Adenomyosis

Complex MONDO:0010888 Pathograph 15 Show in embeddings browser uterine disease endometrium disease

Adenomyosis is the presence of endometrial glands and stroma within the myometrium, surrounded by hypertrophic and hyperplastic smooth muscle. It presents with dysmenorrhea, heavy menstrual bleeding, chronic pelvic pain, and impaired fertility, and it is a common cause of hysterectomy. Two competing origin theories dominate: invagination of the endometrial basalis into the myometrium through a disrupted endometrial-myometrial junction, and metaplasia of displaced Müllerian remnants or resident stem cells. Next-generation sequencing has shifted the balance decisively toward invagination, showing that adenomyotic epithelium carries the same KRAS activating mutations found in the matched intracavitary endometrium and lacking the driver mutations of uterine leiomyoma. Downstream, epigenetic reprogramming of the stromal compartment produces local aromatase-driven estrogen biosynthesis, signaling through estrogen receptor beta, and deficient progesterone receptor expression with consequent progesterone resistance — the same steroid-response lesion shared with endometriosis, and the reason progestin monotherapy often underperforms. Adenomyosis and endometriosis are closely related disorders that frequently coexist and share this pathophysiology.

Ask OpenScientist

Ask a research question about Adenomyosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

7
Pathophys.
1
Histopath.
6
Phenotypes
3
Hypotheses
2
Gaps
15
Pathograph
2
Genes
10
Medical Actions
2
Differentials
1
Deep Research
🏷

Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM
◈

Mechanistic Hypotheses

3
Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
invagination_tiar_model CANONICAL
Evidence balance 2 support
The dominant model holds that adenomyosis begins with microtrauma at the endometrial-myometrial interface, inflicted by chronic uterine peristalsis or hyperperistalsis. Injury activates the physiological tissue injury and repair (TIAR) response, including local estrogen production, which in an estrogen-sensitive organ feeds back to intensify peristalsis and perpetuate the injury. The basalis endometrium then invaginates into the myometrial wall. Molecular genetics supports this route: adenomyotic epithelium carries KRAS mutations shared with the matched eutopic endometrium, placing the origin of the lesion in intracavitary endometrial tissue rather than in situ within the myometrium.
Pathograph links
Uterine Hyperperistalsis and Junctional Zone Microtrauma -> Local Estrogen Production and TIAR Self-Perpetuation DIRECT Activation of the tissue injury and repair response at the injured interface induces local estrogen biosynthesis.
Local Estrogen Production and TIAR Self-Perpetuation -> Basalis Invagination and Myometrial Infiltration DIRECT Sustained auto-traumatization permits infiltration of basal endometrium into the depth of the myometrial wall.
Somatic KRAS Activation in Endometrial Epithelium -> Basalis Invagination and Myometrial Infiltration INDIRECT KNOWN INTERMEDIATES Mutant clones possess the survival and growth capability needed to establish and expand within the myometrium. Intermediates: KRAS-driven survival and proliferation of displaced endometrial epithelium.
Basalis Invagination and Myometrial Infiltration -> Lesional Fibrosis and Myofibroblast Transdifferentiation DIRECT Because adenomyotic lesions are wounds subjected to repeated injury and repair, the same EMT that drives invasion also feeds a fibroblast-to-myofibroblast programme that progressively fibroses the lesion.
Show evidence (2 references)
PMID:19644696 SUPPORT Human Clinical
"chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of 'tissue injury and repair' (TIAR)"
States the TIAR mechanism and localizes the initiating microtrauma to the endometrial-myometrial interface.
PMID:34131719 SUPPORT Human Clinical
"Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis."
Somatic mutation sharing between eutopic endometrium and adenomyotic lesions provides genetic evidence for an invagination origin.
Metaplasia of Müllerian remnants or resident stem/progenitor cells
metaplasia_stem_cell_model ALTERNATIVE
Evidence balance 2 support
The competing model holds that adenomyotic lesions arise de novo within the myometrium, by metaplastic differentiation of displaced embryonic pluripotent Müllerian remnants or of adult endometrial stem/progenitor cells resident in the myometrium, rather than by invasion from the uterine cavity. This model accounts more naturally for deep lesions with no demonstrable continuity with the basalis, but it is not supported by the somatic-mutation concordance between eutopic endometrium and adenomyotic epithelium.
Show evidence (2 references)
PMID:29566849 SUPPORT Human Clinical
"An alternative theory maintains that adenomyotic lesions result from metaplasia of displaced embryonic pluripotent Müllerian remnants or differentiation of adult stem cells."
States the metaplasia alternative that the review sets against the invagination theory.
PMID:34131719 SUPPORT Human Clinical
"there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium"
Confirms that the metaplasia model remains a live competing hypothesis even as sequencing data favor invagination.
Endometrial-myometrial interface disruption (EMID)
emid_model EMERGING
Evidence balance 1 support
A more recent reframing that shifts emphasis from how endometrial tissue gets into the myometrium to what breaches the interface in the first place. EMID holds that iatrogenic or obstetric disruption of the endometrial-myometrial interface is the initiating event, and is supported by epidemiologic data associating adenomyosis with uterine instrumentation and parturition, plus a mouse model. It also implicates Schwann cells in the interface region in lesion genesis, a cell type absent from both the invagination and metaplasia accounts. EMID is compatible with, rather than exclusive of, the TIAR-invagination model — it proposes a specific class of initiating injury for the same repair-driven cascade.
Show evidence (1 reference)
PMID:36099328 SUPPORT Human Clinical
"a new hypothesis, called endometrial-myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis"
Introduces EMID as a distinct pathogenesis hypothesis with epidemiologic and mouse-model support, and flags the Schwann-cell involvement unique to it. Note the quoted sentence spans both human epidemiologic data and a mouse model; the epidemiologic arm is the primary basis for the HUMAN_CLINICAL classification.
?

