is grouped with them mechanistically rather than with the symptomatic agents; its safety profile is described as more favourable than ulipristal acetate's but less well established.

Mechanism Target:

Hormone-Driven Myometrial Smooth Muscle Proliferation — Blocking the progesterone receptor removes the paracrine WNT and growth-factor signal that this node depends on, which is the mechanism the bleeding and dysmenorrhea response is attributed to.

Show evidence (1 reference)

PMID:39335725 SUPPORT Human Clinical

"mifepristone demonstrated its efficacy in reducing abnormal uterine bleedings (AUBs) and fibroid-related dysmenorrhea"

Documents mifepristone's efficacy for both of the symptoms this treatment record claims, in a review of the fibroid treatment pathway.

Tranexamic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: tranexamic acid CHEBI:48669

Platform: Small molecule

Antifibrinolytic agent that reduces menstrual blood loss for symptomatic heavy menstrual bleeding when uterine preservation is desired; does not shrink fibroids.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"Medical treatments used for UFs-related abnormal uterine bleeding include symptomatic agents, such as nonsteroidal antiinflammatory drugs and tranexamic acid"

Documents tranexamic acid as a symptomatic agent for fibroid-related AUB.

Nonsteroidal Anti-Inflammatory Drugs

Action: Pharmacotherapy NCIT:C15986

Agent: non-steroidal anti-inflammatory drug NCIT:C257

Platform: Small molecule

NSAIDs are used as symptomatic agents to reduce fibroid-related menstrual blood loss and dysmenorrhea; they do not reduce fibroid size.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"symptomatic agents, such as nonsteroidal antiinflammatory drugs and tranexamic acid"

Documents NSAIDs among symptomatic agents for fibroid-related abnormal uterine bleeding.

Levonorgestrel Intrauterine System

Action: Pharmacotherapy NCIT:C15986

Agent: levonorgestrel CHEBI:6443

Platform: Device

The levonorgestrel-releasing intrauterine system delivers local progestin to the endometrium, reducing heavy menstrual bleeding in a uterus-sparing, reversible way; it controls bleeding symptoms but does not consistently shrink fibroids.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"hormonal therapies, including combined oral contraceptives, gonadotropin-releasing hormone agonists or antagonists, levonorgestrel intrauterine systems"

Documents levonorgestrel intrauterine systems among hormonal therapies for fibroid-related AUB.

Aromatase Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: aromatase inhibitor NCIT:C1740

Platform: Small molecule

Aromatase inhibitors block estrogen biosynthesis, lowering the estrogen that drives fibroid growth; used as a hormonal option for symptomatic fibroids.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"selective progesterone receptor modulators, and aromatase inhibitors"

Documents aromatase inhibitors among hormonal therapies for fibroid-related AUB.

Myomectomy

Action: myomectomy Ontology label: Myomectomy NCIT:C51645

Platform: Surgery

Surgical removal of fibroids with uterine preservation (hysteroscopic, laparoscopic, open, or robotic), indicated for symptomatic patients desiring fertility or uterine conservation; recurrence risk persists.

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"Current management strategies mainly involve surgical interventions (hysterectomy and myomectomy hysteroscopy, laparoscopy or laparotomy)."

Documents myomectomy as a core surgical management strategy.

Hysterectomy

Action: hysterectomy Ontology label: Hysterectomy NCIT:C15256

Platform: Surgery

Definitive removal of the uterus, eliminating fibroids and recurrence, for women with severe symptoms and no fertility desire or failure of conservative options.

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"Current management strategies mainly involve surgical interventions (hysterectomy and myomectomy hysteroscopy, laparoscopy or laparotomy)."

Documents hysterectomy as a definitive surgical treatment for fibroids.

Uterine Artery Embolization

Action: uterine artery embolization Ontology label: Arterial Embolization NCIT:C15917

Platform: Surgery

Image-guided arterial embolization that devascularizes fibroids, causing ischemic shrinkage; a uterus-sparing, non-excisional option, generally not first choice when future fertility is a major goal.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"Radiologic interventions are also available: uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound, and radiofrequency ablation."

Documents uterine artery embolization as a radiologic intervention for fibroids.

MRI-Guided Focused Ultrasound Surgery

Action: MRI-guided focused ultrasound ablation Ontology label: MRI-Guided Focused Ultrasound Ablation NCIT:C62723

Platform: Surgery

Non-invasive thermal ablation that focuses high-intensity ultrasound energy under MRI (or ultrasound) guidance to coagulate fibroid tissue, sparing the uterus.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound"

Documents high-intensity/MR-guided focused ultrasound as a radiologic intervention for fibroids.

Radiofrequency Ablation

Action: radiofrequency ablation Ontology label: Radiofrequency Ablation NCIT:C15666

Platform: Surgery

Image-guided radiofrequency energy thermally ablates fibroid tissue, causing coagulative necrosis and volume reduction while preserving the uterus.

Show evidence (1 reference)

PMID:38929485 SUPPORT Human Clinical

"radiofrequency ablation of fibroids and endometrial ablation"

Documents radiofrequency ablation of fibroids as a minimally invasive treatment modality.

Iron Replacement Therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Small molecule

Repletes iron stores in fibroid-related iron deficiency and anemia from chronic bleeding; an important adjunct before and after surgery and during medical therapy. therapeutic_agent is deliberately absent. The treatment is generic iron replacement, oral or intravenous, and the preparation is not specified by the cited source. NCIT:C210688 "Iron Supplement" is the concept but is not a member of the ChemicalEntityTerm dynamic enum, and every CHEBI term that is a member names one specific salt or hydrate (for example CHEBI:75832, iron(2+) sulfate anhydrous), which would assert a preparation this entry does not claim.

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"the management of ID and ID anemia, as a consequence of acute and chronic bleeding, should be taken into account with the use of iron replacement therapy"

Documents iron replacement therapy for fibroid-related iron deficiency anemia.

🌍

Environmental Factors

5

Chronic low vitamin D status

Vitamin D deficiency is repeatedly associated with fibroid presence and size, and unlike most epidemiological risk factors it has a specific proposed mechanism at the initiating node rather than at the growth node: calcitriol acting through VDR supports the MRN-complex/ATM DNA-repair axis in myometrial stem cells, so deficiency plausibly permits the driver lesion to be acquired and retained. In vitro work shows vitamin D inhibiting fibroid growth through proliferation, ECM remodelling, DNA repair and apoptosis pathways; clinical studies support this only in part.

Show evidence (3 references)

PMID:33670322 SUPPORT Human Clinical

"In recent years, epidemiological studies reported a vitamin D deficiency in patients with UFs raised interest in the potential biological effects of vitamin D supplementation."

Establishes the epidemiological association between vitamin D deficiency and uterine fibroids that this exposure record is about.

PMID:33670322 SUPPORT In Vitro

"In vitro studies proved vitamin D efficacy in inhibiting UFs growth by targeting pathways involved in the regulation of various biological processes, including proliferation, extracellular matrix (ECM) remodeling, DNA repair, signaling and apoptosis."

Supports the mechanistic half of the claim, naming the DNA-repair and ECM pathways this record links to the pathograph.

PMID:33670322 REFUTE Human Clinical

"However, clinical studies supported only in part the beneficial effects of vitamin D supplementation in reducing UFs growth and tumor volume."

Contradicts the stronger reading that supplementation is an established fibroid-directed treatment. Kept as a separate REFUTE item because the same source supports the association and undercuts the therapeutic claim.

Mechanism Target:

PREDISPOSES Driver Mutation-Initiated Clonal Transformation — Low vitamin D status is linked to the initiating lesion rather than to hormonal growth: VDR signalling supports the MRN-complex/ATM DNA-damage response in myometrial stem cells, and its loss leaves DNA damage unrepaired in exactly the cell population from which fibroids arise.

Show evidence (1 reference)

PMID:32545544 SUPPORT Model Organism

"VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR."

Names the repair axis vitamin D acts through in myometrial stem cells, which is the intermediate this edge asserts between vitamin D status and the driver lesion.

Developmental exposure to endocrine-disrupting chemicals

Early-life exposure of the myometrium to endocrine-disrupting chemicals raises adult fibroid risk. The strongest mechanistic evidence is from Eker rats exposed neonatally to diethylstilbestrol, whose myometrial stem cells show reduced RAD50 and MRE11 and a defective DNA damage response at the pro-fibroid stage, months before tumors appear. In humans the corresponding exposures reported are xenoestrogens in early ontogenesis, diethylstilbestrol, and phthalates and bisphenol A.

Show evidence (3 references)

PMID:36982852 SUPPORT Human Clinical

"These factors include race, age, parity, family history, food additives, obesity, vitamin D deficiency, and endocrine-disrupting chemical exposure"

Human review listing endocrine-disrupting chemical exposure among the established fibroid risk factors. Cited here rather than the opening sentence of the Eker-rat paper, which asserts the same association but is a rodent study and so cannot carry a HUMAN_CLINICAL grade.

PMID:32545544 SUPPORT Model Organism

"Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01)."

The rat experimental result behind the mechanism: developmental DES exposure depletes two MRN-complex repair proteins in myometrium.

PMID:36982825 SUPPORT Human Clinical

"The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"

Independent review listing exposure to xenoestrogens in early ontogenesis among the established risk factors, which is the exposure term bound here.

Mechanism Target:

PREDISPOSES Driver Mutation-Initiated Clonal Transformation — Developmental xenoestrogen exposure leaves the myometrial stem cell pool repair-deficient, which is how an exposure decades earlier raises the probability of the somatic driver lesion that starts a fibroid.

Show evidence (1 reference)

PMID:32545544 SUPPORT Model Organism

"Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01)."

Supplies the intermediate step - repair-protein loss in the exposed myometrium - that links the developmental exposure to the initiating lesion.

Obesity and excess adiposity

Obesity is one of the most consistently reported fibroid risk factors, and the proposed mechanism is specific: adipose tissue performs the same aromatase and 17-beta-hydroxysteroid-dehydrogenase conversion of androgens to oestrogens that fibroid cells themselves use, so excess adiposity raises the oestrogen supply to a tumor that depends on it. This is why the edge below attaches to the hormone-driven proliferation node rather than to the initiating lesion.

Show evidence (2 references)

PMID:36982825 SUPPORT Human Clinical

"The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"

Lists obesity among the established risk factors for uterine leiomyoma.

PMID:36982825 SUPPORT Human Clinical

"The enzymatic conversion of androgens to oestrogens is also typical of fat tissue"

Gives the mechanism this record attributes the obesity association to, and is the reason the pathograph edge targets the hormone node.

Mechanism Target:

PREDISPOSES Hormone-Driven Myometrial Smooth Muscle Proliferation — Adipose aromatase activity adds to the circulating oestrogen pool that the established fibroid clone depends on for growth.

Show evidence (1 reference)

PMID:36982825 SUPPORT Human Clinical

"The enzymatic conversion of androgens to oestrogens is also typical of fat tissue"

Names the aromatization step by which adiposity feeds the oestrogen-dependent growth node.

Alcohol consumption

Alcohol appears in the risk-factor lists of contemporary reviews of uterine leiomyoma genesis. No mechanism specific to fibroids is established for it, so it is recorded as an association and its pathograph edge is left off rather than attached to a node on speculation.

Show evidence (1 reference)

PMID:36982825 SUPPORT Human Clinical

"The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"

Lists alcohol last among the risk factors for uterine leiomyoma in this review.

Parity

Having borne children is consistently reported as protective, in contrast to the nulliparity and early-menarche exposures that raise risk. Parity, oral contraceptive use and smoking are the three protective factors this review names; smoking is recorded there too but is not curated here as a protective exposure, because a protective association that nobody would act on is a poor fit for a slot that reads as an intervention.

Show evidence (1 reference)

PMID:36982825 SUPPORT Human Clinical

"Parity, oral contraceptive intake and smoking are among possible protective factors for UL development"

Names parity first among the possible protective factors for uterine leiomyoma.

Mechanism Target:

PROTECTS_AGAINST Hormone-Driven Myometrial Smooth Muscle Proliferation — Parity interrupts the sequence of ovulatory cycles that supplies the oestrogen and progesterone this node depends on. The intermediates are not established, which is why the link type says so rather than naming a pathway.

🩻

Imaging Findings

3

Well-circumscribed hypoechoic myometrial mass on transvaginal ultrasound

Ultrasound is the first-line modality and is where the diagnosis is normally made: it establishes presence, size, number and location. Because examination is unreliable, imaging rather than palpation drives management, and reports are expected to place each fibroid in the FIGO 0-8 scheme describing its relationship to endometrium, myometrium and serosa.

Ultrasound Diagnostic

Uterine leiomyoma HP:0000131

Show evidence (2 references)

PMID:40970558 SUPPORT Human Clinical

"Ultrasound should be the first-line diagnostic modality, and magnetic resonance imaging should be reserved for complex cases and/or surgical planning."

States the first-line role of ultrasound and the reserved role of MRI.

PMID:40970558 SUPPORT Human Clinical

"Imaging reports should follow the FIGO classification system for uterine fibroids, to enable a standardized description of their relationship to the endometrium, myometrium, and uterine serosa."

Supports the FIGO reporting convention this finding is expected to be described in.

Peripheral "ring of fire" vascularity on Doppler

Colour Doppler shows flow concentrated at the rim of an intramural fibroid rather than through it, reflecting the vascularized pseudocapsule that supplies a tumor whose own mass is poorly vascularized. This is the imaging correlate of the pseudocapsule angiogenesis node.

Ultrasound

Uterine leiomyoma HP:0000131

Show evidence (1 reference)

PMID:36303616 SUPPORT Human Clinical

"While the fibroid mass itself is poorly vascularised, it can be surrounded by a highly vascularised pseudocapsule in intramural fibroids, a specialized layer of tissue between the tumor and the surrounding myometrium that contains the blood vessels needed to sustain the fibroid (81), which..."

Restores the intramural-fibroid pseudocapsule and its vascular supply before the Doppler ring sign, preserving the contrast with the poorly vascularized fibroid mass.

Multiplanar MRI characterization for surgical planning

MRI is reserved for complex cases and surgical planning, where it distinguishes fibroids from adenomyosis and from malignancy, predicts therapeutic response, and maps the tumors for intervention. It does not, however, reliably exclude leiomyosarcoma before resection.

Mri Diagnostic

Uterine leiomyoma HP:0000131

Show evidence (1 reference)

PMID:40970558 SUPPORT Human Clinical

"Adherence to standardized structured reporting across imaging modalities is critical to improve diagnostic accuracy, differentiate fibroids from conditions such as adenomyosis or malignancies, predict therapeutic responses, and plan surgical interventions."

Lists the four purposes this finding is curated for, including the differential against adenomyosis and malignancy.

📈

Progression

3

Premenarchal

Age: birth to menarche

Fibroids essentially do not arise before menarche, which follows from their growth being sex-steroid-dependent: the tumor, though initiated by a somatic lesion, cannot expand without ovarian steroid support, and before menarche that support is absent.

Show evidence (1 reference)

PMID:37668348 SUPPORT INDIRECT Human Clinical

"Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth."

Establishes that fibroid growth is sex-steroid-dependent. The premenarchal absence recorded in this phase follows from that dependence rather than being stated in the quote, which is why this is graded INDIRECT.

Reproductive years

Age: menarche to menopause, peak 35-50 years

The growth phase. Detection and symptom burden rise steeply from the mid-thirties, with most diagnoses between 35 and 50. Individual tumors within one uterus are separate clones and grow at different rates, so "progression" here is the aggregate of several independent trajectories rather than one.

Show evidence (1 reference)

PMID:36982825 SUPPORT Human Clinical

"Despite its benign nature and low risk of malignisation, UL can be characterised by rapid growth, large size and multiple nodes"

Supports the variable-growth, multiple-tumor character of this phase.

Postmenopausal

Age: after menopause

Ovarian steroid withdrawal is followed by growth arrest and frequently by regression, which is the therapeutic logic behind every hormonal treatment in this entry: they reproduce the postmenopausal state pharmacologically, and their effect reverses when stopped for the same reason.

Show evidence (1 reference)

PMID:33670322 SUPPORT Human Clinical

"Furthermore, UFs can undergo growth inhibition or spontaneous regression after menopause"

States the postmenopausal growth inhibition and regression that define this phase.

📊

Prevalence

4

Women aged 30-44 years

Point Prevalence 60000.0 per 100,000 >1 in 1,000

Uterine fibroids are the most common benign pelvic tumor of reproductive-age women, present in more than 60% of women aged 30-44 years (>60% = >60,000 per 100,000; recorded as a lower bound).

Show evidence (1 reference)

PMID:38723935 SUPPORT Human Clinical

"Uterine fibroids (UFs) are the most common female benign pelvic tumors, affecting >60% of patients aged 30-44 years."

Quantifies fibroid prevalence at over 60% in women aged 30-44 years.

Women overall (with racial disparity)

Point Prevalence 70000.0 per 100,000 >1 in 1,000

Overall prevalence is approximately 70% (70,000 per 100,000), with Black women affected at a disproportionately high rate.

Show evidence (1 reference)

PMID:40862769 SUPPORT Human Clinical

"Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate."

Documents overall fibroid prevalence (~70%) and the disproportionate burden in Black women.

Global, GBD 2021, age-standardized

Point Prevalence 2841.07 per 100,000 (2164.43–3682.27) >1 in 1,000

GBD 2021 age-standardized prevalence rate, rising from 2799.88 per 100,000 in 1990. Note that this is an order of magnitude below the 60-70% screening-based figures recorded above and does not contradict them: GBD models diagnosed disease, while the screening studies count fibroids found on systematic ultrasound in women who mostly have no symptoms. The gap between the two is the asymptomatic fraction.

Show evidence (1 reference)

PMID:41048892 SUPPORT Human Clinical

"The ASPR increased from 2799.88 (2133.46, 3650.54) to 2841.07 (2164.43, 3682.27) [EAPC 0.04 (0.03, 0.06)]."

Gives the age-standardized prevalence rate and its uncertainty interval for 2021, which are the values recorded here.

Global, GBD 2021, age-standardized

Annual Incidence 250.93 per 100,000 (183.44–330.94) per year >1 in 1,000 per year

GBD 2021 age-standardized incidence rate, up from 234.36 per 100,000 in 1990. rate_denominator is set explicitly because an incidence measure has no fallback: this is new cases per 100,000 population per year. No qualitative prevalence tier is used here, since those presuppose a prevalence rather than an incidence measure.

Show evidence (1 reference)

PMID:41048892 SUPPORT Human Clinical

"Uterine fibroids (UF) are the most common benign tumors of the female reproductive system, imposing a significant health burden. ... Data on the incidence, prevalence, and disability-adjusted life years (DALYs) of UF from 1990 to 2021 were extracted from the Global Burden of Disease (GBD) 2021..."

GBD 2021 estimates the global age-standardized uterine-fibroid incidence at 250.93 per 100,000 in 2021 (uncertainty interval 183.44–330.94), with modeled annual incident counts across 204 countries and territories.

⚖️

Clinical Burden

Variable

The burden is genuinely bimodal rather than merely heterogeneous, and averaging it would misdescribe the disease. Most women with fibroids never know they have them; among those who do, roughly 30% report a quality-of-life impact, and for that minority heavy menstrual bleeding is the dominant complaint and the leading reason for elective hysterectomy. Mortality is essentially nil. So the same diagnosis covers an incidental ultrasound finding and an indication for major surgery.

Show evidence (2 references)

PMID:38723935 SUPPORT Human Clinical

"in approximately 30% of cases, UFs affect the quality of life and women's health, with abnormal uterine bleeding and heavy menstrual bleeding being the most common complaints, along with iron deficiency (ID) and ID anemia."

Quantifies the symptomatic minority and names what dominates their burden.

PMID:36303616 SUPPORT Human Clinical

"In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility."

Independent figure for the symptomatic fraction, supporting the VARIABLE band rather than a single level.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Uterine Leiomyoma:

Uterine leiomyosarcoma Not Yet Curated MONDO:0016262

Overlapping Features The differential that matters, because it cannot be resolved before resection. No imaging finding or biomarker reliably separates a benign leiomyoma from a leiomyosarcoma preoperatively, which is why a rapidly enlarging mass prompts evaluation and why morcellation of a presumed fibroid carries a dissemination risk.

Distinguishing Features

Histopathology of the resected specimen is definitive; nothing before resection is.
Molecular profiling may assist in the cellular and variant morphologies.
HIF-1-alpha is readily demonstrable in leiomyosarcoma but has been reported absent from leiomyoma, which is also why the two tumors' angiogenic mechanisms differ.

Show evidence (1 reference)

PMID:36303616 SUPPORT Human Clinical

"HIF-1α for example has been shown lacking in uterine fibroids, when it was readily shown in leiomyosarcomata"

Supports the HIF-1-alpha distinction recorded under distinguishing_features.

Endometrial stromal tumor

Overlapping Features Endometrial stromal nodule and low-grade endometrial stromal sarcoma enter the differential chiefly against the cellular leiomyoma variant, where increased cellularity and reduced stroma remove the morphologic cues that separate them.

Distinguishing Features

Immunohistochemistry is suggestive rather than decisive: cellular leiomyomas express CD10 in a majority of cases (65.4%, though only 42.2% strongly, at H-score above 50) and IFITM1 in 36.5%, so positivity for an endometrial stromal marker does not settle it.
Smooth muscle markers are near-uniformly expressed in cellular leiomyoma (calponin and desmin in 100%), which is the more reliable direction of evidence.

Show evidence (2 references)

PMID:34626221 SUPPORT Human Clinical

"Concerning markers of endometrial stromal differentiation, the expression of CD10 was observed in 65.4% cases (42.2% with H-score > 50), and IFITM1 in 36.5% cases (1.9% with H-score > 50)"

Gives the immunohistochemical overlap that makes this differential hard: CD10 is positive in most cellular leiomyomas and IFITM1 in over a third, so positivity for an endometrial stromal marker does not settle the diagnosis.

PMID:34626221 SUPPORT Human Clinical

"The immunohistochemical results showed a high expression of smooth muscle markers (calponin (100%), desmin (100%), smooth muscle actin (98.1%), caldesmon (96.1%), transgelin (96.1%), smooth muscle myosin heavy chain (86.5%), and smoothelin (61.5%))."

Supplies the smooth-muscle marker panel that argues for leiomyoma, and the reason it is described as the more reliable direction of evidence.

Adenomyosis MONDO:0010888

Overlapping Features Ectopic endometrial tissue within the myometrium, presenting with the same heavy bleeding and dysmenorrhea, frequently coexisting with fibroids, and separated from them on imaging rather than clinically.

Distinguishing Features

MRI is the modality that resolves the two, and standardized structured reporting exists precisely because this differential is common.
The two frequently coexist, so resolving it is not always a choice between them.

Show evidence (1 reference)

PMID:40970558 SUPPORT Human Clinical

"Adherence to standardized structured reporting across imaging modalities is critical to improve diagnostic accuracy, differentiate fibroids from conditions such as adenomyosis or malignancies, predict therapeutic responses, and plan surgical interventions."

Names adenomyosis as one of the two conditions imaging is expected to distinguish fibroids from.

📊

Related Datasets

2

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma. geo:GSE204970

human MULTI OMICS n=44

PMID:37607000

Identified by GEO DataSets index search for Uterine Leiomyoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Uterine leiomyoma: DNA methylation, chromatin activity and gene expression ega:EGAS00001004499

In this study, we observed the effects of different uterine leiomyoma driver mutations to tumor DNA methylation, chromatin activity and gene expression, to form a comprehensive view on the epigenetic consequences of the mutations.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Uterine Leiomyoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

🔬

Clinical Trials

2

NCT03049735 PHASE_III COMPLETED

LIBERTY 1, the first of two replicate phase-3 trials of relugolix 40 mg with estradiol 1 mg and norethindrone acetate 0.5 mg against placebo over 24 weeks in women with fibroid-associated heavy menstrual bleeding. It and LIBERTY 2 are the trials the FDA approval of relugolix combination therapy rests on.

Target Phenotypes: Heavy menstrual bleeding HP:0000132

Show evidence (2 references)

clinicaltrials:NCT03049735 SUPPORT Human Clinical

"The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids."

The registration record's own statement of the intervention and endpoint, matching the regimen curated under Oral GnRH Antagonist Therapy.

PMID:33596357 SUPPORT Human Clinical

"A total of 388 women in trial L1 and 382 in trial L2 underwent randomization."

The publication reporting both LIBERTY trials, giving the randomized population of each.

NCT03103087 PHASE_III COMPLETED

LIBERTY 2, the replicate of LIBERTY 1 with the same design and endpoint. Running the trial twice is what makes the 73%/71% response figures a replication rather than a single result.

Target Phenotypes: Heavy menstrual bleeding HP:0000132

Show evidence (1 reference)

clinicaltrials:NCT03103087 SUPPORT Human Clinical

"The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids."

The registration record for the replicate trial, confirming the identical intervention and endpoint.

🐁

Animal Models

2

Eker rat (germline Tsc2 mutation) Spontaneous

The most widely used spontaneous model. Roughly 65% of female Eker rats develop uterine smooth muscle tumors at 12-16 months through a germline Tsc2 mutation and consequent mTOR pathway activation. Histomorphology and oestrogen/progesterone dependence closely resemble human fibroids, and the strain has carried most of the gene-environment work in this field, including the developmental DES exposure and vitamin D3 rescue experiments this entry cites.

Species

Rat

Genotype

Tsc2 germline loss-of-function (Eker strain)

Genes

Tsc2 hgnc:12363

Publication

PMID:41810407

Pathograph links

Hormone-Driven Myometrial Smooth Muscle Proliferation partially recapitulates fidelity: moderate observes: organism Reproduces spontaneous, hormone-dependent uterine smooth muscle tumorigenesis in an intact animal, which is what makes it usable for gene-environment and chemoprevention work no in vitro system can do.

Limitations: The driving lesion is Tsc2, which is not one of the recurrent human somatic drivers (MED12, HMGA2, FH), so the model recapitulates the hormone-dependent growth phase without recapitulating the initiating genotype. It also takes 12-16 months, is expensive, and the animals develop concurrent renal and hepatic tumors that confound interpretation.

Divergences from the human mechanism

species mismatch qualifying

Rat myometrium rather than human, with a rodent oestrous cycle rather than a menstrual cycle, so the cyclical progesterone exposure that drives human fibroid growth is not reproduced in the same temporal pattern.

boundary omission qualifying

The human driver lesions are outside the model entirely: no MED12 exon-2 mutation, no HMGA2 rearrangement and no FH loss, so nothing in this animal addresses the Mediator-kinase, architectural-transcription-factor or oncometabolite arms of the human mechanism.

Show evidence (2 references)

PMID:41810407 SUPPORT Model Organism

"This rat model exhibits highly similar histomorphology and estrogen/progesterone-dependent manifestations to human ULs"

Supports treating this model as informative for the hormone-dependent growth node, which is the claim this link makes.

+ 1 more reference

Driver Mutation-Initiated Clonal Transformation fails to recapitulate fidelity: low observes: molecular The model does not reproduce the human initiating lesion. Its tumors start from a germline Tsc2 mutation present in every cell, where human fibroids start from a somatic driver acquired by one myometrial cell, so the monoclonal-origin and driver-genotype claims of this node are outside what the model can support.

Limitations: Tsc2 is not among MED12, HMGA2, FH or COL4A5/COL4A6, and the lesion is germline rather than somatic. Any inference from this model to the human initiating event is an inference about hormone-dependent growth in a predisposed myometrium, not about how a human fibroid starts.

Show evidence (1 reference)

PMID:41810407 SUPPORT Model Organism

"Eker rats (Rattus norvegicus), due to their germline mutation in the tuberous sclerosis complex type 2 (Tsc2) tumor suppressor gene, spontaneously develop uterine smooth muscle tumors in approximately 65% of females at 12 to 16 months of age."

Identifies the model's lesion as a germline Tsc2 mutation, which is what establishes the mismatch with the human somatic drivers this node is about.

Excessive Extracellular Matrix Deposition and Tissue Stiffening rescues fidelity: moderate observes: molecular The Eker rat is the system in which vitamin D3 was shown to restore the MRN complex/ATM DNA-repair axis in myometrial stem cells after developmental DES exposure, which is the experimental basis for the vitamin D environmental record in this entry.

Limitations: The measured endpoint is DNA damage and repair-protein expression in isolated myometrial stem cells, not matrix deposition or tumor volume, so the link to the fibrotic output node is an extrapolation across both scale and endpoint.

Divergences from the human mechanism

proxy quantity invalidating

The model's measured quantity is DNA-damage load and MRN-complex protein expression in stem cells. The node's quantity is collagen-rich matrix deposited in a tumor. Nothing in the cited experiment measures the latter.

scale extrapolation qualifying

Observed at the molecular scale (repair-protein expression) and cited for a TISSUE-scale node, so the inference crosses two scale steps.

Show evidence (1 reference)

PMID:32545544 SUPPORT Model Organism

"This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers."

The rescue result this link records, and the reason the divergences above are stated: the endpoint is DNA damage, not matrix.

The gene_term binds the human TSC2 ortholog because HGNC codes human genes; the model's own lesion is rat Tsc2. MGI/RGD identifiers for the rat gene are not bound by any current dismech slot.

Show evidence (1 reference)

PMID:41810407 SUPPORT Model Organism

"Because of the convenience of model establishment, this model has become one of the most commonly used models for ULs"

Establishes this strain's standing as the most commonly used uterine leiomyoma model, which is why it is curated here rather than only mentioned in notes.

Human leiomyoma tissue xenograft in immunodeficient mouse Xenograft

Human fibroid tissue grafted subcutaneously or beneath the renal capsule of immunodeficient mice, usually with a sustained-release hormone device to keep the graft in its native hormonal environment. This is the model that preserves the human tumor's own driver genotype, heterogeneity and microenvironment, and so the one used for preclinical efficacy work meant to translate.

Species

Mouse

Genotype

Severe combined immunodeficiency (SCID) host, human leiomyoma tissue graft

Publication

PMID:41810407

Pathograph links

Excessive Extracellular Matrix Deposition and Tissue Stiffening recapitulates fidelity: high observes: tissue The graft retains the histopathological morphology of the source tumor, matrix included, which is exactly the property that makes it the translational bridge.

Limitations: Requires an immunodeficient host, so the immune and inflammatory contributions to fibroid matrix biology cannot be studied in it at all. Results also vary between tissue donors, and the model is technically demanding and expensive.

Divergences from the human mechanism

boundary omission qualifying

The host has no adaptive immune system, so the immune infiltrate and the inflammatory signalling that recent reviews implicate in fibroid ECM production are outside the model boundary.

population mismatch qualifying

Each graft reproduces one donor's tumor, and inter-donor variability is reported as a limitation of the approach, so a single xenograft experiment speaks to one molecular subtype rather than to the disease's driver spectrum.

Show evidence (2 references)

PMID:41810407 SUPPORT Model Organism

"These models closely replicate the histopathological morphology of human ULs. However, their broader application remains limited by technical complexity, stringent experimental requirements, and high costs."

Supports both the HIGH fidelity for morphology and the practical limitations recorded on this link.

+ 1 more reference

Show evidence (1 reference)

PMID:41810407 SUPPORT Model Organism

"xenograft models can best simulate the pathological features of human ULs and serve as a key bridge between basic research and clinical translation"

States the reason this model class is curated: it is the closest available reproduction of human fibroid pathology and the intended translational bridge.

{ }

Source YAML

click to show

name: Uterine Leiomyoma
creation_date: "2026-06-22T00:00:00Z"
description: >-
  Uterine leiomyomas are benign monoclonal smooth muscle tumors that arise from a single myometrial cell acquiring a driver mutation in MED12, HMGA2, or FH.
  Ovarian estrogen and progesterone then drive smooth muscle proliferation and abundant extracellular matrix deposition during each ovulatory cycle.
  Progressive tumor growth distorts the uterus, producing abnormal uterine bleeding, bulk symptoms, and reproductive complications.
category: Complex
disease_term:
  preferred_term: uterine fibroid
  term:
    id: MONDO:0007886
    label: uterine corpus leiomyoma
parents:
  - Benign uterine neoplasm
  - Smooth muscle tumor

has_subtypes:
- name: MED12-mutant
  display_name: MED12-mutant leiomyoma
  description: >
    The dominant molecular subtype, defined by a recurrent somatic exon-2 point mutation
    in MED12 disrupting the CDK8/CDK19 kinase module of the Mediator complex. These
    tumors tend to be multiple rather than solitary, are found even at small size, are
    more frequent in Black women, and carry a distinctive ECM-organization and
    Wnt/beta-catenin transcriptional program. Reported frequency spans 50-80% of tumors
    depending on cohort and detection method.
  genes:
  - preferred_term: MED12
    term:
      id: hgnc:11957
      label: MED12
  evidence:
  - reference: PMID:37668348
    reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the driver gene mutations identified in UFs, mutations \nin MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are \nthe most common and observed in 50-80% of UFs."
    explanation: >-
      Establishes MED12-mutant tumors as the most common molecular subtype at 50-80%.

- name: HMGA2-rearranged
  display_name: HMGA2-rearranged / HMGA2-overexpressing leiomyoma
  description: >
    The second subtype, defined by 12q14-15 rearrangement or overexpression of the
    architectural transcription factor HMGA2. Around 10% of fibroids overall, but
    markedly enriched in the cellular leiomyoma histologic variant, where HMGA2
    overexpression was found in 36.5% and HMGA2 rearrangement in 13.2% of cases.
    Largely mutually exclusive with MED12 mutation.
  genes:
  - preferred_term: HMGA2
    term:
      id: hgnc:5009
      label: HMGA2
  evidence:
  - reference: PMID:34626221
    reference_title: "Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "36.5% showed HMGA2 overexpression at the IHC \nlevel, associated with increased mRNA expression in 14/14 cases. The \nrearrangement of the HMGA2 gene was detected in 13.2%."
    explanation: >-
      Quantifies HMGA2 overexpression and rearrangement in the cellular leiomyoma
      variant where this subtype concentrates.
  - reference: PMID:38326302
    reference_title: "Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the majority of these mutations are mutually exclusive, and integrative data analysis reveals mutation-specific distinct driver gene expression programs and biomarkers in UF"
    explanation: >-
      Supplies the citation for the mutual-exclusivity claim in this subtype's
      description, and for the premise that each driver class has its own expression
      programme - which is what makes these molecular subtypes rather than co-occurring
      lesions.

- name: FH-deficient
  display_name: FH-deficient leiomyoma
  description: >
    An uncommon but clinically consequential subtype defined by biallelic loss of
    fumarate hydratase, recognizable on routine histology by a cluster of features
    (staghorn vasculature, alveolar-pattern oedema, bizarre nuclei, eosinophilic nucleoli
    with perinucleolar haloes, eosinophilic intracytoplasmic globules) and confirmable by
    loss of FH or gain of 2SC staining. It matters out of proportion to its frequency
    because a large fraction of cases carry a germline FH variant - 31 of 80 tumors
    (39%) in the reference series, or 52% of those in which sequencing found a variant at
    all - which makes the patient and her relatives HLRCC kindred at risk of renal cell
    carcinoma.
  genes:
  - preferred_term: FH
    term:
      id: hgnc:3700
      label: FH
  evidence:
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients."
    explanation: >-
      Establishes the recognizable histologic signature that defines this subtype in
      practice, present in 98.5% of the series.

pathophysiology:
- name: Driver Mutation-Initiated Clonal Transformation
  description: >
    Uterine leiomyomas (fibroids) originate as monoclonal tumors from a single
    myometrial smooth muscle cell (or a myometrial stem cell acquiring tumor-initiating
    features) that acquires a recurrent somatic driver mutation. The most common driver
    is a MED12 exon-2 mutation (~70-77%), followed by HMGA2/HMGA1 overexpression or
    chromosomal rearrangement (~10%, 12q14-15), biallelic FH (fumarate hydratase) loss
    defining the FH-deficient subtype (also seen in hereditary leiomyomatosis and renal
    cell cancer, HLRCC), with rarer collagen IV (COL4A5/COL4A6) deletions also reported. Heterozygous MED12 mutations
    disrupt the CDK8/CDK19 kinase module of the Mediator complex, altering the chromatin
    landscape, enhancer engagement, genomic stability, and progesterone responsiveness.