Discussions and Knowledge Gaps

2
Does adenomyosis arise by invagination of basalis endometrium through an injured junctional zone, or by metaplasia of Müllerian remnants and resident stem cells already within the myometrium?
CONTROVERSY OPEN adenomyosis_invagination_vs_metaplasia
Attached to
pathophysiology#Basalis Invagination and Myometrial Infiltration
The two theories predict different origins for the lesional epithelium and therefore different prevention strategies: reducing junctional zone microtrauma versus targeting a resident progenitor population. Next-generation sequencing has moved the field substantially toward invagination, because KRAS mutations map to both adenomyotic lesions and the matched intracavitary endometrium — hard to reconcile with an independent in-situ origin. The debate is nonetheless recorded as live rather than settled: deep lesions without demonstrable continuity with the basalis, and adenomyosis in women without evident junctional zone disruption, are not fully explained by invagination alone. The two mechanisms are not mutually exclusive and may account for different lesion subsets.
Proposed experiments
Spatially resolved clonal lineage mapping from cavity to deep lesion
exp_adenomyosis_clonal_lineage_mapping
Perform spatially resolved single-cell sequencing along a continuous transect from intracavitary endometrium through the junctional zone into deep adenomyotic lesions in hysterectomy specimens, testing whether lesional clones form a contiguous mutational gradient with the eutopic endometrium (invagination) or constitute independent clones lacking shared ancestry (metaplasia). Deep lesions without junctional zone continuity are the informative cases.
Show evidence (2 references)
PMID:29566849 SUPPORT Human Clinical
"Two main theories have been proposed to explain the origin of adenomyosis."
Frames the controversy as the central unresolved question in adenomyosis pathogenesis.
PMID:34131719 SUPPORT Human Clinical
"Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis."
The strongest current evidence favoring invagination over metaplasia.
Are epithelial-mesenchymal transition and collective cell migration sequential phases of a single invasive program in adenomyosis, or alternative programs operating in different lesions?
OPEN QUESTION OPEN adenomyosis_two_phase_invasion
Attached to
pathophysiology#Basalis Invagination and Myometrial Infiltration
EMT evidence comes from human lesions with mouse corroboration and is assigned to early progression; collective migration evidence comes from a baboon model and is assigned to later invasion. The temporal assignment rests on comparing findings across different species and model systems rather than on a single longitudinal series, so the ordering is an inference rather than an observation. Whether invasiveness is genuinely time-dependent — and if so, when the switch occurs — matters for whether an anti-EMT strategy would help established disease or only prevent early spread.
Show evidence (1 reference)
PMID:29566849 SUPPORT Human Clinical
"This suggests that the invasiveness of this complex uterine disorder is not driven by a single mechanism of migration but by a time-dependent combination of two processes."
States the two-process, time-dependent invasion model whose temporal structure remains to be demonstrated within a single system.
⚙

Pathophysiology

7
Uterine Hyperperistalsis and Junctional Zone Microtrauma
The endometrial-myometrial junction, visible on MRI as the junctional zone, is the site of initiating injury. Chronic uterine peristaltic activity, or episodic hyperperistalsis, inflicts repeated microtrauma at this interface, concentrated near the fundo-cornual raphe. Junctional zone thickening is the imaging correlate and the basis of non-invasive diagnosis. The model accommodates both early-onset disease, where an event early in reproductive life triggers hyperperistalsis, and late premenopausal adenomyosis, where cumulative normoperistalsis over decades produces equivalent microtraumatization.
Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
uterine smooth muscle cell CL:0002601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves uterine smooth muscle cell (CL:0002601). CL:0002601 is a cell type from the Cell Ontology.
wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↑ INCREASED
myometrium UBERON:0001296 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myometrium (UBERON:0001296). UBERON:0001296 is an anatomical location from the Uberon multi-species anatomy ontology. endometrium UBERON:0001295 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium (UBERON:0001295). UBERON:0001295 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Local Estrogen Production and TIAR Self-Perpetuation Activation of the tissue injury and repair response at the injured interface induces local estrogen biosynthesis. Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
Show evidence (2 references)
PMID:19644696 SUPPORT Human Clinical
"chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of 'tissue injury and repair' (TIAR)"
Identifies peristalsis-driven microtrauma at the junctional zone as the initiating lesion.
PMID:19644696 SUPPORT Human Clinical
"as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life leads to the same extent of microtraumatization"
Explains late premenopausal adenomyosis as cumulative injury from normal peristalsis, unifying early- and late-onset disease under one mechanism.
Local Estrogen Production and TIAR Self-Perpetuation
The tissue injury and repair response includes local estrogen production at the site of injury. Because uterine peristalsis is itself under ovarian steroid control, locally produced estrogen acts in a paracrine fashion to override that control, driving further hyperperistalsis and further injury. This feed-forward loop is what converts a self-limited repair response into a self-perpetuating disease process, and it explains why adenomyosis progresses across the reproductive years and regresses after menopause.
Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
estrogen biosynthetic process GO:0006703 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased estrogen biosynthetic process (GO:0006703). GO:0006703 is a biological process from the Gene Ontology. ↑ INCREASED cellular response to estrogen stimulus GO:0071391 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to estrogen stimulus (GO:0071391). GO:0071391 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Basalis Invagination and Myometrial Infiltration Sustained auto-traumatization permits infiltration of basal endometrium into the depth of the myometrial wall. Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
Aromatase-Driven Estrogen Signaling and Progesterone Resistance Local estrogen excess is reinforced at the molecular level by aberrant steroid receptor and aromatase expression in lesional stroma.
Show evidence (1 reference)
PMID:19644696 SUPPORT Human Clinical
"With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process."
Describes the paracrine estrogen feed-forward loop that makes the injury process self-sustaining.
Somatic KRAS Activation in Endometrial Epithelium
Adenomyotic epithelial cells carry activating KRAS mutations almost exclusively, and the same mutations map to matched intracavitary endometrial tissue — the genetic argument that the lesion originates from eutopic endometrium rather than arising in situ. Mutations are restricted to endometrial-type epithelial cells and are absent from the surrounding smooth muscle; conversely, the driver mutations characteristic of uterine fibroids are not found in adenomyosis, separating the two commonest myometrial disorders at the molecular level. Activated KRAS signaling increases cell survival and proliferation and is associated with progesterone resistance.
Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
glandular epithelial cell of endometrium CL:0009084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glandular epithelial cell of endometrium (CL:0009084). CL:0009084 is a cell type from the Cell Ontology.
KRAS hgnc:6407 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee.
Ras protein signal transduction GO:0007265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Basalis Invagination and Myometrial Infiltration Mutant clones possess the survival and growth capability needed to establish and expand within the myometrium. Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
Show evidence (3 references)
PMID:34131719 SUPPORT Human Clinical
"KRAS and other less frequent mutations are limited to endometrial-type epithelial cells."
Localizes the somatic driver to the epithelial compartment, not the myometrial smooth muscle.
PMID:34131719 SUPPORT Human Clinical
"Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis."
Links the KRAS driver to the survival/proliferation advantage and to the progesterone-resistant phenotype.
PMID:34131719 SUPPORT Human Clinical
"Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis."
Molecular separation of adenomyosis from uterine leiomyoma, its main clinical mimic.
Basalis Invagination and Myometrial Infiltration
Endometrial basalis glands and stroma invaginate into and infiltrate the myometrial wall. Invasion is not driven by a single migratory program: epithelial-mesenchymal transition is implicated in the early stages of progression and spread, while collective cell migration appears to mediate the later invasive events, making invasiveness a time-dependent combination of two processes. Lesions develop predominantly in the median region of the upper two-thirds of the uterine wall.
Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
glandular epithelial cell of endometrium CL:0009084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glandular epithelial cell of endometrium (CL:0009084). CL:0009084 is a cell type from the Cell Ontology. endometrial stromal cell CL:0002255 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial stromal cell, annotated with stromal cell of endometrium (CL:0002255). CL:0002255 is a cell type from the Cell Ontology.
epithelial to mesenchymal transition GO:0001837 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epithelial to mesenchymal transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology. ↑ INCREASED cell migration GO:0016477 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell migration (GO:0016477). GO:0016477 is a biological process from the Gene Ontology. ↑ INCREASED
myometrium UBERON:0001296 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myometrium (UBERON:0001296). UBERON:0001296 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Myometrial Hypertrophy and Uterine Enlargement Ectopic endometrial islands provoke hypertrophy and hyperplasia of the surrounding smooth muscle.
Lesional Fibrosis and Myofibroblast Transdifferentiation Because adenomyotic lesions are wounds subjected to repeated injury and repair, the same EMT that drives invasion also feeds a fibroblast-to-myofibroblast programme that progressively fibroses the lesion. Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
Show evidence (3 references)
PMID:29566849 SUPPORT Human Clinical
"Previous investigations performed in human adenomyotic lesions and corroborated by studies in mice supported the involvement of the epithelial-mesenchymal transition process in the early stages of progression and spread of adenomyosis."
Establishes EMT as the early invasive mechanism in human lesions with mouse corroboration.
PMID:29566849 SUPPORT Model Organism
"studies conducted in a recently developed baboon model indicate that collective cell migration may be implicated in the later events of invasion"
Baboon model evidence that a second, collective-migration mechanism operates in later invasion, distinct from EMT.
PMID:19644696 SUPPORT Human Clinical
"Overt auto-traumatization of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues."
Describes myometrial infiltration of basalis endometrium as the consequence of sustained auto-traumatization.
Lesional Fibrosis and Myofibroblast Transdifferentiation
Adenomyotic lesions behave as wounds undergoing repeated tissue injury and repair, and their natural history is progressive fibrosis via three linked routes: epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. This is the same central-effector step conserved across organs in the fibrotic_response module, with the uterine specialization that smooth muscle metaplasia contributes alongside classical myofibroblast conversion. Fibrosis is not confined to the lesion: it propagates into the neighbouring endometrial-myometrial interface and endometrium, which is what converts a focal lesion into the diffuse uterine phenotype and links the lesion directly to heavy menstrual bleeding.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology. uterine smooth muscle cell CL:0002601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves uterine smooth muscle cell (CL:0002601). CL:0002601 is a cell type from the Cell Ontology.
epithelial to mesenchymal transition GO:0001837 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epithelial to mesenchymal transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology. ↑ INCREASED extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ⚠ ABNORMAL
myometrium UBERON:0001296 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myometrium (UBERON:0001296). UBERON:0001296 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Myometrial Hypertrophy and Uterine Enlargement Myofibroblast-driven matrix deposition and smooth muscle metaplasia together generate the stiff, hypertrophic myometrium around lesions.
Show evidence (2 references)
PMID:36099328 SUPPORT Human Clinical
"adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia"
States the three-route fibrotic programme and frames adenomyotic lesions as repeatedly injured wounds, the basis for conformance to the fibrotic_response module.
PMID:36099328 SUPPORT Human Clinical
"Increasing lesional fibrosis propagates into the neighboring EMI and endometrium."
Establishes spread of fibrosis beyond the lesion into the interface and endometrium, the step that couples lesional fibrosis to the endometrial bleeding phenotype.
Aromatase-Driven Estrogen Signaling and Progesterone Resistance
Epigenetic abnormalities in lesional stromal cells produce an abnormal nuclear receptor expression pattern. The consequences are excessive local estrogen biosynthesis by aromatase, abnormal estrogen action routed through estrogen receptor beta, and deficient progesterone receptor expression yielding progesterone resistance. This receptor lesion is shared with endometriosis and is clinically consequential: it is the mechanistic reason progestin-based therapy is variably effective, and the rationale for combining or substituting agents that lower estrogen exposure.
endometrial stromal cell CL:0002255 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial stromal cell, annotated with stromal cell of endometrium (CL:0002255). CL:0002255 is a cell type from the Cell Ontology.
estrogen biosynthetic process GO:0006703 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased estrogen biosynthetic process (GO:0006703). GO:0006703 is a biological process from the Gene Ontology. ↑ INCREASED response to progesterone GO:0032570 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased response to progesterone (GO:0032570). GO:0032570 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Myometrial Hypertrophy and Uterine Enlargement Sustained local estrogen excess drives the smooth muscle response around ectopic endometrial islands.
Show evidence (2 references)
PMID:36925057 SUPPORT Human Clinical
"These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-β."
Specifies aromatase-driven local estrogen excess and ER-beta-routed signaling as the downstream consequence of stromal epigenetic defects.
PMID:36925057 SUPPORT Human Clinical
"Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis."
Establishes progesterone resistance and its receptor-level basis, shared with endometriosis.
Myometrial Hypertrophy and Uterine Enlargement
Islands of ectopic endometrial tissue within the myometrium are surrounded by hypertrophic smooth muscle. The resulting globular uterine enlargement, distorted architecture, and disrupted junctional zone produce the clinical syndrome: dysmenorrhea, excessive uterine bleeding with consequent anemia, and impaired implantation. Lesional neuroangiogenesis and chronic inflammation contribute to the pain phenotype.
uterine smooth muscle cell CL:0002601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves uterine smooth muscle cell (CL:0002601). CL:0002601 is a cell type from the Cell Ontology.
uterine smooth muscle cell proliferation GO:0048659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased uterine smooth muscle cell proliferation, annotated with smooth muscle cell proliferation (GO:0048659). GO:0048659 is a biological process from the Gene Ontology. ↑ INCREASED angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
myometrium UBERON:0001296 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myometrium (UBERON:0001296). UBERON:0001296 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:34131719 SUPPORT Human Clinical
"Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of diagnosis and management."
Defines the characteristic histopathology of endometrial islands ringed by hypertrophic smooth muscle.
PMID:34131719 SUPPORT Human Clinical
"Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility."
Links the structural lesion to the four cardinal clinical manifestations.
✶