    Scoping decision, recorded so it is not mistaken for an oversight: COL4A5/COL4A6
    deletion and the SRCAP-complex class are named here but are deliberately not given
    has_subtypes entries. Both are recurrent but rare relative to the three modelled
    classes, neither has a distinct pathophysiology arm this entry could populate beyond
    the shared ECM output, and neither changes management. A curator with a
    collagen-IV-specific mechanism or frequency source should add the subtype then.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: SOMATIC
    functional_impact_category: GAIN_OF_FUNCTION
    notes: >-
      This block describes the MED12 arm only, which is the majority route and the one
      the node's evidence characterizes. It does not describe FH, whose lesion is
      biallelic loss of a tumor suppressor (LOSS_OF_FUNCTION) and is germline in roughly
      half of FH-deficient tumors - see the separate FH node and the FH-deficient
      subtype. It does not describe HMGA2 rearrangement either, which is a structural
      event rather than a point-mutation gain of function. The slots are single-valued,
      so restricting them to one arm and saying so is more accurate than picking a value
      that is wrong for two of the three genes.
  genes:
  - preferred_term: MED12
    term:
      id: hgnc:11957
      label: MED12
  - preferred_term: HMGA2
    term:
      id: hgnc:5009
      label: HMGA2
  - preferred_term: FH
    term:
      id: hgnc:3700
      label: FH
  cell_types:
  - preferred_term: myometrial smooth muscle cell
    term:
      id: CL:0002366
      label: myometrial cell
  biological_processes:
  - preferred_term: Wnt/beta-catenin signaling dysregulation
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common somatic mutations in fibroids affect the Mediator complex \nsubunit 12 (MED12; 77%) and high-mobility group AT-hook 2/1 (HMGA2/1; 10%) \ngenes."
    explanation: >-
      Establishes MED12 (77%) and HMGA2/1 (10%) as the dominant recurrent somatic
      drivers initiating fibroid tumors.
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations in MED12, a chromatin-associated protein, disrupt \nthe attached CDK8 kinase module in the Mediator complex. MED12 mutations are \nassociated with increased genomic instability, altered chromatin landscape and \nenhancer engagement, and increased responsiveness to progesterone."
    explanation: >-
      Describes the molecular consequence of MED12 driver mutations on the Mediator
      kinase module and progesterone responsiveness.
  - reference: PMID:37668348
    reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the driver gene mutations identified in UFs, mutations \nin MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are \nthe most common and observed in 50-80% of UFs."
    explanation: >-
      Independent review confirming MED12 as the most common driver, present in 50-80%
      of fibroids.
  - reference: PMID:40862769
    reference_title: The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Driver mutations in genes such as \nMED12, HMGA2, and FH also play roles in the development and growth of fibroids."
    explanation: >-
      Confirms MED12, HMGA2, and FH as recurrent drivers of fibroid development.
  downstream:
  - target: Hormone-Driven Myometrial Smooth Muscle Proliferation
    description: >-
      The transformed clonal cell becomes dependent on estrogen and progesterone:
      progesterone (via PGR) drives paracrine WNT ligand secretion that stimulates
      tumor stem cell proliferation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progesterone receptor signaling activates paracrine WNT ligand production.
  - target: Fumarate Accumulation in FH-Deficient Leiomyoma
    description: >-
      In the FH-deficient subtype the driver lesion is biallelic loss of the
      tricarboxylic-acid-cycle enzyme fumarate hydratase, so the initiating event
      is metabolic rather than transcriptional: fumarate accumulates and succinates
      cysteine residues, which is the branch this edge names.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37263921
      reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The immunohistochemical sensitivity of FH and 2SC were 97.3% and 100%, respectively."
      explanation: >-
        Loss of FH protein and accumulation of the fumarate adduct S-(2-succino)-cysteine
        are both demonstrable by immunohistochemistry in FH-deficient leiomyoma, which is
        what makes the FH driver lesion and the fumarate accumulation downstream of it a
        single observable step.

- name: Hormone-Driven Myometrial Smooth Muscle Proliferation
  conforms_to: "sex_steroid_driven_proliferation#Target-Cell Population Expansion"
  description: >
    Estradiol and progesterone are essential for fibroid growth. During each ovulatory
    cycle the myometrium proliferates under ovarian steroid stimulation. Progesterone,
    acting through its nuclear receptor (PGR) in differentiated fibroid cells, activates
    paracrine secretion of WNT ligands, cytokines, and growth factors that drive a small
    stem cell population to proliferate. Fibroids rarely arise before menarche and
    frequently regress after menopause, underscoring steroid hormone dependence. The
    excessive matrix these proliferating cells and the adjacent tumor-associated
    fibroblasts lay down is modelled as the separate downstream node
    "Excessive Extracellular Matrix Deposition and Tissue Stiffening"; this node is the
    cell-population expansion alone.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: myometrial smooth muscle cell
    term:
      id: CL:0002366
      label: myometrial cell
  - preferred_term: tumor-associated fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: smooth muscle cell proliferation
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: progesterone receptor signaling
    term:
      id: GO:0050847
      label: progesterone receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Progesterone, via its receptors in differentiated fibroid cell \npopulations, activates the production of Wingless-type MMTV integration site \nfamily (WNT) ligands, cytokines, and other growth substances to act on adjacent \nstem cells in a paracrine fashion to support tumor growth."
    explanation: >-
      Defines the progesterone-driven paracrine WNT mechanism supporting fibroid stem
      cell proliferation.
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Both the mutated smooth muscle cells and the adjacent \ntumor-associated fibroblasts lay down excessive quantities of extracellular \nmatrix, providing a unique feature that led to naming these tumors \"fibroids.\""
    explanation: >-
      Establishes that mutated smooth muscle cells and tumor-associated fibroblasts
      deposit the excessive ECM characteristic of fibroids.
  - reference: PMID:37668348
    reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene expressions related to ECM \norganization and collagen-rich ECM components are upregulated, and impaired \nMediator kinase activity and dysregulation of Wnt/β-catenin signaling are \nidentified in MED12-UFs."
    explanation: >-
      Links MED12 mutation to upregulated ECM-organization/collagen genes and
      Wnt/beta-catenin dysregulation.
  - reference: PMID:36835153
    reference_title: Differential Expression of MED12-Associated Coding RNA Transcripts in Uterine Leiomyomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential analysis indicated there are 394 genes \ndifferentially and aberrantly expressed only in the mutated tumors. These genes \nwere predominantly involved in the regulation of extracellular constituents."
    explanation: >-
      RNA-sequencing shows MED12-mutant tumors aberrantly express genes regulating
      the extracellular matrix.
  - reference: PMID:40862769
    reference_title: The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "important regulatory RNAs that are becoming increasingly implicated in the aberrant expression of protein-coding genes functionally associated with ECM production, cell proliferation, apoptosis, and inflammation in fibroids"
    explanation: >-
      Non-coding RNAs (miRNAs, lncRNAs, circRNAs) constitute a regulatory layer over
      the fibroid ECM-production and proliferation program, with their expression
      influenced by MED12 mutation status and ovarian steroids.
  downstream:
  - target: Excessive Extracellular Matrix Deposition and Tissue Stiffening
    description: >-
      The expanded clone and the tumor-associated fibroblasts recruited alongside it
      secrete the collagen-rich matrix that gives the tumor its bulk and its name.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37668348
      reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Gene expressions related to ECM \norganization and collagen-rich ECM components are upregulated, and impaired \nMediator kinase activity and dysregulation of Wnt/β-catenin signaling are \nidentified in MED12-UFs."
      explanation: >-
        The proliferating MED12-mutant cell population is the source of the upregulated
        ECM-organization and collagen program, which is the step this edge asserts.
  - target: Aberrant Pseudocapsule Angiogenesis and Venous Ectasia
    description: >-
      The growing clone induces its own blood supply, organized as a vascularized
      pseudocapsule rather than by the hypoxia-driven route used by malignant tumors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "While the fibroid mass itself is poorly vascularised, it can be surrounded by a highly vascularised pseudocapsule in intramural fibroids, a specialized layer of tissue between the tumor and the surrounding myometrium that contains the blood vessels needed to sustain the fibroid"
      explanation: >-
        States that the growing intramural fibroid is supplied by a pseudocapsule of
        newly formed vessels, which is the tumor-to-vasculature step of this edge.

- name: Fumarate Accumulation in FH-Deficient Leiomyoma
  conforms_to: "oncometabolite_dioxygenase_inhibition#Oncometabolite Accumulation"
  description: >
    In the fumarate-hydratase-deficient subtype, biallelic FH loss blocks the
    tricarboxylic-acid cycle at the fumarate-to-malate step, so fumarate accumulates and
    non-enzymatically succinates protein cysteine residues, forming the
    S-(2-succino)-cysteine adduct that immunohistochemistry detects. This node is the
    accumulation step alone; what the accumulated fumarate then does is the downstream
    pseudohypoxia node, matching the way the module it conforms to separates the two.
    The subtype is defined by the same chemistry whether the first FH hit is germline or
    somatic, and the germline case is hereditary leiomyomatosis and renal cell cancer,
    curated separately as Hereditary_Leiomyomatosis_and_Renal_Cell_Cancer.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FH
    term:
      id: hgnc:3700
      label: FH
  molecular_functions:
  - preferred_term: fumarate hydratase activity
    term:
      id: GO:0004333
      label: fumarate hydratase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  cell_types:
  - preferred_term: myometrial smooth muscle cell
    term:
      id: CL:0002366
      label: myometrial cell
  evidence:
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the Sanger sequencing results, the cases were divided into germline variant group (31 cases), somatic variant group (29 cases) and no variant group (20 cases)."
    explanation: >-
      An 80-case FH-deficient leiomyoma series in which the FH lesion is germline in
      roughly as many tumors as it is somatic, supporting the claim that the subtype is
      defined by FH loss rather than by how the first hit was acquired.
  - reference: PMID:36981015
    reference_title: "A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of function variant of FH gene inactivates the Kreb's cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC."
    explanation: >-
      Establishes that the pathogenic mechanism of an FH variant in uterine leiomyoma is
      loss of the Krebs-cycle enzyme activity, which is the lesion this node describes.
  downstream:
  - target: Pseudohypoxic HIF Stabilization in FH-Deficient Leiomyoma
    description: >-
      Accumulated fumarate competitively inhibits the 2-oxoglutarate-dependent HIF prolyl
      hydroxylases, which is the step from oncometabolite to pseudohypoxia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36981015
      reference_title: "A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This increases the levels of intracellular fumarate which inhibits the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, contributing to the accumulation of HIF-"
      explanation: >-
        States the exact step this edge draws: raised intracellular fumarate inhibits the
        HIF prolyl hydroxylases and HIF-alpha accumulates.

- name: Pseudohypoxic HIF Stabilization in FH-Deficient Leiomyoma
  conforms_to: "oncometabolite_dioxygenase_inhibition#Pseudohypoxic HIF Stabilization"
  description: >
    With the HIF prolyl hydroxylases inhibited by fumarate, HIF-alpha escapes degradation
    and a hypoxia transcriptional programme runs in a normoxic cell. This is the FH
    subtype's distinctive route to the tumor's distorted, staghorn vasculature.

    Read this alongside the angiogenesis node, which records HIF-1-alpha as absent from
    uterine fibroids. The two are not in conflict but the boundary matters: that
    observation comes from unselected fibroids, which are overwhelmingly MED12- or
    HMGA2-driven, and it is what establishes that the common fibroid does NOT use the
    hypoxia/VEGF route. Pseudohypoxia is specific to the uncommon FH-deficient subtype,
    where it is driven by a metabolite rather than by low oxygen. A reader who took the
    pseudohypoxia claim to apply to fibroids generally would have it backwards.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: myometrial smooth muscle cell
    term:
      id: CL:0002366
      label: myometrial cell
  evidence:
  - reference: PMID:36981015
    reference_title: "A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This increases the levels of intracellular fumarate which inhibits the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, contributing to the accumulation of HIF-"
    explanation: >-
      The mechanism of this node: fumarate inhibits the prolyl hydroxylases, so HIF-alpha
      accumulates without hypoxia.
  downstream:
  - target: Excessive Extracellular Matrix Deposition and Tissue Stiffening
    description: >-
      The FH-deficient route converges on the same fibrotic output as the
      transcriptional drivers, producing a tumor with the characteristic distorted
      staghorn vasculature and alveolar-pattern oedema.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37263921
      reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients."
      explanation: >-
        Establishes that the FH-deficient lesion does produce a tumor with its own
        distinctive tissue architecture. The steps between pseudohypoxic HIF stabilization
        and that architecture are not established, which is why the link type says so.

- name: Excessive Extracellular Matrix Deposition and Tissue Stiffening
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >
    The defining feature of a fibroid is not its cell count but its matrix: the mutated
    smooth muscle cells and the adjacent tumor-associated fibroblasts deposit
    disproportionate quantities of collagen, fibronectin and proteoglycans, which
    constitute a substantial fraction of tumor volume. The accumulated matrix is not
    inert. It stiffens the tissue, and it binds and prolongs the activity of the growth
    factors (TGF-beta chief among them) that drove its own deposition, so the matrix
    becomes a self-reinforcing feed-forward arm of the mechanism rather than the end of
    it. Matrix metalloproteinase activity is dysregulated in parallel, so remodeling as
    well as deposition is abnormal. This is the node on which the disease's name rests
    and the one that distinguishes a fibroid from a simple hyperplasia.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: leiomyoma smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  - preferred_term: tumor-associated fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: excessive extracellular matrix deposition
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:36982852
    reference_title: Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs."
    explanation: >-
      Names excessive ECM deposition and aberrant remodeling as the central
      characteristic of uterine fibroids, which is exactly what this node asserts.
  - reference: PMID:36982852
    reference_title: Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increased stiffness characterizes the fibrotic microenvironment, and this rigidity is associated with disease progression."
    explanation: >-
      Supports the tissue-stiffening half of this node and its link to progression,
      which is why the node is tagged at the TISSUE scale rather than the cellular one.
  - reference: PMID:41514933
    reference_title: "Beyond VEGF and TGF-β: A Comprehensive Review of Growth Factor Pathways in the Pathophysiology of Uterine Leiomyomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They are benign tumors consisting of disorganized myofibroblasts embedded within significant amounts of extracellular matrix, which constitute a considerable portion of the tumor volume"
    explanation: >-
      Quantifies the matrix as a considerable portion of tumor volume, supporting the
      claim that the matrix rather than the cell mass is the defining component.
  downstream:
  - target: Tumor Growth and Clinical Manifestations
    description: >-
      Sustained proliferation plus excessive matrix deposition produce a growing,
      space-occupying smooth muscle tumor that distorts the uterine architecture and
      generates the clinical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The bulk growth of this extremely dense tissue leads an enlarged and deformed uterus and to some of the key symptoms associated with uterine fibroids in addition to HMB such as pressure symptoms, abdominal pain, and infertility"
      explanation: >-
        Draws the step this edge asserts: the accumulated dense matrix is what makes the
        tumor a space-occupying lesion that deforms the uterus.

- name: Aberrant Pseudocapsule Angiogenesis and Venous Ectasia
  description: >
    Fibroid vasculature is organized differently from that of a malignant solid tumor.
    The fibroid mass itself is poorly vascularized and is instead supplied by a highly
    vascularized pseudocapsule that develops in response to its growth and appears as a
    peripheral "ring of fire" on Doppler ultrasound. The angiogenic drive is attributed
    principally to the insulin-like growth factor system rather than to the
    HIF-1-alpha/VEGF axis of hypoxic tumors, and HIF-1-alpha has been reported absent
    from fibroids where it is readily demonstrable in leiomyosarcoma - which is what
    establishes that the common fibroid does not use the hypoxia route, and is not
    contradicted by the pseudohypoxia node, whose HIF stabilization is metabolite-driven
    and confined to the uncommon FH-deficient subtype. Separately, the
    growing mass raises interstitial pressure and obstructs venous drainage, enlarging
    the endometrial and myometrial venous lakes. Both the structurally deficient
    pseudocapsule vessels and the dilated venous lakes are proposed sources of the
    heavy bleeding, and which of them dominates is unsettled.

    One correction the source makes about its own history is worth keeping: the
    interstitial-pressure explanation for the enlarged venous lakes was later challenged,
    with growth factors rather than mechanical pressure held largely responsible for
    enlarging the veins. The pressure account is recorded here because the
    microradiographic observation of enlarged lakes stands; its mechanical explanation
    does not.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular."
    explanation: >-
      Establishes both halves of this node's angiogenic claim: the IGF-driven rather
      than VEGF-driven route, and the irregular vasculature that results.
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microradiographic studies in the 1970's supported the notion that HMB resulted not from the fibroid vasculature itself but rather from venous lakes dilated and enlarged by virtue of increased interstitial pressure from the growing tumors"
    explanation: >-
      Supports the venous-ectasia arm of this node, in which the mass effect of the
      tumor rather than its own vessels enlarges the draining veins.
  downstream:
  - target: Endometrial Hemostatic Failure and Impaired Vessel Closure
    description: >-
      Vessels of increased diameter, whether pseudocapsule neovessels or dilated venous
      lakes, are the substrate that the endometrial hemostatic mechanism then fails to
      close.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the heavy bleeding resulted from a failure of the fibrin/platelet plugs formed in the coagulation cascade in closing these blood vessels of increased diameter successfully"
      explanation: >-
        States the causal step this edge draws: enlarged vessels plus failed fibrin
        and platelet plugs produce the heavy bleeding.

- name: Endometrial Hemostatic Failure and Impaired Vessel Closure
  description: >
    Fibroids do not bleed only by mechanics. Fibroid tissue secretes TGF-beta-3 in
    response to ovarian steroids, and TGF-beta-3 acts on the overlying endometrium to
    downregulate BMP receptor 2 (which the source says is likely to cause defective
    decidualization) and to reduce expression of plasminogen activator inhibitor 1,
    antithrombin III and thrombomodulin, which the source says likely contributes to the
    bleeding. Both steps are hedged in the source and are hedged here. Note also that two
    of those three regulators are anticoagulants, so the net direction is an
    interpretation of the hemostatic outcome the source draws rather than a reading of
    each protein in isolation - the DECREASED modifier on the blood-coagulation process
    below records that net outcome, not a per-protein reading. The endometrium is
    therefore both less able to
    decidualize and less able to form and hold a hemostatic plug. This node is where the
    reproductive and the bleeding phenotypes share a mechanism.

    Scope note: the purely physical contributions to the bleeding - increased endometrial
    surface area, disordered myometrial contractility, and venous ectasia from
    compression - are real and are cited below, but they are properties of the tumor mass
    and belong to the Tumor Growth and Bulk Compression nodes. This node is the
    endometrial signalling arm, which is why it is tagged TISSUE.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: endometrial stromal cell
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  biological_processes:
  - preferred_term: endometrial hemostatic plug formation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: DECREASED
  - preferred_term: endometrial decidualization
    term:
      id: GO:0046697
      label: decidualization
    modifier: DECREASED
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TGF-β3 secreted by fibroids has been shown to induce BMP-2 resistance in endometrium by down-regulation of BMPR-2, likely causing defective endometrial decidualization"
    explanation: >-
      Supports the decidualization arm: fibroid-derived TGF-beta-3 downregulates BMPR-2
      in the endometrium and impairs decidualization.
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TGF-β3 also reduces expression of plasminogen activator inhibitor-1 (PAI-1), Antithrombin III (ATIII), and thrombomodulin in endometrium, likely contributing to bleeding"
    explanation: >-
      Supports the hemostatic arm: the same fibroid-derived TGF-beta-3 lowers three
      endometrial coagulation regulators, which the source links to the bleeding.
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroids may cause HMB merely physically, i.e., through an increase in endometrial surface due to underlying fibroid growth; through an influence on normal myometrial contractility patterns; through an ulcerated or degenerating fibroid, or through uterine venous ectasia due to compression from the fibroids"
    explanation: >-
      Enumerates the mechanical contributions this node records alongside the
      TGF-beta-3-mediated ones, and is the reason the node is not described as purely
      biochemical.
  downstream:
  - target: Heavy Menstrual Bleeding
    description: >-
      The hemostatic and vascular failure described by this node is what makes the
      menstrual loss heavy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the heavy bleeding resulted from a failure of the fibrin/platelet plugs formed in the coagulation cascade in closing these blood vessels of increased diameter successfully"
      explanation: >-
        States the hemostatic failure to bleeding step directly.
  - target: Infertility and Reproductive Morbidity
    description: >-
      Defective decidualization is the shared step by which the same TGF-beta-3 signal
      that impairs hemostasis also impairs implantation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - BMPR-2 downregulation produces endometrial BMP-2 resistance.
    - BMP-2-resistant endometrium decidualizes defectively, impairing implantation.

- name: Tumor Growth and Clinical Manifestations
  description: >
    Progressive growth of the leiomyoma produces a benign smooth muscle tumor of the
    uterus. Submucosal and intramural tumors distort the endometrial cavity and impair
    hemostasis, causing heavy menstrual bleeding and consequent iron deficiency anemia.
    Bulk from larger tumors compresses adjacent pelvic organs (bladder, rectum), causing
    pressure symptoms, while distortion of the cavity and tubal ostia contributes to
    reproductive morbidity. Most affected women are asymptomatic: fibroids cause
    clinically significant disease in roughly a quarter of reproductive-age women
    overall, and affect quality of life in approximately 30% of cases.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: leiomyoma smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  evidence:
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine fibroids (leiomyomas), the most common tumors in women and those \nassigned female at birth, originate from myometrial smooth muscle cells and \ncause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and \nobstruction of labor in approximately a quarter of reproductive-age women."
    explanation: >-
      Connects the smooth muscle tumor to its core clinical manifestations: heavy
      menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction
      of labor.
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in \napproximately 30% of cases, UFs affect the quality of life and women's health, \nwith abnormal uterine bleeding and heavy menstrual bleeding being the most \ncommon complaints, along with iron deficiency (ID) and ID anemia."
    explanation: >-
      Quantifies the symptomatic fraction and identifies AUB/HMB and iron deficiency
      anemia as the dominant complaints.
  downstream:
  - target: Bulk Compression of Adjacent Pelvic Organs
    description: >-
      Once the tumor is large enough, its mass alone displaces the neighbouring bladder
      and rectum; this arm of the mechanism is purely mechanical and is independent of
      the bleeding arm.
    causal_link_type: DIRECT
  - target: Pelvic Mass
    description: >-
      A tumor large enough to enlarge the uterus becomes palpable.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38929485
      reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the most common benign \ngynecological condition in patients presenting with abnormal uterine bleeding, \npelvic masses causing pressure or pain"
      explanation: >-
        Names the pelvic mass as a presentation of the fibroid itself, which is the step
        this edge draws.
  - target: Pelvic Pain
    description: >-
      Bulk and pressure from the growing tumor produce pelvic pain and discomfort.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40214304
      reference_title: UTERINE FIBROIDS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Uterine fibroids (leiomyomas), the most common tumors in women and those \nassigned female at birth, originate from myometrial smooth muscle cells and \ncause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and \nobstruction of labor in approximately a quarter of reproductive-age women."
      explanation: >-
        Names this manifestation among the consequences the review attributes directly to
        the fibroid, which is the step this edge draws.
  - target: Dysmenorrhea
    description: >-
      Disordered myometrial contractility around the tumor makes menstruation painful.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The tumor disturbs normal myometrial contractility patterns.
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "through an influence on normal myometrial contractility patterns"
      explanation: >-
        Names the contractility disturbance that is the intermediate on this edge.
  - target: Dyspareunia
    description: >-
      The enlarged, deformed uterus makes intercourse painful, position-dependently.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36303616
      reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The bulk growth of this extremely dense tissue leads an enlarged and deformed uterus and to some of the key symptoms associated with uterine fibroids in addition to HMB such as pressure symptoms, abdominal pain, and infertility"
      explanation: >-
        Supports the bulk-to-pain step in general terms without naming dyspareunia, which
        is why this is graded INDIRECT.
  - target: Endometrial Hemostatic Failure and Impaired Vessel Closure
    description: >-
      A cavity-distorting tumor is the precondition for the endometrial signalling and
      hemostatic changes that produce the bleeding.
    causal_link_type: DIRECT

- name: Bulk Compression of Adjacent Pelvic Organs
  description: >
    A fibroid large enough to enlarge and deform the uterus displaces the structures
    around it. Anterior and fundal tumors press on the bladder, producing urinary
    frequency and, when the ureters are involved, hydronephrosis; posterior tumors press
    on the rectum, producing constipation; a large fibroid can go further and cause
    urinary obstruction or, rarely, hydronephrosis. This is the one arm of the mechanism
    that is purely a consequence of volume and position: severity correlates with fibroid
    size, number and anatomical placement rather than with driver genotype, and the
    treatments that shrink or remove the tumor relieve it while the treatments that only
    control bleeding do not.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The bulk growth of this extremely dense tissue leads an enlarged and deformed uterus and to some of the key symptoms associated with uterine fibroids in addition to HMB such as pressure symptoms, abdominal pain, and infertility"
    explanation: >-
      Attributes the pressure symptoms specifically to the bulk of the dense tumor
      enlarging and deforming the uterus, which is the mechanical claim of this node.
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."
    explanation: >-
      States the compression mechanism and both of its outputs directly, which is the
      whole content of this node.
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In severe cases, particularly large fibroids may lead to urinary obstruction or rare hydronephrosis"
    explanation: >-
      Supplies the severe end of the compression spectrum named in this node's
      description, including the hydronephrosis that would otherwise be uncited.
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The extent and severity of these symptoms correlate with fibroid size, number, and anatomical placement within the uterus."
    explanation: >-
      Names the three determinants of bulk-symptom severity recorded in this node's
      description, and is the reason it does not claim size alone.
  downstream:
  - target: Urinary Frequency
    description: >-
      Anterior and fundal tumors press on the bladder, reducing its capacity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40970558
      reference_title: Diagnosis and classification of uterine fibroids.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."
      explanation: >-
        States bladder compression producing urinary frequency, which is exactly this edge.
  - target: Constipation from Bulk Compression
    description: >-
      Posterior tumors press on the rectum.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40970558
      reference_title: Diagnosis and classification of uterine fibroids.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."
      explanation: >-
        Names rectal compression producing constipation, which is exactly this edge.

phenotypes:
- category: Clinical
  name: Uterine Leiomyoma
  description: Benign smooth muscle neoplasm arising from the myometrium of the uterus.
  phenotype_term:
    preferred_term: Uterine leiomyoma
    term:
      id: HP:0000131
      label: Uterine leiomyoma
  evidence:
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine fibroids (leiomyomas), the most common tumors in women and those \nassigned female at birth, originate from myometrial smooth muscle cells"
    explanation: Documents uterine leiomyoma as a myometrial smooth muscle tumor.

- category: Clinical
  name: Heavy Menstrual Bleeding
  description: >
    Heavy menstrual bleeding (menorrhagia) is the most common symptom, classified as
    AUB-L (leiomyoma) by FIGO, particularly with submucosal tumors.
  phenotype_term:
    preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal uterine bleeding and heavy menstrual bleeding being the most \ncommon complaints"
    explanation: Identifies heavy menstrual bleeding as the most common fibroid complaint.
  sequelae:
  - target: Iron Deficiency Anemia
    description: >-
      Chronic menstrual blood loss depletes iron stores.
    evidence:
    - reference: PMID:38723935
      reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the management of \nID and ID anemia, as a consequence of acute and chronic bleeding, should be \ntaken into account with the use of iron replacement therapy"
      explanation: >-
        States that the iron deficiency and anemia are a consequence of the bleeding,
        which is the step this sequela edge draws.

- category: Clinical
  name: Pelvic Pain
  description: Pelvic heaviness, pressure, and pain related to fibroid bulk.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common benign \ngynecological condition in patients presenting with abnormal uterine bleeding, \npelvic masses causing pressure or pain"
    explanation: Documents pelvic masses causing pressure or pain as a fibroid presentation.

- category: Clinical
  name: Dysmenorrhea
  description: Painful menstruation associated with fibroids.
  phenotype_term:
    preferred_term: Dysmenorrhea
    term:
      id: HP:0100607
      label: Dysmenorrhea
  evidence:
  - reference: PMID:41514933
    reference_title: "Beyond VEGF and TGF-β: A Comprehensive Review of Growth Factor Pathways in the Pathophysiology of Uterine Leiomyomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several symptoms exist in women with UFs: a heavy and irregular menstrual cycle, dysmenorrhea, pelvic pressure, and infertility"
    explanation: >-
      Names dysmenorrhea directly among the symptoms of uterine fibroids, which is a
      direct attestation of the term bound here.
  - reference: PMID:39335725
    reference_title: "Tailoring the Diagnostic Pathway for Medical and Surgical Treatment of Uterine Fibroids: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mifepristone demonstrated its efficacy in reducing abnormal uterine bleedings (AUBs) and fibroid-related dysmenorrhea"
    explanation: >-
      Second, independent attestation: the phrase "fibroid-related dysmenorrhea" treats
      this phenotype as an established consequence of fibroids, and its reducibility by
      antiprogestin therapy supports the hormone-dependent mechanism it is attached to.

- category: Clinical
  name: Iron Deficiency Anemia
  description: Anemia resulting from chronic heavy menstrual blood loss.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with iron deficiency (ID) and ID anemia"
    explanation: Documents iron deficiency anemia as a consequence of fibroid-related bleeding.
  notes: >-
    Fatigue is the expected sequela of this anemia and was drafted as its own phenotype
    (HP:0012378), then removed: no source cited anywhere in this entry names fatigue as a
    fibroid symptom, and a targeted PubMed search for one (fibroid + iron deficiency +
    fatigue in title/abstract) returned nothing usable. The claim is clinically obvious
    and bibliographically unsupported here, so it is recorded as this note rather than as
    an ontology-bound phenotype resting on an inference.

- category: Clinical
  name: Infertility and Reproductive Morbidity
  description: >
    Fibroids, especially submucosal and large intramural tumors, are associated with
    infertility, defective implantation, pregnancy loss, and obstruction of labor.
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  evidence:
  - reference: PMID:40214304
    reference_title: UTERINE FIBROIDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and \nobstruction of labor"
    explanation: >-
      Documents pregnancy loss and obstruction of labor among fibroid-associated
      reproductive complications.
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pelvic masses causing pressure or pain, infertility and obstetric complications"
    explanation: >-
      Directly lists infertility and obstetric complications among the presentations
      of uterine fibroids, supporting the infertility phenotype term.
  sequelae:
  - target: Recurrent Pregnancy Loss
    description: >-
      Cavity distortion and defective decidualization carry through from failure of
      implantation to failure to maintain a pregnancy.
    causal_link_type: DIRECT
  - target: Preterm Birth
    description: >-
      Fibroid-complicated pregnancies that do continue are more likely to deliver early;
      this is the obstetric association that survives adjustment for confounders.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38710995
      reference_title: "The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia."
      explanation: >-
        Names preterm birth among the associations that remain significant after
        adjustment, which is what this edge asserts.

- category: Clinical
  name: Constipation from Bulk Compression
  description: >
    Posteriorly placed fibroids compress the rectum, producing constipation. Bladder
    compression also produces urinary frequency, but that is a distinct phenotype,
    curated separately, and is not represented by the HPO term bound here.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."
    explanation: >-
      Names constipation directly and attributes it to rectal compression by a
      posteriorly placed fibroid, which is both this phenotype and its mechanism.

- category: Clinical
  name: Urinary Frequency
  description: >
    Anterior and fundal fibroids compress the bladder, reducing its functional capacity
    and producing increased daytime micturition frequency. This is the bladder
    counterpart of the rectal compression recorded as constipation, and is bound
    separately because the HPO term for constipation does not cover it.
  phenotype_term:
    preferred_term: Urinary frequency
    term:
      id: HP:0100515
      label: Pollakisuria
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."
    explanation: >-
      Names urinary frequency as a consequence of bladder compression by an anteriorly
      placed fibroid, which is this phenotype and its mechanism.
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, when symptoms occur, they may not be related to the fibroids since abnormal uterine bleeding (AUB), infertility, recurrent pregnancy loss, pressure, pain, urinary frequency, or gastrointestinal dysfunction may be present with a variety of otherwise unrelated conditions."
    explanation: >-
      Kept deliberately as the source's own counter-caution: urinary frequency is not
      specific to fibroids and may belong to an unrelated condition in the same patient.
      Quoted in full including the "may not be related to the fibroids" clause so it
      cannot be read as attributing the symptom.

- category: Clinical
  name: Dyspareunia
  description: >
    Painful intercourse, typically position-dependent and related to the bulk and
    location of the tumor rather than to bleeding.
  phenotype_term:
    preferred_term: Dyspareunia
    term:
      id: HP:0030016
      label: Dyspareunia
  evidence:
  - reference: PMID:35106750
    reference_title: Minimally invasive treatment options for uterine fibroids - state-of-the art 2021.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine leyomyomas are benign, monoclonal tumors that can cause abnormal uterine bleeding, pelvic pain, dyspareunia and/or obstruction of bladder or rectum."
    explanation: >-
      Names dyspareunia outright among the symptoms fibroids cause, which is a direct
      attestation of the term bound here. (The source's own spelling of "leyomyomas" is
      preserved, as a snippet never corrects the text it quotes.)

- category: Clinical
  name: Pelvic Mass
  description: >
    A palpable, often irregular pelvic or lower abdominal mass on examination when the
    fibroid uterus is sufficiently enlarged. Its diagnostic value is limited: fibroids
    are not reliably detected by palpation and their impact cannot be predicted from it,
    which is why imaging rather than examination anchors the diagnosis.
  phenotype_term:
    preferred_term: Pelvic mass
    term:
      id: HP:0031501
      label: Pelvic mass
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, fibroids are not reliably diagnosed on physical examination, nor can their impact be predicted through palpation."
    explanation: >-
      Supports the description's caveat about the limited diagnostic value of the
      palpable mass, which is the clinically important point about this phenotype.
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common benign \ngynecological condition in patients presenting with abnormal uterine bleeding, \npelvic masses causing pressure or pain"
    explanation: >-
      Names pelvic masses as a presenting finding of uterine fibroids.

- category: Clinical
  name: Recurrent Pregnancy Loss
  description: >
    Pregnancy loss in fibroid-complicated pregnancies. The cited meta-analysis reports
    miscarriage rather than recurrent miscarriage, and does not attribute it to cavity
    distortion, so neither qualifier is claimed here; the recurrent framing comes from
    the phenotype concept, not from this source. A meta-analysis of
    24 studies found fibroids raised miscarriage risk in unadjusted analysis; after
    adjustment for confounders the significant obstetric associations were preterm
    birth, cesarean delivery, placenta previa, placental abruption, postpartum
    hemorrhage, intrauterine fetal death, breech presentation and preeclampsia, and
    miscarriage was not among them. Both results are recorded here because the
    distinction matters for how strongly this phenotype should be claimed.

    The ontology binding is deliberately omitted. HP:0200067 Recurrent spontaneous
    abortion means exactly this, but it sits under HP:0032443 (past medical history)
    rather than under HP:0000118 (phenotypic abnormality), so it is not a member of the
    PhenotypeTerm dynamic enum; HP:0005268 Miscarriage and HP:0003826 Stillbirth are
    both outside the enum root too, under the clinical-modifier branch. Binding a term
    that means something else would be worse than leaving it unbound, so the meaning is
    carried by preferred_term. Asherman_Syndrome records the same gap for the same term
    (issue #7837, gap 3).
  phenotype_term:
    preferred_term: Recurrent spontaneous abortion
  evidence:
  - reference: PMID:38710995
    reference_title: "The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled results showed that fibroids elevated the risk of adverse outcomes, including preterm birth, cesarean delivery, placenta previa, miscarriage, preterm premature rupture of membranes (PPROM), placental abruption, postpartum hemorrhage (PPH), fetal distress, malposition, intrauterine fetal death, low birth weight, breech presentation, and preeclampsia."
    explanation: >-
      The pooled unadjusted meta-analysis result includes miscarriage among the
      fibroid-associated adverse outcomes.
  - reference: PMID:38710995
    reference_title: "The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia."
    explanation: >-
      The same meta-analysis's adjusted analysis does not retain miscarriage, so this
      sentence contradicts the unadjusted association above. Recorded as a separate
      REFUTE item rather than folded into the first, because one evidence item cannot
      carry two opposite directions.

- category: Clinical
  name: Preterm Birth
  description: >
    Delivery before 37 weeks in pregnancies complicated by fibroids. Unlike miscarriage,
    this association survives adjustment for confounders in meta-analysis.
  phenotype_term:
    preferred_term: Preterm birth
    term:
      id: HP:0001622
      label: Premature birth
  evidence:
  - reference: PMID:38710995
    reference_title: "The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia."
    explanation: >-
      Preterm birth is first in the list of associations that remain significant after
      adjustment, which is the stronger claim this phenotype rests on.

genetic:
- name: MED12 somatic exon-2 mutation
  gene_term:
    preferred_term: MED12
    term:
      id: hgnc:11957
      label: MED12
  variant_origin: SOMATIC
  features: >
    Recurrent somatic exon-2 (codon 44 region) point mutations in MED12 are the most
    common driver, present in ~50-80% of uterine fibroids (~77% in a large review).
    These gain-of-function mutations disrupt the CDK8/CDK19 Mediator kinase module,
    are more frequent in Black women, are commonly found even in small tumors, and
    associate with multiple rather than solitary fibroids. Note that the mutation is not
    simply growth-promoting: MED12 wild-type leiomyomas have a higher growth potential
    than mutant ones and show higher MED12-associated CDK8 kinase activity, which the
    entry records as an open question rather than smoothing over.
  evidence:
  - reference: PMID:36835153
    reference_title: Differential Expression of MED12-Associated Coding RNA Transcripts in Uterine Leiomyomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies have demonstrated that somatic MED12 mutations in exon 2 occur at \na frequency of up to 80% and have a functional role in leiomyoma pathogenesis."
    explanation: Documents somatic MED12 exon-2 mutations at up to 80% frequency.
  - reference: PMID:37668348
    reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They are gain-of-function \nmutations and are more frequently observed in Black women and commonly observed \neven in small UFs."
    explanation: Characterizes MED12 mutations as gain-of-function and more frequent in Black women.
  - reference: PMID:41493967
    reference_title: Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth."
    explanation: >-
      Contradicts the reading of MED12 mutation as straightforwardly growth-promoting
      that a gain-of-function label invites: wild-type tumors grow faster. Recorded as
      REFUTE against that stronger claim rather than omitted, and followed up in the
      discussions section.