Histopathology

1
Endometrial glands and stroma within the myometrium
The defining histological finding is islands of endometrial glands and accompanying stroma located within the myometrium, beyond the normal endometrial-myometrial interface, encircled by hypertrophic and hyperplastic smooth muscle. Diagnosis was historically made only on hysterectomy specimens, which is the principal reason prevalence estimates vary so widely; MRI and transvaginal ultrasound now permit non-invasive diagnosis based on junctional zone thickening and myometrial architecture.
Show evidence (1 reference)
PMID:34131719 SUPPORT Human Clinical
"Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium"
States the defining histopathological criterion for adenomyosis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adenomyosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 2
Heavy menstrual bleeding Menorrhagia HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34131719 SUPPORT Human Clinical
"Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility."
Lists excessive uterine bleeding among the cardinal presenting features.
PMID:36099328 SUPPORT Human Clinical
"The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB."
Supplies the mechanism linking lesional fibrosis to heavy menstrual bleeding — stiffness-driven failure of endometrial repair rather than simple surface-area or contractility effects.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34131719 SUPPORT Human Clinical
"Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility."
Lists anemia as a recognized manifestation, consequent on heavy bleeding.
Genitourinary 2
Dyspareunia HP:0030016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspareunia (HP:0030016). HP:0030016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"reduction in pelvic pain (dysmenorrhea, dyspareunia, chronic pelvic pain)"
National guideline lists dyspareunia among the pain outcomes targeted in adenomyosis, establishing it as a recognized component of the phenotype.
Infertility and impaired IVF outcomes HP:0000789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infertility (HP:0000789). HP:0000789 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28865548 SUPPORT Human Clinical
"The rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live birth among women with adenomyosis were significantly lower than in those without adenomyosis."
Meta-analysis of 11 comparative studies quantifying reduced IVF success across every fertility outcome measured.
PMID:28865548 SUPPORT Human Clinical
"The miscarriage rate in women with adenomyosis was higher than in those without adenomyosis."
Documents increased pregnancy loss as a distinct component of the fertility phenotype.
Constitutional 2
Dysmenorrhea HP:0100607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmenorrhea (HP:0100607). HP:0100607 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29566849 SUPPORT Human Clinical
"Adenomyosis is a commonly diagnosed estrogen-dependent gynecological disorder that causes pelvic pain, abnormal uterine bleeding, and infertility."
Confirms pain as a cardinal manifestation of adenomyosis.
PMID:25241270 SUPPORT Human Clinical
"Cystic cornual angle adenomyosis was a distinct phenomenon that was only observed in patients suffering from extreme primary dysmenorrhea."
Associates a specific adenomyotic lesion subtype with the most severe dysmenorrhea phenotype.
Pelvic pain HP:0034267 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pelvic pain (HP:0034267). HP:0034267 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29566849 SUPPORT Human Clinical
"Adenomyosis is a commonly diagnosed estrogen-dependent gynecological disorder that causes pelvic pain, abnormal uterine bleeding, and infertility."
Confirms pelvic pain as a defining clinical feature.
🧬

Genetic Associations

2
KRAS (Activating somatic KRAS mutations are the characteristic genetic lesion of adenomyosis, confined to endometrial-type epithelial cells and shared with matched eutopic endometrium and with endometriosis, while absent from the driver landscape of uterine leiomyoma. They confer survival and proliferative advantage and are associated with progesterone resistance.)
Gene: KRAS hgnc:6407 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER
Show evidence (4 references)
PMID:36925057 SUPPORT Human Clinical
"Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations."
Establishes KRAS as the near-exclusive somatic driver in adenomyotic epithelium.
PMID:34131719 SUPPORT Human Clinical
"Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis."
Connects the KRAS driver to both the growth advantage and the progesterone-resistant treatment phenotype.
PMID:31857578 SUPPORT Human Clinical
"Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis."
Multi-regional sequencing establishes adenomyosis as oligoclonal and finds shared mutations in normal endometrium, independently reinforcing the invagination origin.
+ 1 more reference
ARID1A (ARID1A, a SWI/SNF chromatin-remodelling subunit, is the second most frequently mutated gene in adenomyotic lesions after KRAS. Its loss is a recurrent event across endometriosis-associated lesions generally, consistent with the shared mutational signature between adenomyosis and deep infiltrating endometriosis.)
Gene: ARID1A hgnc:11110 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARID1A (hgnc:11110). hgnc:11110 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER
Show evidence (1 reference)
PMID:36708516 SUPPORT Human Clinical
"These findings indicate that mutations in the KRAS, ARID1A, FBXW7 and STAG2 genes may play a critical role in the pathogenesis of adenomyosis."
Names ARID1A among the somatic drivers implicated in adenomyosis pathogenesis.
💊

Medical Actions

10
Dienogest
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dienogest CHEBI:70708 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dienogest (CHEBI:70708). CHEBI:70708 is a therapeutic agent from Chemical Entities of Biological Interest.
Dienogest, an oral progestin, ranked as the most effective hormonal option for adenomyosis-associated pelvic pain in a network meta-analysis of randomized trials, outperforming both placebo and the levonorgestrel intrauterine system at 3 months on visual analog scale pain scores.
Mechanism Target:
INHIBITS Local Estrogen Production and TIAR Self-Perpetuation — Progestin-induced decidualization and subsequent endometrial atrophy, together with suppression of ovulatory estrogen exposure, reduce the estrogen drive sustaining the lesion.
Show evidence (2 references)
PMID:40166680 SUPPORT Human Clinical
"At 3 months, women who received a placebo or a levonorgestrel-based intrauterine system (LNG-IUS) experienced more AAPP than those who received dienogest"
Network meta-analysis of randomized trials ranking dienogest above both placebo and LNG-IUS for adenomyosis-associated pelvic pain at 3 months.
PMID:31857578 SUPPORT In Vitro
"DNG's anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS."
Qualifies the efficacy evidence above: KRAS-mutant lesions may respond less well to dienogest because mutant KRAS drives epigenetic PR silencing. Shown in immortalized cells, hence IN_VITRO, so this is a mechanistic caveat rather than established clinical stratification.
Levonorgestrel-releasing intrauterine system
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levonorgestrel CHEBI:6443 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levonorgestrel (CHEBI:6443). CHEBI:6443 is a therapeutic agent from Chemical Entities of Biological Interest.
The LNG-IUS delivers progestin locally to the endometrium, reducing menstrual blood loss and pain while preserving the uterus. It is a mainstay of conservative management, though the randomized evidence places it behind dienogest for pain control at 3 months.
Mechanism Target:
INHIBITS Local Estrogen Production and TIAR Self-Perpetuation — Local progestin exposure induces endometrial atrophy, opposing the estrogen-driven proliferative signal at the lesion.
Show evidence (1 reference)
PMID:40166680 SUPPORT Human Clinical
"At 3 months, women who received a placebo or a levonorgestrel-based intrauterine system (LNG-IUS) experienced more AAPP than those who received dienogest"
Places LNG-IUS behind dienogest for pain control at 3 months in the randomized evidence, while remaining a widely used uterus-sparing option.
GnRH agonist therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: leuprolide CHEBI:6427 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses leuprolide (CHEBI:6427). CHEBI:6427 is a therapeutic agent from Chemical Entities of Biological Interest.
GnRH agonists induce a hypoestrogenic state that suppresses the estrogen drive sustaining the lesion. Beyond symptom control, long-term GnRH agonist pretreatment before embryo transfer improves fertility outcomes in women with adenomyosis, and appears to increase spontaneous pregnancy rates.
Mechanism Target:
INHIBITS Aromatase-Driven Estrogen Signaling and Progesterone Resistance — Ovarian suppression removes the systemic estrogen supply that compounds local aromatase-derived estrogen at the lesion.
Show evidence (2 references)
PMID:28865548 SUPPORT Human Clinical
"Pretreatment with the use of long-term GnRHa or long protocol could be beneficial."
Meta-analytic conclusion supporting GnRH agonist pretreatment to improve IVF outcomes in adenomyosis.
PMID:28865548 SUPPORT Human Clinical
"It appears that surgical treatment or treatment withf GnRHa increases the spontaneous pregnancy rate in women with adenomyosis."
Reports improved spontaneous pregnancy rates with GnRH agonist or surgical treatment. The quoted sentence contains a typographical error present in the published abstract.
Combined oral contraceptives
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: oral contraceptive NCIT:C389 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses oral contraceptive (NCIT:C389). NCIT:C389 is a therapeutic agent from the NCI Thesaurus.
Combined oral contraceptives are a first-line medical option for adenomyosis-associated heavy menstrual bleeding and pain, suppressing ovulatory cycling and inducing endometrial atrophy.
Mechanism Target:
INHIBITS Local Estrogen Production and TIAR Self-Perpetuation — Suppressing ovulatory cycling removes the systemic steroid drive on which lesion severity depends.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"medical options (non-steroidal anti-inflammatory drugs, tranexamic acid, combined oral contraceptives, levonorgestrel intrauterine system, dienogest, other progestins, gonadotropin-releasing analogues)"
National guideline listing combined oral contraceptives among recommended medical options for adenomyosis.
Non-steroidal anti-inflammatory drugs
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: nonsteroidal anti-inflammatory drug NCIT:C257 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nonsteroidal anti-inflammatory drug, annotated with Nonsteroidal Antiinflammatory Drug (NCIT:C257). NCIT:C257 is a therapeutic agent from the NCI Thesaurus.
NSAIDs reduce prostaglandin-mediated dysmenorrhea and menstrual blood loss. Like tranexamic acid they act on the symptom endpoint rather than the lesion, so they carry no target_mechanisms link.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"medical options (non-steroidal anti-inflammatory drugs, tranexamic acid, combined oral contraceptives, levonorgestrel intrauterine system, dienogest, other progestins, gonadotropin-releasing analogues)"
National guideline listing NSAIDs first among recommended medical options for adenomyosis.
Tranexamic acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest.
An antifibrinolytic used symptomatically for heavy menstrual bleeding. It does not act on the adenomyotic lesion, so it carries no target_mechanisms link — it treats the bleeding endpoint rather than the mechanism producing it.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"medical options (non-steroidal anti-inflammatory drugs, tranexamic acid, combined oral contraceptives, levonorgestrel intrauterine system, dienogest, other progestins, gonadotropin-releasing analogues)"
National guideline listing tranexamic acid among recommended medical options for adenomyosis-associated bleeding.
Uterine artery embolization
Action: uterine artery embolizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is uterine artery embolization, annotated with Embolization Therapy (NCIT:C15230). NCIT:C15230 is a clinical intervention from the NCI Thesaurus. Ontology label: Embolization Therapy NCIT:C15230
Catheter-directed embolization of the uterine arteries devascularizes adenomyotic lesions while preserving the uterus. It is the interventional middle ground between medical therapy and hysterectomy, and lesion vascularity is itself a predictor of response.
Mechanism Target:
INHIBITS Myometrial Hypertrophy and Uterine Enlargement — Devascularization induces infarction and shrinkage of the hypertrophic, hypervascular lesional myometrium.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"interventional options (uterine artery embolization)"
National guideline recognizing uterine artery embolization as an established interventional option.
Endometrial ablation
Action: endometrial ablationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is endometrial ablation (NCIT:C157834). NCIT:C157834 is a clinical intervention from the NCI Thesaurus. Ontology label: Endometrial Ablation NCIT:C157834
Destruction of the endometrial lining to control heavy menstrual bleeding. Because adenomyotic tissue lies within the myometrium beyond the reach of an ablation, it addresses the bleeding endpoint rather than the lesion, and outcomes are less durable than in bleeding without adenomyosis.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"surgical options (endometrial ablation, excision of adenomyosis, hysterectomy)"
National guideline listing endometrial ablation among surgical options.
Hysterectomy
Action: hysterectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hysterectomy (NCIT:C15256). NCIT:C15256 is a clinical intervention from the NCI Thesaurus. Ontology label: Hysterectomy NCIT:C15256
Hysterectomy is definitive treatment for adenomyosis and remains a common endpoint for women with severe symptoms who have completed childbearing. It was also historically the only route to a confirmed diagnosis, which is why older prevalence estimates are drawn from surgical series and are not generalizable.
Mechanism Target:
INHIBITS Basalis Invagination and Myometrial Infiltration — Removal of the uterus eliminates the diseased organ outright — definitive rather than mechanism-modifying, and the reason it remains the endpoint for refractory disease.
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"surgical options (endometrial ablation, excision of adenomyosis, hysterectomy)"
National guideline listing hysterectomy among the surgical options for adenomyosis.
Uterus-sparing conservative surgery
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Adenomyomectomy and related cytoreductive techniques excise or reduce adenomyotic tissue while preserving the uterus, offered to women who wish to retain fertility. Surgical treatment appears to increase spontaneous pregnancy rates.
Mechanism Target:
INHIBITS Basalis Invagination and Myometrial Infiltration — Direct excision of infiltrating adenomyotic tissue reduces lesion burden while preserving the uterus.
Show evidence (1 reference)
PMID:28865548 SUPPORT Human Clinical
"It appears that surgical treatment or treatment withf GnRHa increases the spontaneous pregnancy rate in women with adenomyosis."
Supports conservative surgery as a fertility-directed intervention. The quoted sentence contains a typographical error present in the published abstract.
🌍