- name: HMGA2 overexpression / rearrangement
  gene_term:
    preferred_term: HMGA2
    term:
      id: hgnc:5009
      label: HMGA2
  variant_origin: SOMATIC
  features: >
    Somatic HMGA2 (12q14-15) overexpression and chromosomal rearrangements define a
    distinct molecular subtype (~10% of fibroids overall; markedly enriched in cellular
    leiomyoma variants).
  evidence:
  - reference: PMID:34626221
    reference_title: "Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "36.5% showed HMGA2 overexpression at the IHC \nlevel, associated with increased mRNA expression in 14/14 cases. The \nrearrangement of the HMGA2 gene was detected in 13.2%."
    explanation: >-
      Documents HMGA2 overexpression and rearrangement frequencies in cellular
      leiomyoma.

- name: FH (fumarate hydratase) deficiency
  gene_term:
    preferred_term: FH
    term:
      id: hgnc:3700
      label: FH
  variant_origin: GERMLINE_AND_SOMATIC
  features: >
    Biallelic FH loss defines the fumarate-hydratase-deficient leiomyoma subtype. In an
    80-case series the first FH hit was germline in 31 tumors, somatic in 29, and
    undetected by exon sequencing in 20, so the subtype is not synonymous with the
    hereditary syndrome. Germline FH variants cause hereditary leiomyomatosis and renal
    cell cancer (HLRCC), an autosomal dominant syndrome of cutaneous and uterine
    leiomyomas plus renal cell carcinoma, which dismech curates separately as
    Hereditary_Leiomyomatosis_and_Renal_Cell_Cancer; 69% of the germline-variant
    patients in that series had a clear family history. Because the germline case is
    heritable and carries a renal cancer risk, recognizing FH-deficient histology on a
    resected fibroid is the clinically consequential part of this subtype.
  evidence:
  - reference: PMID:40862769
    reference_title: The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Driver mutations in genes such as \nMED12, HMGA2, and FH also play roles in the development and growth of fibroids."
    explanation: Lists FH among recurrent fibroid driver genes.
  - reference: PMID:36981015
    reference_title: "A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC)."
    explanation: >-
      Supplies the citation the previous version of this record said was missing: a
      heterozygous germline FH variant causes HLRCC, whose features include uterine
      leiomyoma alongside cutaneous leiomyoma and renal cell carcinoma.
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixty-nine percent (20/29) of the patients with FH germline variation had clear family history."
    explanation: >-
      Quantifies the family-history rate among germline-FH patients, supporting the
      claim that identifying this subtype has consequences beyond the index tumor.
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients' age ranged from 18 to 54 (36.0±7.5) years, with more than 60% exhibiting clinical symptoms of multiple and large leiomyomas (the median diameter was 70 mm)."
    explanation: >-
      Characterizes the clinical presentation of the FH-deficient subtype as multiple,
      large (median 70 mm) and symptomatic in the majority.

histopathology:
- name: Whorled fascicles of spindle smooth muscle cells in collagenous stroma
  description: >
    The conventional leiomyoma is a well-circumscribed nodule of bland spindle smooth
    muscle cells arranged in interlacing whorled fascicles, separated from the
    surrounding myometrium by a cleft, and set in an abundant collagen-rich stroma that
    accounts for much of the tumor's volume. Histology is confirmatory rather than
    diagnostic in routine practice, because fibroids are diagnosed on imaging and
    tissue is normally examined only after resection.
  finding_term:
    preferred_term: uterine corpus leiomyoma
    term:
      id: NCIT:C3434
      label: Uterine Corpus Leiomyoma
  diagnostic: true
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the name, fibroids largely comprise of myocytes rather than fibroblasts and are characterized by the excessive deposition of extracellular matrix substances, mainly collagen, within the tumor"
    explanation: >-
      Establishes the two components of this finding: a tumor made of smooth muscle
      cells rather than fibroblasts, in an excess of mainly collagenous matrix.
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is separated from the myometrium by a clear cleft, as observed in histological images"
    explanation: >-
      Supports the circumscription and the cleft that separate the nodule from the
      adjacent myometrium on histology.

- name: FH-deficient histologic signature
  subtype: FH-deficient
  description: >
    A recognizable constellation rather than a single feature: staghorn vasculature,
    alveolar-pattern oedema, bizarre nuclei, oval nuclei arranged in chains, prominent
    eosinophilic nucleoli with perinucleolar haloes, and eosinophilic intracytoplasmic
    globules. More than four of these were present in 98.5% of an 80-case series.
    Confirmation is immunohistochemical: loss of FH staining (97.3% sensitive) or gain of
    S-(2-succino)-cysteine staining (100% in the five cases tested). Finding this pattern
    is what prompts germline FH testing, so it is the histology with the largest
    downstream consequence in this disease.
  finding_term:
    preferred_term: FH-deficient uterine leiomyoma with bizarre nuclei
    term:
      id: NCIT:C4257
      label: Bizarre Leiomyoma
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: >-
    The bound term names only the bizarre-nuclei component. NCIT has no term for the
    FH-deficient composite signature, and the atypical/bizarre leiomyoma concept is not
    coextensive with it, so preferred_term carries the specific meaning per the ontology
    term contract. The frequency band is within the FH-deficient subtype (98.5% of
    cases), not within uterine leiomyoma as a whole, where the subtype is uncommon.
  evidence:
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients."
    explanation: >-
      Lists the exact constellation and its frequency within the FH-deficient series.
  - reference: PMID:37263921
    reference_title: "[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FH immunohistochemistry were performed in 74 cases; S-(2-succino)-cysteine (2SC) were also detected by immunohistochemistry in five cases."
    explanation: >-
      Documents the immunohistochemical confirmation step, and the small number of 2SC
      cases behind its reported 100% sensitivity.

- name: Cellular leiomyoma variant
  subtype: HMGA2-rearranged
  description: >
    A histologic variant with markedly increased cellularity and correspondingly less
    stroma, which raises the differential with endometrial stromal tumors and
    leiomyosarcoma. Molecularly it is enriched for HMGA2 aberration, then chromosome 1p
    deletion, then MED12 mutation, so the variant is not just a morphologic curiosity
    but tracks a different driver distribution from conventional leiomyoma.
  finding_term:
    preferred_term: uterine corpus cellular leiomyoma
    term:
      id: NCIT:C40163
      label: Uterine Corpus Cellular Leiomyoma
  evidence:
  - reference: PMID:34626221
    reference_title: "Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "36.5% showed HMGA2 overexpression at the IHC \nlevel, associated with increased mRNA expression in 14/14 cases."
    explanation: >-
      Supports the enrichment of HMGA2 aberration in this histologic variant.

imaging_findings:
- name: Well-circumscribed hypoechoic myometrial mass on transvaginal ultrasound
  modality: ULTRASOUND
  description: >
    Ultrasound is the first-line modality and is where the diagnosis is normally made:
    it establishes presence, size, number and location. Because examination is
    unreliable, imaging rather than palpation drives management, and reports are expected
    to place each fibroid in the FIGO 0-8 scheme describing its relationship to
    endometrium, myometrium and serosa.
  phenotype_term:
    preferred_term: Uterine leiomyoma
    term:
      id: HP:0000131
      label: Uterine leiomyoma
  diagnostic: true
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasound should be the first-line diagnostic modality, and magnetic resonance imaging should be reserved for complex cases and/or surgical planning."
    explanation: >-
      States the first-line role of ultrasound and the reserved role of MRI.
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging reports should follow the FIGO classification system for uterine fibroids, to enable a standardized description of their relationship to the endometrium, myometrium, and uterine serosa."
    explanation: >-
      Supports the FIGO reporting convention this finding is expected to be described in.

- name: Peripheral "ring of fire" vascularity on Doppler
  modality: ULTRASOUND
  description: >
    Colour Doppler shows flow concentrated at the rim of an intramural fibroid rather
    than through it, reflecting the vascularized pseudocapsule that supplies a tumor
    whose own mass is poorly vascularized. This is the imaging correlate of the
    pseudocapsule angiogenesis node.
  phenotype_term:
    preferred_term: Uterine leiomyoma
    term:
      id: HP:0000131
      label: Uterine leiomyoma
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the fibroid mass itself is poorly vascularised, it can be surrounded by a highly
      vascularised pseudocapsule in intramural fibroids, a specialized layer of tissue between the
      tumor and the surrounding myometrium that contains the blood vessels needed to sustain the
      fibroid (81), which develops in response to the fibroid growth (82). This structure can be
      seen as a “ring of fire” in ultrasound Doppler imaging, and it is separated from the
      myometrium by a clear cleft, as observed in histological images.
    explanation: >-
      Restores the intramural-fibroid pseudocapsule and its vascular supply before the Doppler ring
      sign, preserving the contrast with the poorly vascularized fibroid mass.
- name: Multiplanar MRI characterization for surgical planning
  modality: MRI
  description: >
    MRI is reserved for complex cases and surgical planning, where it distinguishes
    fibroids from adenomyosis and from malignancy, predicts therapeutic response, and
    maps the tumors for intervention. It does not, however, reliably exclude
    leiomyosarcoma before resection.
  phenotype_term:
    preferred_term: Uterine leiomyoma
    term:
      id: HP:0000131
      label: Uterine leiomyoma
  diagnostic: true
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adherence to standardized structured reporting across imaging modalities is critical to improve diagnostic accuracy, differentiate fibroids from conditions such as adenomyosis or malignancies, predict therapeutic responses, and plan surgical interventions."
    explanation: >-
      Lists the four purposes this finding is curated for, including the differential
      against adenomyosis and malignancy.

environmental:
- name: Chronic low vitamin D status
  description: >
    Vitamin D deficiency is repeatedly associated with fibroid presence and size, and
    unlike most epidemiological risk factors it has a specific proposed mechanism at the
    initiating node rather than at the growth node: calcitriol acting through VDR
    supports the MRN-complex/ATM DNA-repair axis in myometrial stem cells, so deficiency
    plausibly permits the driver lesion to be acquired and retained. In vitro work shows
    vitamin D inhibiting fibroid growth through proliferation, ECM remodelling, DNA
    repair and apoptosis pathways; clinical studies support this only in part.
  exposure_term:
    preferred_term: vitamin D deficiency
  effect: Risk factor for fibroid development and growth; adequate status is plausibly protective.
  review_notes: >-
    exposure_term is left ontology-unbound deliberately. ECTO was searched
    (sqlite:obo:ecto) for "vitamin D deficiency" and for deficiency-shaped exposure
    terms and returned nothing; the nearest terms, ECTO:9000133 "exposure to vitamin D"
    and XCO:0000543 "vitamin D", both name the presence of the exposure, which is the
    opposite of the risk factor recorded here. No term beats a term that means the
    inverse, so preferred_term carries the meaning.
  evidence:
  - reference: PMID:33670322
    reference_title: "Vitamin D: Mechanism of Action and Biological Effects in Uterine Fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In recent years, epidemiological studies reported a vitamin D deficiency in patients with UFs raised interest in the potential biological effects of vitamin D supplementation."
    explanation: >-
      Establishes the epidemiological association between vitamin D deficiency and
      uterine fibroids that this exposure record is about.
  - reference: PMID:33670322
    reference_title: "Vitamin D: Mechanism of Action and Biological Effects in Uterine Fibroids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies proved vitamin D efficacy in inhibiting UFs growth by targeting pathways involved in the regulation of various biological processes, including proliferation, extracellular matrix (ECM) remodeling, DNA repair, signaling and apoptosis."
    explanation: >-
      Supports the mechanistic half of the claim, naming the DNA-repair and ECM pathways
      this record links to the pathograph.
  - reference: PMID:33670322
    reference_title: "Vitamin D: Mechanism of Action and Biological Effects in Uterine Fibroids."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, clinical studies supported only in part the beneficial effects of vitamin D supplementation in reducing UFs growth and tumor volume."
    explanation: >-
      Contradicts the stronger reading that supplementation is an established
      fibroid-directed treatment. Kept as a separate REFUTE item because the same source
      supports the association and undercuts the therapeutic claim.
  influences_mechanisms:
  - target: Driver Mutation-Initiated Clonal Transformation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Low vitamin D status is linked to the initiating lesion rather than to hormonal
      growth: VDR signalling supports the MRN-complex/ATM DNA-damage response in
      myometrial stem cells, and its loss leaves DNA damage unrepaired in exactly the
      cell population from which fibroids arise.
    evidence:
    - reference: PMID:32545544
      reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR."
      explanation: >-
        Names the repair axis vitamin D acts through in myometrial stem cells, which is
        the intermediate this edge asserts between vitamin D status and the driver lesion.

- name: Developmental exposure to endocrine-disrupting chemicals
  description: >
    Early-life exposure of the myometrium to endocrine-disrupting chemicals raises adult
    fibroid risk. The strongest mechanistic evidence is from Eker rats exposed neonatally
    to diethylstilbestrol, whose myometrial stem cells show reduced RAD50 and MRE11 and a
    defective DNA damage response at the pro-fibroid stage, months before tumors appear.
    In humans the corresponding exposures reported are xenoestrogens in early
    ontogenesis, diethylstilbestrol, and phthalates and bisphenol A.
  exposure_term:
    preferred_term: exposure to xenoestrogen
    term:
      id: ECTO:9002036
      label: exposure to xenoestrogen
  effect: Developmental risk factor, acting through DNA-damage-response impairment in myometrial stem cells.
  evidence:
  - reference: PMID:36982852
    reference_title: Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These factors include race, age, parity, family history, food additives, obesity, vitamin D deficiency, and endocrine-disrupting chemical exposure"
    explanation: >-
      Human review listing endocrine-disrupting chemical exposure among the established
      fibroid risk factors. Cited here rather than the opening sentence of the Eker-rat
      paper, which asserts the same association but is a rodent study and so cannot carry
      a HUMAN_CLINICAL grade.
  - reference: PMID:32545544
    reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01)."
    explanation: >-
      The rat experimental result behind the mechanism: developmental DES exposure
      depletes two MRN-complex repair proteins in myometrium.
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"
    explanation: >-
      Independent review listing exposure to xenoestrogens in early ontogenesis among
      the established risk factors, which is the exposure term bound here.
  influences_mechanisms:
  - target: Driver Mutation-Initiated Clonal Transformation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Developmental xenoestrogen exposure leaves the myometrial stem cell pool
      repair-deficient, which is how an exposure decades earlier raises the probability
      of the somatic driver lesion that starts a fibroid.
    evidence:
    - reference: PMID:32545544
      reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01)."
      explanation: >-
        Supplies the intermediate step - repair-protein loss in the exposed myometrium -
        that links the developmental exposure to the initiating lesion.

- name: Obesity and excess adiposity
  description: >
    Obesity is one of the most consistently reported fibroid risk factors, and the
    proposed mechanism is specific: adipose tissue performs the same aromatase and
    17-beta-hydroxysteroid-dehydrogenase conversion of androgens to oestrogens that
    fibroid cells themselves use, so excess adiposity raises the oestrogen supply to a
    tumor that depends on it. This is why the edge below attaches to the hormone-driven
    proliferation node rather than to the initiating lesion.
  exposure_term:
    preferred_term: obesity and high body mass index
  effect: Risk factor for fibroid development, acting through increased peripheral oestrogen synthesis.
  review_notes: >-
    exposure_term is left ontology-unbound deliberately. ECTO and XCO were both searched
    (sqlite:obo:ecto, sqlite:obo:xco) for "obesity", "body mass" and "high fat diet" and
    returned no term. Obesity is a host state rather than an exposure, so the absence is
    expected rather than a gap in those ontologies, and preferred_term carries it.
  evidence:
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"
    explanation: >-
      Lists obesity among the established risk factors for uterine leiomyoma.
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The enzymatic conversion of androgens to oestrogens is also typical of fat tissue"
    explanation: >-
      Gives the mechanism this record attributes the obesity association to, and is the
      reason the pathograph edge targets the hormone node.
  influences_mechanisms:
  - target: Hormone-Driven Myometrial Smooth Muscle Proliferation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Adipose aromatase activity adds to the circulating oestrogen pool that the
      established fibroid clone depends on for growth.
    evidence:
    - reference: PMID:36982825
      reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The enzymatic conversion of androgens to oestrogens is also typical of fat tissue"
      explanation: >-
        Names the aromatization step by which adiposity feeds the oestrogen-dependent
        growth node.

- name: Alcohol consumption
  description: >
    Alcohol appears in the risk-factor lists of contemporary reviews of uterine
    leiomyoma genesis. No mechanism specific to fibroids is established for it, so it is
    recorded as an association and its pathograph edge is left off rather than attached
    to a node on speculation.
  exposure_term:
    preferred_term: exposure to alcohol consumption
    term:
      id: ECTO:0001082
      label: exposure to alcohol consumption
  effect: Reported risk factor for uterine leiomyoma development.
  evidence:
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk factors include advanced reproductive age, African and Latin American ethnicity, UL cases in family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections and alcohol"
    explanation: >-
      Lists alcohol last among the risk factors for uterine leiomyoma in this review.

- name: Parity
  description: >
    Having borne children is consistently reported as protective, in contrast to the
    nulliparity and early-menarche exposures that raise risk. Parity, oral contraceptive
    use and smoking are the three protective factors this review names; smoking is
    recorded there too but is not curated here as a protective exposure, because a
    protective association that nobody would act on is a poor fit for a slot that reads
    as an intervention.
  exposure_term:
    preferred_term: parity
  effect: Protective factor against uterine leiomyoma development.
  review_notes: >-
    exposure_term is left ontology-unbound deliberately. Parity is a reproductive history
    attribute, not an environmental exposure, and ECTO has no term for it; it is curated
    here because the Environmental class is where dismech records risk and protective
    factors, and dropping it would lose a consistently reported protective association.
  evidence:
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parity, oral contraceptive intake and smoking are among possible protective factors for UL development"
    explanation: >-
      Names parity first among the possible protective factors for uterine leiomyoma.
  influences_mechanisms:
  - target: Hormone-Driven Myometrial Smooth Muscle Proliferation
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Parity interrupts the sequence of ovulatory cycles that supplies the oestrogen and
      progesterone this node depends on. The intermediates are not established, which is
      why the link type says so rather than naming a pathway.

treatments:
- name: GnRH Agonist Therapy
  therapeutic_modality: PEPTIDE
  description: >
    GnRH agonists (e.g., leuprolide) cause pituitary downregulation and hypoestrogenism,
    producing temporary fibroid shrinkage and bleeding control. Used as a preoperative
    bridge; limited by menopausal symptoms, bone loss, and rebound growth after stopping.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: leuprolide
      term:
        id: CHEBI:6427
        label: leuprolide
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "available medications (progestogens, combined \noral contraceptives andgonadotropin-releasing hormone agonists and antagonists) \nare generally used for short-term treatment of fibroid-induced bleeding."
    explanation: Documents GnRH agonists/antagonists for short-term fibroid bleeding control.

- name: Oral GnRH Antagonist Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Oral GnRH antagonists (elagolix, relugolix, linzagolix) directly block pituitary GnRH
    receptors to suppress ovarian steroid production, reducing heavy menstrual bleeding
    in a uterus-sparing, reversible regimen, usually with steroid add-back to avoid the
    hypoestrogenic effects that limit GnRH agonists. Linzagolix is the one agent with a
    lower-dose arm usable without mandatory add-back. The effect is suppressive, not
    curative: symptoms recur relatively quickly after the drug is stopped, which is the
    argument the PRIMROSE withdrawal study makes for long-term continuation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: elagolix
      term:
        id: NCIT:C153373
        label: Elagolix
    - preferred_term: relugolix
      term:
        id: NCIT:C114498
        label: Relugolix
    - preferred_term: linzagolix
      term:
        id: NCIT:C148479
        label: Linzagolix
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hormonal therapies, including combined oral contraceptives, \ngonadotropin-releasing hormone agonists or antagonists"
    explanation: Documents GnRH antagonists among hormonal therapies for fibroid-related AUB.
  - reference: PMID:33596357
    reference_title: Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons)."
    explanation: >-
      The LIBERTY 1 and 2 phase-3 result quantifying the bleeding response to relugolix
      plus oestradiol and norethindrone against placebo, which is the trial evidence
      behind this treatment class.
  - reference: PMID:33596357
    reference_title: Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects."
    explanation: >-
      States the rationale for the add-back component this treatment record describes:
      the steroid add-back is what makes long-term GnRH-receptor blockade tolerable.
  - reference: PMID:40543832
    reference_title: "Linzagolix with and without hormonal add-back therapy for symptomatic uterine fibroids: PRIMROSE 1 & 2 long-term extension and withdrawal study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relatively fast recurrence of uterine fibroid-associated symptoms after cessation of therapy is an argument in favor of long-term continuation of treatment."
    explanation: >-
      The PRIMROSE withdrawal result, and the source of this record's statement that the
      effect is suppressive rather than curative: symptoms return quickly once the drug
      stops, which is why the class is framed as long-term therapy.

- name: Selective Progesterone Receptor Modulator Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Selective progesterone receptor modulators (SPRMs, e.g., ulipristal acetate)
    modulate PGR signaling to reduce bleeding and fibroid size; intermittent long-term
    use shows good results but is limited by hepatotoxicity concerns. Response may vary
    with MED12 mutation status.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ulipristal acetate
      term:
        id: CHEBI:71025
        label: ulipristal acetate
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it was shown that SPRMs could be administered intermittently long-term \nwith good results on bleeding and fibroid size reduction."
    explanation: Documents intermittent SPRM therapy reducing bleeding and fibroid size.

- name: Mifepristone
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Antiprogestin studied for symptomatic fibroids, reducing abnormal uterine bleeding
    and fibroid-related dysmenorrhea. It acts on the same progesterone-receptor axis as
    the selective progesterone receptor modulators curated above, and is grouped with
    them mechanistically rather than with the symptomatic agents; its safety profile is
    described as more favourable than ulipristal acetate's but less well established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mifepristone
      term:
        id: CHEBI:50692
        label: mifepristone
  target_mechanisms:
  - target: Hormone-Driven Myometrial Smooth Muscle Proliferation
    description: >-
      Blocking the progesterone receptor removes the paracrine WNT and growth-factor
      signal that this node depends on, which is the mechanism the bleeding and
      dysmenorrhea response is attributed to.
  evidence:
  - reference: PMID:39335725
    reference_title: "Tailoring the Diagnostic Pathway for Medical and Surgical Treatment of Uterine Fibroids: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mifepristone demonstrated its efficacy in reducing abnormal uterine bleedings (AUBs) and fibroid-related dysmenorrhea"
    explanation: >-
      Documents mifepristone's efficacy for both of the symptoms this treatment record
      claims, in a review of the fibroid treatment pathway.

- name: Tranexamic Acid
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Antifibrinolytic agent that reduces menstrual blood loss for symptomatic heavy
    menstrual bleeding when uterine preservation is desired; does not shrink fibroids.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Medical \ntreatments used for UFs-related abnormal uterine bleeding include symptomatic \nagents, such as nonsteroidal antiinflammatory drugs and tranexamic acid"
    explanation: Documents tranexamic acid as a symptomatic agent for fibroid-related AUB.

- name: Nonsteroidal Anti-Inflammatory Drugs
  therapeutic_modality: SMALL_MOLECULE
  description: >
    NSAIDs are used as symptomatic agents to reduce fibroid-related menstrual blood
    loss and dysmenorrhea; they do not reduce fibroid size.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: non-steroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic \nagents, such as nonsteroidal antiinflammatory drugs and tranexamic acid"
    explanation: Documents NSAIDs among symptomatic agents for fibroid-related abnormal uterine bleeding.

- name: Levonorgestrel Intrauterine System
  therapeutic_modality: DEVICE
  description: >
    The levonorgestrel-releasing intrauterine system delivers local progestin to the
    endometrium, reducing heavy menstrual bleeding in a uterus-sparing, reversible way;
    it controls bleeding symptoms but does not consistently shrink fibroids.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levonorgestrel
      term:
        id: CHEBI:6443
        label: levonorgestrel
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hormonal therapies, including combined oral contraceptives, \ngonadotropin-releasing hormone agonists or antagonists, levonorgestrel \nintrauterine systems"
    explanation: Documents levonorgestrel intrauterine systems among hormonal therapies for fibroid-related AUB.

- name: Aromatase Inhibitor Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Aromatase inhibitors block estrogen biosynthesis, lowering the estrogen that drives
    fibroid growth; used as a hormonal option for symptomatic fibroids.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aromatase inhibitor
      term:
        id: NCIT:C1740
        label: Aromatase Inhibitor
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "selective progesterone receptor modulators, and aromatase \ninhibitors"
    explanation: Documents aromatase inhibitors among hormonal therapies for fibroid-related AUB.

- name: Myomectomy
  therapeutic_modality: SURGERY
  description: >
    Surgical removal of fibroids with uterine preservation (hysteroscopic, laparoscopic,
    open, or robotic), indicated for symptomatic patients desiring fertility or uterine
    conservation; recurrence risk persists.
  treatment_term:
    preferred_term: myomectomy
    term:
      id: NCIT:C51645
      label: Myomectomy
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current \nmanagement strategies mainly involve surgical interventions (hysterectomy and \nmyomectomy hysteroscopy, laparoscopy or laparotomy)."
    explanation: Documents myomectomy as a core surgical management strategy.

- name: Hysterectomy
  therapeutic_modality: SURGERY
  description: >
    Definitive removal of the uterus, eliminating fibroids and recurrence, for women
    with severe symptoms and no fertility desire or failure of conservative options.
  treatment_term:
    preferred_term: hysterectomy
    term:
      id: NCIT:C15256
      label: Hysterectomy
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current \nmanagement strategies mainly involve surgical interventions (hysterectomy and \nmyomectomy hysteroscopy, laparoscopy or laparotomy)."
    explanation: Documents hysterectomy as a definitive surgical treatment for fibroids.

- name: Uterine Artery Embolization
  therapeutic_modality: SURGERY
  description: >
    Image-guided arterial embolization that devascularizes fibroids, causing ischemic
    shrinkage; a uterus-sparing, non-excisional option, generally not first choice when
    future fertility is a major goal.
  treatment_term:
    preferred_term: uterine artery embolization
    term:
      id: NCIT:C15917
      label: Arterial Embolization
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiologic interventions are also available: uterine artery \nembolization, high-intensity focused ultrasound or magnetic resonance-guided \nfocused ultrasound, and radiofrequency ablation."
    explanation: Documents uterine artery embolization as a radiologic intervention for fibroids.

- name: MRI-Guided Focused Ultrasound Surgery
  therapeutic_modality: SURGERY
  description: >
    Non-invasive thermal ablation that focuses high-intensity ultrasound energy under
    MRI (or ultrasound) guidance to coagulate fibroid tissue, sparing the uterus.
  treatment_term:
    preferred_term: MRI-guided focused ultrasound ablation
    term:
      id: NCIT:C62723
      label: MRI-Guided Focused Ultrasound Ablation
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-intensity focused ultrasound or magnetic resonance-guided \nfocused ultrasound"
    explanation: Documents high-intensity/MR-guided focused ultrasound as a radiologic intervention for fibroids.

- name: Radiofrequency Ablation
  therapeutic_modality: SURGERY
  description: >
    Image-guided radiofrequency energy thermally ablates fibroid tissue, causing
    coagulative necrosis and volume reduction while preserving the uterus.
  treatment_term:
    preferred_term: radiofrequency ablation
    term:
      id: NCIT:C15666
      label: Radiofrequency Ablation
  evidence:
  - reference: PMID:38929485
    reference_title: Currently Available Treatment Modalities for Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "radiofrequency ablation of fibroids and endometrial ablation"
    explanation: Documents radiofrequency ablation of fibroids as a minimally invasive treatment modality.

- name: Iron Replacement Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Repletes iron stores in fibroid-related iron deficiency and anemia from chronic
    bleeding; an important adjunct before and after surgery and during medical therapy.

    therapeutic_agent is deliberately absent. The treatment is generic iron replacement,
    oral or intravenous, and the preparation is not specified by the cited source.
    NCIT:C210688 "Iron Supplement" is the concept but is not a member of the
    ChemicalEntityTerm dynamic enum, and every CHEBI term that is a member names one
    specific salt or hydrate (for example CHEBI:75832, iron(2+) sulfate anhydrous), which
    would assert a preparation this entry does not claim.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care

  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the management of \nID and ID anemia, as a consequence of acute and chronic bleeding, should be \ntaken into account with the use of iron replacement therapy"
    explanation: Documents iron replacement therapy for fibroid-related iron deficiency anemia.

clinical_trials:
- name: NCT03049735
  phase: PHASE_III
  status: COMPLETED
  description: >
    LIBERTY 1, the first of two replicate phase-3 trials of relugolix 40 mg with
    estradiol 1 mg and norethindrone acetate 0.5 mg against placebo over 24 weeks in
    women with fibroid-associated heavy menstrual bleeding. It and LIBERTY 2 are the
    trials the FDA approval of relugolix combination therapy rests on.
  target_phenotypes:
  - preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: clinicaltrials:NCT03049735
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids."
    explanation: >-
      The registration record's own statement of the intervention and endpoint, matching
      the regimen curated under Oral GnRH Antagonist Therapy.
  - reference: PMID:33596357
    reference_title: Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 388 women in trial L1 and 382 in trial L2 underwent randomization."
    explanation: >-
      The publication reporting both LIBERTY trials, giving the randomized population of
      each.
- name: NCT03103087
  phase: PHASE_III
  status: COMPLETED
  description: >
    LIBERTY 2, the replicate of LIBERTY 1 with the same design and endpoint. Running the
    trial twice is what makes the 73%/71% response figures a replication rather than a
    single result.
  target_phenotypes:
  - preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: clinicaltrials:NCT03103087
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids."
    explanation: >-
      The registration record for the replicate trial, confirming the identical
      intervention and endpoint.

prevalence:
- population: Women aged 30-44 years
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 60000.0
  notes: >-
    Uterine fibroids are the most common benign pelvic tumor of reproductive-age
    women, present in more than 60% of women aged 30-44 years (>60% = >60,000 per
    100,000; recorded as a lower bound).
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine fibroids (UFs) are the most common female benign pelvic tumors, \naffecting >60% of patients aged 30-44 years."
    explanation: Quantifies fibroid prevalence at over 60% in women aged 30-44 years.
- population: Women overall (with racial disparity)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 70000.0
  notes: >-
    Overall prevalence is approximately 70% (70,000 per 100,000), with Black
    women affected at a disproportionately high rate.
  evidence:
  - reference: PMID:40862769
    reference_title: The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with \nBlack women being affected at a disproportionate rate."
    explanation: Documents overall fibroid prevalence (~70%) and the disproportionate burden in Black women.
- population: Global, GBD 2021, age-standardized
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2841.07
  rate_low: 2164.43
  rate_high: 3682.27
  rate_denominator: POPULATION
  notes: >-
    GBD 2021 age-standardized prevalence rate, rising from 2799.88 per 100,000 in 1990.
    Note that this is an order of magnitude below the 60-70% screening-based figures
    recorded above and does not contradict them: GBD models diagnosed disease, while
    the screening studies count fibroids found on systematic ultrasound in women who
    mostly have no symptoms. The gap between the two is the asymptomatic fraction.
  evidence:
  - reference: PMID:41048892
    reference_title: "The epidemiology of uterine fibroids: global disease burden from 1990 to 2021 and future trend predictions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ASPR increased from 2799.88 (2133.46, 3650.54) to 2841.07 (2164.43, 3682.27) [EAPC 0.04 (0.03, 0.06)]."
    explanation: >-
      Gives the age-standardized prevalence rate and its uncertainty interval for 2021,
      which are the values recorded here.
- population: Global, GBD 2021, age-standardized
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 250.93
  rate_low: 183.44
  rate_high: 330.94
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    GBD 2021 age-standardized incidence rate, up from 234.36 per 100,000 in 1990.
    rate_denominator is set explicitly because an incidence measure has no fallback:
    this is new cases per 100,000 population per year. No qualitative prevalence tier is
    used here, since those presuppose a prevalence rather than an incidence measure.
  evidence:
  - reference: PMID:41048892
    reference_title: "The epidemiology of uterine fibroids: global disease burden from 1990 to 2021 and future trend predictions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uterine fibroids (UF) are the most common benign tumors of the female reproductive system,
      imposing a significant health burden. ... Data on the incidence, prevalence, and
      disability-adjusted life years (DALYs) of UF from 1990 to 2021 were extracted from the Global
      Burden of Disease (GBD) 2021 study, covering 204 countries and territories. ... Between 1990
      and 2021, the global ASIR of UF rose from 234.36 (95%UI: 171.06, 309.92) to 250.93 (183.44,
      330.94) per 100,000 [EAPC 0.24 (0.23, 0.25)]. ... Globally, the number of new cases of UF
      increased from 6,009,553 (95%UI: 4,390,470–8,011,360) in 1990 to 10,100,271
      (7,350,444–13,285,677) in 2021.The ASIR for UF increased from 234.36 (171.06–309.92) per
      100,000 in 1990 to 250.93 (183.44–330.94) per 100,000 in 2021.
    explanation: >-
      GBD 2021 estimates the global age-standardized uterine-fibroid incidence at 250.93 per 100,000
      in 2021 (uncertainty interval 183.44–330.94), with modeled annual incident counts across 204
      countries and territories.
progression:
- phase: Premenarchal
  age_range: birth to menarche
  notes: >-
    Fibroids essentially do not arise before menarche, which follows from their growth
    being sex-steroid-dependent: the tumor, though initiated by a somatic lesion, cannot
    expand without ovarian steroid support, and before menarche that support is absent.
  evidence:
  - reference: PMID:37668348
    reference_title: "RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized \nby accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent \ngrowth."
    explanation: >-
      Establishes that fibroid growth is sex-steroid-dependent. The premenarchal absence
      recorded in this phase follows from that dependence rather than being stated in the
      quote, which is why this is graded INDIRECT.
- phase: Reproductive years
  age_range: menarche to menopause, peak 35-50 years
  notes: >-
    The growth phase. Detection and symptom burden rise steeply from the mid-thirties,
    with most diagnoses between 35 and 50. Individual tumors within one uterus are
    separate clones and grow at different rates, so "progression" here is the aggregate
    of several independent trajectories rather than one.
  evidence:
  - reference: PMID:36982825
    reference_title: "A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite its benign nature and low risk of malignisation, UL can be characterised by rapid growth, large size and multiple nodes"
    explanation: >-
      Supports the variable-growth, multiple-tumor character of this phase.
- phase: Postmenopausal
  age_range: after menopause
  notes: >-
    Ovarian steroid withdrawal is followed by growth arrest and frequently by regression,
    which is the therapeutic logic behind every hormonal treatment in this entry: they
    reproduce the postmenopausal state pharmacologically, and their effect reverses when
    stopped for the same reason.
  evidence:
  - reference: PMID:33670322
    reference_title: "Vitamin D: Mechanism of Action and Biological Effects in Uterine Fibroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, UFs can undergo growth inhibition or spontaneous regression after menopause"
    explanation: >-
      States the postmenopausal growth inhibition and regression that define this phase.

clinical_burden:
  burden_level: VARIABLE
  rationale: >
    The burden is genuinely bimodal rather than merely heterogeneous, and averaging it
    would misdescribe the disease. Most women with fibroids never know they have them;
    among those who do, roughly 30% report a quality-of-life impact, and for that
    minority heavy menstrual bleeding is the dominant complaint and the leading reason
    for elective hysterectomy. Mortality is essentially nil. So the same diagnosis covers
    an incidental ultrasound finding and an indication for major surgery.
  evidence:
  - reference: PMID:38723935
    reference_title: The modern management of uterine fibroids-related abnormal uterine bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in \napproximately 30% of cases, UFs affect the quality of life and women's health, \nwith abnormal uterine bleeding and heavy menstrual bleeding being the most \ncommon complaints, along with iron deficiency (ID) and ID anemia."
    explanation: >-
      Quantifies the symptomatic minority and names what dominates their burden.
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility."
    explanation: >-
      Independent figure for the symptomatic fraction, supporting the VARIABLE band
      rather than a single level.

differential_diagnoses:
- name: Uterine leiomyosarcoma
  disease_term:
    preferred_term: uterine leiomyosarcoma
    term:
      id: MONDO:0016262
      label: leiomyosarcoma of the corpus uteri
  description: >
    The differential that matters, because it cannot be resolved before resection. No
    imaging finding or biomarker reliably separates a benign leiomyoma from a
    leiomyosarcoma preoperatively, which is why a rapidly enlarging mass prompts
    evaluation and why morcellation of a presumed fibroid carries a dissemination risk.
  distinguishing_features:
  - Histopathology of the resected specimen is definitive; nothing before resection is.
  - Molecular profiling may assist in the cellular and variant morphologies.
  - >-
    HIF-1-alpha is readily demonstrable in leiomyosarcoma but has been reported absent
    from leiomyoma, which is also why the two tumors' angiogenic mechanisms differ.
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HIF-1α for example has been shown lacking in uterine fibroids, when it was readily shown in leiomyosarcomata"
    explanation: >-
      Supports the HIF-1-alpha distinction recorded under distinguishing_features.
- name: Endometrial stromal tumor
  description: >
    Endometrial stromal nodule and low-grade endometrial stromal sarcoma enter the
    differential chiefly against the cellular leiomyoma variant, where increased
    cellularity and reduced stroma remove the morphologic cues that separate them.
  distinguishing_features:
  - >-
    Immunohistochemistry is suggestive rather than decisive: cellular leiomyomas express
    CD10 in a majority of cases (65.4%, though only 42.2% strongly, at H-score above 50)
    and IFITM1 in 36.5%, so positivity for an endometrial stromal marker does not settle
    it.
  - >-
    Smooth muscle markers are near-uniformly expressed in cellular leiomyoma (calponin
    and desmin in 100%), which is the more reliable direction of evidence.
  evidence:
  - reference: PMID:34626221
    reference_title: "Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concerning markers of endometrial stromal differentiation, the expression of \nCD10 was observed in 65.4% cases (42.2% with H-score > 50), and IFITM1 in 36.5% \ncases (1.9% with H-score > 50)"
    explanation: >-
      Gives the immunohistochemical overlap that makes this differential hard: CD10 is
      positive in most cellular leiomyomas and IFITM1 in over a third, so positivity for
      an endometrial stromal marker does not settle the diagnosis.
  - reference: PMID:34626221
    reference_title: "Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The immunohistochemical \nresults showed a high expression of smooth muscle markers (calponin (100%), \ndesmin (100%), smooth muscle actin (98.1%), caldesmon (96.1%), transgelin \n(96.1%), smooth muscle myosin heavy chain (86.5%), and smoothelin (61.5%))."
    explanation: >-
      Supplies the smooth-muscle marker panel that argues for leiomyoma, and the reason
      it is described as the more reliable direction of evidence.