Environmental Factors

1
Ovulatory cycling and cumulative estrogen exposure
Adenomyosis is estrogen-dependent and its severity tracks with ovarian steroid exposure and ovulatory cycles — a feature that distinguishes it from many other uterine disorders and underlies both its progression through the reproductive years and its regression after menopause or ovarian suppression.
Show evidence (1 reference)
PMID:34131719 SUPPORT Human Clinical
"Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis."
States the steroid- and cycle-dependence of disease severity, the basis for hormonal and surgical treatment strategies.
🔬

Diagnosis

1
Transvaginal sonography and MRI
Adenomyosis is now diagnosed non-invasively. Transvaginal sonography is the first-line modality and MRI the adjunct, with junctional zone thickening the principal MRI criterion. This replaced the historical position in which diagnosis required a hysterectomy specimen — the single biggest reason older prevalence estimates are not comparable with modern ones.
transvaginal sonography and MRI NCIT:C16502 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37244746 SUPPORT Human Clinical
"Diagnostic options include transvaginal sonography and magnetic resonance imaging."
National guideline establishing the two accepted non-invasive diagnostic modalities for adenomyosis.
🩻

Imaging Findings

1
Junctional zone thickening on MRI
Thickening of the junctional zone — the inner myometrium adjacent to the endometrium — is the principal MRI criterion for adenomyosis. Careful multiplanar visualization is required to distinguish true adenomyotic lesions from transient junctional zone enlargement caused by peristaltic waves or sporadic myometrial contractions, which otherwise mimic the diagnosis.
Show evidence (2 references)
PMID:25241270 SUPPORT Human Clinical
"By this method of "visualization" all transient enlargement of the JZ, such as peristaltic waves of the archimyometrium and sporadic neometral contractions that might mimic adenomyotic lesions could be excluded."
Documents the imaging pitfall — transient peristaltic junctional zone enlargement mimicking adenomyosis — and the visualization method used to avoid it.
PMID:25241270 SUPPORT Human Clinical
"As concluded from their localization within the uterine wall, the adenomyotic lesions predominantly developed in the median region of the upper two-thirds of the uterine wall."
Establishes the characteristic anatomical distribution of adenomyotic lesions on MRI.
📊

Prevalence

6
Worldwide, general population
Point Prevalence 1000.0 per 100,000 (0.0–2000.0) >1 in 1,000
Pooled general-population prevalence 1% (95% CI 0-2%) from 59 adenomyosis studies. Note the very wide interval and the contrast with the symptom-selected and imaging-selected estimates below — ascertainment, not biology, drives most of the spread.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"The global prevalence of adenomyosis and endometriosis in the general population worldwide is 1% (95%CI, 0%-2%), and 5% (95%CI, 2%-9%), respectively."
Meta-analysis of 127 studies covering ~199 million women, giving the general-population baseline.
Women with infertility
Point Prevalence 31000.0 per 100,000 (10000.0–58000.0) >1 in 1,000
Pooled prevalence 31% (95% CI 10-58%) among women presenting with infertility.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"The prevalence of adenomyosis and endometriosis among women experiencing infertility was 31% (95%CI, 10%-58%) and 38% (95%CI, 25%-51%), respectively."
Quantifies the strong enrichment of adenomyosis in infertile populations, complementing the IVF-outcome data curated under the infertility phenotype.
Worldwide, focal adenomyosis
Point Prevalence 17000.0 per 100,000 (7000.0–30000.0) >1 in 1,000
Pooled prevalence of the focal subtype, 17% (95% CI 7-30%); the diffuse subtype was 15% (95% CI 9-23%) in the same analysis.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"The prevalence of focal and diffuse adenomyosis was found to be 17% (95%CI, 7%-30%) and 15% (95%CI, 9%-23%), respectively."
Subtype-resolved pooled prevalence for focal versus diffuse adenomyosis.
Worldwide, histopathology-diagnosed series
Point Prevalence 35100.0 per 100,000 (30900.0–39400.0) >1 in 1,000
Ascertainment-stratified. Histopathology 35.1% and MRI 35.0% both exceed ultrasound at 30.7% — the quantitative anchor for the ascertainment caveat recorded under epidemiology, and the reason estimates from surgical series are not comparable with imaging-based ones.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"histopathology (35.1%; 95%CI, 30.9%−39.4%) and MRI (35.0%; 95%CI, 22.6%−48.4%) reveal a greater prevalence of adenomyosis compared to ultrasound (30.7%; 95%CI, 25.2%−48.4%)"
Modality-stratified subgroup analysis quantifying how much of the spread in reported prevalence is attributable to diagnostic method.
Worldwide, ultrasound-diagnosed series
Point Prevalence 30700.0 per 100,000 (25200.0–48400.0) >1 in 1,000
Lowest of the three diagnostic modalities in the same subgroup analysis.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"histopathology (35.1%; 95%CI, 30.9%−39.4%) and MRI (35.0%; 95%CI, 22.6%−48.4%) reveal a greater prevalence of adenomyosis compared to ultrasound (30.7%; 95%CI, 25.2%−48.4%)"
Same subgroup analysis; ultrasound, the most widely used first-line modality, yields the lowest pooled estimate.
Women undergoing hysterectomy for benign indications
Point Prevalence 42300.0 per 100,000 (35800.0–48900.0) >1 in 1,000
42.3% versus 31.9% when the hysterectomy was performed for malignant indications — selection bias made numerical, and the clearest single illustration of why hysterectomy-series prevalence overstates the population figure.
Show evidence (1 reference)
PMID:41257733 SUPPORT Human Clinical
"(42.3%; 95%CI, 35.8%−48.9%) than among those who have the procedure for malignant conditions (31.9%; 95%CI, 15.1%−51.4%)"
Quantifies the surgical-indication selection effect underlying historical hysterectomy-based prevalence estimates.
🌍

Epidemiology

1
Diagnostic ascertainment and prevalence uncertainty
Adenomyosis prevalence estimates vary widely because the diagnosis was historically confined to hysterectomy specimens, biasing series toward severe symptomatic disease in older parous women. Imaging-based diagnosis has broadened ascertainment but introduced its own variability, since junctional zone criteria differ between studies and transient peristaltic junctional zone enlargement can mimic disease. Adenomyosis remains, on the authors' assessment, among the most challenging uterine disorders to diagnose.
Show evidence (2 references)
PMID:34131719 SUPPORT Human Clinical
"is one of the most challenging uterine disorders in terms of diagnosis and management"
Characterizes the diagnostic difficulty that underlies the wide spread of published prevalence estimates.
PMID:25241270 SUPPORT Human Clinical
"this method allowed to lower the limit of detection in terms of thickness of the JZ for assured diagnosis of adenomyosis"
Shows that the detection threshold used for the junctional zone directly determines how many cases are ascertained, a methodological driver of prevalence variation.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Adenomyosis:

Uterine leiomyoma
Overlapping Features Uterine fibroids are the principal clinical mimic, sharing heavy menstrual bleeding, pelvic pain, and uterine enlargement. The two are separable molecularly: the driver mutations of uterine fibroid smooth muscle are absent from adenomyosis, whose driver (KRAS) is confined to endometrial-type epithelium. Imaging distinguishes the diffuse, ill-defined junctional zone thickening of adenomyosis from the discrete, well-circumscribed leiomyoma.
Show evidence (1 reference)
PMID:34131719 SUPPORT Human Clinical
"Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis."
Molecular basis for distinguishing adenomyosis from its principal differential diagnosis.
Endometriosis
Overlapping Features Endometriosis is not so much a differential as a frequent co-diagnosis with shared pathophysiology; in one MRI series the prevalence of endometriosis in adenomyosis was 80.6% and of adenomyosis in endometriosis 91.1%. Both arise from eutopic endometrium, both carry KRAS-mutant epithelial clones, and both show the same stromal epigenetic lesion producing local estrogen excess and progesterone resistance. They differ in destination: peritoneal or ovarian surfaces via retrograde menstruation versus entrapment in the myometrium.
Show evidence (2 references)
PMID:36925057 SUPPORT Human Clinical
"Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis."
States the common origin and the single branch point that separates endometriosis from adenomyosis.
PMID:25241270 SUPPORT Human Clinical
"The prevalence of endometriosis in adenomyosis was 80.6% and the prevalence of adenomyosis in endometriosis was 91.1%."
Quantifies the near-universal co-occurrence of the two conditions in an MRI-based series, supporting shared pathogenesis.
{ }