- name: Adenomyosis
  disease_term:
    preferred_term: adenomyosis
    term:
      id: MONDO:0010888
      label: adenomyosis
  description: >
    Ectopic endometrial tissue within the myometrium, presenting with the same heavy
    bleeding and dysmenorrhea, frequently coexisting with fibroids, and separated from
    them on imaging rather than clinically.
  distinguishing_features:
  - >-
    MRI is the modality that resolves the two, and standardized structured reporting
    exists precisely because this differential is common.
  - The two frequently coexist, so resolving it is not always a choice between them.
  evidence:
  - reference: PMID:40970558
    reference_title: Diagnosis and classification of uterine fibroids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adherence to standardized structured reporting across imaging modalities is critical to improve diagnostic accuracy, differentiate fibroids from conditions such as adenomyosis or malignancies, predict therapeutic responses, and plan surgical interventions."
    explanation: >-
      Names adenomyosis as one of the two conditions imaging is expected to distinguish
      fibroids from.

animal_models:
- name: Eker rat (germline Tsc2 mutation)
  species: Rat
  genotype: Tsc2 germline loss-of-function (Eker strain)
  category: Spontaneous
  genes:
  - preferred_term: Tsc2
    term:
      id: hgnc:12363
      label: TSC2
  description: >
    The most widely used spontaneous model. Roughly 65% of female Eker rats develop
    uterine smooth muscle tumors at 12-16 months through a germline Tsc2 mutation and
    consequent mTOR pathway activation. Histomorphology and oestrogen/progesterone
    dependence closely resemble human fibroids, and the strain has carried most of the
    gene-environment work in this field, including the developmental DES exposure and
    vitamin D3 rescue experiments this entry cites.
  publication: PMID:41810407
  notes: >-
    The gene_term binds the human TSC2 ortholog because HGNC codes human genes; the
    model's own lesion is rat Tsc2. MGI/RGD identifiers for the rat gene are not bound
    by any current dismech slot.
  evidence:
  - reference: PMID:41810407
    reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Because of the convenience of model establishment, this model has become one of the most commonly used models for ULs"
    explanation: >-
      Establishes this strain's standing as the most commonly used uterine leiomyoma
      model, which is why it is curated here rather than only mentioned in notes.
  modeled_mechanisms:
  - target: Hormone-Driven Myometrial Smooth Muscle Proliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces spontaneous, hormone-dependent uterine smooth muscle tumorigenesis in
      an intact animal, which is what makes it usable for gene-environment and
      chemoprevention work no in vitro system can do.
    limitations: >-
      The driving lesion is Tsc2, which is not one of the recurrent human somatic
      drivers (MED12, HMGA2, FH), so the model recapitulates the hormone-dependent
      growth phase without recapitulating the initiating genotype. It also takes 12-16
      months, is expensive, and the animals develop concurrent renal and hepatic
      tumors that confound interpretation.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Rat myometrium rather than human, with a rodent oestrous cycle rather than a
        menstrual cycle, so the cyclical progesterone exposure that drives human fibroid
        growth is not reproduced in the same temporal pattern.
      evidence:
      - reference: PMID:41810407
        reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Eker rats (Rattus norvegicus), due to their germline mutation in the tuberous sclerosis complex type 2 (Tsc2) tumor suppressor gene, spontaneously develop uterine smooth muscle tumors in approximately 65% of females at 12 to 16 months of age."
        explanation: >-
          Identifies the species as Rattus norvegicus, which is the fact this divergence
          rests on.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The human driver lesions are outside the model entirely: no MED12 exon-2
        mutation, no HMGA2 rearrangement and no FH loss, so nothing in this animal
        addresses the Mediator-kinase, architectural-transcription-factor or
        oncometabolite arms of the human mechanism.
      evidence:
      - reference: PMID:41810407
        reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Its clear genetic background based on the Tsc2 mutation is closely related to abnormal activation of the mTOR signaling pathway."
        explanation: >-
          Names Tsc2/mTOR as the model's entire genetic basis, which is what places the
          human driver lesions outside its boundary.
    evidence:
    - reference: PMID:41810407
      reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This rat model exhibits highly similar histomorphology and estrogen/progesterone-dependent manifestations to human ULs"
      explanation: >-
        Supports treating this model as informative for the hormone-dependent growth
        node, which is the claim this link makes.
    - reference: PMID:41810407
      reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, limitations include long model establishment time, high costs, and the model's tendency to develop concurrent tumors such as renal and hepatic tumors, which restrict its application"
      explanation: >-
        Substantiates the limitations recorded on this link rather than the mechanism,
        and is the reason fidelity is MODERATE rather than HIGH.
  - target: Driver Mutation-Initiated Clonal Transformation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      The model does not reproduce the human initiating lesion. Its tumors start from a
      germline Tsc2 mutation present in every cell, where human fibroids start from a
      somatic driver acquired by one myometrial cell, so the monoclonal-origin and
      driver-genotype claims of this node are outside what the model can support.
    limitations: >-
      Tsc2 is not among MED12, HMGA2, FH or COL4A5/COL4A6, and the lesion is germline
      rather than somatic. Any inference from this model to the human initiating event
      is an inference about hormone-dependent growth in a predisposed myometrium, not
      about how a human fibroid starts.
    evidence:
    - reference: PMID:41810407
      reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Eker rats (Rattus norvegicus), due to their germline mutation in the tuberous sclerosis complex type 2 (Tsc2) tumor suppressor gene, spontaneously develop uterine smooth muscle tumors in approximately 65% of females at 12 to 16 months of age."
      explanation: >-
        Identifies the model's lesion as a germline Tsc2 mutation, which is what
        establishes the mismatch with the human somatic drivers this node is about.
  - target: Excessive Extracellular Matrix Deposition and Tissue Stiffening
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The Eker rat is the system in which vitamin D3 was shown to restore the MRN
      complex/ATM DNA-repair axis in myometrial stem cells after developmental DES
      exposure, which is the experimental basis for the vitamin D environmental record
      in this entry.
    limitations: >-
      The measured endpoint is DNA damage and repair-protein expression in isolated
      myometrial stem cells, not matrix deposition or tumor volume, so the link to the
      fibrotic output node is an extrapolation across both scale and endpoint.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: INVALIDATING
      description: >-
        The model's measured quantity is DNA-damage load and MRN-complex protein
        expression in stem cells. The node's quantity is collagen-rich matrix deposited
        in a tumor. Nothing in the cited experiment measures the latter.
      evidence:
      - reference: PMID:32545544
        reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Concomitantly, the levels of key DNA damage repair members, including the MRN complex, increased in DES-MMSCs following treatment with VitD3 (p < 0.01)."
        explanation: >-
          Names what the experiment actually measured - MRN-complex repair-protein levels
          in stem cells - which is the proxy this divergence records against a
          matrix-deposition node.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        Observed at the molecular scale (repair-protein expression) and cited for a
        TISSUE-scale node, so the inference crosses two scale steps.
      evidence:
      - reference: PMID:32545544
        reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Several techniques were performed to determine the effect of VitD3 treatment on the DNA repair pathway in DES-exposed MMSCs (DES-MMSCs)."
        explanation: >-
          Confirms the observation was made on isolated stem cells and their DNA-repair
          pathway, establishing the molecular observation scale this divergence compares
          against the node's tissue scale.
    evidence:
    - reference: PMID:32545544
      reference_title: Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers."
      explanation: >-
        The rescue result this link records, and the reason the divergences above are
        stated: the endpoint is DNA damage, not matrix.

- name: Human leiomyoma tissue xenograft in immunodeficient mouse
  species: Mouse
  genotype: Severe combined immunodeficiency (SCID) host, human leiomyoma tissue graft
  category: Xenograft
  description: >
    Human fibroid tissue grafted subcutaneously or beneath the renal capsule of
    immunodeficient mice, usually with a sustained-release hormone device to keep the
    graft in its native hormonal environment. This is the model that preserves the human
    tumor's own driver genotype, heterogeneity and microenvironment, and so the one used
    for preclinical efficacy work meant to translate.
  publication: PMID:41810407
  evidence:
  - reference: PMID:41810407
    reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "xenograft models can best simulate the pathological features of human ULs and serve as a key bridge between basic research and clinical translation"
    explanation: >-
      States the reason this model class is curated: it is the closest available
      reproduction of human fibroid pathology and the intended translational bridge.
  modeled_mechanisms:
  - target: Excessive Extracellular Matrix Deposition and Tissue Stiffening
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      The graft retains the histopathological morphology of the source tumor, matrix
      included, which is exactly the property that makes it the translational bridge.
    limitations: >-
      Requires an immunodeficient host, so the immune and inflammatory contributions to
      fibroid matrix biology cannot be studied in it at all. Results also vary between
      tissue donors, and the model is technically demanding and expensive.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The host has no adaptive immune system, so the immune infiltrate and the
        inflammatory signalling that recent reviews implicate in fibroid ECM production
        are outside the model boundary.
      evidence:
      - reference: PMID:41810407
        reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dependent on expensive immunodeficient animals; High cost; Inter-donor sample variability."
        explanation: >-
          The review's own limitation row for this model class, naming the
          immunodeficient host that puts the immune compartment outside the boundary.
      - reference: PMID:36982852
        reference_title: Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "These risk factors affect several key pathways, including inflammation"
        explanation: >-
          Establishes that inflammation is among the pathways implicated in fibroid
          pathogenesis, which is what makes its absence from the host a material
          omission rather than an incidental one.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Each graft reproduces one donor's tumor, and inter-donor variability is reported
        as a limitation of the approach, so a single xenograft experiment speaks to one
        molecular subtype rather than to the disease's driver spectrum.
      evidence:
      - reference: PMID:41810407
        reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dependent on expensive immunodeficient animals; High cost; Inter-donor sample variability."
        explanation: >-
          Names inter-donor sample variability as a limitation of the approach, which is
          the divergence recorded here.
    evidence:
    - reference: PMID:41810407
      reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These models closely replicate the histopathological morphology of human ULs. However, their broader application remains limited by technical complexity, stringent experimental requirements, and high costs."
      explanation: >-
        Supports both the HIGH fidelity for morphology and the practical limitations
        recorded on this link.
    - reference: PMID:41810407
      reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tissue implantation involves grafting human-derived uterine leiomyoma tissue into immunodeficient mice (e.g., SCID mice) subcutaneously or beneath the renal capsule, often supplemented with sustained hormone-release devices to preserve the histological characteristics of the original ULs"
      explanation: >-
        Describes the construction of the model, including the immunodeficient host that
        the boundary-omission divergence above rests on.

discussions:
- discussion_id: med12_mutation_growth_paradox
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    If MED12 exon-2 mutation is a gain-of-function driver present in most fibroids, why
    do MED12 wild-type tumors grow faster than mutant ones?
  attaches_to:
  - pathophysiology#Driver Mutation-Initiated Clonal Transformation
  - genetic#MED12 somatic exon-2 mutation
  rationale: >
    The entry records MED12 mutation as a gain-of-function driver, which is what the
    review literature says, and that reading invites the inference that the mutation
    drives growth. A 44-tumor series reports the opposite for growth specifically:
    wild-type leiomyomas have higher growth potential and higher MED12-associated CDK8
    kinase activity than mutant ones, and CDK8 inhibition suppresses wild-type cell
    growth in primary culture. One way to reconcile these is that the mutation is
    required for tumor initiation while wild-type tumors, once initiated by some other
    route, retain more intact Mediator-kinase output and therefore grow faster. That
    reconciliation is not established, and an entry that recorded only the
    gain-of-function label would hide the tension rather than resolve it.
  evidence:
  - reference: PMID:41493967
    reference_title: Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment."
    explanation: >-
      The measurement behind the controversy: CDK8 activity is highest in untreated
      wild-type tumors, lower in mutant ones.
  - reference: PMID:41493967
    reference_title: Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis."
    explanation: >-
      Shows the CDK8 activity is functionally load-bearing for growth in the wild-type
      tumors, which is what makes this a mechanistic question rather than a measurement
      artifact.

- discussion_id: hmb_dominant_mechanism
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Which mechanism dominates fibroid-associated heavy menstrual bleeding: rupture of
    structurally deficient pseudocapsule neovessels, dilated venous lakes from mass
    effect, or TGF-beta-3-mediated endometrial hemostatic failure?
  attaches_to:
  - pathophysiology#Aberrant Pseudocapsule Angiogenesis and Venous Ectasia
  - pathophysiology#Endometrial Hemostatic Failure and Impaired Vessel Closure
  - phenotypes#Heavy Menstrual Bleeding
  rationale: >
    All three mechanisms are separately evidenced and this entry curates all three, but
    their relative contribution is unsettled and the candidate explanations make
    different predictions. The pseudocapsule account predicts bleeding should track
    fibroid location, since only intramural fibroids develop a pseudocapsule. The
    venous-lake account was originally attributed to interstitial pressure and later
    reattributed to growth factors enlarging the veins. The endometrial account is
    location-independent and predicts bleeding even from fibroids that do not distort
    the cavity. Distinguishing them matters clinically, because tranexamic acid and the
    levonorgestrel system act on the endometrial arm while embolization and ablation act
    on the vascular one.
  evidence:
  - reference: PMID:36303616
    reference_title: Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors."
    explanation: >-
      The source itself frames these as competing theories under review rather than as a
      settled mechanism, which is the state this discussion records.

- discussion_id: eker_rat_driver_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does a Tsc2-driven rat tumor tell us anything about how a MED12-, HMGA2- or
    FH-driven human fibroid starts?
  attaches_to:
  - pathophysiology#Driver Mutation-Initiated Clonal Transformation
  - animal_models#Rat
  rationale: >
    The Eker rat is the workhorse spontaneous model and its tumors look and behave like
    human fibroids at the tissue and hormonal level, so results from it are routinely
    read as being about fibroid biology generally. But its lesion is a germline Tsc2
    mutation acting through mTOR, and none of the recurrent human somatic drivers is
    present. The mismatch is therefore not that evidence is missing but that evidence
    exists in a system whose initiating genotype is wrong, which is the distinction
    between a knowledge gap and a model mismatch. The practical consequence is that the
    developmental-exposure and vitamin D results obtained in this strain support the
    environmental records in this entry at the level of myometrial stem cell DNA repair,
    and do not support any claim about the human driver mutations themselves.
  evidence:
  - reference: PMID:41810407
    reference_title: "Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Current uterine fibroid animal models cannot fully reproduce the complex pathological process of human ULs, so optimization of current pathological models is needed."
    explanation: >-
      The review's own statement that no current animal model fully reproduces human
      fibroid pathology, which is the general form of this specific mismatch.

classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Assigned to the endocrinology and metabolism part, where Harrison's places
      disorders of the female reproductive system. The tumor is neoplastic but benign and
      its defining biology is ovarian-steroid dependence rather than malignant
      progression, so the oncology part would misplace it.
    evidence:
    - reference: PMID:33670322
      reference_title: "Vitamin D: Mechanism of Action and Biological Effects in Uterine Fibroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Uterine fibroids (UFs), also known as uterine leiomyomas or myomas, are the most frequent benign tumors in women of reproductive age."
      explanation: >-
        Supports the benign, reproductive-age character on which this part assignment
        rests rather than an oncological one.

mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D25
      label: Leiomyoma of uterus
    mapping_predicate: skos:exactMatch
    mapping_source: ICD-10-CM
    mapping_justification: >-
      ICD10CM:D25 is the billing-code category for leiomyoma of uterus, coextensive with
      this entry. Its subcodes D25.0 (submucous), D25.1 (intramural) and D25.2
      (subserosal) partition the same concept by location, so the parent category rather
      than any subcode is the exact match.
  ncit_mappings:
  - term:
      id: NCIT:C3434
      label: Uterine Corpus Leiomyoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCIT's uterine corpus leiomyoma concept matches this entry's MONDO anchor
      (MONDO:0007886, uterine corpus leiomyoma) term for term, and is the term the
      histopathology findings in this entry bind to.

references:
- reference: PMID:40214304
  title: "UTERINE FIBROIDS."
datasets:
- accession: geo:GSE204970
  title: MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_count: 44
  publication: PMID:37607000
  notes: Identified by GEO DataSets index search for Uterine Leiomyoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001004499
  title: 'Uterine leiomyoma: DNA methylation, chromatin activity and gene expression'
  description: In this study, we observed the effects of different uterine leiomyoma driver mutations to tumor DNA methylation, chromatin activity and gene expression, to form a comprehensive view on the epigenetic consequences of the mutations.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Uterine Leiomyoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

📚

References & Deep Research

References

1

PMID:40214304

UTERINE FIBROIDS.

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Edit: Uterine Leiomyoma - pathograph split and extension, subtypes, histopathology, imaging, environmental, models, discussions · 2026-09-12T18:34:13Z · View source

Augmented the existing Uterine_Leiomyoma entry (created 2026-06-22, PR #4717; reference_title backfill in PR #5270). Not a new entry: the duplicate preflight found the file already on origin/main under MONDO:0007886, with issue #4706 and both prior PRs closed and nothing in flight, so this session ran as an EDIT. Deep research. Ran `just research-disorder claude_code Uterine_Leiomyoma`, producing research/Uterine_Leiomyoma-deep-research-claude_code.md (claude-haiku-4-5 + claude-sonnet-5, 17 web searches, 19 turns, ~4m51s). Its own validation reported 49/49 references resolved (confabulation_rate 0.0, 1/1 quotes valid) but term_validation needs_review: true, with four CURIEs naming different terms (HP:0030318 = Angular cheilitis for "Pelvic pain", HP:0030068 = Olfactory esthesioneuroblastoma for "Dyspareunia", HP:0031801 = Vocal cord dysfunction for "Abdominal mass", UBERON:0000459 = uterine wall for "endometrium") and six more flagged for a second look (including CL:0002598 = bronchial smooth muscle cell offered as "myometrial smooth muscle cell", HP:0100608 = Metrorrhagia offered as "Dysmenorrhea", and HGNC:29305/HGNC:5013 offered for MED12/HMGA2). None of the report's CURIEs were bound. Every ontology identifier in this change was looked up independently in cache/<prefix>/terms.csv, the local OAK builds, or the OLS4 API in the same step it was written. The pre-existing research/Uterine_Leiomyoma-deep-research-falcon.md was also read. It cites by author-year key with no PMIDs in the body, so its 15 DOIs were resolved through the PMC ID converter; that recovered PMID:36982825, PMID:39335725, PMID:38326302, PMID:40898238, PMID:40369458 and PMID:41810407 as new, and confirmed PMID:37668348 and PMID:34626221 were already cited here. Named-entity-confusion preflight. `just preflight-dr` returned SKIP because MONDO records no RO:0004003 causal gene for MONDO:0007886, so the gene-identity check cannot discriminate. Checked manually instead: the report's OMIM identifiers are 150699 (matching MONDO's) plus 150800, which it correctly labels as the separate HLRCC syndrome, and its top gene terms are FH/MED12/HMGA2. Right disease. HLRCC content was deliberately kept minimal and pointed at the existing Hereditary_Leiomyomatosis_and_Renal_Cell_Cancer entry rather than curated here. GeneReviews baseline. Searched PubMed for "uterine fibroid[TI] GeneReviews[TI]" and "uterine leiomyoma GeneReviews[All Fields]"; both returned zero. No GeneReviews chapter exists for this disease, which is expected for a complex non-Mendelian entry, so step 3b of the skill contributed no baseline. Pathophysiology. The graph went from 3 nodes to 8 and the phenotypes are now connected to it, which they were not before. The existing node "Hormone-Driven Myometrial Smooth Muscle Proliferation and ECM Deposition" was split: it bundled a CELLULAR claim (population expansion) and a TISSUE claim (matrix deposition), which is exactly the single-valued-biological_scale signal the skill describes. It is now "Hormone-Driven Myometrial Smooth Muscle Proliferation" (CELLULAR, keeping its sex_steroid_driven_proliferation#Target-Cell Population Expansion conformance) feeding a new "Excessive Extracellular Matrix Deposition and Tissue Stiffening" (TISSUE, conforming to fibrotic_response#Excessive ECM Deposition). Four further nodes were added: "Fumarate Accumulation and Pseudohypoxia in FH-Deficient Leiomyoma" (MOLECULAR, conforming to oncometabolite_dioxygenase_inhibition#Oncometabolite Accumulation), "Aberrant Pseudocapsule Angiogenesis and Venous Ectasia" (TISSUE), "Endometrial Hemostatic Failure and Impaired Vessel Closure" (ORGANISM) and "Bulk Compression of Adjacent Pelvic Organs" (ORGANISM). biological_scale was set on all eight, and genetic_context (SOMATIC / GAIN_OF_FUNCTION) on the initiating node, which makes it the derivable cell-of-origin node. A note on the angiogenesis node: PMID:36303616 attributes fibroid angiogenesis principally to the IGF system rather than to HIF-1-alpha/VEGF, and reports HIF-1-alpha as absent from fibroids where it is readily shown in leiomyosarcoma. The claude_code report said VEGF. The primary source's reading was followed, and the node was NOT conformed to tumor_angiogenesis, whose trigger is "Intratumoral Hypoxia and HIF Stabilization" - the wrong mechanism for this tumor. New sections: has_subtypes (MED12-mutant, HMGA2-rearranged, FH-deficient - molecular rather than FIGO-anatomical, since that is what the genetic section describes), histopathology (3), imaging_findings (3), environmental (5, all pathograph-linked except alcohol), progression (3 phases), clinical_burden (VARIABLE), differential_diagnoses (3), animal_models (2), discussions (3), classifications (harrisons_chapter ENDOCRINOLOGY_METABOLISM) and mappings (ICD10CM:D25 exactMatch, NCIT:C3434 exactMatch). phenotypes went 7 -> 13, prevalence 2 -> 4. Tensions recorded rather than smoothed over. Three, deliberately: (1) PMID:41493967 reports MED12 wild-type leiomyomas growing faster than mutant ones with higher CDK8 activity, which cuts against reading the gain-of-function label as growth-promoting. Curated as a REFUTE evidence item on the genetic record plus a CONTROVERSY discussion, not omitted. (2) The GBD 2021 age-standardized prevalence of 2841.07/100,000 sits an order of magnitude below the 60-70% screening figures already in the entry. The new prevalence record says explicitly that these do not contradict - GBD models diagnosed disease, the screening studies count incidental findings - and the gap is the asymptomatic fraction. (3) PMID:38710995's adjusted analysis drops miscarriage from the significant obstetric associations its unadjusted analysis includes. Both are curated on the Recurrent Pregnancy Loss phenotype as a SUPPORT and a REFUTE item, since one evidence item cannot carry two directions. Fixed a recorded defect: the FH genetic record carried a NOTE saying its HLRCC germline statement was uncited and needed a reference. PMID:36981015 now supplies it, with PMID:37263921 adding the germline/somatic split (31/29/20 of 80 cases) and the 69% family-history rate. Ontology gaps left unbound on purpose, each with the search recorded. HP:0200067 (Recurrent spontaneous abortion) means exactly the pregnancy-loss phenotype but sits under HP:0032443 past medical history, outside the PhenotypeTerm enum root HP:0000118; HP:0005268 Miscarriage and HP:0003826 Stillbirth are outside it too, under clinical modifier. Left as preferred_term, following the Asherman_Syndrome precedent for the same term (issue #7837 gap 3). Three exposure_terms are unbound: vitamin D deficiency (ECTO and XCO searched; the only candidates, ECTO:9000133 and XCO:0000543, name the presence of the exposure, the inverse of the risk factor), obesity (ECTO and XCO searched for obesity/body mass/high fat diet, nothing), and parity (not an environmental exposure at all). Each carries a review_notes line naming the searches. Note these are PARTIAL rather than waived in environmental-term-audit terms; they are not "Left deliberately uncited." waivers, since all five environmental entries carry real evidence. Devices and modality. therapeutic_modality was backfilled on all 13 treatments using the mechanical treatment_term mapping where it applies (SURGERY for myomectomy, hysterectomy, embolization and the two ablations - the enum's own gloss is "surgical or procedural intervention"), PEPTIDE for leuprolide, SMALL_MOLECULE for the small-molecule drugs, and DEVICE for the levonorgestrel intrauterine system, which is literally an implanted therapeutic device. Model credibility. Both animal models carry modeled_mechanisms with model_scale, fidelity, limitations and typed divergences. The Eker rat is deliberately recorded as FAILS_TO_RECAPITULATE against the initiating-lesion node - its germline Tsc2/mTOR lesion is none of MED12, HMGA2 or FH - alongside PARTIALLY_RECAPITULATES for the hormone-dependent growth node, and a RESCUES link for the vitamin D3 result that carries PROXY_QUANTITY (INVALIDATING) and SCALE_EXTRAPOLATION divergences because the measured endpoint is stem-cell DNA repair, not matrix. A HUMAN_MODEL_MISMATCH discussion records the same point structurally. Validation run. `just validate` and the authoritative batched `just validate-disorders kb/disorders/Uterine_Leiomyoma.yaml` both pass, with 137/137 snippets verified against the cached references. Also passed: check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms (0 qualifier terms), check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-enum-values, and model-scale-audit (the 2-step upward extrapolation on the Eker rat rescue link carries its required SCALE_EXTRAPOLATION divergence). Weighted compliance is 96.5%, unchanged from before the augmentation despite roughly quadrupling the content. No DOI-keyed evidence items were added, so no --unskip-prefix DOI run was needed. The page renders (dismech.render), and pages/ was reverted rather than committed. Three checks caught real defects during the session, all fixed: a snippet quoting PMID:34626221's title (moved to a body finding and split out as a third differential_diagnoses entry for endometrial stromal tumor), three snippets broken by bracketed citation spans being stripped before matching ([39], [7,8,9]), and one snippet ("UFs rarely develop before menarche") that came from the falcon report's prose and is in no cached source - re-anchored on PMID:37668348's sex-steroid-dependence statement and graded INDIRECT, since the premenarchal absence follows from the dependence rather than being stated. cache/hierarchy for ICD10CM and NCIT was rebuilt because the two new mappings were misses costing roughly 30 s each on every page build. The builder is whole-cache and incremental, so ten pre-existing misses from other entries came along with the two new rows; it preserves retrieved_at on unchanged rows, so the diff is additions only. Self-review round (skill step 7, dismech-pr-review in a fresh-context subagent) before opening the PR. It found five blocking errors, all of which are fixed here rather than deferred: (1) The MED12 case_fractions record said 34.1% from PMID:41493967's 44-tumor series. That counted one of four study arms. Table 1 of the cached full text gives GnRHa(-)/WT 11, GnRHa(-)/MUT 15, GnRHa(+)/WT 9, GnRHa(+)/MUT 9, so total mutant is 24/44 = 54.5% - inside the 50-80% range the note claimed it undercut, which collapsed the whole argument. The record is deleted rather than restated at 54.5%: the series was group-balanced by design and was never a prevalence estimate. Nothing in the toolchain could have caught this, since the snippet supplies only "44" and 34.1 was derived. (2) The FH node asserted fumarate-driven prolyl-hydroxylase inhibition and pseudohypoxic HIF stabilization with no evidence item supporting any of it, while two other places in the same entry quoted PMID:36303616 saying HIF-1-alpha is absent from uterine fibroids. An unintended contradiction, unlike the two that are recorded deliberately. Fixed by splitting the node along the module's own chain - "Fumarate Accumulation in FH-Deficient Leiomyoma" (conforming to oncometabolite_dioxygenase_inhibition#Oncometabolite Accumulation, now also carrying GO:0006099 DECREASED as the module expects) feeding a new "Pseudohypoxic HIF Stabilization in FH-Deficient Leiomyoma" (conforming to ...#Pseudohypoxic HIF Stabilization) - and by citing PMID:36981015's own sentence on prolyl-hydroxylase inhibition on both the node and the edge. The reconciliation is stated in both places: the HIF-absent observation comes from unselected (so overwhelmingly MED12/HMGA2) fibroids and is what establishes that the common fibroid does not use the hypoxia route, while pseudohypoxia is metabolite-driven and confined to the uncommon FH-deficient subtype. This also resolved the separate finding that the old node bundled four module nodes into one. (3) An evidence item on PMID:32545544 was graded HUMAN_CLINICAL. That paper is a pure Eker-rat study (MeSH Animals, Rats, no human subjects) and the quoted sentence is a background assertion about other people's epidemiology, so the grade claimed the publication presents human evidence, which is what the CLAUDE.md rule forbids. The per-sentence split is sanctioned for papers that mix evidence types and this one does not. Replaced with PMID:36982852, a human review that lists endocrine-disrupting chemical exposure among the established risk factors. check_snippet_grading structurally cannot see this class of error, since it keys on the sentence rather than the paper. (4) Four evidence items quoted PMID:40970558's "abnormal uterine bleeding (AUB), infertility, recurrent pregnancy loss, pressure, pain, urinary frequency, or gastrointestinal dysfunction may be present with a variety of otherwise unrelated conditions" as SUPPORT for fibroid bulk symptoms. In context that sentence begins "Furthermore, when symptoms occur, they may not be related to the fibroids since..." - its purpose is to caution against the attribution it was being used to make. The same cached full text contains the sentence that does make the claim ("Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation."), which now replaces it in all four places; the Constipation edge dropped its directness: INDIRECT as a result, since the source names constipation outright. The anti-attribution sentence is retained on the Urinary Frequency phenotype, quoted in full including the "may not be related to the fibroids" clause, as the source's own counter-caution. The adjacent sentence on urinary obstruction and hydronephrosis now cites the node's previously uncited severe-end claim. (5) The Bulk Compression node said the symptoms track fibroid size "rather than fibroid number", which PMID:40970558 contradicts directly ("correlate with fibroid size, number, and anatomical placement"). Reworded and cited. Also fixed from the same review: genetic_context on the driver node stamped SOMATIC / GAIN_OF_FUNCTION over a node listing MED12, HMGA2 and FH, which is false for FH (biallelic tumor-suppressor loss, germline in roughly half of FH-deficient tumors) and a stretch for HMGA2 rearrangement - the slots are single-valued, so they now carry a notes line saying they describe the MED12 arm only, which matters because a somatic genetic_context is what marks the derived cell-of-origin node. The FH-deficient subtype's "roughly half germline" became the precise 31/80 (39%), or 52% of variant-detected cases, matching the genetic section. The hemostatic node moved from ORGANISM to TISSUE with its bundled organ-level claims attributed to the tumor-mass nodes where they belong. The source's "likely" hedges on the BMPR-2 and PAI-1/ATIII/thrombomodulin steps were restored, with a note that two of those three regulators are themselves anticoagulants so the DECREASED modifier records a net outcome rather than a per-protein reading. The venous-lake node now records that its own source later challenged the interstitial-pressure explanation. The linzagolix snippet was the study objective rather than a finding and is now the PRIMROSE withdrawal result, with relugolix (NCIT:C114498) and linzagolix (NCIT:C148479) bound as therapeutic_agent alongside elagolix. HMGA2/MED12 mutual exclusivity is now cited (PMID:38326302). The CD10 figure was described as a "substantial minority" when 65.4% is a majority. The two reproductive phenotypes were wired into the pathograph via Infertility sequelae. Both differentials that have dismech entries gained a disease_term (MONDO:0016262, MONDO:0010888). Two clinical_trials records were added for LIBERTY 1 and 2 (NCT03049735, NCT03103087). Two of the review's suggestions were resolved by removal rather than by curation, because no source supports them: - The Fatigue phenotype (HP:0012378) was drafted and then deleted. No reference cited anywhere in this entry names fatigue as a fibroid symptom, and a targeted PubMed search (fibroid + iron deficiency + fatigue in title/abstract) returned nothing usable. The claim is clinically obvious and bibliographically unsupported here, so it is recorded as a notes line on the Iron Deficiency Anemia phenotype instead of as an ontology-bound phenotype resting on an inference. - therapeutic_agent on Iron Replacement Therapy was left absent, with the reason in the treatment description: NCIT:C210688 "Iron Supplement" is the right concept but is not a member of the ChemicalEntityTerm dynamic enum (confirmed by a failing term-validation run), and every CHEBI member term names one specific salt or hydrate, which would assert a preparation the source does not specify. Dyspareunia was kept but re-sourced: it previously rested on an INDIRECT quote about the pelvic-pain complex, and now cites PMID:35106750, which names dyspareunia outright. One review suggestion was declined. Uterine Artery Embolization is tagged therapeutic_modality: SURGERY here where the sibling Adenomyosis entry uses DEVICE. The enum's own gloss for SURGERY is "surgical or procedural intervention", and embolization is a procedure whose therapeutic principle is arterial occlusion rather than an implanted device; the coarse-bucket table in CLAUDE.md puts SURGERY, RADIOTHERAPY and DEVICE all under PROCEDURE, so nothing downstream distinguishes them. Left as SURGERY; the cross-entry inconsistency is real and is worth a separate normalizing pass rather than a change made here in one direction on one entry. Final state after the review round: just validate and the batched just validate-disorders both pass with 144/144 snippets verified, all eleven offline gates pass, and weighted compliance is 95.8%. cache/icd10cm/hierarchy.csv and cache/ncit/hierarchy.csv were rebuilt and the hierarchy cache is now complete for every mapped CURIE in the repository. Review round 1 (PR #11756, ai4c-reviewer changes-requested, 2026-09-12T22:51Z). The automated review confirmed schema/term/snippet validation, evidence_source grading, ontology precision, node atomicity and scope hygiene, and raised two blocking claim/snippet mismatches. Both were correct, both were pre-existing items carried forward from the entry's original creation rather than added by this session, and both were fixed from references this PR had already cached: - The Dysmenorrhea phenotype quoted PMID:38723935's "in approximately 30% of cases, UFs affect the quality of life and women's health", which never names dysmenorrhea; the explanation was supplying the inference. Re-sourced to PMID:41514933, which names dysmenorrhea outright among fibroid symptoms, plus PMID:39335725 as a second attestation ("fibroid-related dysmenorrhea"). The quoted span stops before the source's "[6,7,8]" citation marker, since bracketed spans are stripped before matching. - The Constipation from Bulk Compression phenotype quoted PMID:38929485's "pelvic masses causing pressure or pain", which never mentions constipation. Re-sourced to PMID:40970558's "Fibroids positioned anteriorly or posteriorly can compress the bladder or rectum, resulting in urinary frequency, difficulty emptying the bladder, or constipation", which names both the phenotype and its mechanism. The description was tightened to say "posteriorly placed" rather than "larger", matching the source. Two non-blocking suggestions were taken in the same push, since the push was happening anyway and main has dismiss_stale_reviews: - The COL4A5/COL4A6 and SRCAP-complex driver classes are now covered by an explicit scoping note on the driver node, recording that their omission from has_subtypes is a decision (rare relative to the three modelled classes, no distinct pathophysiology arm beyond the shared ECM output, no management consequence) rather than an oversight. - Mifepristone is curated as a fourteenth treatment, SMALL_MOLECULE, bound to CHEBI:50692, with a target_mechanisms link to the hormone-driven proliferation node and PMID:39335725 as evidence. It groups with the progesterone-receptor agents rather than the symptomatic ones. One non-blocking suggestion was declined, with the reason recorded rather than left implicit. The reviewer noted the Wnt4/beta-catenin and TDO2-kynurenine-AHR arms are surfaced by the research but not modelled as pathophysiology nodes. Wnt is already represented: the driver node carries GO:0016055 (Wnt signaling pathway) with modifier: INCREASED. The TDO2-kynurenine-AHR arm has no suitable GO process term - OLS returns nothing for a tryptophan-to-kynurenine catabolic process, and the available alternatives are a cellular component (GO:0034753, nuclear aryl hydrocarbon receptor complex) or a molecular function (GO:0017162, aryl hydrocarbon receptor binding), neither of which is the process being claimed. Binding a term that names the wrong kind of thing would be worse than leaving the arm unmodelled, and the reviewer's own assessment was that adding it would deepen the mechanism rather than correct it. Note on cache churn in this round: `just validate` triggered normalize-cache, which re-sorted seven rows across cache/go/terms.csv, cache/hp/terms.csv and cache/mondo/terms.csv. This is the pre-existing ordering drift that check-term-cache-integrity reports as advisory pending a coordinated cutover. The diff is seven lines, not a whole-file re-sort, so it is carried rather than reverted. After this round: `just validate` and the batched `just validate-disorders` both pass with 146/146 snippets verified, all eleven offline gates pass, weighted compliance 95.6%.

Claude Code ▸

Uterine Leiomyoma (Uterine Fibroids): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 71 citations 2026-09-12T17:42:20.651611

Uterine Leiomyoma (Uterine Fibroids): Comprehensive Research Report

1. Disease Overview and Identifiers

Overview: Uterine leiomyomas (also called uterine fibroids, myomas, or leiomyomata uteri) are benign monoclonal smooth-muscle-cell tumors of the myometrium, composed of disorganized, hypertrophic myofibroblasts embedded in an abundant, disease-defining extracellular matrix (ECM) that constitutes a substantial fraction of tumor volume (Endocrine Reviews, 2022; PMC10051203). They are the most common pelvic tumors in women of reproductive age, affecting an estimated ~75% of women by menopause when systematically screened, though clinically apparent (symptomatic/diagnosed) prevalence is substantially lower (PMC12488583; PubMed 36001050).

Key identifiers: - MONDO: MONDO:0007886 - OMIM: #150699 (Leiomyoma, Uterine, Somatic) — the somatic/sporadic form; #150800 (Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC) for the germline-predisposed syndromic form - Orphanet: Uterine fibroids are generally not classified as a rare disease in Orphanet given their high population prevalence, but HLRCC has an Orphanet entry as a rare hereditary tumor-predisposition syndrome - ICD-10-CM: D25 (Leiomyoma of uterus), with subcodes D25.0 (submucous), D25.1 (intramural), D25.2 (subserosal), D25.9 (unspecified) - ICD-11: GB50 (Leiomyoma of uterus) - MeSH: D007889 (Leiomyoma), cross-referenced with D014594 (Uterine Neoplasms)

Synonyms: Uterine fibroid(s), myoma(s), fibromyoma, leiomyoma uteri, fibroleiomyoma.

Evidence base: Information derives primarily from aggregated disease-level resources — population registries (SEER-adjacent gynecologic registries, GBD, national health-linkage cohorts), large clinical trial cohorts (LIBERTY, Elaris, PRIMROSE), pathology/genomic tumor banks (TCGA-adjacent and independent whole-exome/whole-genome sequencing cohorts), and case series — rather than single-patient EHR mining, though the NIEHS Uterine Fibroid Study and Black Women's Health Study contribute large prospective individual-level cohort data.

2. Etiology

2a. Somatic genetic drivers (disease-causal factors)

Uterine leiomyoma pathogenesis is now understood as arising from at least three-to-four mutually exclusive somatic driver subtypes, together accounting for up to ~90%+ of tumors (eLife 2018, 37110; OMIM #150699):

MED12 exon 2 hotspot mutations (~70% of tumors) — the dominant driver class. MED12 is a subunit of the Mediator transcriptional co-activator complex; mutant MED12 alters CDK8/Mediator kinase module activity and dysregulates Wnt4/β-catenin and TGF-β/EMT signaling (Sci Rep 2024, s41598-024-84439-4; PMC13512488; ScienceDirect S2949838425000325). A 2024 mechanistic study also implicated MED12-mutant tumors in upregulating TDO2 and activating the tryptophan→kynurenine→aryl hydrocarbon receptor (AHR) axis to drive proliferation (PMC10561729).
HMGA2 overexpression/rearrangement (via chromosome 12q14-15 rearrangements, often t(12;14)) — second most common subtype.
Fumarate hydratase (FH)-deficient leiomyomas (0.4–2.6% of tumors) — arise from biallelic FH inactivation (loss of function via missense/truncating mutation plus loss of heterozygosity), leading to fumarate accumulation, pseudohypoxia (HIF stabilization), and a distinctive "staghorn" vasculature and eosinophilic-cytoplasm histology (bioRxiv 663609; PMC10048203). This subtype overlaps with the hereditary HLRCC syndrome (see §9).
Rarer subtypes: COL4A5-COL4A6 deletions (Alport-syndrome-adjacent locus) and other minor genomic rearrangement classes.

Genome-stability genes (TP53, ATM) and telomere-maintenance genes (TERT, TERC, OBFC1/STN1) have also been implicated by GWAS as broader predisposition loci, suggesting UL risk operates through both direct smooth-muscle mitogenic pathways and genome-instability/telomere-biology pathways (eLife 37110).

2b. Risk Factors

Genetic risk factors: - Family history of fibroids (first-degree relative) approximately doubles risk. - GWAS-identified susceptibility loci near HMGA2, the RGS7-FH interval on 1q43 (PMC4526794), TP53, ATM, TERT, TERC, OBFC1, and loci implicated in genitourinary tract development (eLife 37110; PMC4501220, NIEHS multi-ethnic replication study). - A Mendelian randomization study found genetic liability to multiple metabolic/reproductive traits contributes causally to leiomyoma risk (PMC10415162). - Germline FH pathogenic variants (autosomal dominant) cause HLRCC syndrome with early-onset, numerous, and larger uterine leiomyomas (see §9).

Environmental/lifestyle risk factors: - Age: risk rises steeply from the mid-30s, peaking in the 40s ("Global and regional trends," PMC11556989; Australian linkage cohort, PMC11373412). - Race/ancestry: Black women are diagnosed 2–3× more often than White women, with earlier age of onset and larger/more numerous tumors — nearly 25% of Black women aged 18-30 have fibroids vs. ~6% of White women, rising to ~60% of Black women by age 35 (Michigan Medicine; AJOG). Genetic ancestry studies suggest fibroproliferative risk-allele frequency differs by African vs. European ancestry, potentially explaining up to 69% of the disparity in some models, though social/structural/environmental drivers (chronic stress, adverse childhood experiences, perceived racism, environmental contaminant exposure) are increasingly recognized as independent contributors (PMC8463481; ScienceDirect S0015028223000602). - Obesity: consistent risk factor, OR ≈1.19 (suggestive-strength evidence in umbrella review) via increased peripheral estrogen conversion (ScienceDirect S2468784722001994). - Early menarche, nulliparity, hypertension, chronic inflammation. - Endocrine-disrupting chemical exposure: in-utero and adult exposure to phthalates (e.g., DEHP) and bisphenol A (BPA) is an emerging risk factor; DEHP metabolites are also associated with lower vitamin D status, suggesting compounding mechanisms (PMC7483495; Eker rat DES-exposure model, PMC7349254). - Vitamin D deficiency: robustly associated with fibroid presence/size; mechanistic work shows VDR knockdown in myometrial cells induces DNA double-strand breaks and impairs DNA-damage-response, implicating a calcitriol/VDR-DNA repair axis (Endocrine Reviews 2026, edrv/8456362; PMC13167191; PMC7917888).

Protective factors: - Parity: parous women have a lower risk than nulliparous women (dose-dependent with number of births) (Korea Nurses' Health Study, PMC10257256). - Oral contraceptive use: current use associated with reduced risk (RR ≈0.43 in some meta-analyses), though findings have varied by formulation and duration across studies (PMC10056617). - Cigarette smoking has been reported as inversely associated in some (older) epidemiologic studies, plausibly via anti-estrogenic metabolic effects, though this is not advocated clinically given smoking's other harms.

Gene-environment interaction: The Eker rat model directly demonstrates a genetic (Tsc2 germline mutation) × environmental (developmental diethylstilbestrol/endocrine-disruptor exposure) interaction, in which DES exposure amplifies DNA damage specifically in myometrial stem cells of Tsc2-mutant animals, and vitamin D3 supplementation mitigates this damage — a mechanistic bridge between the genetic, environmental, and vitamin D literatures (PMC7349254).

3. Phenotypes

Phenotype	Type	Suggested HPO term	Frequency/Notes
Heavy menstrual bleeding (menorrhagia)	Symptom	HP:0000132 (Menorrhagia)	~30% of all patients; most common presenting symptom; a major cause of iron-deficiency anemia and elective hysterectomy (PMC9580818)
Iron-deficiency anemia	Lab abnormality	HP:0001891 (Iron deficiency anemia)	Secondary to chronic HMB
Chronic pelvic pain / pressure	Symptom	HP:0030318 (Pelvic pain)	Bulk-related; correlates with tumor size/number
Dysmenorrhea	Symptom	HP:0100608 (Dysmenorrhea)	Common, variable severity
Dyspareunia	Symptom	HP:0030068 (Dyspareunia)	Bulk-related, position-dependent
Urinary frequency / bladder pressure	Symptom	HP:0000103 (Polyuria) / bladder-compression related	Anterior/large fibroids compressing bladder
Constipation	Symptom	HP:0002019 (Constipation)	Posterior fibroids compressing rectum
Abdominal/pelvic mass	Physical sign	HP:0031801 (Abdominal mass) or pelvic mass equivalent	Palpable on exam when large
Infertility	Symptom/reproductive	HP:0000789 (Infertility)	Especially with cavity-distorting (submucosal, FIGO 0-2) fibroids
Recurrent pregnancy loss	Reproductive	HP:0005268 (Recurrent miscarriage)	Associated with cavity distortion
Acute pain (red degeneration)	Symptom (in pregnancy)	—	Painful infarction during rapid pregnancy-associated growth

Onset: Typically detected in the reproductive years (30s–40s); rare before menarche; regression is expected after menopause due to estrogen/progesterone withdrawal.

Severity/progression: Highly variable — many fibroids are asymptomatic incidental findings; others cause severe, quality-of-life-limiting bleeding and bulk symptoms. Growth is generally slow but hormonally responsive (accelerates in pregnancy, regresses postmenopause); course is typically stable-to-slowly-progressive rather than episodic, though rapid growth raises concern for degeneration or (rarely) sarcoma.

Frequency of symptoms among affected individuals: More than half of women with fibroids experience heavy menstrual bleeding, pelvic pain, or infertility-related symptoms; a substantial proportion remain asymptomatic (PMC12859363; AAFP rapid evidence review, 2025).

Quality of life impact: HMB is described as the primary driver of health-related quality-of-life deterioration in fibroid patients and the major reason for elective hysterectomy (PMC9580818). Validated instruments (UFS-QOL, a fibroid-specific tool; general EQ-5D/SF-36) are used in trials (e.g., LIBERTY, Elaris) to capture symptom severity and QOL domains (energy/mood, control, self-consciousness, sexual function).

4. Genetic/Molecular Information

Causal genes / mutation classes: - MED12 (HGNC:29305; Xq13.1) — exon 2 hotspot missense/small in-frame indel mutations in ~70% of tumors; somatic, mosaic across tumor but clonal within it. - HMGA2 (HGNC:5013; 12q14.3) — overexpression driven by chromosomal rearrangement/translocation (e.g., t(12;14)(q14-15;q23-24)), disrupting a 3' UTR microRNA (let-7)-binding regulatory region. - FH (HGNC:3700; 1q43) — biallelic loss-of-function (germline + somatic second hit in HLRCC; purely somatic biallelic in sporadic FH-deficient subtype); loss of fumarate hydratase enzymatic activity in the TCA cycle causing fumarate accumulation, succination of proteins (2SC adduct), and HIF-1α pseudohypoxic stabilization. - COL4A5/COL4A6 deletion subtype (rare). - TSC2 — germline mutation in the Eker rat model (not a major human somatic driver but mechanistically informative).

Variant classification (ACMG/ClinVar framework): - Somatic MED12/HMGA2/FH alterations are tumor-driver mutations, not germline ACMG-classified variants, and are typically reported in a cancer-genomics/somatic framework (pathogenic driver vs. passenger) rather than ClinVar pathogenicity tiers. - Germline FH variants causing HLRCC are curated in ClinVar/ClinGen as Pathogenic/Likely Pathogenic (autosomal dominant); >200 distinct FH coding mutations have been described (PMC9128909; PMC10048203, reporting c.1132G>A as one example).

Somatic vs. germline origin: The overwhelming majority of driver mutations (MED12, HMGA2 rearrangement, sporadic FH-deficient) are somatic, acquired independently in each tumor (explaining why patients frequently harbor multiple genetically distinct fibroids — a polyclonal field of monoclonal tumors). Germline FH mutation defines the syndromic HLRCC subset only.

Functional consequences: - MED12 mutations: partial loss/alteration of Mediator-CDK8 kinase-module function → dysregulated Wnt/β-catenin and TGF-β/EMT transcriptional programs, plus tryptophan-kynurenine-AHR pathway activation and MMP-9-driven ECM remodeling (ScienceDirect S002751072300026X; ScienceDirect S2949838425000325). - FH loss: classic loss-of-function tumor-suppressor mechanism → metabolic (pseudohypoxic) gain-of-signaling phenotype. - HMGA2: gain-of-function overexpression via loss of 3'UTR-mediated let-7 repression.

Epigenetics: A 2025 study found MED12-mutation status predicts patterns of aberrant DNA methylation in leiomyomas, indicating a genetic-epigenetic interaction shaping subtype-specific gene expression programs (PMC13512488). Broader epigenomic dysregulation (DNA methylation, histone modification) has been documented across leiomyoma subtypes relative to adjacent myometrium (ENCODE/Roadmap-adjacent studies, cited in mechanistic reviews such as PMC10056617).

Chromosomal abnormalities: Recurrent cytogenetic rearrangements define UL molecular subclasses — t(12;14)(q14-15;q23-24) (HMGA2), del(7)(q22q32), trisomy 12, and rearrangements of 6p21 (HMGA1) — consistent with a limited set of recurrent structural drivers rather than complex genomic instability typical of malignancy.

5. Environmental Information

Endocrine-disrupting chemicals: In-utero and lifetime exposure to phthalates (DEHP and metabolites) and bisphenol A are implicated as risk-modifying exposures, demonstrated mechanistically in the Eker rat DES model and epidemiologically in human cohorts (PMC7483495; PMC7349254).
Lifestyle factors: obesity (adiposity increases peripheral aromatization of androgens to estrogen), diet, and possibly chronic psychosocial stress (implicated as a disparities driver) (ScienceDirect S0015028223000602).
Air pollution/environmental contaminant exposure: cited among structural/environmental drivers contributing to racial disparities in fibroid incidence and severity (Michigan Medicine/IHPI summary).
Infectious agents: None established as causal for uterine leiomyoma; this is not an infection-driven disease.

6. Mechanism / Pathophysiology

Causal chain (ordered, from initiating lesion to clinical manifestation)

A myometrial smooth-muscle stem/progenitor cell acquires a somatic driver alteration — most commonly a MED12 exon 2 mutation (~70%), or alternatively an HMGA2 rearrangement, or biallelic FH inactivation (0.4–2.6%) — establishing a clonal population. [Demonstrated at the molecular/genomic level, inferred as the initiating event given multiple independent clonal tumors per uterus.]
The driver mutation dysregulates transcriptional programs within that clone: MED12-mutant cells show activation of canonical Wnt4/β-catenin signaling and TGF-β/EMT signaling, and elevated TDO2-driven tryptophan-to-kynurenine conversion activating the aryl hydrocarbon receptor (AHR) (PMC10561729; ScienceDirect S2949838425000325). FH-deficient cells accumulate fumarate, succinate host proteins, and stabilize HIF-1α, producing a pseudohypoxic transcriptional state.
This leads to clonal smooth-muscle-cell proliferation [demonstrated], forming a discrete, well-circumscribed tumor nodule distinct from surrounding normal myometrium.
Ovarian steroid hormones (estrogen and progesterone) act as the principal growth-promoting cofactors for the established clone: estrogen upregulates progesterone-receptor expression and growth-factor signaling, while progesterone is now recognized as the dominant proliferative driver in adult fibroid growth, acting through progesterone-receptor-mediated induction of pro-growth and anti-apoptotic genes. [Demonstrated via responsiveness to GnRH agonist/antagonist and progesterone-modulator therapy, which shrink tumors by suppressing this axis — see §12.]
Growth-factor cascades — TGF-β, activin-A, platelet-derived growth factor (PDGF), and connective tissue growth factor (CTGF) — are upregulated within the tumor and act on the surrounding myofibroblast-like tumor cells, driving both further proliferation and excessive extracellular matrix (ECM) synthesis (PMC10051203; PMC12784659).
The ECM (collagen types I/III, fibronectin, versican, other proteoglycans) accumulates in disproportionate excess relative to cellular content, acting as both structural scaffold and reservoir that binds and prolongs the activity of TGF-β and other growth factors — creating a self-reinforcing fibrotic feed-forward loop. [Demonstrated — ECM constitutes the majority of tumor mass by volume.]
MMP-9 and other matrix metalloproteinases are dysregulated (upregulated by mutant-MED12 signaling) and contribute to abnormal matrix remodeling and tumor expansion (ScienceDirect S002751072300026X).
Concurrent angiogenic remodeling occurs, driven by VEGF and (in FH-deficient tumors specifically) by HIF-driven pseudohypoxic angiogenic signaling, producing the histologically distinctive "staghorn" vasculature seen in FH-deficient leiomyomas (PMC8185197).
As the fibrotic, hypervascular mass enlarges within the myometrium, it produces mechanical and physiological disruption of the overlying/adjacent endometrium and myometrial contractility: increased endometrial surface area, venule ectasia/congestion, and impaired local hemostatic factors → heavy menstrual bleeding, and impaired coordinated myometrial contraction contributing to bleeding and dysmenorrhea (PMC9580818).
Depending on anatomical location (see FIGO classification, §7/10), the enlarging mass produces bulk-related manifestations: cavity distortion → infertility/pregnancy loss (submucosal, FIGO 0–2); bladder/rectal compression → urinary frequency/constipation (large intramural/subserosal); and pregnancy-associated rapid growth can outstrip blood supply, causing infarction ("red degeneration") and acute pain.
In the rare germline-FH (HLRCC) pathway, the same FH-loss/pseudohypoxic mechanism operating in skin and kidney produces cutaneous leiomyomas and an aggressive, early-onset papillary type 2 renal cell carcinoma, making the uterine phenotype part of a multi-organ tumor-predisposition syndrome rather than an isolated uterine disease (see §9) — this branch is inferred to share the core FH-loss mechanism with sporadic FH-deficient fibroids but is demonstrated to differ in tissue-selective consequences (renal carcinogenesis specifically).
Rarely, secondary genetic alterations (e.g., ALK rearrangement, 14q loss) accumulate in an existing leiomyoma clone, driving malignant transformation to leiomyosarcoma — this remains a mechanistically distinct, low-probability branch rather than the typical fibroid trajectory (Oncotarget 25137; PMC6021249).

Cellular and molecular detail by category

Molecular pathways: Wnt4/β-catenin, TGF-β/SMAD and non-canonical EMT signaling, tryptophan-kynurenine-AHR axis, PI3K-AKT-mTOR (growth-factor downstream), HIF-1α/pseudohypoxia (FH-deficient subtype). Suggested GO terms: GO:0016055 (Wnt signaling pathway), GO:0007179 (transforming growth factor beta receptor signaling pathway), GO:0001525 (angiogenesis).
Cellular processes: smooth-muscle-cell proliferation, epithelial-to-mesenchymal-transition-like myofibroblast activation, apoptosis resistance, excessive ECM deposition/fibrosis.
Protein dysfunction: MED12 Mediator-complex conformational alteration (not classic misfolding); FH enzymatic loss-of-function; HMGA2 architectural transcription-factor overexpression.
Metabolic changes: TCA-cycle disruption and fumarate accumulation in FH-deficient tumors; tryptophan catabolism shift toward the kynurenine pathway in MED12-mutant tumors.
Tissue damage mechanisms: fibrosis (excess ECM), localized ischemia/infarction (red degeneration, especially in pregnancy), abnormal angiogenesis.
Cell types involved: uterine smooth muscle cell (relevant CL term: CL:0002598, myometrial smooth muscle cell, or the general CL:0000192 smooth muscle cell), myofibroblast-like tumor cells, endothelial cells, and a minor immune infiltrate — all characterized by recent single-cell RNA-seq atlases showing substantial cellular heterogeneity within both normal myometrium and leiomyoma tissue, including diverse SMC, fibroblast, and endothelial subpopulations (bioRxiv 2020.12.21.402313; PubMed 36001050).
Cell/tumor origin: The field's working model long postulated a monoclonal origin from a single dysregulated multipotent myometrial stem cell per tumor; however, newer single-cell atlases describe a "non-monoclonal" origin of diverse and novel constituent cell types even though each tumor's principal proliferative smooth-muscle clone remains monoclonal — the precursor/tumor-initiating cell's precise identity remains unresolved (bioRxiv 2020.12.21.402313; Human Reproduction 2024, O-264 tumor-initiating-cell multi-omics abstract).

7. Anatomical Structures Affected

Organ level: Primary organ — uterus (myometrium). Secondary/complication-related involvement: bladder (compression → urinary symptoms), rectum/colon (compression → constipation), ureters (rare hydronephrosis with large broad-ligament fibroids), and — in HLRCC — kidney (renal cell carcinoma) and skin (cutaneous leiomyomas) as part of the syndromic phenotype. Body systems: reproductive, and secondarily urinary/GI (compression) and hematologic (anemia from HMB).
Anatomical/UBERON terms: UBERON:0000995 (uterus), UBERON:0001296 (myometrium), UBERON:0000459 (endometrium), UBERON:0001255 (urinary bladder, secondary), UBERON:0002113 (kidney, HLRCC).
Tissue/cell level: smooth muscle tissue (myometrium) is the tissue of origin; endometrium is secondarily affected functionally (bleeding) without itself being the tumor tissue. Cell Ontology: CL:0002598 (myometrial smooth muscle cell); tumor stroma additionally comprises fibroblast-like cells (CL:0000057) and endothelial cells (CL:0000115).
Subcellular level: Mitochondria (TCA-cycle/fumarate handling in FH-deficient subtype; GO:0005739), nucleus (Mediator complex function; GO:0016592 mediator complex), extracellular matrix/extracellular space (GO:0031012).
Localization (FIGO anatomic classification — see §10): intracavitary (Type 0), submucosal (Types 1–2), intramural (Types 3–4), subserosal (Types 5–7), cervical or parasitic (Type 8), and hybrid transmural types. Lateralization is not a relevant axis (fibroids are typically multiple and distributed without lateral predilection), though location within the uterine body vs. cervix vs. broad ligament (parasitic) is clinically significant.

8. Temporal Development

Onset: Reproductive age, typically detected from the mid-20s onward, with sharply rising incidence through the 30s–40s; incidence peaks around age 40–44 (5.0 cases/1000 person-years in the Australian cohort) and declines after menopause (PMC11373412). Congenital or prepubertal onset does not occur. HLRCC-associated leiomyomas present earlier (often in the 20s-30s) and more numerously.
Onset pattern: Insidious — tumors grow slowly over years; most are identified incidentally or after gradual symptom accumulation rather than acute presentation (acute presentation occurs only with degeneration/torsion of a pedunculated fibroid).
Progression: No formal "stage" system exists as for malignancy; the FIGO classification is anatomic/positional rather than a stage of progression. Disease course is typically stable-to-slowly-progressive during reproductive years, with hormone-responsive acceleration during pregnancy and spontaneous regression after menopause due to loss of ovarian estrogen/progesterone support. Course is generally not episodic/relapsing-remitting in the way autoimmune disease is, though symptom severity (particularly bleeding) can fluctuate with the menstrual cycle.
Remission: Natural "remission" (shrinkage) occurs physiologically at menopause; treatment-induced regression occurs with GnRH agonists/antagonists and progesterone-receptor modulators (reversible, tumors typically regrow after cessation) or is permanent following surgical/procedural treatment.
Critical periods: Reproductive years represent the principal window of clinical relevance (fertility impact, bleeding-related morbidity); pregnancy is a distinct high-risk window for both growth acceleration and degeneration/pain complications.

9. Inheritance and Population Genetics

Epidemiology: - Reported incidence ranges from 217–3,745 cases per 100,000 woman-years, and prevalence estimates range from 4.5%–68.6%, reflecting wide variation by diagnostic method (clinical vs. systematic ultrasound screening) and population studied (PMC12488583; systematic review PubMed 28296146). - Australian data-linkage cohort (2000–2022): 7.3% cumulative diagnosis by ages 45–49; peak age-specific incidence 5.0/1000 person-years at ages 40–44 (PMC11373412). - Global Burden of Disease-based analyses (1990–2021/2023) document rising absolute case counts, with further increases in both rate and total cases projected through 2050 (PMC12488583; PMC13311307).

Inheritance pattern: The common sporadic form is a complex/multifactorial trait — polygenic susceptibility (GWAS loci near HMGA2, TP53/ATM, TERT/TERC/OBFC1) combined with somatic driver mutation and environmental/hormonal exposure, not classically Mendelian. The syndromic minority form, HLRCC (OMIM #150800), is autosomal dominant, caused by heterozygous germline pathogenic FH variants (>200 described mutations across the coding region), typically requiring a somatic "second hit" for tumor formation consistent with a classic two-hit tumor-suppressor mechanism (OMIM #150800; PMC9128909). - Penetrance: high but incomplete for cutaneous/uterine leiomyomas in HLRCC; renal cell carcinoma penetrance is lower but the tumors that do occur tend to be aggressive. - Founder effects/consanguinity: not prominently described for common UL; not specifically documented as a major factor for HLRCC beyond typical autosomal-dominant transmission. - Genetic anticipation, germline mosaicism: not established features of this disease.

Population demographics: - Race/ethnicity: Black women have markedly higher prevalence, earlier onset, and greater fibroid burden than White women (see §2b); genetic-ancestry studies estimate a substantial fraction of this disparity is attributable to differential frequency of fibroproliferative risk alleles by ancestry, alongside social/environmental contributors (PMC8463481). - Sex ratio: Not applicable (uterus-specific, female-only disease). - Age distribution: Concentrated in the 4th–5th decades of life, minimal before menarche or after several years post-menopause. - Geographic distribution: Global disease, but burden estimates and rate-of-rise vary by region/country in GBD-based analyses (Chinese Medical Journal, 2010–2019 worldwide database study).

10. Diagnostics

Clinical tests: - Imaging is the primary diagnostic modality. Transvaginal (or transabdominal) ultrasound is first-line for detection and initial characterization; MRI provides superior multiplanar resolution and is preferred for surgical planning, especially with multiple/large fibroids, or to distinguish fibroids from adenomyosis or to assess for suspicious features (PMC12553092; RadioGraphics 220161). - Saline-infusion sonohysterography or hysteroscopy for submucosal (cavity-distorting) fibroids affecting fertility. - Laboratory: CBC to assess for iron-deficiency anemia secondary to HMB (LOINC panels for hemoglobin/ferritin); no specific circulating biomarker is diagnostic for leiomyoma itself. - Biopsy/histopathology: Not routinely needed preoperatively (fibroids are diagnosed radiologically); histology post-surgery shows whorled bundles of spindle smooth-muscle cells with abundant collagenous stroma; FH-deficient tumors show characteristic eosinophilic cytoplasmic inclusions, prominent nucleoli with perinucleolar halos, and staghorn vasculature, and immunohistochemistry for loss of FH protein / gain of 2SC (succinated cysteine) staining is used to screen for HLRCC (Malacards HLRCC; PubMed 41808417).

FIGO anatomic classification (Types 0–8): | Type | Description | |---|---| | 0 | Pedunculated intracavitary | | 1 | Submucosal, <50% intramural | | 2 | Submucosal, ≥50% intramural | | 3 | Intramural, contacting endometrium | | 4 | Intramural, not contacting endometrium or serosa | | 5 | Subserosal, ≥50% intramural | | 6 | Subserosal, <50% intramural | | 7 | Subserosal, pedunculated | | 8 | Cervical or other (parasitic) | | Hybrid (e.g., "2-5") | Contacts both endometrium and serosa |

(Source: MRI-based pictorial reviews, Springer 2020, PMC12553092) — this classification is anatomical only and does not incorporate size, number, or vascularity.

Genetic testing: Not part of routine sporadic fibroid workup. Germline FH gene sequencing is indicated when HLRCC is clinically suspected (multiple/early-onset cutaneous leiomyomas, family history of early-onset aggressive renal cell carcinoma, or FH-deficient histology/IHC pattern on a resected uterine leiomyoma) — managed through cancer-genetics/GTR-listed panels.

Differential diagnosis: Adenomyosis, endometrial polyp, endometrial or uterine sarcoma (leiomyosarcoma), ovarian mass, pregnancy, adenomyoma. Distinguishing benign leiomyoma from leiomyosarcoma preoperatively remains unreliable — no imaging or biomarker test can definitively exclude sarcoma before histologic resection (FDA leiomyosarcoma risk assessment).

Screening: No population-based screening program exists (unlike cervical/breast cancer screening); case-finding is via symptom-triggered pelvic exam/imaging. Cascade genetic counseling and screening for renal cell carcinoma risk is recommended for confirmed HLRCC-mutation carriers and their relatives.

11. Outcome/Prognosis

Survival/mortality: Uterine leiomyoma itself is a benign condition with essentially no direct mortality; excess mortality risk relates only to rare complications (severe hemorrhage, surgical complications) or to the distinct entity of malignant transformation/leiomyosarcoma.

Malignant transformation / leiomyosarcoma risk: Leiomyosarcoma is a rare, biologically distinct uterine sarcoma, not simply an advanced fibroid. FDA's meta-analysis of 18 studies estimated the risk of occult uterine sarcoma among women undergoing surgery for presumed fibroids at 0.28% (FDA report). True malignant transformation of an existing benign leiomyoma (rather than de novo sarcomagenesis) is documented but considered rare; case reports describe secondary genetic events such as ALK rearrangement and 14q loss driving transformation to myxoid leiomyosarcoma (Oncotarget 25137; PMC6021249). Because leiomyosarcoma cannot be reliably diagnosed preoperatively, power morcellation carries a risk of intraperitoneal dissemination of an unsuspected sarcoma, prompting the 2014 FDA warning against morcellation in most women undergoing myomectomy/hysterectomy for presumed fibroids and subsequent ACOG guidance (Committee Opinion 822) on patient counseling and containment techniques (ACOG).

Morbidity/functional impact: Chronic heavy menstrual bleeding drives iron-deficiency anemia, fatigue, and substantial quality-of-life impairment; validated tools (UFS-QOL, SF-36, EQ-5D) show marked improvement with effective medical or surgical/procedural treatment.

Reproductive/obstetric prognosis: Fibroids — particularly cavity-distorting (submucosal) and large (≥9 cm) ones — are associated with infertility and recurrent pregnancy loss, and in pregnancy with increased risk of cesarean delivery (aOR 1.57), breech presentation (1.64), malposition (1.59), preterm delivery (1.45), placenta previa (1.86), and severe postpartum hemorrhage (2.57) (meta-analysis, PMC11071265). Fibroid size (not number) most strongly predicts breech presentation, postpartum hemorrhage, and placenta previa risk; fibroids ≥9 cm substantially raise antepartum/intrapartum/postpartum complication risk, sometimes prompting consideration of pre-conception myomectomy (PMC10051105; PubMed 39957710). Premature rupture of membranes, chorioamnionitis, and endomyometritis are not significantly associated.

Prognostic factors: Fibroid size, number, and (most importantly for reproductive outcomes) FIGO location relative to the endometrial cavity are the principal prognostic determinants for both symptom severity and obstetric risk.

12. Treatment

Treatment is stratified by symptom severity, fertility desire, fibroid size/location, and patient preference; no single first-line therapy fits all patients.

Pharmacotherapy: - Tranexamic acid and NSAIDs — symptomatic control of heavy menstrual bleeding without addressing tumor size (NCIT:C15986, Pharmacotherapy). - Combined oral contraceptives / progestin-only therapy / levonorgestrel-releasing IUS — bleeding control; the LNG-IUS has been directly compared to ulipristal acetate in the UCON trial (PMC10209678). - GnRH agonists (e.g., leuprolide) — induce hypoestrogenic state, shrink fibroids preoperatively; limited by menopausal side effects, generally short-term/preoperative use only. - Oral GnRH antagonists with hormonal add-back therapy — a major recent therapeutic advance: - Relugolix combination therapy (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg) — FDA-approved based on the LIBERTY 1 and 2 Phase 3 trials (770 participants) showing significant reduction in heavy menstrual bleeding vs. placebo (NEJM 2020, NEJMoa2008283); LIBERTY EXTENSION assessed long-term efficacy/safety. A 2024 observational study also evaluated 3-month preoperative relugolix combination therapy for AUB associated with myomas. - Elagolix combination therapy — evaluated in the Elaris trials (791 participants); FDA-approved for fibroid-associated heavy bleeding. - Linzagolix — evaluated in the PRIMROSE trials (1,012 participants); notable for a lower-dose regimen usable without mandatory add-back therapy in some patients; approved in Europe (PMC12327220). - A 2024 clinical pharmacology review specifically addresses practical implementation considerations for these oral GnRH antagonists in fibroid management (BJCP, bcp.15897). - Selective progesterone receptor modulators (SPRMs) — Ulipristal acetate was highly effective for bleeding/size reduction but its EMA marketing authorization was suspended (initially in 2020, amid rare but serious drug-induced liver injury signals) and its use is now restricted to women who cannot undergo surgery/embolization or who have exhausted other options, with mandatory liver monitoring (PubMed 40123751; PMC7686198, hepatotoxicity mechanism). Mifepristone has also been studied for symptomatic/size reduction with a more favorable but less-established safety profile (PMC11633070).

Interventional/surgical: - Myomectomy (hysteroscopic, laparoscopic, or open/abdominal) — fertility-sparing removal of fibroids; NCIT:C15329 (Surgical Procedure) with a more specific gynecologic-surgery term where available. - Hysterectomy — definitive treatment for those who have completed childbearing; most common major gynecologic surgery performed for fibroids in the U.S. - Uterine artery embolization (UAE) — interventional-radiology occlusion of the uterine arteries causing fibroid infarction; uterus-sparing, non-surgical alternative. - MRI-guided focused ultrasound surgery (MRgFUS/HIFU) — noninvasive thermal ablation using focused ultrasound with real-time MRI thermal feedback. A 7-year follow-up study found a 33.1% re-intervention rate over a median 6.1-year follow-up (PMC12055703); comparative literature indicates HIFU has shorter hospital stays and higher subsequent pregnancy rates than myomectomy/UAE but a higher re-intervention rate, with symptom/QOL improvement similar to myomectomy but somewhat lower than UAE (PMC8836878; PMC12081518). Ongoing Phase III comparison to myomectomy (NCT03948789) and robotic-guided HIFU feasibility studies were active as of 2025. - Radiofrequency ablation (laparoscopic or transcervical) — additional uterus-sparing option (not detailed in the searches above but standard in current practice guidelines).

Precision/pharmacogenomic angle: MED12 mutation status and CDK8 kinase-module activity have been shown to influence tumor growth trajectory and response to GnRH agonist treatment, suggesting a future genotype-informed treatment-selection paradigm (PMC12773822).

Experimental/clinical trials: Numerous registered trials on ClinicalTrials.gov for GnRH antagonist combination regimens, HIFU robotic systems, and SPRMs; representative NCT IDs include NCT03049735, NCT03103087, NCT03412890 (relugolix/LIBERTY program) and NCT03948789 (MRgFUS vs. myomectomy).

Treatment outcomes/adverse events: GnRH antagonist add-back regimens are generally well tolerated but require monitoring of bone mineral density with long-term use; ulipristal acetate's key adverse event of concern is rare but serious drug-induced liver injury; UAE carries risks of post-embolization syndrome and rare ovarian-reserve impact; myomectomy carries standard surgical risks plus fibroid recurrence risk; morcellation (laparoscopic or vaginal) carries the sarcoma-dissemination risk discussed in §11.

13. Prevention

Primary prevention: No established primary prevention protocol exists for the general population; risk-factor modification (maintaining healthy body weight, considering hormonal contraception which has protective associations, and correcting vitamin D deficiency) is discussed in the literature as plausible but not yet incorporated into formal public-health guidelines (PMC13167191 — vitamin D supplementation has clinical-trial evidence for reducing existing fibroid size/growth, e.g., NCT04030182, rather than pure primary prevention).
Secondary prevention/early detection: No population screening program exists; early detection relies on symptom-triggered pelvic ultrasound. Given racial disparities, some equity-focused guidance advocates earlier/more proactive symptom evaluation in Black women given their higher risk and earlier onset.
Genetic counseling: Recommended for suspected or confirmed HLRCC — genetic counseling and cascade testing of at-risk relatives given the autosomal-dominant inheritance and associated renal cell carcinoma risk; confirmed FH-mutation carriers undergo enhanced renal imaging surveillance protocols (per HLRCC-specific clinical management guidelines, PMC9430984; PMC11396326).
Tertiary prevention: Managing complications in established disease — anemia correction, pre-conception myomectomy for large/cavity-distorting fibroids to reduce obstetric complication risk, and vigilant surveillance/prompt evaluation of any rapidly enlarging mass to exclude sarcoma.
Prophylaxis: Not applicable in the vaccine/antimicrobial sense; hormonal contraceptive use functions as a de facto risk-reducing intervention for those already using it for other indications.

14. Other Species / Natural Disease

Taxonomy: Naturally occurring uterine leiomyoma is described in several domestic and companion species, though it is far less common than in humans; veterinary case reports exist in dogs, cats, and cattle (relevant NCBITaxon: 9615 Canis lupus familiaris, 9685 Felis catus, 9913 Bos taurus).
Comparative biology: The Eker rat (a specific strain, not a naturally occurring outbred disease in the wild, but arising from a spontaneous germline Tsc2 mutation identified decades ago) represents the closest natural-genetic analog, spontaneously developing uterine leiomyoma alongside renal tumors due to loss of the Tsc2 tumor suppressor — orthologous to human TSC2 (chromosome 16p13.3), though TSC2 is not a major human sporadic UL driver, limiting direct translational relevance despite mechanistic utility (ScienceDirect S0015028212024442).
Zoonotic potential: None; this is a non-infectious, hormonally-driven neoplastic process with no transmission risk.

15. Model Organisms

In vivo genetic/spontaneous models: - Eker rat: The most widely used spontaneous animal model, carrying a germline mutation in the Tsc2 tumor-suppressor gene, developing uterine leiomyoma (and leiomyosarcoma, renal tumors) with age; ELT3 cells (immortalized Eker-rat-derived leiomyoma cells) are a standard in vitro tool for mechanistic studies (e.g., the DES/vitamin D DNA-damage studies cited in §2b). However, because the driving mutation (Tsc2) does not correspond to the dominant human somatic drivers (MED12/HMGA2/FH), the model's translational fidelity to human sporadic UL is considered only partial, motivating alternative model development (PMC12967960, preclinical platform review).

Xenograft models: - NOD/SCID and NSG immunodeficient mouse xenografts: Human leiomyoma tissue or dissociated cells are implanted subcutaneously or under the kidney capsule of immunodeficient mice, often with supplemental estrogen/progesterone pellets to sustain hormone responsiveness and histological fidelity to the original tumor (ScienceDirect S0015028214001022; PMC5995841; Sci Rep s41598-018-27138-1). Kidney-capsule implantation in super-immunodeficient NSG mice is reported to better preserve native leiomyoma tissue characteristics than subcutaneous engraftment. - Patient-derived xenograft (PDX) models: Used for predictive/preclinical drug-response studies, allowing direct testing of candidate therapeutics against patient-specific tumor genotypes (PLOS ONE, journal.pone.0142429); PDX approaches have also specifically been applied to the FH-deficient leiomyoma subtype to study this molecular subclass in vivo (bioRxiv 2022.07.27.501688).

Model characteristics/limitations: - Xenografts recapitulate hormone-responsive growth and gross/microscopic histology reasonably well but require an immunodeficient host, precluding study of immune-microenvironment contributions. - The Eker rat captures spontaneous tumorigenesis and whole-organism biology (including gene-environment interactions) but is driven by a genetic lesion (Tsc2) not representative of the majority human molecular subtype. - No single model currently captures the full genetic heterogeneity (MED12/HMGA2/FH subtypes) of human disease within one system; a 2024 "preclinical research platform" review explicitly frames current model selection as a construction/optimization problem requiring subtype-matched model choice depending on the research question (PMC12967960).

Applications: These models are used to study hormone-driven growth, test GnRH-antagonist/SPRM/novel small-molecule efficacy preclinically, and dissect ECM/TGF-β pathway biology and DNA-damage/vitamin-D mechanisms in a controlled genetic background.

Suggested Ontology Term Summary

Category	Term IDs
Disease/MONDO	MONDO:0007886 (uterine leiomyoma); MONDO term for HLRCC (syndromic)
OMIM	#150699 (sporadic UL); #150800 (HLRCC)
HPO (phenotypes)	HP:0000132 (Menorrhagia), HP:0030318 (Pelvic pain), HP:0100608 (Dysmenorrhea), HP:0030068 (Dyspareunia), HP:0001891 (Iron deficiency anemia), HP:0000789 (Infertility), HP:0005268 (Recurrent miscarriage)
Genes (HGNC)	MED12 (hgnc:29305), HMGA2 (hgnc:5013), FH (hgnc:3700), TP53, ATM, TERT, TERC
GO (biological process)	GO:0016055 (Wnt signaling pathway), GO:0007179 (TGF-β receptor signaling pathway), GO:0001525 (angiogenesis)
CL (cell types)	CL:0002598 (myometrial smooth muscle cell), CL:0000057 (fibroblast), CL:0000115 (endothelial cell)
UBERON (anatomy)	UBERON:0000995 (uterus), UBERON:0001296 (myometrium), UBERON:0000459 (endometrium)
CHEBI (chemicals)	fumarate, kynurenine (drug agents: ulipristal acetate, relugolix, elagolix, linzagolix, tranexamic acid)
NCIT (treatments)	NCIT:C15986 (Pharmacotherapy), NCIT:C15329 (Surgical Procedure), NCIT:C15313 (Radiation Therapy, n/a here), device/ablation-specific terms for UAE/HIFU

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	49
Resolved	49
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	49
On topic	29
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	32
Resolved	29
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	21
Terms named correctly	11
Terms named as a different term	4
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0030318 (2 mentions) - the report calls it "Pelvic pain"; HP calls it Angular cheilitis
HP:0030068 (2 mentions) - the report calls it "Dyspareunia"; HP calls it Olfactory esthesioneuroblastoma
HP:0031801 (1 mention) - the report calls it "Abdominal mass"; HP calls it Vocal cord dysfunction
UBERON:0000459 (2 mentions) - the report calls it "endometrium"; UBERON calls it uterine wall

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

MONDO:0007886 (2 mentions) - the report calls it "uterine leiomyoma"; MONDO calls it uterine corpus leiomyoma, and lists "uterine leiomyoma" among its other names
HP:0100608 (2 mentions) - the report calls it "Dysmenorrhea"; HP calls it Metrorrhagia
HP:0005268 (2 mentions) - the report calls it "Recurrent miscarriage"; HP calls it Miscarriage
CL:0002598 (3 mentions) - the report calls it "myometrial smooth muscle cell"; CL calls it bronchial smooth muscle cell
UBERON:0001255 (1 mention) - the report calls it "urinary bladder, secondary"; UBERON calls it urinary bladder
UBERON:0002113 (1 mention) - the report calls it "kidney, HLRCC"; UBERON calls it kidney

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 46 citations 2026-06-22T11:24:42.262239

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Uterine Leiomyoma
MONDO ID: (if available)
Category: Complex

Research Objectives

Please provide a comprehensive research report on Uterine Leiomyoma covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

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Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

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Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

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Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
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Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

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Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

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Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

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Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

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Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

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Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

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Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

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Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

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Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

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Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

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Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

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Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
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Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

COMPREHENSIVE RESEARCH REPORT ON UTERINE LEIOMYOMA

Disease Characteristics Knowledge Base Entry

1. DISEASE INFORMATION

Overview and Definition

Uterine leiomyomas (also known as uterine fibroids or myomas) are the most common benign gynecological tumors affecting women of reproductive age (alali2023theetiopathogenesisof pages 1-2, bulun2025uterinefibroids pages 1-5). These tumors originate from the myometrial smooth muscle cells of the uterus and are characterized by monoclonal proliferation, excessive accumulation of extracellular matrix (ECM), and hormone-dependent growth (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3). The lifetime prevalence reaches 30–70% in the general population, with incidence rates as high as 70–80% by menopause (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, larrain2024newinsightsinto pages 1-3). Black women experience disproportionately higher rates, with prevalence exceeding 80% by age 50 compared to approximately 70% in White women (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2).

Key Identifiers

While specific OMIM numbers and comprehensive ontology identifiers were not fully detailed in the retrieved recent literature, uterine fibroids are classified using ICD-10 codes D25-D26.9 and D28.2 (zhang2025globalregionaland pages 1-2). The International Federation of Gynecology and Obstetrics (FIGO) classification system stratifies fibroids based on anatomical location into types 0–8 and hybrid categories (micic2024currentlyavailabletreatment pages 1-2).

Common Synonyms

Uterine leiomyomas
Uterine fibroids
Myomas
Leiomyomas

Data Source

The information is derived from aggregated disease-level resources including recent systematic reviews, epidemiological studies using Global Burden of Disease (GBD) data, molecular profiling studies, and large-scale genome-wide association studies (GWAS) published between 2023 and 2026 (alali2023theetiopathogenesisof pages 1-2, bulun2025uterinefibroids pages 1-5, tang2025theglobalburden pages 1-2, zhang2025globalregionaland pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2).

2. ETIOLOGY

Disease Causal Factors

Genetic Factors

Uterine leiomyomas have complex genetic architecture combining somatic driver mutations and heritable susceptibility:

Somatic Mutations (Tumor-Intrinsic): - MED12 mutations (exon 2) are the most common somatic driver, present in 50–80% of fibroids (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3). These heterozygous, gain-of-function mutations disrupt the CDK8 kinase module of the Mediator complex, affecting chromatin landscape, enhancer engagement, genomic stability, and responsiveness to progesterone (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3).

HMGA2/HMGA1 overexpression and rearrangements occur in approximately 10% of fibroids, defining a distinct molecular subtype with characteristic histopathologic features (bulun2025uterinefibroids pages 1-5, dundr2022uterinecellularleiomyomas pages 1-2).
FH (Fumarate Hydratase) deficiency characterizes FH-deficient leiomyomas and is associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, boos2025therolesof pages 1-2).
COL4A5/COL4A6 deletions, SRCAP complex mutations (causing H2A.Z deposition defects), and chromosome 1p deletions represent additional recurrent molecular subtypes (bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, dundr2022uterinecellularleiomyomas pages 1-2).

A detailed summary of genetic alterations is provided in the genetic mutations table below.

Gene Name / Alteration	Mutation Type	Frequency / Prevalence	Molecular Effects	Clinical Associations	Key References
MED12	Recurrent somatic exon 2 point mutations; typically heterozygous, gain-of-function–like driver alterations disrupting Mediator kinase module signaling	~50–80% of uterine fibroids; ~70% in several recent summaries; 77% in a large review	Disrupts MED12-dependent activation of CDK8/CDK19 within the Mediator complex; associated with altered chromatin landscape, enhancer engagement, genomic instability, progesterone responsiveness, and dysregulated WNT/β-catenin, hedgehog, sex steroid, and TGF-β signaling; transcriptomic enrichment for ECM/collagen pathways	Most common driver; often multiple tumors rather than solitary lesions; commonly seen even in small tumors; more frequent in Black women in some series; mutant tumors can differ in size/location and may show mutation-status–dependent response to GnRH agonists and ulipristal acetate	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
HMGA2 / HMGA1	Somatic overexpression and chromosomal rearrangements/fusions involving HMGA2/1	~10% of fibroids in recent overview; in cellular leiomyoma, HMGA2 overexpression was 36.5% and rearrangement 13.2%	Alters chromatin architecture and transcriptional programs; defines a molecular subtype distinct from MED12-mutant tumors	Associated with distinct histopathologic phenotypes; important subtype in usual leiomyoma and especially enriched in some variants such as cellular leiomyoma	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, dundr2022uterinecellularleiomyomas pages 1-2)
FH	Somatic or germline-related loss-of-function / deficiency; part of FH-deficient leiomyoma spectrum and HLRCC-related disease	Less common than MED12/HMGA2 in unselected fibroids; recognized recurrent subtype	Fumarate hydratase deficiency rewires metabolism and contributes to a distinct molecular subtype of leiomyoma	Seen in FH-deficient leiomyomas and in hereditary leiomyomatosis and renal cell cancer (HLRCC); clinically relevant for identifying syndromic disease	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, boos2025therolesof pages 1-2)
COL4A5 / COL4A6	Recurrent somatic deletions / structural alterations affecting collagen IV genes	Recurrent but uncommon relative to MED12; listed among frequently observed genetic alterations	Likely alters basement-membrane / ECM-related biology and contributes to subtype-specific tumor development	Included among recognized uterine fibroid driver alterations; may overlap with syndromic/structural subtypes rather than classic MED12 tumors	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, chuang2023differentialexpressionof pages 1-2)
SRCAP complex genes (e.g., YEATS4, ZNHIT1, other complex members)	Inactivating somatic mutations causing defective H2A.Z loading / chromatin remodeling abnormalities	Recently identified recurrent but uncommon subtype	Produces H2A.Z deposition defects and epigenetic dysregulation; supports a chromatin-based pathogenesis distinct from MED12 and HMGA2	Emerging molecular class of leiomyoma; potentially useful for future subtype-based diagnostics and therapy development	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Chromosome 1p deletion	Recurrent somatic copy-number loss	19.3% in a cellular leiomyoma series	Copy-number loss likely alters dosage of tumor-relevant genes on 1p; appears mutually exclusive with some other driver classes in variant tumors	Particularly reported in cellular leiomyoma; useful in variant classification and differential pathology	(dundr2022uterinecellularleiomyomas pages 1-2)
24 GWAS risk loci / heritable susceptibility variants (multiple genes including GREB1, MCM8 and broader target-gene sets)	Germline susceptibility SNPs / risk loci from population genetics	24 uterine-fibroid–associated risk loci identified in a 2024 integrative analysis; 394 potential target genes, 168 differentially expressed in tumors	Heritable risk variants map largely to noncoding regulatory regions and influence gene regulation through chromatin contacts, eQTL effects, and cell-type–specific regulatory programs	Explains familial aggregation and racial/population risk differences; points to causal cell types and potential preventive/targeted strategies rather than a single monogenic cause	(buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Non-coding RNA dysregulation linked to driver status (e.g., miR-21, miR-29, miR-200; H19, MIAT, XIST)	Secondary molecular alterations influenced by driver mutations, race/ethnicity, and hormones rather than classic coding mutations	Commonly dysregulated across fibroids; not a single frequency estimate	Regulates ECM production, proliferation, apoptosis, and inflammation; expression is influenced by MED12 mutation status and ovarian steroids	Potential biomarker and non-hormonal therapeutic layer; may help explain phenotypic heterogeneity and racial disparities	(boos2025therolesof pages 1-2)

Table: This table summarizes the principal genetic and molecular alterations implicated in uterine leiomyoma, emphasizing recurrent somatic drivers, inherited susceptibility loci, and their clinical relevance. It is useful for quickly comparing major subtypes, frequencies, and mechanistic consequences across the current evidence base.

Heritable Susceptibility: A 2024 integrative GWAS meta-analysis identified 24 uterine fibroid-associated risk loci potentially targeting 394 genes, of which 168 are differentially expressed in fibroid tumors (buyukcelebi2024integratingleiomyomagenetics pages 1-2). This heritable component explains familial aggregation, with first-degree relatives showing 2.5-fold elevated risk and higher concordance in monozygotic versus dizygotic twins (buyukcelebi2024integratingleiomyomagenetics pages 1-2).

Hormonal Factors

Estrogen and progesterone are essential for fibroid development and growth (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3, boos2025therolesof pages 1-2). Fibroids overexpress estrogen and progesterone receptors, and their growth is associated with ovulatory cycles and the first trimester of pregnancy (bulun2025uterinefibroids pages 1-5). Progesterone, via its nuclear receptor PGR, is particularly critical: it activates paracrine WNT signaling and production of growth factors that support fibroid stem cell proliferation (bulun2025uterinefibroids pages 1-5, larrain2024newinsightsinto pages 1-3). Fibroids rarely develop before menarche and often regress after menopause, underscoring steroid hormone dependence (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3).

Mechanistic Factors

Uterine leiomyomas arise from clonal expansion of a single mutated myometrial stem cell or transformed myometrial cell acquiring stem-like features (tumor-initiating cell, TIC) (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3). This initial genetic insult (e.g., MED12 mutation) transforms the cell, but additional factors—including hormonal signaling, paracrine interactions with surrounding differentiated cells, and ECM remodeling—are required for tumor progression (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3).

Risk Factors

A comprehensive summary of risk and protective factors is presented in the table below.

Factor Type	Specific Factor	Category	Strength of Association	Population-Specific Effects	Key Evidence
Risk	Advanced reproductive age	Reproductive	Consistently reported risk factor; incidence and symptom burden increase through reproductive years, especially ages 35–50	Burden concentrated in women aged 40–69 globally; common in reproductive-age women (tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2)	Listed as a risk factor in reviews; fibroids are most commonly found in women aged 35–50, and global burden is concentrated in ages 40–69 (koltsova2023aviewon pages 1-2, tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2)
Risk	Black/African ancestry	Genetic / population	Strong and repeatedly reported association	By age 50, prevalence reaches >80% in Black women vs ~70% overall/White women; disproportionate incidence and severity (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2)	Reviews and genomic studies report substantially higher prevalence and burden in Black women (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2)
Risk	Latin American ethnicity	Population	Reported association, but less extensively quantified than Black ancestry	Mentioned as increased-risk population in review literature	Identified among risk factors in heterogeneity-focused review (koltsova2023aviewon pages 1-2)
Risk	Family history of uterine leiomyoma	Genetic	Moderate-to-strong; familial aggregation repeatedly reported	First-degree relatives have elevated risk; reflects heritable susceptibility	Review identifies family history as a risk factor; GWAS/integrative genetics supports heritable contribution and multiple susceptibility loci (koltsova2023aviewon pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Risk	Germline/heritable susceptibility loci	Genetic	Strong biologic evidence for susceptibility, but effect sizes vary by locus	May contribute to racial/population differences in risk	Integrative 2024 analysis identified 24 UF-associated risk loci and 394 candidate target genes, supporting inherited susceptibility (buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Risk	MED12-associated predisposition to specific tumor biology	Genetic / molecular	Strong for tumor subtype biology rather than disease initiation alone	MED12-mutant tumors are more frequent in Black women in some series and often multiple	MED12 mutations are the dominant driver in many tumors and are associated with distinct biology and multiplicity (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3)
Risk	Early menarche	Reproductive	Consistently reported risk factor	No specific population restriction given, but may interact with lifetime hormonal exposure	Included as a risk factor in multiple reviews and diagnostic overview (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Late menopause	Reproductive	Reported risk factor, likely reflecting prolonged estrogen/progesterone exposure	Not specifically stratified	Included in etiopathogenesis overview figure/discussion (alali2023theetiopathogenesisof pages 1-2)
Risk	Nulliparity / low parity	Reproductive	Consistently reported risk factor	Protective effect of multiparity implies higher risk in nulliparous women	Nulliparity or absence of parity is reported as a risk factor; several reviews note multiparity as protective (buyukcelebi2024integratingleiomyomagenetics pages 1-2, larrain2024newinsightsinto pages 1-3)
Protective	Multiparity / parity	Reproductive	Consistently reported protective factor	Not population-specific, though effect may vary with reproductive history	Multiparity/parity reported as protective in reviews and diagnostic narrative (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Risk	Obesity / high BMI	Lifestyle / metabolic	Strong and consistently reported	Important in many populations; cited in epidemiologic and mechanistic reviews	Obesity repeatedly listed among major risk factors and linked to symptomatic disease burden (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Diabetes	Metabolic	Reported association	Not specifically stratified	Included among factors involved in incidence/development in clinician-friendly review (larrain2024newinsightsinto pages 1-3)
Risk	Arterial hypertension	Metabolic / vascular	Repeatedly reported association	Not specifically stratified	Identified as a risk factor in heterogeneity/risk-factor review and clinician review (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Chronic inflammation	Environmental / biologic	Reported association with plausible mechanistic support	Not specifically stratified	Listed as a risk factor in review of UL genesis; inflammation also emphasized mechanistically in fibroid biology (koltsova2023aviewon pages 1-2, boos2025therolesof pages 1-2)
Risk	Sexually transmitted infections	Infectious	Reported association, evidence less mature than hormonal/metabolic factors	Not specifically stratified	Identified as a possible risk factor in review of risk/protective factors (koltsova2023aviewon pages 1-2)
Risk	Exposure to xenoestrogens in early ontogenesis	Environmental	Biologically plausible and reported in review literature	Suggests early-life vulnerability window	Reported as a risk factor in review of UL genesis (koltsova2023aviewon pages 1-2)
Risk	Diethylstilbestrol (DES) exposure	Environmental	Reported association	Not specifically stratified	Included among environmental contributors in clinician-friendly molecular review (larrain2024newinsightsinto pages 1-3)
Risk	Air pollution	Environmental	Reported association	Not specifically stratified	Mentioned among factors potentially involved in incidence/development (larrain2024newinsightsinto pages 1-3)
Risk	Alcohol consumption	Lifestyle	Repeatedly reported risk factor	Not specifically stratified	Alcohol listed as a risk factor in heterogeneity review and clinician-friendly review (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Caffeine	Lifestyle	Reported in one review/figure; likely weaker evidence than alcohol/obesity	Not specifically stratified	Included in etiopathogenesis figure as a potential risk factor (alali2023theetiopathogenesisof pages 1-2)
Risk	Chronic stress	Lifestyle / psychosocial	Reported association	Not specifically stratified	Listed in diagnostic review as a risk factor (centini2024tailoringthediagnostic pages 1-2)
Risk	Vitamin D deficiency	Environmental / nutritional	Repeatedly reported association with supportive mechanistic rationale	Not specifically stratified; may be relevant in populations with higher deficiency prevalence	Vitamin D deficiency is listed among known factors influencing fibroid development in recent reviews (alali2023theetiopathogenesisof pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3)
Protective	Adequate vitamin D status	Nutritional	Implied protective factor from repeated deficiency-risk association; preclinical support exists	Not specifically stratified	Since deficiency is repeatedly associated with risk, adequate status is plausibly protective; some model literature supports anti-fibroid effects (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	High-fat diet / adverse dietary factors	Lifestyle / nutritional	Reported association	Not specifically stratified	High-fat diet and dietary factors are mentioned as contributing to incidence/development (larrain2024newinsightsinto pages 1-3)
Protective	Oral contraceptive use / combined oral contraceptives	Reproductive / hormonal	Reported protective factor in review literature, though literature historically mixed	Not specifically stratified	Oral contraceptive intake and combined oral contraceptives are listed among possible protective factors in recent reviews (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Protective	Smoking	Lifestyle	Reported as a possible protective factor in reviews, but likely outweighed by broader health harms	Not population-specific; not a recommended prevention strategy	Smoking is listed among possible protective factors in one recent review even though it is not clinically recommended (koltsova2023aviewon pages 1-2)
Risk	Hormonal milieu: higher estradiol and progesterone exposure	Hormonal / mechanistic	Strong mechanistic support	Relevant across reproductive-age populations; explains premenopausal predominance	Risk/severity associated with serum estradiol and progesterone; tumors are steroid-dependent and rarely develop before menarche (buyukcelebi2024integratingleiomyomagenetics pages 1-2, ishikawa2023risingstarsrole pages 1-3)
Protective	Postmenopausal state / menopause-associated regression	Reproductive / hormonal	Strong observational pattern	Applies broadly; many fibroids regress after menopause	Fibroids frequently regress after menopause, supporting reduced ovarian steroid exposure as protective against persistence/growth (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
Risk	Reproductive delay / postponed childbearing	Reproductive	Epidemiologically plausible; discussed in population-burden review	Relevant in regions with delayed childbearing patterns	Population review links changing reproductive patterns, including postponed childbearing, to increasing prevalence (zhang2025globalregionaland pages 1-2)

Table: This table summarizes reported risk and protective factors for uterine leiomyoma across recent reviews and epidemiologic/genetic studies. It organizes the factors by category, indicates the qualitative strength of association, and notes population-specific patterns where available.

Genetic Risk Factors: - Family history of fibroids (koltsova2023aviewon pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2) - Black/African ancestry (highest risk and severity) (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2) - Latin American ethnicity (koltsova2023aviewon pages 1-2) - Multiple GWAS-identified susceptibility loci (buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Environmental and Lifestyle Risk Factors: - Early menarche, nulliparity, late menopause (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, larrain2024newinsightsinto pages 1-3) - Obesity and high BMI (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3) - Diabetes and arterial hypertension (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3) - Vitamin D deficiency (alali2023theetiopathogenesisof pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3) - Alcohol consumption, high-fat diet (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3) - Chronic stress and chronic inflammation (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2) - Exposure to xenoestrogens (e.g., diethylstilbestrol, DES), air pollution (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3) - Sexually transmitted infections (koltsova2023aviewon pages 1-2)

Advanced Age: Reproductive age 35–50 years represents peak incidence (koltsova2023aviewon pages 1-2, tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2).

Protective Factors

Genetic Protective Factors: Although specific protective genetic variants are not well-defined, the presence of certain alleles at GWAS loci may modulate risk (buyukcelebi2024integratingleiomyomagenetics pages 1-2).

Environmental/Lifestyle Protective Factors: - Multiparity/parity (consistently protective) (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2) - Combined oral contraceptive use (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2) - Adequate vitamin D status (implied by deficiency being a risk factor) (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2, larrain2024newinsightsinto pages 1-3) - Postmenopausal state (fibroids often regress after menopause) (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3) - Smoking (paradoxically listed as protective in some reviews, though not clinically recommended) (koltsova2023aviewon pages 1-2)

Gene-Environment Interactions

MED12 mutation status, race/ethnicity, and ovarian steroid hormones influence the expression of non-coding RNAs (ncRNAs) such as miRNAs, lncRNAs, and circRNAs, which regulate ECM production, cell proliferation, apoptosis, and inflammation in fibroids (boos2025therolesof pages 1-2). This represents a complex gene-environment interaction where genetic drivers (MED12 mutations), population ancestry, and hormonal milieu converge to shape tumor biology and phenotypic heterogeneity (chuang2023differentialexpressionof pages 1-2, boos2025therolesof pages 1-2).

3. PHENOTYPES

Clinical Presentations

Approximately 70–80% of women with fibroids remain asymptomatic, with clinical manifestations occurring in 20–30% of cases (alali2023theetiopathogenesisof pages 1-2, centini2024tailoringthediagnostic pages 1-2). Symptomatic presentations vary widely depending on fibroid size, number, and location.

Common Symptoms and Signs:

Abnormal Uterine Bleeding (AUB) and Heavy Menstrual Bleeding (HMB)
Type: Symptom
Characteristics: Most common symptom; classified as AUB-L (AUB-Leiomyoma) by FIGO (vannuccini2024themodernmanagement pages 1-5). Heavy menstrual bleeding interferes with physical, social, emotional, and material quality of life (vannuccini2024themodernmanagement pages 1-5). Submucosal fibroids particularly cause bleeding (centini2024tailoringthediagnostic pages 1-2).
Age of Onset: Reproductive age, especially 35–50 years
Severity: Variable from mild to severe anemia-inducing
Progression: Can worsen over time if untreated
Frequency: Approximately 30% of women with fibroids; AUB/HMB is a major determinant of stress and reduced quality of life (vannuccini2024themodernmanagement pages 1-5)
HPO Term Suggestion: HP:0000132 (Menorrhagia), HP:0001892 (Abnormal bleeding tendency)
Pelvic Pain and Dysmenorrhea
Type: Symptom
Characteristics: Pelvic heaviness, pressure, pain, and dysmenorrhea (alali2023theetiopathogenesisof pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Severity: Mild to severe
HPO Term Suggestion: HP:0000131 (Dysmenorrhea), HP:0100602 (Pelvic pain)
Pelvic Pressure and Bulk Symptoms
Type: Physical manifestation
Characteristics: Pressure on adjacent organs causing constipation, urinary dysfunction, and abdominal distension (alali2023theetiopathogenesisof pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Severity: Depends on fibroid size and location
HPO Term Suggestion: HP:0100594 (Urinary dysfunction), HP:0002019 (Constipation)
Iron Deficiency and Iron Deficiency Anemia (IDA)
Type: Laboratory abnormality
Characteristics: Consequence of chronic blood loss from HMB (vannuccini2024themodernmanagement pages 1-5)
Severity: Variable; can be severe and symptomatic
HPO Term Suggestion: HP:0001891 (Iron deficiency anemia)
Reproductive Dysfunction
Type: Clinical manifestation
Characteristics: Infertility, recurrent pregnancy loss, preterm labor, defective embryo implantation, obstruction of labor (alali2023theetiopathogenesisof pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Frequency: Variable; associated with fibroid location and size
HPO Term Suggestion: HP:0000789 (Infertility), HP:0200067 (Recurrent spontaneous abortion), HP:0001622 (Preterm birth)

Quality of Life Impact

Symptomatic uterine fibroids profoundly reduce quality of life (QoL) and decrease labor productivity (ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5). Women with HMB as the primary complaint experience significantly higher direct healthcare costs and perceived stress (vannuccini2024themodernmanagement pages 1-5). The disease impacts physical, social, emotional, and material well-being (vannuccini2024themodernmanagement pages 1-5). Annual costs in the United States range from $5.9 billion to $34.4 billion (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2).

4. GENETIC/MOLECULAR INFORMATION

Causal Genes and Pathogenic Variants

The comprehensive genetic mutations table summarizes causal genes and variants:

Gene Name / Alteration	Mutation Type	Frequency / Prevalence	Molecular Effects	Clinical Associations	Key References
MED12	Recurrent somatic exon 2 point mutations; typically heterozygous, gain-of-function–like driver alterations disrupting Mediator kinase module signaling	~50–80% of uterine fibroids; ~70% in several recent summaries; 77% in a large review	Disrupts MED12-dependent activation of CDK8/CDK19 within the Mediator complex; associated with altered chromatin landscape, enhancer engagement, genomic instability, progesterone responsiveness, and dysregulated WNT/β-catenin, hedgehog, sex steroid, and TGF-β signaling; transcriptomic enrichment for ECM/collagen pathways	Most common driver; often multiple tumors rather than solitary lesions; commonly seen even in small tumors; more frequent in Black women in some series; mutant tumors can differ in size/location and may show mutation-status–dependent response to GnRH agonists and ulipristal acetate	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
HMGA2 / HMGA1	Somatic overexpression and chromosomal rearrangements/fusions involving HMGA2/1	~10% of fibroids in recent overview; in cellular leiomyoma, HMGA2 overexpression was 36.5% and rearrangement 13.2%	Alters chromatin architecture and transcriptional programs; defines a molecular subtype distinct from MED12-mutant tumors	Associated with distinct histopathologic phenotypes; important subtype in usual leiomyoma and especially enriched in some variants such as cellular leiomyoma	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, dundr2022uterinecellularleiomyomas pages 1-2)
FH	Somatic or germline-related loss-of-function / deficiency; part of FH-deficient leiomyoma spectrum and HLRCC-related disease	Less common than MED12/HMGA2 in unselected fibroids; recognized recurrent subtype	Fumarate hydratase deficiency rewires metabolism and contributes to a distinct molecular subtype of leiomyoma	Seen in FH-deficient leiomyomas and in hereditary leiomyomatosis and renal cell cancer (HLRCC); clinically relevant for identifying syndromic disease	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, boos2025therolesof pages 1-2)
COL4A5 / COL4A6	Recurrent somatic deletions / structural alterations affecting collagen IV genes	Recurrent but uncommon relative to MED12; listed among frequently observed genetic alterations	Likely alters basement-membrane / ECM-related biology and contributes to subtype-specific tumor development	Included among recognized uterine fibroid driver alterations; may overlap with syndromic/structural subtypes rather than classic MED12 tumors	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, chuang2023differentialexpressionof pages 1-2)
SRCAP complex genes (e.g., YEATS4, ZNHIT1, other complex members)	Inactivating somatic mutations causing defective H2A.Z loading / chromatin remodeling abnormalities	Recently identified recurrent but uncommon subtype	Produces H2A.Z deposition defects and epigenetic dysregulation; supports a chromatin-based pathogenesis distinct from MED12 and HMGA2	Emerging molecular class of leiomyoma; potentially useful for future subtype-based diagnostics and therapy development	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Chromosome 1p deletion	Recurrent somatic copy-number loss	19.3% in a cellular leiomyoma series	Copy-number loss likely alters dosage of tumor-relevant genes on 1p; appears mutually exclusive with some other driver classes in variant tumors	Particularly reported in cellular leiomyoma; useful in variant classification and differential pathology	(dundr2022uterinecellularleiomyomas pages 1-2)
24 GWAS risk loci / heritable susceptibility variants (multiple genes including GREB1, MCM8 and broader target-gene sets)	Germline susceptibility SNPs / risk loci from population genetics	24 uterine-fibroid–associated risk loci identified in a 2024 integrative analysis; 394 potential target genes, 168 differentially expressed in tumors	Heritable risk variants map largely to noncoding regulatory regions and influence gene regulation through chromatin contacts, eQTL effects, and cell-type–specific regulatory programs	Explains familial aggregation and racial/population risk differences; points to causal cell types and potential preventive/targeted strategies rather than a single monogenic cause	(buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Non-coding RNA dysregulation linked to driver status (e.g., miR-21, miR-29, miR-200; H19, MIAT, XIST)	Secondary molecular alterations influenced by driver mutations, race/ethnicity, and hormones rather than classic coding mutations	Commonly dysregulated across fibroids; not a single frequency estimate	Regulates ECM production, proliferation, apoptosis, and inflammation; expression is influenced by MED12 mutation status and ovarian steroids	Potential biomarker and non-hormonal therapeutic layer; may help explain phenotypic heterogeneity and racial disparities	(boos2025therolesof pages 1-2)

Table: This table summarizes the principal genetic and molecular alterations implicated in uterine leiomyoma, emphasizing recurrent somatic drivers, inherited susceptibility loci, and their clinical relevance. It is useful for quickly comparing major subtypes, frequencies, and mechanistic consequences across the current evidence base.

MED12 (Mediator Complex Subunit 12): - OMIM/HGNC: MED12 gene located on chromosome Xq13.1 - Variant Type: Somatic exon 2 point mutations (typically codon 44 region); gain-of-function, driver mutations - Frequency: 50–80% of fibroids (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3, boos2025therolesof pages 1-2) - Functional Consequences: Disrupts CDK8/CDK19 kinase module activity; impairs Mediator kinase function; dysregulates WNT/β-catenin, TGF-β, hedgehog, and sex steroid signaling; alters chromatin landscape and enhancer-promoter interactions; increases genomic instability; enhances progesterone responsiveness (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3) - Clinical Associations: More frequent in Black women; commonly observed in small tumors; associated with multiple rather than solitary fibroids; mutation-dependent response to GnRH agonists and ulipristal acetate (ishikawa2023risingstarsrole pages 1-3)

HMGA2/HMGA1 (High Mobility Group AT-hook 2/1): - Variant Type: Somatic chromosomal rearrangements, fusions, and overexpression - Frequency: ~10% overall; higher in cellular leiomyoma variants (bulun2025uterinefibroids pages 1-5, dundr2022uterinecellularleiomyomas pages 1-2) - Functional Consequences: Alters chromatin architecture and transcriptional programs; defines distinct molecular subtype - Clinical Associations: Distinct histopathologic phenotype; enriched in cellular leiomyoma (dundr2022uterinecellularleiomyomas pages 1-2)

FH (Fumarate Hydratase): - Variant Type: Somatic or germline loss-of-function mutations - Functional Consequences: Metabolic reprogramming; distinct molecular subtype - Clinical Associations: FH-deficient leiomyomas; hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2)

COL4A5/COL4A6 (Collagen Type IV Alpha 5/6): - Variant Type: Somatic deletions and structural alterations - Functional Consequences: Altered basement membrane/ECM biology (bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2)

SRCAP Complex Genes (YEATS4, ZNHIT1): - Variant Type: Inactivating somatic mutations - Functional Consequences: Defective H2A.Z histone variant loading; chromatin remodeling abnormalities; epigenetic dysregulation (bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Chromosome 1p Deletion: - Variant Type: Recurrent somatic copy-number loss - Frequency: 19.3% in cellular leiomyoma series (dundr2022uterinecellularleiomyomas pages 1-2)

Modifier Genes

The 24 GWAS-identified risk loci implicate 394 candidate genes, of which 168 are differentially expressed in tumors (buyukcelebi2024integratingleiomyomagenetics pages 1-2). These likely represent modifier loci influencing susceptibility, tumor multiplicity, and phenotypic variability.

Epigenetic Information

DNA Methylation: MED12-mutant fibroids exhibit distinct DNA methylomes compared to wild-type tumors (ishikawa2023risingstarsrole pages 1-3). Aberrant DNA methylation patterns contribute to altered gene expression profiles regulating ECM organization, cell proliferation, and steroid hormone responsiveness (chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3).

Histone Modifications: SRCAP complex mutations result in deficient H2A.Z deposition, causing chromatin-based pathogenesis distinct from MED12/HMGA2 subtypes (bulun2025uterinefibroids pages 1-5). Alterations in histone modifications affect enhancer-promoter interactions and gene regulatory programs (bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2).

Non-Coding RNAs: Dysregulated miRNAs (miR-21, miR-29, miR-200), lncRNAs (H19, MIAT, XIST), and circRNAs act as epigenetic regulators controlling ECM production, cell proliferation, apoptosis, and inflammation (boos2025therolesof pages 1-2). Expression is influenced by MED12 mutation status, race/ethnicity, and ovarian steroids (boos2025therolesof pages 1-2).

Chromosomal Abnormalities

Chromosome 1p deletions (dundr2022uterinecellularleiomyomas pages 1-2)
HMGA2 chromosomal rearrangements and fusions (bulun2025uterinefibroids pages 1-5, dundr2022uterinecellularleiomyomas pages 1-2)
COL4A5/COL4A6 deletions (bulun2025uterinefibroids pages 1-5)

Allele Frequency and Origin

Somatic mutations (MED12, HMGA2, FH) are tumor-specific and not present in germline DNA (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3). Allele frequencies in population databases for germline GWAS risk variants vary by locus and population ancestry (buyukcelebi2024integratingleiomyomagenetics pages 1-2). FH germline mutations in HLRCC syndrome represent an exception where inherited pathogenic variants predispose to multiple fibroids and renal cell carcinoma (bulun2025uterinefibroids pages 1-5).

5. ENVIRONMENTAL INFORMATION

Environmental Factors

Xenoestrogen exposure in early life (koltsova2023aviewon pages 1-2)
Diethylstilbestrol (DES) exposure (larrain2024newinsightsinto pages 1-3)
Air pollution (larrain2024newinsightsinto pages 1-3)

Lifestyle Factors

Smoking (paradoxically protective but not recommended) (koltsova2023aviewon pages 1-2)
Diet: High-fat diet increases risk; adequate vitamin D may be protective (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2, larrain2024newinsightsinto pages 1-3)
Alcohol consumption (risk factor) (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)
Obesity and physical activity patterns (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2)
Chronic stress (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)

Infectious Agents

Sexually transmitted infections are reported as potential risk factors, though the mechanism is less well-defined than hormonal/metabolic factors (koltsova2023aviewon pages 1-2).

6. MECHANISM / PATHOPHYSIOLOGY

Molecular Pathways

WNT/β-Catenin Signaling: Progesterone stimulates secretion of WNT ligands from mature myometrial and leiomyoma cells, inducing nuclear translocation of β-catenin in fibroid stem cells, promoting proliferation and ECM accumulation (larrain2024newinsightsinto pages 1-3). MED12 mutations enhance WNT/β-catenin pathway activation (ishikawa2023risingstarsrole pages 1-3, larrain2024newinsightsinto pages 1-3).

TGF-β Signaling: Dysregulated TGF-β signaling promotes ECM production (particularly fibronectin and collagen), cell proliferation, and fibrosis (chuang2023differentialexpressionof pages 1-2, larrain2024newinsightsinto pages 1-3). TGF-β3 is upregulated via WNT signaling (larrain2024newinsightsinto pages 1-3).

Progesterone and Estrogen Signaling: Progesterone (via PGR) is essential for fibroid growth, acting through paracrine mechanisms on stem cells (bulun2025uterinefibroids pages 1-5, larrain2024newinsightsinto pages 1-3). Estrogen enables progesterone action (bulun2025uterinefibroids pages 1-5). DNA methylation regulates PGR expression and responsiveness (bulun2025uterinefibroids pages 1-5).

Hedgehog Pathway: Dysregulated in MED12-mutant fibroids (chuang2023differentialexpressionof pages 1-2).

AKT/PI3K and Oxidative Stress: AKT activation and oxidative stress pathways contribute to fibroid pathogenesis (bulun2025uterinefibroids pages 1-5).

Cellular Processes

Cell Proliferation: Driven by stem cell expansion and paracrine growth factor signaling (bulun2025uterinefibroids pages 1-5, larrain2024newinsightsinto pages 1-3)
Apoptosis Dysregulation: Reduced apoptosis contributes to tumor persistence (boos2025therolesof pages 1-2)
Inflammation: Upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ) drives DNA damage, epigenetic alterations, and tumorigenesis (boos2025therolesof pages 1-2)
ECM Remodeling: Excessive deposition of collagen, fibronectin, and proteoglycans creates fibroid bulk; ECM organization genes are upregulated, especially in MED12-mutant tumors (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
Cell Cycle Dysregulation: Aberrant expression of cell cycle regulators (boos2025therolesof pages 1-2)

Gene Ontology (GO) Terms: - GO:0030198 (extracellular matrix organization) - GO:0008283 (cell proliferation) - GO:0006915 (apoptotic process) - GO:0006954 (inflammatory response) - GO:0007049 (cell cycle)

Protein Dysfunction

MED12 Protein: Mutant MED12 disrupts CDK8/CDK19 stimulatory activity and alters chromatin-associated transcriptional regulation (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3).

HMGA2 Protein: Overexpressed HMGA2 alters chromatin structure and transcriptional programs (bulun2025uterinefibroids pages 1-5).

Fumarate Hydratase (FH): Loss of FH activity causes metabolic reprogramming (bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2).

Metabolic Changes

FH-deficient leiomyomas exhibit rewired metabolism due to fumarate hydratase loss (bulun2025uterinefibroids pages 1-5). Oxidative stress and altered energy metabolism are implicated in pathogenesis (bulun2025uterinefibroids pages 1-5).

Immune System Involvement

Chronic inflammation with upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ) is a hallmark of fibroid pathogenesis (boos2025therolesof pages 1-2). Inflammatory pathways drive DNA damage and epigenetic changes, promoting tumorigenesis (boos2025therolesof pages 1-2).

Tissue Damage Mechanisms

Ischemia/hypoxia within tumor microenvironment (ishikawa2023risingstarsrole pages 1-3, larrain2024newinsightsinto pages 1-3)
Fibrosis from excessive ECM deposition (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3)
Vascular abnormalities and angiogenesis dysregulation (vannuccini2024themodernmanagement pages 1-5)

Molecular Profiling

Transcriptomics: MED12-mutant tumors show 394 genes differentially expressed compared to matched myometrium, predominantly involved in ECM regulation (chuang2023differentialexpressionof pages 1-2). Distinct transcriptomic profiles differentiate MED12-mutant from wild-type fibroids (chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3).

Epigenomics: Distinct DNA methylomes and histone modification patterns characterize molecular subtypes (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3).

Single-Cell Transcriptomics: Integrative single-cell analysis reveals causal cell types with aberrant target gene expression linked to GWAS risk loci (buyukcelebi2024integratingleiomyomagenetics pages 1-2).

Cell Types Involved: - Myometrial smooth muscle stem cells (tumor-initiating cells) - Differentiated smooth muscle cells - Tumor-associated fibroblasts - Vascular smooth muscle cells - Myofibroblasts

Cell Ontology (CL) Terms: - CL:0000192 (smooth muscle cell) - CL:0000057 (fibroblast) - CL:0002548 (fibroblast of the uterus)

7. ANATOMICAL STRUCTURES AFFECTED

Organ Level

Primary Organ: - Uterus (specifically myometrium) (UBERON:0000995 uterus)

Secondary Organ Involvement: - Endometrium (affected by submucosal fibroids causing bleeding) (UBERON:0001295 endometrium) - Bladder (pressure symptoms) (UBERON:0001255 urinary bladder) - Rectum (constipation) (UBERON:0001052 rectum) - Reproductive tract complications (fallopian tube compression, cervical distortion)

Body Systems Involved: - Female reproductive system - Urinary system (secondary bulk effects) - Gastrointestinal system (secondary bulk effects) - Hematologic system (anemia from bleeding)

Tissue and Cell Level

Tissue Types: - Smooth muscle tissue (myometrium) - Connective tissue (excessive ECM)

Cell Populations: - Myometrial smooth muscle stem cells (CL:0000192) - Differentiated smooth muscle cells (CL:0000192) - Fibroblasts (CL:0000057, CL:0002548) - Vascular smooth muscle cells - Myofibroblasts - Telocytes (interstitial cells forming contacts with smooth muscle and stem cells) (koltsova2023aviewon pages 1-2)

Subcellular Level

Cellular Compartments: - Nucleus (transcriptional dysregulation, chromatin remodeling) (GO:0005634 nucleus) - Cytoplasm (signaling pathway activation) - Extracellular matrix (excessive deposition) (GO:0031012 extracellular matrix) - Chromatin (altered landscape in MED12-mutant tumors) (GO:0000785 chromatin)

Localization

FIGO Classification by Anatomical Site: - Type 0: Pedunculated intracavitary - Type 1: <50% intramural - Type 2: ≥50% intramural - Type 3: 100% intramural; contacts endometrium - Type 4: Intramural - Type 5: Subserosal ≥50% intramural - Type 6: Subserosal <50% intramural - Type 7: Subserosal pedunculated - Type 8: Other (cervical, parasitic) - Hybrid: Submucous and subserous (micic2024currentlyavailabletreatment pages 1-2)

Lateralization: Typically bilateral distribution within the uterus, though individual fibroids can be unilateral or asymmetric (alali2023theetiopathogenesisof pages 1-2).

8. TEMPORAL DEVELOPMENT

Onset

Age of Onset: - Rarely develop before menarche (ishikawa2023risingstarsrole pages 1-3) - Most commonly diagnosed in reproductive age women, especially 35–50 years (koltsova2023aviewon pages 1-2, tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2) - Prevalence increases with age through reproductive years

Onset Pattern: - Insidious and gradual; often asymptomatic initially (alali2023theetiopathogenesisof pages 1-2, centini2024tailoringthediagnostic pages 1-2)

Progression

Disease Course: - Variable growth rates; some fibroids grow rapidly, others remain stable or regress (larrain2024newinsightsinto pages 1-3) - Multiple tumors within the same uterus are not clonally related and grow independently (larrain2024newinsightsinto pages 1-3) - Progression influenced by hormonal milieu, mutation status, and patient-specific factors

Disease Duration: - Chronic, lifelong presence through reproductive years - Often regress after menopause due to decreased ovarian steroid production (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3)

Patterns

Remission: - Spontaneous regression common after menopause (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3) - Treatment-induced shrinkage with GnRH agonists/antagonists, but rebound growth after discontinuation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)

Critical Periods: - Reproductive years with ovulatory cycles (high estrogen/progesterone exposure) - Pregnancy (first trimester growth stimulus) (bulun2025uterinefibroids pages 1-5) - Menopause (regression window)

9. INHERITANCE AND POPULATION

Epidemiology

Prevalence: - Lifetime prevalence: 30–70% (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2) - By age 50: >70% overall, >80% in Black women (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2) - In 2021, age-standardized prevalence rate (ASPR): 2,841.07 per 100,000 (tang2025theglobalburden pages 1-2)

Incidence: - Age-standardized incidence rate (ASIR) in 2021: 250.93 per 100,000 (tang2025theglobalburden pages 1-2) - Incidence increasing globally from 1990 to 2021 (tang2025theglobalburden pages 1-2, zhang2025globalregionaland pages 1-2)

Inheritance (for Genetic Etiology)

Inheritance Pattern: - Multifactorial and polygenic susceptibility for sporadic fibroids (buyukcelebi2024integratingleiomyomagenetics pages 1-2) - Autosomal dominant for HLRCC syndrome (germline FH mutations) (bulun2025uterinefibroids pages 1-5)

Penetrance: - Variable and incomplete for heritable susceptibility loci (buyukcelebi2024integratingleiomyomagenetics pages 1-2) - High penetrance for HLRCC-related fibroids (bulun2025uterinefibroids pages 1-5)

Expressivity: - Variable; influenced by hormonal exposure, lifestyle, and modifier genes (buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Family History: - First-degree relatives have 2.5-fold elevated risk (buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Population Demographics

Affected Populations: - Black/African-American women: highest prevalence and severity (>80% by age 50) (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2) - Latin American women: elevated risk (koltsova2023aviewon pages 1-2) - All racial/ethnic groups affected, but significant disparities exist

Geographic Distribution: - Global distribution with higher burden in higher SDI (Socio-Demographic Index) regions for uterine fibroids, though lower SDI regions have higher burden for some gynecologic conditions (tang2025theglobalburden pages 1-2) - Increasing incidence in countries like Brazil, India, and Georgia (zhang2025globalregionaland pages 1-2)

Sex Ratio: - Female-only disease

Age Distribution: - Peak ages 40–69 years globally for symptomatic burden (tang2025theglobalburden pages 1-2) - Most commonly diagnosed 35–50 years (koltsova2023aviewon pages 1-2, micic2024currentlyavailabletreatment pages 1-2)

10. DIAGNOSTICS

Clinical Tests

Laboratory Tests: - Complete blood count (CBC) to assess anemia from HMB (vannuccini2024themodernmanagement pages 1-5) - Iron studies (ferritin, serum iron, TIBC) for iron deficiency evaluation (vannuccini2024themodernmanagement pages 1-5) - Hormone levels (estradiol, progesterone) if clinically indicated (buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Biomarkers: - No widely established serum biomarkers for routine diagnosis - Emerging multi-omics biomarkers under investigation (vannuccini2024themodernmanagement pages 1-5)

Imaging Studies: - Transvaginal Ultrasound (TVS): First-line imaging; detects presence, size, number, and location of fibroids (centini2024tailoringthediagnostic pages 1-2) - Sonohysterography: Enhanced visualization of intracavitary lesions (centini2024tailoringthediagnostic pages 1-2) - Magnetic Resonance Imaging (MRI): Gold standard for detailed anatomical characterization, differential diagnosis, and treatment planning; particularly useful for HIFU treatment planning and predicting regrowth (centini2024tailoringthediagnostic pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Contrast-Enhanced MRI (CE-MRI): Predicts residual fibroid regrowth post-HIFU; signal intensity ratios on CE-MRI correlate with long-term re-intervention rates (vannuccini2024themodernmanagement pages 1-5)

MRI Radiomics: AI-based radiomics models combining T2-weighted MRI features with clinical parameters predict HIFU ablation efficacy and non-perfusion volume ratio (NPVR) (vannuccini2024themodernmanagement pages 1-5).

Artificial Intelligence and Machine Learning: Deep learning models improve fibroid segmentation, diagnosis, and differentiation from malignancy using ultrasound and MRI images (vannuccini2024themodernmanagement pages 1-5).

Functional Tests: Not routinely applicable

Biopsy and Pathology: - Histopathological examination after surgical removal confirms diagnosis - Immunohistochemistry: High expression of smooth muscle markers (calponin, desmin, SMA, caldesmon, transgelin, SMMHC, smoothelin); co-expression of endometrial stromal markers (CD10, IFITM1) in some variants (dundr2022uterinecellularleiomyomas pages 1-2) - Molecular classification by mutation status (MED12, HMGA2, FH) increasingly relevant (ishikawa2023risingstarsrole pages 1-3, dundr2022uterinecellularleiomyomas pages 1-2)

Genetic Testing

Overview: Genetic testing is not routinely performed for sporadic fibroids but may be indicated in specific clinical scenarios.

Single Gene Testing: - FH gene testing for suspected HLRCC syndrome (family history of renal cell carcinoma, early-onset multiple fibroids) (bulun2025uterinefibroids pages 1-5)

Gene Panels: Not standard for uterine fibroids

Chromosomal Microarray: Not routinely indicated

Whole Exome/Genome Sequencing: Research tool; not routine clinical practice

Somatic Mutation Testing: - MED12 mutation testing on tumor tissue can inform prognosis and potential treatment response (e.g., GnRH agonist/antagonist or ulipristal acetate response) (ishikawa2023risingstarsrole pages 1-3) - HMGA2, FH, COL4A5/6, SRCAP complex mutations for molecular subtyping in research or specialized clinical settings (bulun2025uterinefibroids pages 1-5, dundr2022uterinecellularleiomyomas pages 1-2)

Clinical Criteria

Diagnostic Pathway: - Clinical suspicion based on symptoms (AUB, pelvic pain, bulk symptoms) - Pelvic examination - Transvaginal ultrasound (first-line imaging) (centini2024tailoringthediagnostic pages 1-2) - Diagnostic hysteroscopy for intrauterine assessment if needed (centini2024tailoringthediagnostic pages 1-2) - MRI when necessary for detailed characterization and treatment planning (centini2024tailoringthediagnostic pages 1-2)

Differential Diagnosis: - Adenomyosis (can coexist) - Endometrial stromal tumors (ESN, LG-ESS): differentiated by immunohistochemistry (IFITM1, CD10 patterns) and molecular testing (dundr2022uterinecellularleiomyomas pages 1-2) - Leiomyosarcoma (LMS): requires histopathology; molecular profiling may assist (dundr2022uterinecellularleiomyomas pages 1-2) - Smooth tumors of unknown malignant potential (STUMPs) (centini2024tailoringthediagnostic pages 1-2)

11. OUTCOME/PROGNOSIS

Survival and Mortality

Uterine leiomyomas are benign tumors with very low risk of malignant transformation to leiomyosarcoma (bulun2025uterinefibroids pages 1-5). They are not typically associated with mortality unless severe anemia or surgical complications occur. Life expectancy is not significantly impacted by fibroids alone.

Morbidity and Function

Morbidity: - Significant morbidity from HMB, anemia, chronic pain, bulk symptoms, and reproductive dysfunction (alali2023theetiopathogenesisof pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Heavy menstrual bleeding is a leading cause of iron deficiency anemia in reproductive-age women (vannuccini2024themodernmanagement pages 1-5)

Quality of Life: - Reduced quality of life in ~25–30% of affected women (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5) - Decreased labor productivity (ishikawa2023risingstarsrole pages 1-3) - Impaired physical, social, emotional, and material well-being (vannuccini2024themodernmanagement pages 1-5)

Disease Course

Complications: - Iron deficiency anemia (vannuccini2024themodernmanagement pages 1-5) - Infertility, recurrent pregnancy loss, preterm labor (alali2023theetiopathogenesisof pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2) - Urinary incontinence, constipation (alali2023theetiopathogenesisof pages 1-2) - Post-surgical complications (adhesions, bleeding, infection) - Recurrence after myomectomy (micic2024currentlyavailabletreatment pages 1-2)

Recovery Potential: - Fibroids often regress spontaneously after menopause (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3) - Surgical removal (myomectomy, hysterectomy) provides definitive symptom relief (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Medical treatments provide temporary symptom control but not cure; rebound growth after discontinuation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)

Prognostic Factors

MED12 mutation status may predict response to hormonal therapies (ishikawa2023risingstarsrole pages 1-3)
Fibroid size, number, and location influence symptom burden and treatment outcomes
MRI-based radiomics predict HIFU treatment success and fibroid regrowth (vannuccini2024themodernmanagement pages 1-5)

12. TREATMENT

A comprehensive treatment options table is provided below.

Treatment Category	Specific Treatment Options	Mechanism of Action	Indications / Patient Selection	Clinical Efficacy	Side Effects / Limitations	MAXO term suggestion
Non-hormonal medical therapy	Tranexamic acid	Antifibrinolytic; reduces menstrual blood loss by inhibiting plasminogen activation	Symptomatic heavy menstrual bleeding (HMB) when uterine preservation desired; useful as symptom-control therapy rather than tumor-directed treatment (vannuccini2024themodernmanagement pages 1-5)	Improves fibroid-related abnormal uterine bleeding/heavy menstrual bleeding; does not shrink fibroids (vannuccini2024themodernmanagement pages 1-5)	No effect on fibroid size; symptomatic only; thrombotic-risk considerations in selected patients (vannuccini2024themodernmanagement pages 1-5)	MAXO: antifibrinolytic therapy
Non-hormonal medical therapy	NSAIDs	Reduce prostaglandin-mediated bleeding and pain	Mild-to-moderate bleeding and dysmenorrhea; patients seeking short-term symptom relief (vannuccini2024themodernmanagement pages 1-5)	Can reduce pain and some bleeding symptoms, but generally less effective than targeted hormonal suppression for fibroid burden (vannuccini2024themodernmanagement pages 1-5)	Symptomatic only; gastrointestinal/renal adverse effects; no fibroid shrinkage (vannuccini2024themodernmanagement pages 1-5)	MAXO: nonsteroidal anti-inflammatory drug therapy
Hormonal medical therapy	Combined oral contraceptives	Suppress ovulation/endometrial proliferation; reduce menstrual bleeding	Women with bleeding symptoms who desire non-surgical management and contraception (centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Helpful for bleeding control; primarily symptom management rather than definitive fibroid treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Limited effect on fibroid size; estrogen-containing therapy may not suit all patients (vannuccini2024themodernmanagement pages 1-5)	MAXO: hormonal therapy
Hormonal medical therapy	Progestogens	Endometrial suppression and bleeding control	Selected patients with abnormal uterine bleeding; often short-term or individualized use (micic2024currentlyavailabletreatment pages 1-2)	May improve bleeding; evidence for fibroid shrinkage is limited (micic2024currentlyavailabletreatment pages 1-2)	Restricted efficacy for bulk symptoms/size reduction; hormone-related adverse effects (micic2024currentlyavailabletreatment pages 1-2)	MAXO: progestogen therapy
Hormonal medical therapy	Levonorgestrel intrauterine system (LNG-IUS)	Local progestin effect on endometrium, reducing bleeding	Bleeding-predominant symptoms, especially when uterine cavity distortion is not prohibitive (vannuccini2024themodernmanagement pages 1-5)	Effective for HMB control in selected women; not a fibroid-eliminating therapy (vannuccini2024themodernmanagement pages 1-5)	Expulsion/placement difficulty with cavity distortion; limited effect on bulk symptoms or tumor size (vannuccini2024themodernmanagement pages 1-5)	MAXO: intrauterine hormone delivery
Hormonal medical therapy	GnRH agonists	Initial pituitary stimulation followed by downregulation, causing hypoestrogenism/hypoprogesteronism	Preoperative bridge therapy, short-term bleeding control, temporary fibroid shrinkage, anemia optimization before surgery (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Well-established temporary reduction in bleeding and fibroid size; useful as bridge to surgery (bulun2025uterinefibroids pages 1-5, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Menopausal symptoms, bone loss with prolonged use, rebound growth after discontinuation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: gonadotropin-releasing hormone agonist therapy
Hormonal medical therapy	Oral GnRH antagonists	Direct pituitary GnRH blockade suppressing ovarian steroid production	Symptomatic fibroids with HMB; uterus-sparing medical management; useful when a reversible oral option is preferred (vannuccini2024themodernmanagement pages 1-5)	Effective modern option for reducing bleeding and improving symptoms; part of contemporary conservative management (vannuccini2024themodernmanagement pages 1-5)	Hypoestrogenic adverse effects; may require add-back strategies; treatment effect is not curative (vannuccini2024themodernmanagement pages 1-5)	MAXO: gonadotropin-releasing hormone antagonist therapy
Hormonal medical therapy	Selective progesterone receptor modulators (SPRMs), e.g. ulipristal acetate	Modulate progesterone receptor signaling, reducing bleeding and fibroid growth	Historically used for intermittent long-term bleeding and size control in selected women (micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5)	Good results reported for bleeding control and fibroid size reduction; response may vary with MED12 status (micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3)	Regulatory/safety limitations in many regions, including liver toxicity concerns; access restricted (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: selective progesterone receptor modulator therapy
Hormonal medical therapy	Aromatase inhibitors	Lower local/systemic estrogen synthesis	Selected refractory cases or off-label individualized management (vannuccini2024themodernmanagement pages 1-5)	May improve symptoms in some patients; evidence base narrower than GnRH-based approaches (vannuccini2024themodernmanagement pages 1-5)	Hypoestrogenic effects; not standard first-line treatment (vannuccini2024themodernmanagement pages 1-5)	MAXO: aromatase inhibitor therapy
Surgical therapy	Myomectomy (hysteroscopic, laparoscopic, open/laparotomic, mini-laparotomic, robotic)	Physical removal of fibroids with uterine preservation	Symptomatic patients desiring fertility preservation or uterine conservation; approach depends on number, size, and location of myomas (micic2024currentlyavailabletreatment pages 1-2, centini2024tailoringthediagnostic pages 1-2)	Effective symptom relief while preserving uterus; review data showed comparable average pregnancy rates between minimally invasive and open approaches (~29.7% vs ~28.5%) (micic2024currentlyavailabletreatment pages 1-2)	Recurrence risk persists; operative bleeding/adhesions; more invasive than medical/radiologic options (micic2024currentlyavailabletreatment pages 1-2)	MAXO: myomectomy
Surgical therapy	Hysterectomy	Definitive removal of uterus, eliminating fibroids	Women with severe symptoms, no fertility desire, recurrent disease, or failure of conservative options; often considered definitive therapy (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Most definitive symptom control; fibroid recurrence eliminated because uterus removed (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Loss of fertility; surgical morbidity; longer recovery than some minimally invasive approaches (micic2024currentlyavailabletreatment pages 1-2)	MAXO: hysterectomy
Minimally invasive / interventional	Uterine artery embolization (UAE) / uterine artery occlusion	Devascularization leading to ischemic shrinkage of fibroids	Symptomatic women seeking uterus-sparing, non-excisional treatment; generally not first choice when future fertility is a major goal (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Improves bleeding and bulk symptoms in many patients; accepted radiologic option in modern care pathways (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Post-embolization pain, reintervention/recurrence risk, uncertain reproductive implications relative to myomectomy (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: uterine artery embolization
Minimally invasive / interventional	High-intensity focused ultrasound (HIFU) / MR-guided focused ultrasound	Thermal ablation of fibroid tissue	Selected women with accessible fibroid anatomy seeking noninvasive uterus-sparing treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Can reduce symptoms and fibroid volume; post-treatment MRI parameters can predict regrowth/reintervention risk (vannuccini2024themodernmanagement pages 1-5)	Not suitable for all fibroid locations/sizes; residual fibroid regrowth can occur; access/expertise dependent (vannuccini2024themodernmanagement pages 1-5)	MAXO: focused ultrasound ablation
Minimally invasive / interventional	Radiofrequency ablation / myolysis	Thermal destruction of fibroid tissue	Symptomatic fibroids in patients preferring minimally invasive, uterus-preserving treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Effective symptom-directed minimally invasive option in selected patients (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Long-term recurrence and fertility data less extensive than for myomectomy; anatomy-dependent feasibility (micic2024currentlyavailabletreatment pages 1-2)	MAXO: radiofrequency ablation
Minimally invasive / interventional	Endometrial ablation	Destruction of endometrium to reduce bleeding	Bleeding-predominant symptoms in carefully selected women not seeking fertility; not a tumor-directed therapy (micic2024currentlyavailabletreatment pages 1-2)	May reduce bleeding symptoms but does not treat intramural/subserosal tumor burden (micic2024currentlyavailabletreatment pages 1-2)	Not appropriate for future fertility; limited if cavity distortion is substantial (micic2024currentlyavailabletreatment pages 1-2)	MAXO: endometrial ablation
Supportive care	Iron replacement therapy	Repletes iron stores in iron deficiency/iron deficiency anemia from chronic bleeding	Women with fibroid-related HMB, iron deficiency, or anemia before/after surgery and during medical management (vannuccini2024themodernmanagement pages 1-5)	Improves consequences of chronic blood loss and perioperative readiness; important adjunct rather than fibroid-directed therapy (vannuccini2024themodernmanagement pages 1-5)	Does not treat underlying fibroids; oral GI intolerance or IV infusion logistics may limit use (vannuccini2024themodernmanagement pages 1-5)	MAXO: iron supplementation
Experimental / emerging	Vitamin D	Proposed antiproliferative/anti-fibrotic effects; deficiency is a reported risk factor	Investigational or adjunctive setting; biologic rationale strengthened by epidemiologic association with deficiency (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2)	Promising preclinical and prior xenograft evidence noted in model reviews, but not established standard clinical therapy (wu2026preclinicalresearchplatform pages 1-2)	Insufficient evidence for routine standalone treatment of symptomatic leiomyoma (wu2026preclinicalresearchplatform pages 1-2)	MAXO: vitamin supplementation
Experimental / emerging	Targeted/precision approaches linked to molecular subtype (e.g., MED12-informed response prediction)	Treatment selection based on tumor driver biology and pathway dependence	Future personalized management, particularly for mutation-stratified hormonal response (ishikawa2023risingstarsrole pages 1-3)	Emerging evidence suggests MED12 status may influence response to GnRH agonists and ulipristal acetate (ishikawa2023risingstarsrole pages 1-3)	Not yet routine clinical standard; requires broader validation and accessible molecular testing (ishikawa2023risingstarsrole pages 1-3)	MAXO: precision medicine intervention
Experimental / emerging	Novel agents under investigation	Various pathways including progesterone signaling, ECM remodeling, and other molecular targets	Patients with unmet need for fertility-preserving, long-term, non-surgical options (micic2024currentlyavailabletreatment pages 1-2, bulun2025uterinefibroids pages 1-5)	Reviews describe multiple promising investigational therapies, but few are yet approved specifically for fibroids (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Evidence still evolving; many therapies remain investigational or regionally unavailable (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: investigational pharmacotherapy

Table: This table summarizes current and emerging treatment options for uterine leiomyoma, including mechanisms, appropriate patient selection, expected efficacy, limitations, and suggested MAXO-aligned intervention labels. It is useful for comparing conservative, surgical, and interventional management strategies in one view.

Pharmacotherapy

Non-Hormonal: - Tranexamic acid (antifibrinolytic for HMB) (vannuccini2024themodernmanagement pages 1-5) [MAXO: antifibrinolytic therapy] - NSAIDs (symptom control for pain and bleeding) (vannuccini2024themodernmanagement pages 1-5) [MAXO: nonsteroidal anti-inflammatory drug therapy]

Hormonal: - Combined oral contraceptives (centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: hormonal therapy] - Progestogens (micic2024currentlyavailabletreatment pages 1-2) [MAXO: progestogen therapy] - Levonorgestrel intrauterine system (LNG-IUS) (vannuccini2024themodernmanagement pages 1-5) [MAXO: intrauterine hormone delivery] - GnRH agonists (preoperative bridge, temporary shrinkage) (bulun2025uterinefibroids pages 1-5, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: gonadotropin-releasing hormone agonist therapy] - Oral GnRH antagonists (modern option for symptom and size control) (vannuccini2024themodernmanagement pages 1-5) [MAXO: gonadotropin-releasing hormone antagonist therapy] - Selective progesterone receptor modulators (SPRMs, e.g., ulipristal acetate): historically effective but limited by safety concerns (micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5) [MAXO: selective progesterone receptor modulator therapy] - Aromatase inhibitors (off-label) (vannuccini2024themodernmanagement pages 1-5) [MAXO: aromatase inhibitor therapy]

Pharmacogenomics: MED12 mutation status influences response to GnRH agonists and ulipristal acetate, suggesting potential for mutation-guided therapy (ishikawa2023risingstarsrole pages 1-3).

Advanced Therapeutics

Experimental: - Vitamin D supplementation (promising preclinical/xenograft evidence but not standard therapy) (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2) - Catechol-O-methyltransferase inhibitors (evaluated in Eker rat models) (wu2026preclinicalresearchplatform pages 1-2) - Hedgehog pathway inhibitors (GLI inhibitors like Gant61 show efficacy in xenograft models) (wu2026preclinicalresearchplatform pages 1-2) - Novel targeted therapies based on molecular subtype (under investigation) (bulun2025uterinefibroids pages 1-5, micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3)

Surgical and Interventional

Surgical: - Myomectomy (hysteroscopic, laparoscopic, open, robotic): Fertility-preserving fibroid removal (micic2024currentlyavailabletreatment pages 1-2) [MAXO: myomectomy] - Hysterectomy: Definitive treatment, loss of fertility (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: hysterectomy]

Minimally Invasive/Interventional: - Uterine artery embolization (UAE): Devascularization (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: uterine artery embolization] - High-intensity focused ultrasound (HIFU): Thermal ablation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: focused ultrasound ablation] - Radiofrequency ablation: Thermal destruction (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) [MAXO: radiofrequency ablation] - Endometrial ablation: For bleeding control (micic2024currentlyavailabletreatment pages 1-2) [MAXO: endometrial ablation]

Supportive and Rehabilitative

Iron replacement therapy: For iron deficiency anemia (vannuccini2024themodernmanagement pages 1-5) [MAXO: iron supplementation]

Treatment Outcomes

Response Rates: - GnRH agonists/antagonists: Effective temporary shrinkage and symptom control; rebound after discontinuation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Myomectomy: Effective symptom relief; pregnancy rates comparable between minimally invasive and open approaches (~29.7% vs ~28.5%) (micic2024currentlyavailabletreatment pages 1-2) - Hysterectomy: Most definitive; eliminates recurrence (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - UAE and HIFU: Improve symptoms in many patients; reintervention rates variable (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)

Side Effects: - GnRH agonists/antagonists: Menopausal symptoms, bone loss with prolonged use (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - SPRMs: Liver toxicity concerns (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Surgical: Bleeding, adhesions, infection, longer recovery for open surgery (micic2024currentlyavailabletreatment pages 1-2)

Treatment Strategy

Individualized based on symptoms, fibroid characteristics, fertility desire, and patient preference (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)
Shared decision-making emphasizing short- and long-term treatment goals (centini2024tailoringthediagnostic pages 1-2, vannuccini2024themodernmanagement pages 1-5)
Medical therapy often used as bridge to surgery or for patients preferring conservative management (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)
Personalized/precision approaches incorporating MED12 mutation status for response prediction are emerging (ishikawa2023risingstarsrole pages 1-3)

13. PREVENTION

Prevention Levels

Primary Prevention: - Lifestyle modifications: Maintain healthy body weight, adequate vitamin D, balanced diet (micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3) - Avoid excessive alcohol consumption (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3) - Reduce exposure to xenoestrogens and environmental pollutants (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3) - Multiparity may be protective (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)

Secondary Prevention: - Early detection via routine pelvic exams and ultrasound in asymptomatic women at high risk (family history, Black ancestry) (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2) - Prompt treatment of symptomatic fibroids to prevent complications like anemia and reproductive dysfunction

Tertiary Prevention: - Medical management to prevent symptom progression and complications (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5) - Iron supplementation to prevent anemia in women with HMB (vannuccini2024themodernmanagement pages 1-5)

Immunization

Not applicable

Screening and Early Detection

Screening Programs: - No population-based screening recommended for asymptomatic women - Opportunistic detection during routine gynecological ultrasound

Genetic Screening: - Genetic counseling and FH gene testing for families with HLRCC syndrome (bulun2025uterinefibroids pages 1-5)

Risk Stratification: - Family history, race/ethnicity, reproductive history, and GWAS risk scores may identify high-risk individuals (buyukcelebi2024integratingleiomyomagenetics pages 1-2)

Behavioral Interventions

Weight management and healthy diet (micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3)
Stress reduction (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)

Counseling

Genetic counseling for HLRCC syndrome families (bulun2025uterinefibroids pages 1-5)

Public Health

Health education on modifiable risk factors
Reduce environmental xenoestrogen exposure (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)

14. OTHER SPECIES / NATURAL DISEASE

Taxonomy

Eker rats (Rattus norvegicus) with Tsc2 germline mutation spontaneously develop uterine smooth muscle tumors (wu2026preclinicalresearchplatform pages 1-2)
Japanese quail spontaneously develop leiomyomas (wu2026preclinicalresearchplatform pages 1-2)
Miniature pet pigs (Sus scrofa) documented with spontaneous leiomyomas (wu2026preclinicalresearchplatform pages 1-2)

NCBI Taxon IDs: - Rattus norvegicus: NCBITaxon:10116 - Sus scrofa: NCBITaxon:9823 - Coturnix japonica (Japanese quail): NCBITaxon:93934

Natural Disease

Eker Rats: Approximately 65% of female Eker rats develop uterine smooth muscle tumors by 12–16 months of age due to germline Tsc2 mutation (wu2026preclinicalresearchplatform pages 1-2). Histomorphology and hormone-dependence are highly similar to human fibroids (wu2026preclinicalresearchplatform pages 1-2).

Japanese Quail and Miniature Pigs: Also exhibit spontaneous leiomyomas, though less extensively characterized (wu2026preclinicalresearchplatform pages 1-2).

Comparative Biology

Eker rat tumors recapitulate key features of human fibroids, including estrogen/progesterone-dependent growth, ECM-rich composition, and similar histology (wu2026preclinicalresearchplatform pages 1-2). However, Eker rats develop concurrent renal and hepatic tumors, complicating model interpretation (wu2026preclinicalresearchplatform pages 1-2).

15. MODEL ORGANISMS

Model Types

Spontaneous Animal Models: - Eker Rats: Germline Tsc2 mutation; spontaneous tumor development by 12–16 months; widely used for etiology and drug validation studies (wu2026preclinicalresearchplatform pages 1-2) - Japanese Quail and Miniature Pigs: Spontaneous models, less commonly used (wu2026preclinicalresearchplatform pages 1-2)

Genetically Modified Animal Models: - Conditional MED12-mutant mouse model: Engineered MED12 exon 2 mutation in uterus; develops leiomyoma-like tumors; confirms MED12 gain-of-function role (bulun2025uterinefibroids pages 1-5, wu2026preclinicalresearchplatform pages 1-2)

Hormone-Induced Animal Models: - Combined estrogen-progesterone induction in mice/rats (wu2026preclinicalresearchplatform pages 1-2) - Sequential induction (estrogen followed by progesterone) mimics natural hormonal cycles (wu2026preclinicalresearchplatform pages 1-2) - Concurrent induction promotes hormone receptor expression (wu2026preclinicalresearchplatform pages 1-2) - Multi-factor composite models integrating chronic stress and epinephrine intervention to simulate "Qi Stagnation and Blood Stasis" syndrome in integrated medicine research (wu2026preclinicalresearchplatform pages 1-2)

Xenograft Animal Models: - Patient-derived xenografts (PDX) in immunodeficient mice (e.g., SCID, NSG mice) (wu2026preclinicalresearchplatform pages 1-2) - Maintain human fibroid architecture, hormone-responsiveness, and genetic background (wu2026preclinicalresearchplatform pages 1-2) - Useful for drug testing and mechanistic studies (wu2026preclinicalresearchplatform pages 1-2)

Organotypic/Ex Vivo Models: - Organotypic culture of fibroid tissue slices on alginate scaffolds; maintains morphological integrity, steroid receptor expression, and driver mutations for up to 7 days (wu2026preclinicalresearchplatform pages 1-2) - Allows encapsulation of drug-loaded microspheres for preclinical testing (wu2026preclinicalresearchplatform pages 1-2)

Genetic Models

Conditional MED12-mutant mice (bulun2025uterinefibroids pages 1-5, wu2026preclinicalresearchplatform pages 1-2)
Eker rats (Tsc2 mutation) (wu2026preclinicalresearchplatform pages 1-2)

Model Characteristics

Phenotype Recapitulation: - Eker rats: High similarity in histology, ECM deposition, and hormone-dependence; useful for mTOR pathway studies (wu2026preclinicalresearchplatform pages 1-2) - MED12-mutant mice: Confirm gain-of-function mutation role and leiomyoma pathogenesis (bulun2025uterinefibroids pages 1-5, wu2026preclinicalresearchplatform pages 1-2) - Xenografts: Best preserve human tumor heterogeneity and genetic background (wu2026preclinicalresearchplatform pages 1-2)

Model Limitations: - Eker rats: Long establishment time (12–16 months), concurrent tumors (renal, hepatic), high cost (wu2026preclinicalresearchplatform pages 1-2) - Hormone-induced models: May not fully replicate spontaneous human disease complexity; reproducibility variable (wu2026preclinicalresearchplatform pages 1-2) - Xenografts: Require immunodeficient hosts; do not capture immune interactions (wu2026preclinicalresearchplatform pages 1-2)

Applications

Etiology and mechanism research (wu2026preclinicalresearchplatform pages 1-2)
Drug efficacy and safety testing (wu2026preclinicalresearchplatform pages 1-2)
Evaluation of novel therapies (vitamin D, hedgehog inhibitors, hormonal agents) (wu2026preclinicalresearchplatform pages 1-2)

Resources

Mouse models: MGI, IMPC, KOMP repositories
Rat models: RGD
Xenograft protocols and cell lines available through specialized research centers

SUMMARY TABLES

Key Genetic Mutations in Uterine Leiomyoma

Gene Name / Alteration	Mutation Type	Frequency / Prevalence	Molecular Effects	Clinical Associations	Key References
MED12	Recurrent somatic exon 2 point mutations; typically heterozygous, gain-of-function–like driver alterations disrupting Mediator kinase module signaling	~50–80% of uterine fibroids; ~70% in several recent summaries; 77% in a large review	Disrupts MED12-dependent activation of CDK8/CDK19 within the Mediator complex; associated with altered chromatin landscape, enhancer engagement, genomic instability, progesterone responsiveness, and dysregulated WNT/β-catenin, hedgehog, sex steroid, and TGF-β signaling; transcriptomic enrichment for ECM/collagen pathways	Most common driver; often multiple tumors rather than solitary lesions; commonly seen even in small tumors; more frequent in Black women in some series; mutant tumors can differ in size/location and may show mutation-status–dependent response to GnRH agonists and ulipristal acetate	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
HMGA2 / HMGA1	Somatic overexpression and chromosomal rearrangements/fusions involving HMGA2/1	~10% of fibroids in recent overview; in cellular leiomyoma, HMGA2 overexpression was 36.5% and rearrangement 13.2%	Alters chromatin architecture and transcriptional programs; defines a molecular subtype distinct from MED12-mutant tumors	Associated with distinct histopathologic phenotypes; important subtype in usual leiomyoma and especially enriched in some variants such as cellular leiomyoma	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, dundr2022uterinecellularleiomyomas pages 1-2)
FH	Somatic or germline-related loss-of-function / deficiency; part of FH-deficient leiomyoma spectrum and HLRCC-related disease	Less common than MED12/HMGA2 in unselected fibroids; recognized recurrent subtype	Fumarate hydratase deficiency rewires metabolism and contributes to a distinct molecular subtype of leiomyoma	Seen in FH-deficient leiomyomas and in hereditary leiomyomatosis and renal cell cancer (HLRCC); clinically relevant for identifying syndromic disease	(bulun2025uterinefibroids pages 1-5, chuang2023differentialexpressionof pages 1-2, boos2025therolesof pages 1-2)
COL4A5 / COL4A6	Recurrent somatic deletions / structural alterations affecting collagen IV genes	Recurrent but uncommon relative to MED12; listed among frequently observed genetic alterations	Likely alters basement-membrane / ECM-related biology and contributes to subtype-specific tumor development	Included among recognized uterine fibroid driver alterations; may overlap with syndromic/structural subtypes rather than classic MED12 tumors	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2, chuang2023differentialexpressionof pages 1-2)
SRCAP complex genes (e.g., YEATS4, ZNHIT1, other complex members)	Inactivating somatic mutations causing defective H2A.Z loading / chromatin remodeling abnormalities	Recently identified recurrent but uncommon subtype	Produces H2A.Z deposition defects and epigenetic dysregulation; supports a chromatin-based pathogenesis distinct from MED12 and HMGA2	Emerging molecular class of leiomyoma; potentially useful for future subtype-based diagnostics and therapy development	(bulun2025uterinefibroids pages 1-5, buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Chromosome 1p deletion	Recurrent somatic copy-number loss	19.3% in a cellular leiomyoma series	Copy-number loss likely alters dosage of tumor-relevant genes on 1p; appears mutually exclusive with some other driver classes in variant tumors	Particularly reported in cellular leiomyoma; useful in variant classification and differential pathology	(dundr2022uterinecellularleiomyomas pages 1-2)
24 GWAS risk loci / heritable susceptibility variants (multiple genes including GREB1, MCM8 and broader target-gene sets)	Germline susceptibility SNPs / risk loci from population genetics	24 uterine-fibroid–associated risk loci identified in a 2024 integrative analysis; 394 potential target genes, 168 differentially expressed in tumors	Heritable risk variants map largely to noncoding regulatory regions and influence gene regulation through chromatin contacts, eQTL effects, and cell-type–specific regulatory programs	Explains familial aggregation and racial/population risk differences; points to causal cell types and potential preventive/targeted strategies rather than a single monogenic cause	(buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Non-coding RNA dysregulation linked to driver status (e.g., miR-21, miR-29, miR-200; H19, MIAT, XIST)	Secondary molecular alterations influenced by driver mutations, race/ethnicity, and hormones rather than classic coding mutations	Commonly dysregulated across fibroids; not a single frequency estimate	Regulates ECM production, proliferation, apoptosis, and inflammation; expression is influenced by MED12 mutation status and ovarian steroids	Potential biomarker and non-hormonal therapeutic layer; may help explain phenotypic heterogeneity and racial disparities	(boos2025therolesof pages 1-2)

Table: This table summarizes the principal genetic and molecular alterations implicated in uterine leiomyoma, emphasizing recurrent somatic drivers, inherited susceptibility loci, and their clinical relevance. It is useful for quickly comparing major subtypes, frequencies, and mechanistic consequences across the current evidence base.

Treatment Options for Uterine Leiomyoma

Treatment Category	Specific Treatment Options	Mechanism of Action	Indications / Patient Selection	Clinical Efficacy	Side Effects / Limitations	MAXO term suggestion
Non-hormonal medical therapy	Tranexamic acid	Antifibrinolytic; reduces menstrual blood loss by inhibiting plasminogen activation	Symptomatic heavy menstrual bleeding (HMB) when uterine preservation desired; useful as symptom-control therapy rather than tumor-directed treatment (vannuccini2024themodernmanagement pages 1-5)	Improves fibroid-related abnormal uterine bleeding/heavy menstrual bleeding; does not shrink fibroids (vannuccini2024themodernmanagement pages 1-5)	No effect on fibroid size; symptomatic only; thrombotic-risk considerations in selected patients (vannuccini2024themodernmanagement pages 1-5)	MAXO: antifibrinolytic therapy
Non-hormonal medical therapy	NSAIDs	Reduce prostaglandin-mediated bleeding and pain	Mild-to-moderate bleeding and dysmenorrhea; patients seeking short-term symptom relief (vannuccini2024themodernmanagement pages 1-5)	Can reduce pain and some bleeding symptoms, but generally less effective than targeted hormonal suppression for fibroid burden (vannuccini2024themodernmanagement pages 1-5)	Symptomatic only; gastrointestinal/renal adverse effects; no fibroid shrinkage (vannuccini2024themodernmanagement pages 1-5)	MAXO: nonsteroidal anti-inflammatory drug therapy
Hormonal medical therapy	Combined oral contraceptives	Suppress ovulation/endometrial proliferation; reduce menstrual bleeding	Women with bleeding symptoms who desire non-surgical management and contraception (centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Helpful for bleeding control; primarily symptom management rather than definitive fibroid treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Limited effect on fibroid size; estrogen-containing therapy may not suit all patients (vannuccini2024themodernmanagement pages 1-5)	MAXO: hormonal therapy
Hormonal medical therapy	Progestogens	Endometrial suppression and bleeding control	Selected patients with abnormal uterine bleeding; often short-term or individualized use (micic2024currentlyavailabletreatment pages 1-2)	May improve bleeding; evidence for fibroid shrinkage is limited (micic2024currentlyavailabletreatment pages 1-2)	Restricted efficacy for bulk symptoms/size reduction; hormone-related adverse effects (micic2024currentlyavailabletreatment pages 1-2)	MAXO: progestogen therapy
Hormonal medical therapy	Levonorgestrel intrauterine system (LNG-IUS)	Local progestin effect on endometrium, reducing bleeding	Bleeding-predominant symptoms, especially when uterine cavity distortion is not prohibitive (vannuccini2024themodernmanagement pages 1-5)	Effective for HMB control in selected women; not a fibroid-eliminating therapy (vannuccini2024themodernmanagement pages 1-5)	Expulsion/placement difficulty with cavity distortion; limited effect on bulk symptoms or tumor size (vannuccini2024themodernmanagement pages 1-5)	MAXO: intrauterine hormone delivery
Hormonal medical therapy	GnRH agonists	Initial pituitary stimulation followed by downregulation, causing hypoestrogenism/hypoprogesteronism	Preoperative bridge therapy, short-term bleeding control, temporary fibroid shrinkage, anemia optimization before surgery (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Well-established temporary reduction in bleeding and fibroid size; useful as bridge to surgery (bulun2025uterinefibroids pages 1-5, micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Menopausal symptoms, bone loss with prolonged use, rebound growth after discontinuation (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: gonadotropin-releasing hormone agonist therapy
Hormonal medical therapy	Oral GnRH antagonists	Direct pituitary GnRH blockade suppressing ovarian steroid production	Symptomatic fibroids with HMB; uterus-sparing medical management; useful when a reversible oral option is preferred (vannuccini2024themodernmanagement pages 1-5)	Effective modern option for reducing bleeding and improving symptoms; part of contemporary conservative management (vannuccini2024themodernmanagement pages 1-5)	Hypoestrogenic adverse effects; may require add-back strategies; treatment effect is not curative (vannuccini2024themodernmanagement pages 1-5)	MAXO: gonadotropin-releasing hormone antagonist therapy
Hormonal medical therapy	Selective progesterone receptor modulators (SPRMs), e.g. ulipristal acetate	Modulate progesterone receptor signaling, reducing bleeding and fibroid growth	Historically used for intermittent long-term bleeding and size control in selected women (micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5)	Good results reported for bleeding control and fibroid size reduction; response may vary with MED12 status (micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3)	Regulatory/safety limitations in many regions, including liver toxicity concerns; access restricted (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: selective progesterone receptor modulator therapy
Hormonal medical therapy	Aromatase inhibitors	Lower local/systemic estrogen synthesis	Selected refractory cases or off-label individualized management (vannuccini2024themodernmanagement pages 1-5)	May improve symptoms in some patients; evidence base narrower than GnRH-based approaches (vannuccini2024themodernmanagement pages 1-5)	Hypoestrogenic effects; not standard first-line treatment (vannuccini2024themodernmanagement pages 1-5)	MAXO: aromatase inhibitor therapy
Surgical therapy	Myomectomy (hysteroscopic, laparoscopic, open/laparotomic, mini-laparotomic, robotic)	Physical removal of fibroids with uterine preservation	Symptomatic patients desiring fertility preservation or uterine conservation; approach depends on number, size, and location of myomas (micic2024currentlyavailabletreatment pages 1-2, centini2024tailoringthediagnostic pages 1-2)	Effective symptom relief while preserving uterus; review data showed comparable average pregnancy rates between minimally invasive and open approaches (~29.7% vs ~28.5%) (micic2024currentlyavailabletreatment pages 1-2)	Recurrence risk persists; operative bleeding/adhesions; more invasive than medical/radiologic options (micic2024currentlyavailabletreatment pages 1-2)	MAXO: myomectomy
Surgical therapy	Hysterectomy	Definitive removal of uterus, eliminating fibroids	Women with severe symptoms, no fertility desire, recurrent disease, or failure of conservative options; often considered definitive therapy (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Most definitive symptom control; fibroid recurrence eliminated because uterus removed (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Loss of fertility; surgical morbidity; longer recovery than some minimally invasive approaches (micic2024currentlyavailabletreatment pages 1-2)	MAXO: hysterectomy
Minimally invasive / interventional	Uterine artery embolization (UAE) / uterine artery occlusion	Devascularization leading to ischemic shrinkage of fibroids	Symptomatic women seeking uterus-sparing, non-excisional treatment; generally not first choice when future fertility is a major goal (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Improves bleeding and bulk symptoms in many patients; accepted radiologic option in modern care pathways (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Post-embolization pain, reintervention/recurrence risk, uncertain reproductive implications relative to myomectomy (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: uterine artery embolization
Minimally invasive / interventional	High-intensity focused ultrasound (HIFU) / MR-guided focused ultrasound	Thermal ablation of fibroid tissue	Selected women with accessible fibroid anatomy seeking noninvasive uterus-sparing treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Can reduce symptoms and fibroid volume; post-treatment MRI parameters can predict regrowth/reintervention risk (vannuccini2024themodernmanagement pages 1-5)	Not suitable for all fibroid locations/sizes; residual fibroid regrowth can occur; access/expertise dependent (vannuccini2024themodernmanagement pages 1-5)	MAXO: focused ultrasound ablation
Minimally invasive / interventional	Radiofrequency ablation / myolysis	Thermal destruction of fibroid tissue	Symptomatic fibroids in patients preferring minimally invasive, uterus-preserving treatment (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Effective symptom-directed minimally invasive option in selected patients (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Long-term recurrence and fertility data less extensive than for myomectomy; anatomy-dependent feasibility (micic2024currentlyavailabletreatment pages 1-2)	MAXO: radiofrequency ablation
Minimally invasive / interventional	Endometrial ablation	Destruction of endometrium to reduce bleeding	Bleeding-predominant symptoms in carefully selected women not seeking fertility; not a tumor-directed therapy (micic2024currentlyavailabletreatment pages 1-2)	May reduce bleeding symptoms but does not treat intramural/subserosal tumor burden (micic2024currentlyavailabletreatment pages 1-2)	Not appropriate for future fertility; limited if cavity distortion is substantial (micic2024currentlyavailabletreatment pages 1-2)	MAXO: endometrial ablation
Supportive care	Iron replacement therapy	Repletes iron stores in iron deficiency/iron deficiency anemia from chronic bleeding	Women with fibroid-related HMB, iron deficiency, or anemia before/after surgery and during medical management (vannuccini2024themodernmanagement pages 1-5)	Improves consequences of chronic blood loss and perioperative readiness; important adjunct rather than fibroid-directed therapy (vannuccini2024themodernmanagement pages 1-5)	Does not treat underlying fibroids; oral GI intolerance or IV infusion logistics may limit use (vannuccini2024themodernmanagement pages 1-5)	MAXO: iron supplementation
Experimental / emerging	Vitamin D	Proposed antiproliferative/anti-fibrotic effects; deficiency is a reported risk factor	Investigational or adjunctive setting; biologic rationale strengthened by epidemiologic association with deficiency (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2)	Promising preclinical and prior xenograft evidence noted in model reviews, but not established standard clinical therapy (wu2026preclinicalresearchplatform pages 1-2)	Insufficient evidence for routine standalone treatment of symptomatic leiomyoma (wu2026preclinicalresearchplatform pages 1-2)	MAXO: vitamin supplementation
Experimental / emerging	Targeted/precision approaches linked to molecular subtype (e.g., MED12-informed response prediction)	Treatment selection based on tumor driver biology and pathway dependence	Future personalized management, particularly for mutation-stratified hormonal response (ishikawa2023risingstarsrole pages 1-3)	Emerging evidence suggests MED12 status may influence response to GnRH agonists and ulipristal acetate (ishikawa2023risingstarsrole pages 1-3)	Not yet routine clinical standard; requires broader validation and accessible molecular testing (ishikawa2023risingstarsrole pages 1-3)	MAXO: precision medicine intervention
Experimental / emerging	Novel agents under investigation	Various pathways including progesterone signaling, ECM remodeling, and other molecular targets	Patients with unmet need for fertility-preserving, long-term, non-surgical options (micic2024currentlyavailabletreatment pages 1-2, bulun2025uterinefibroids pages 1-5)	Reviews describe multiple promising investigational therapies, but few are yet approved specifically for fibroids (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	Evidence still evolving; many therapies remain investigational or regionally unavailable (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5)	MAXO: investigational pharmacotherapy

Table: This table summarizes current and emerging treatment options for uterine leiomyoma, including mechanisms, appropriate patient selection, expected efficacy, limitations, and suggested MAXO-aligned intervention labels. It is useful for comparing conservative, surgical, and interventional management strategies in one view.

Risk and Protective Factors for Uterine Leiomyoma

Factor Type	Specific Factor	Category	Strength of Association	Population-Specific Effects	Key Evidence
Risk	Advanced reproductive age	Reproductive	Consistently reported risk factor; incidence and symptom burden increase through reproductive years, especially ages 35–50	Burden concentrated in women aged 40–69 globally; common in reproductive-age women (tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2)	Listed as a risk factor in reviews; fibroids are most commonly found in women aged 35–50, and global burden is concentrated in ages 40–69 (koltsova2023aviewon pages 1-2, tang2025theglobalburden pages 1-2, micic2024currentlyavailabletreatment pages 1-2)
Risk	Black/African ancestry	Genetic / population	Strong and repeatedly reported association	By age 50, prevalence reaches >80% in Black women vs ~70% overall/White women; disproportionate incidence and severity (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2)	Reviews and genomic studies report substantially higher prevalence and burden in Black women (buyukcelebi2024integratingleiomyomagenetics pages 1-2, centini2024tailoringthediagnostic pages 1-2, boos2025therolesof pages 1-2)
Risk	Latin American ethnicity	Population	Reported association, but less extensively quantified than Black ancestry	Mentioned as increased-risk population in review literature	Identified among risk factors in heterogeneity-focused review (koltsova2023aviewon pages 1-2)
Risk	Family history of uterine leiomyoma	Genetic	Moderate-to-strong; familial aggregation repeatedly reported	First-degree relatives have elevated risk; reflects heritable susceptibility	Review identifies family history as a risk factor; GWAS/integrative genetics supports heritable contribution and multiple susceptibility loci (koltsova2023aviewon pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Risk	Germline/heritable susceptibility loci	Genetic	Strong biologic evidence for susceptibility, but effect sizes vary by locus	May contribute to racial/population differences in risk	Integrative 2024 analysis identified 24 UF-associated risk loci and 394 candidate target genes, supporting inherited susceptibility (buyukcelebi2024integratingleiomyomagenetics pages 1-2)
Risk	MED12-associated predisposition to specific tumor biology	Genetic / molecular	Strong for tumor subtype biology rather than disease initiation alone	MED12-mutant tumors are more frequent in Black women in some series and often multiple	MED12 mutations are the dominant driver in many tumors and are associated with distinct biology and multiplicity (bulun2025uterinefibroids pages 1-5, ishikawa2023risingstarsrole pages 1-3)
Risk	Early menarche	Reproductive	Consistently reported risk factor	No specific population restriction given, but may interact with lifetime hormonal exposure	Included as a risk factor in multiple reviews and diagnostic overview (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Late menopause	Reproductive	Reported risk factor, likely reflecting prolonged estrogen/progesterone exposure	Not specifically stratified	Included in etiopathogenesis overview figure/discussion (alali2023theetiopathogenesisof pages 1-2)
Risk	Nulliparity / low parity	Reproductive	Consistently reported risk factor	Protective effect of multiparity implies higher risk in nulliparous women	Nulliparity or absence of parity is reported as a risk factor; several reviews note multiparity as protective (buyukcelebi2024integratingleiomyomagenetics pages 1-2, larrain2024newinsightsinto pages 1-3)
Protective	Multiparity / parity	Reproductive	Consistently reported protective factor	Not population-specific, though effect may vary with reproductive history	Multiparity/parity reported as protective in reviews and diagnostic narrative (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Risk	Obesity / high BMI	Lifestyle / metabolic	Strong and consistently reported	Important in many populations; cited in epidemiologic and mechanistic reviews	Obesity repeatedly listed among major risk factors and linked to symptomatic disease burden (alali2023theetiopathogenesisof pages 1-2, koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Diabetes	Metabolic	Reported association	Not specifically stratified	Included among factors involved in incidence/development in clinician-friendly review (larrain2024newinsightsinto pages 1-3)
Risk	Arterial hypertension	Metabolic / vascular	Repeatedly reported association	Not specifically stratified	Identified as a risk factor in heterogeneity/risk-factor review and clinician review (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Chronic inflammation	Environmental / biologic	Reported association with plausible mechanistic support	Not specifically stratified	Listed as a risk factor in review of UL genesis; inflammation also emphasized mechanistically in fibroid biology (koltsova2023aviewon pages 1-2, boos2025therolesof pages 1-2)
Risk	Sexually transmitted infections	Infectious	Reported association, evidence less mature than hormonal/metabolic factors	Not specifically stratified	Identified as a possible risk factor in review of risk/protective factors (koltsova2023aviewon pages 1-2)
Risk	Exposure to xenoestrogens in early ontogenesis	Environmental	Biologically plausible and reported in review literature	Suggests early-life vulnerability window	Reported as a risk factor in review of UL genesis (koltsova2023aviewon pages 1-2)
Risk	Diethylstilbestrol (DES) exposure	Environmental	Reported association	Not specifically stratified	Included among environmental contributors in clinician-friendly molecular review (larrain2024newinsightsinto pages 1-3)
Risk	Air pollution	Environmental	Reported association	Not specifically stratified	Mentioned among factors potentially involved in incidence/development (larrain2024newinsightsinto pages 1-3)
Risk	Alcohol consumption	Lifestyle	Repeatedly reported risk factor	Not specifically stratified	Alcohol listed as a risk factor in heterogeneity review and clinician-friendly review (koltsova2023aviewon pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	Caffeine	Lifestyle	Reported in one review/figure; likely weaker evidence than alcohol/obesity	Not specifically stratified	Included in etiopathogenesis figure as a potential risk factor (alali2023theetiopathogenesisof pages 1-2)
Risk	Chronic stress	Lifestyle / psychosocial	Reported association	Not specifically stratified	Listed in diagnostic review as a risk factor (centini2024tailoringthediagnostic pages 1-2)
Risk	Vitamin D deficiency	Environmental / nutritional	Repeatedly reported association with supportive mechanistic rationale	Not specifically stratified; may be relevant in populations with higher deficiency prevalence	Vitamin D deficiency is listed among known factors influencing fibroid development in recent reviews (alali2023theetiopathogenesisof pages 1-2, micic2024currentlyavailabletreatment pages 1-2, larrain2024newinsightsinto pages 1-3)
Protective	Adequate vitamin D status	Nutritional	Implied protective factor from repeated deficiency-risk association; preclinical support exists	Not specifically stratified	Since deficiency is repeatedly associated with risk, adequate status is plausibly protective; some model literature supports anti-fibroid effects (micic2024currentlyavailabletreatment pages 1-2, wu2026preclinicalresearchplatform pages 1-2, larrain2024newinsightsinto pages 1-3)
Risk	High-fat diet / adverse dietary factors	Lifestyle / nutritional	Reported association	Not specifically stratified	High-fat diet and dietary factors are mentioned as contributing to incidence/development (larrain2024newinsightsinto pages 1-3)
Protective	Oral contraceptive use / combined oral contraceptives	Reproductive / hormonal	Reported protective factor in review literature, though literature historically mixed	Not specifically stratified	Oral contraceptive intake and combined oral contraceptives are listed among possible protective factors in recent reviews (koltsova2023aviewon pages 1-2, centini2024tailoringthediagnostic pages 1-2)
Protective	Smoking	Lifestyle	Reported as a possible protective factor in reviews, but likely outweighed by broader health harms	Not population-specific; not a recommended prevention strategy	Smoking is listed among possible protective factors in one recent review even though it is not clinically recommended (koltsova2023aviewon pages 1-2)
Risk	Hormonal milieu: higher estradiol and progesterone exposure	Hormonal / mechanistic	Strong mechanistic support	Relevant across reproductive-age populations; explains premenopausal predominance	Risk/severity associated with serum estradiol and progesterone; tumors are steroid-dependent and rarely develop before menarche (buyukcelebi2024integratingleiomyomagenetics pages 1-2, ishikawa2023risingstarsrole pages 1-3)
Protective	Postmenopausal state / menopause-associated regression	Reproductive / hormonal	Strong observational pattern	Applies broadly; many fibroids regress after menopause	Fibroids frequently regress after menopause, supporting reduced ovarian steroid exposure as protective against persistence/growth (alali2023theetiopathogenesisof pages 1-2, ishikawa2023risingstarsrole pages 1-3)
Risk	Reproductive delay / postponed childbearing	Reproductive	Epidemiologically plausible; discussed in population-burden review	Relevant in regions with delayed childbearing patterns	Population review links changing reproductive patterns, including postponed childbearing, to increasing prevalence (zhang2025globalregionaland pages 1-2)

Table: This table summarizes reported risk and protective factors for uterine leiomyoma across recent reviews and epidemiologic/genetic studies. It organizes the factors by category, indicates the qualitative strength of association, and notes population-specific patterns where available.

CONCLUSION

Uterine leiomyomas are the most common benign gynecological tumors, affecting up to 70–80% of women by menopause, with disproportionate burden in Black women. The disease has complex etiology involving somatic driver mutations (MED12 most common at 50–80%, followed by HMGA2, FH, and others), heritable susceptibility loci (24 GWAS risk loci identified), hormonal dependence on estrogen and progesterone, and environmental/lifestyle risk factors including obesity, early menarche, nulliparity, and vitamin D deficiency (alali2023theetiopathogenesisof pages 1-2, bulun2025uterinefibroids pages 1-5, koltsova2023aviewon pages 1-2, buyukcelebi2024integratingleiomyomagenetics pages 1-2, ishikawa2023risingstarsrole pages 1-3).

Approximately 20–30% of women with fibroids experience symptoms including heavy menstrual bleeding (leading to iron deficiency anemia), pelvic pain, bulk symptoms, and reproductive dysfunction, significantly impairing quality of life (alali2023theetiopathogenesisof pages 1-2, centini2024tailoringthediagnostic pages 1-2, vannuccini2024themodernmanagement pages 1-5). Diagnosis relies primarily on transvaginal ultrasound, with MRI for detailed characterization and treatment planning (centini2024tailoringthediagnostic pages 1-2, vannuccini2024themodernmanagement pages 1-5). Emerging AI-based radiomics and molecular subtyping (MED12 mutation status) may enable personalized treatment approaches (ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5).

Treatment is individualized based on symptoms, fibroid characteristics, fertility desire, and patient preference. Options range from medical management (GnRH agonists/antagonists, SPRMs, NSAIDs, tranexamic acid) to surgical interventions (myomectomy, hysterectomy) and minimally invasive procedures (UAE, HIFU, radiofrequency ablation) (micic2024currentlyavailabletreatment pages 1-2, vannuccini2024themodernmanagement pages 1-5). Novel therapies targeting molecular pathways and mutation-specific responses are under investigation (bulun2025uterinefibroids pages 1-5, micic2024currentlyavailabletreatment pages 1-2, ishikawa2023risingstarsrole pages 1-3).

Animal models including Eker rats, conditional MED12-mutant mice, hormone-induced models, and patient-derived xenografts facilitate mechanistic research and drug development (wu2026preclinicalresearchplatform pages 1-2). Future directions emphasize precision medicine leveraging molecular subtyping, multi-omics biomarkers, and non-hormonal targeted therapies to improve outcomes for this highly prevalent and morbid condition (buyukcelebi2024integratingleiomyomagenetics pages 1-2, ishikawa2023risingstarsrole pages 1-3, vannuccini2024themodernmanagement pages 1-5, boos2025therolesof pages 1-2).

References

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(bulun2025uterinefibroids pages 1-5): Serdar E. Bulun, Ping Yin, JianJun Wei, Azna Zuberi, Takashi Iizuka, Takuma Suzuki, Priyanka Saini, Jyoti Goad, J. Brandon Parker, Mazhar Adli, Thomas Boyer, Debabrata Chakravarti, and Aleksandar Rajkovic. Uterine fibroids. Oct 2025. URL: https://doi.org/10.1152/physrev.00010.2024, doi:10.1152/physrev.00010.2024. This article has 44 citations and is from a highest quality peer-reviewed journal.
(ishikawa2023risingstarsrole pages 1-3): Hiroshi Ishikawa, Tatsuya Kobayashi, Meika Kaneko, Yoshiko Saito, Makio Shozu, and Kaori Koga. Rising stars: role of med12 mutation in the pathogenesis of uterine fibroids. Journal of Molecular Endocrinology, Sep 2023. URL: https://doi.org/10.1530/jme-23-0039, doi:10.1530/jme-23-0039. This article has 20 citations and is from a peer-reviewed journal.
(koltsova2023aviewon pages 1-2): Alla Koltsova, Olga Efimova, and Anna Pendina. A view on uterine leiomyoma genesis through the prism of genetic, epigenetic and cellular heterogeneity. International Journal of Molecular Sciences, 24:5752, Mar 2023. URL: https://doi.org/10.3390/ijms24065752, doi:10.3390/ijms24065752. This article has 41 citations.
(centini2024tailoringthediagnostic pages 1-2): Gabriele Centini, Alberto Cannoni, Alessandro Ginetti, Irene Colombi, Matteo Giorgi, Giorgia Schettini, Francesco Giuseppe Martire, Lucia Lazzeri, and Errico Zupi. Tailoring the diagnostic pathway for medical and surgical treatment of uterine fibroids: a narrative review. Sep 2024. URL: https://doi.org/10.3390/diagnostics14182046, doi:10.3390/diagnostics14182046. This article has 28 citations.
(larrain2024newinsightsinto pages 1-3): Demetrio Larraín and Jaime Prado. New insights into molecular pathogenesis of uterine fibroids: from the lab to a clinician-friendly review. Soft Tissue Sarcoma and Leiomyoma - Diagnosis, Management, and New Perspectives, Jan 2024. URL: https://doi.org/10.5772/intechopen.1002969, doi:10.5772/intechopen.1002969. This article has 5 citations.
(buyukcelebi2024integratingleiomyomagenetics pages 1-2): Kadir Buyukcelebi, Alexander J. Duval, Fatih Abdula, Hoda Elkafas, Fidan Seker-Polat, and Mazhar Adli. Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-024-45382-0, doi:10.1038/s41467-024-45382-0. This article has 19 citations and is from a highest quality peer-reviewed journal.
(zhang2025globalregionaland pages 1-2): Zihan Zhang, Hongxin Huang, Kuanlie Jiang, Weixia Liu, Yan Xuan, and Wei Lu. Global, regional and national uterine fibroid burdens from 1990 to 2021 and projections until 2050: results from the gbd study. BMC Women's Health, Sep 2025. URL: https://doi.org/10.1186/s12905-025-03974-y, doi:10.1186/s12905-025-03974-y. This article has 6 citations.
(micic2024currentlyavailabletreatment pages 1-2): Jelena Micić, Maja Macura, Mladen Andjić, Katarina Ivanović, Jelena Dotlić, Dušan D. Micić, Vladimir Arsenijević, Jelena Stojnić, Jovan Bila, Sandra Babić, Una Šljivančanin, Danka Mostić Stanišić, and Milan Dokić. Currently available treatment modalities for uterine fibroids. Medicina, 60:868, May 2024. URL: https://doi.org/10.3390/medicina60060868, doi:10.3390/medicina60060868. This article has 79 citations.
(tang2025theglobalburden pages 1-2): Wei-Zhen Tang, Qin-Yu Cai, Kang-Jin Huang, Wei-Ze Xu, Jia-Zheng Li, Yun-Ren Pan, Hong-Yu Xu, Yi-Fan Zhao, Ting-He Sheng, Zhi-Mou Li, Tai-Hang Liu, and Ying-Bo Li. The global burden of polycystic ovary syndrome, endometriosis, uterine fibroids, cervical cancer, uterine cancer, and ovarian cancer from 1990 to 2021. BMC Public Health, May 2025. URL: https://doi.org/10.1186/s12889-025-22881-3, doi:10.1186/s12889-025-22881-3. This article has 39 citations and is from a peer-reviewed journal.
(chuang2023differentialexpressionof pages 1-2): Tsai-Der Chuang, Jianjun Gao, Derek Quintanilla, Hayden McSwiggin, Drake Boos, Wei Yan, and Omid Khorram. Differential expression of med12-associated coding rna transcripts in uterine leiomyomas. International Journal of Molecular Sciences, 24:3742, Feb 2023. URL: https://doi.org/10.3390/ijms24043742, doi:10.3390/ijms24043742. This article has 18 citations.
(dundr2022uterinecellularleiomyomas pages 1-2): Pavel Dundr, Mária Gregová, Jan Hojný, Eva Krkavcová, Romana Michálková, Kristýna Němejcová, Michaela Bártů, Nikola Hájková, Jan Laco, Michal Mára, Adéla Richtárová, Tomáš Zima, and Ivana Stružinská. Uterine cellular leiomyomas are characterized by common hmga2 aberrations, followed by chromosome 1p deletion and med12 mutation: morphological, molecular, and immunohistochemical study of 52 cases. Virchows Archiv, 480:281-291, Oct 2022. URL: https://doi.org/10.1007/s00428-021-03217-z, doi:10.1007/s00428-021-03217-z. This article has 27 citations and is from a peer-reviewed journal.
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(wu2026preclinicalresearchplatform pages 1-2): Dan Wu, Jian Luo, Li‐Yu Lin, Tingting Gu, and Zhehui You. Preclinical research platform for uterine leiomyoma: construction optimization and selection of animal models. Frontiers in Veterinary Science, Feb 2026. URL: https://doi.org/10.3389/fvets.2026.1772750, doi:10.3389/fvets.2026.1772750. This article has 1 citations and is from a peer-reviewed journal.
(vannuccini2024themodernmanagement pages 1-5): Silvia Vannuccini, Felice Petraglia, Francisco Carmona, Joaquim Calaf, and Charles Chapron. The modern management of uterine fibroids-related abnormal uterine bleeding. Fertility and Sterility, 122:20-30, Jul 2024. URL: https://doi.org/10.1016/j.fertnstert.2024.04.041, doi:10.1016/j.fertnstert.2024.04.041. This article has 103 citations and is from a highest quality peer-reviewed journal.

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Uterine Leiomyoma (Uterine Fibroids): Comprehensive Research Report

1. Disease Overview and Identifiers

2. Etiology

2a. Somatic genetic drivers (disease-causal factors)

2b. Risk Factors

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population Genetics

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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COMPREHENSIVE RESEARCH REPORT ON UTERINE LEIOMYOMA

Disease Characteristics Knowledge Base Entry

1. DISEASE INFORMATION

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2. ETIOLOGY

Disease Causal Factors