Source YAML

click to show 
name: Adenomyosis
creation_date: '2026-08-02T12:00:00Z'
category: Complex
synonyms:
- adenomyosis uteri
- endometriosis interna
- uterine adenomyosis
description: >-
  Adenomyosis is the presence of endometrial glands and stroma within the
  myometrium, surrounded by hypertrophic and hyperplastic smooth muscle. It
  presents with dysmenorrhea, heavy menstrual bleeding, chronic pelvic pain, and
  impaired fertility, and it is a common cause of hysterectomy. Two competing
  origin theories dominate: invagination of the endometrial basalis into the
  myometrium through a disrupted endometrial-myometrial junction, and metaplasia
  of displaced Müllerian remnants or resident stem cells. Next-generation
  sequencing has shifted the balance decisively toward invagination, showing
  that adenomyotic epithelium carries the same KRAS activating mutations found
  in the matched intracavitary endometrium and lacking the driver mutations of
  uterine leiomyoma. Downstream, epigenetic reprogramming of the stromal
  compartment produces local aromatase-driven estrogen biosynthesis, signaling
  through estrogen receptor beta, and deficient progesterone receptor expression
  with consequent progesterone resistance — the same steroid-response lesion
  shared with endometriosis, and the reason progestin monotherapy often
  underperforms. Adenomyosis and endometriosis are closely related disorders
  that frequently coexist and share this pathophysiology.
disease_term:
  preferred_term: adenomyosis
  term:
    id: MONDO:0010888
    label: adenomyosis
parents:
- uterine disease
- endometrium disease
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
mechanistic_hypotheses:
- hypothesis_group_id: invagination_tiar_model
  hypothesis_label: Basalis invagination driven by tissue injury and repair at the endometrial-myometrial junction
  status: CANONICAL
  description: >-
    The dominant model holds that adenomyosis begins with microtrauma at the
    endometrial-myometrial interface, inflicted by chronic uterine peristalsis
    or hyperperistalsis. Injury activates the physiological tissue injury and
    repair (TIAR) response, including local estrogen production, which in an
    estrogen-sensitive organ feeds back to intensify peristalsis and perpetuate
    the injury. The basalis endometrium then invaginates into the myometrial
    wall. Molecular genetics supports this route: adenomyotic epithelium carries
    KRAS mutations shared with the matched eutopic endometrium, placing the
    origin of the lesion in intracavitary endometrial tissue rather than in situ
    within the myometrium.
  evidence:
  - reference: PMID:19644696
    reference_title: "The pathophysiology of endometriosis and adenomyosis: tissue injury and repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic uterine peristaltic activity or phases of hyperperistalsis induce,
      at the endometrial-myometrial interface near the fundo-cornual raphe,
      microtraumatizations with the activation of the mechanism of 'tissue
      injury and repair' (TIAR)
    explanation: >-
      States the TIAR mechanism and localizes the initiating microtrauma to the
      endometrial-myometrial interface.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of KRAS map to both intracavitary endometrial tissue and
      proximally located adenomyotic samples, supporting the invagination theory
      of pathogenesis.
    explanation: >-
      Somatic mutation sharing between eutopic endometrium and adenomyotic
      lesions provides genetic evidence for an invagination origin.
- hypothesis_group_id: metaplasia_stem_cell_model
  hypothesis_label: Metaplasia of Müllerian remnants or resident stem/progenitor cells
  status: ALTERNATIVE
  description: >-
    The competing model holds that adenomyotic lesions arise de novo within the
    myometrium, by metaplastic differentiation of displaced embryonic
    pluripotent Müllerian remnants or of adult endometrial stem/progenitor cells
    resident in the myometrium, rather than by invasion from the uterine cavity.
    This model accounts more naturally for deep lesions with no demonstrable
    continuity with the basalis, but it is not supported by the somatic-mutation
    concordance between eutopic endometrium and adenomyotic epithelium.
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An alternative theory maintains that adenomyotic lesions result from
      metaplasia of displaced embryonic pluripotent Müllerian remnants or
      differentiation of adult stem cells.
    explanation: >-
      States the metaplasia alternative that the review sets against the
      invagination theory.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is continuing debate on the origins of adenomyosis; two competing
      theories describe the invagination of basal endometrium into the
      myometrium or the metaplastic differentiation of remnant endometrial
      stem/progenitor cells within the myometrium
    explanation: >-
      Confirms that the metaplasia model remains a live competing hypothesis
      even as sequencing data favor invagination.
- hypothesis_group_id: emid_model
  hypothesis_label: Endometrial-myometrial interface disruption (EMID)
  status: EMERGING
  description: >-
    A more recent reframing that shifts emphasis from how endometrial tissue
    gets into the myometrium to what breaches the interface in the first place.
    EMID holds that iatrogenic or obstetric disruption of the
    endometrial-myometrial interface is the initiating event, and is supported
    by epidemiologic data associating adenomyosis with uterine instrumentation
    and parturition, plus a mouse model. It also implicates Schwann cells in the
    interface region in lesion genesis, a cell type absent from both the
    invagination and metaplasia accounts. EMID is compatible with, rather than
    exclusive of, the TIAR-invagination model — it proposes a specific class of
    initiating injury for the same repair-driven cascade.
  evidence:
  - reference: PMID:36099328
    reference_title: "Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a new hypothesis, called endometrial-myometrial interface disruption
      (EMID), which is backed by extensive epidemiologic data and demonstrated
      by a mouse model, is reviewed, along with recent data implicating the role
      of Schwann cells in the EMI area in the genesis of adenomyosis
    explanation: >-
      Introduces EMID as a distinct pathogenesis hypothesis with epidemiologic
      and mouse-model support, and flags the Schwann-cell involvement unique to
      it. Note the quoted sentence spans both human epidemiologic data and a
      mouse model; the epidemiologic arm is the primary basis for the
      HUMAN_CLINICAL classification.
pathophysiology:
- name: Uterine Hyperperistalsis and Junctional Zone Microtrauma
  biological_scale: TISSUE
  description: >-
    The endometrial-myometrial junction, visible on MRI as the junctional zone,
    is the site of initiating injury. Chronic uterine peristaltic activity, or
    episodic hyperperistalsis, inflicts repeated microtrauma at this interface,
    concentrated near the fundo-cornual raphe. Junctional zone thickening is the
    imaging correlate and the basis of non-invasive diagnosis. The model
    accommodates both early-onset disease, where an event early in reproductive
    life triggers hyperperistalsis, and late premenopausal adenomyosis, where
    cumulative normoperistalsis over decades produces equivalent
    microtraumatization.
  locations:
  - preferred_term: myometrium
    term:
      id: UBERON:0001296
      label: myometrium
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  cell_types:
  - preferred_term: uterine smooth muscle cell
    term:
      id: CL:0002601
      label: uterine smooth muscle cell
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: INCREASED
  evidence:
  - reference: PMID:19644696
    reference_title: "The pathophysiology of endometriosis and adenomyosis: tissue injury and repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic uterine peristaltic activity or phases of hyperperistalsis induce,
      at the endometrial-myometrial interface near the fundo-cornual raphe,
      microtraumatizations with the activation of the mechanism of 'tissue
      injury and repair' (TIAR)
    explanation: >-
      Identifies peristalsis-driven microtrauma at the junctional zone as the
      initiating lesion.
  - reference: PMID:19644696
    reference_title: "The pathophysiology of endometriosis and adenomyosis: tissue injury and repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as indicated by the high prevalence of the disease, it appears to be
      unavoidable that, with time, chronic normoperistalsis throughout the
      reproductive period of life leads to the same extent of
      microtraumatization
    explanation: >-
      Explains late premenopausal adenomyosis as cumulative injury from normal
      peristalsis, unifying early- and late-onset disease under one mechanism.
  downstream:
  - target: Local Estrogen Production and TIAR Self-Perpetuation
    causal_link_type: DIRECT
    hypothesis_groups:
    - invagination_tiar_model
    description: >-
      Activation of the tissue injury and repair response at the injured
      interface induces local estrogen biosynthesis.
- name: Local Estrogen Production and TIAR Self-Perpetuation
  biological_scale: TISSUE
  description: >-
    The tissue injury and repair response includes local estrogen production at
    the site of injury. Because uterine peristalsis is itself under ovarian
    steroid control, locally produced estrogen acts in a paracrine fashion to
    override that control, driving further hyperperistalsis and further injury.
    This feed-forward loop is what converts a self-limited repair response into
    a self-perpetuating disease process, and it explains why adenomyosis
    progresses across the reproductive years and regresses after menopause.
  biological_processes:
  - preferred_term: estrogen biosynthetic process
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
    modifier: INCREASED
  - preferred_term: cellular response to estrogen stimulus
    term:
      id: GO:0071391
      label: cellular response to estrogen stimulus
    modifier: INCREASED
  evidence:
  - reference: PMID:19644696
    reference_title: "The pathophysiology of endometriosis and adenomyosis: tissue injury and repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With ongoing peristaltic activity, such sites might increase and the
      increasingly produced estrogens interfere in a paracrine fashion with the
      ovarian control over uterine peristaltic activity, resulting in permanent
      hyperperistalsis and a self-perpetuation of the disease process.
    explanation: >-
      Describes the paracrine estrogen feed-forward loop that makes the injury
      process self-sustaining.
  downstream:
  - target: Basalis Invagination and Myometrial Infiltration
    causal_link_type: DIRECT
    hypothesis_groups:
    - invagination_tiar_model
    description: >-
      Sustained auto-traumatization permits infiltration of basal endometrium
      into the depth of the myometrial wall.
  - target: Aromatase-Driven Estrogen Signaling and Progesterone Resistance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Epigenetic reprogramming of nuclear receptor expression in the stromal compartment.
    description: >-
      Local estrogen excess is reinforced at the molecular level by aberrant
      steroid receptor and aromatase expression in lesional stroma.
- name: Somatic KRAS Activation in Endometrial Epithelium
  biological_scale: MOLECULAR
  description: >-
    Adenomyotic epithelial cells carry activating KRAS mutations almost
    exclusively, and the same mutations map to matched intracavitary endometrial
    tissue — the genetic argument that the lesion originates from eutopic
    endometrium rather than arising in situ. Mutations are restricted to
    endometrial-type epithelial cells and are absent from the surrounding smooth
    muscle; conversely, the driver mutations characteristic of uterine fibroids
    are not found in adenomyosis, separating the two commonest myometrial
    disorders at the molecular level. Activated KRAS signaling increases cell
    survival and proliferation and is associated with progesterone resistance.
  cell_types:
  - preferred_term: glandular epithelial cell of endometrium
    term:
      id: CL:0009084
      label: glandular epithelial cell of endometrium
  genes:
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KRAS and other less frequent mutations are limited to endometrial-type
      epithelial cells.
    explanation: >-
      Localizes the somatic driver to the epithelial compartment, not the
      myometrial smooth muscle.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activating mutations of KRAS stimulate specific pathways to increase cell
      survival and proliferation and are associated with progesterone resistance
      in adenomyosis.
    explanation: >-
      Links the KRAS driver to the survival/proliferation advantage and to the
      progesterone-resistant phenotype.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Driver mutations found in smooth muscle cells of uterine fibroids are
      absent in adenomyosis.
    explanation: >-
      Molecular separation of adenomyosis from uterine leiomyoma, its main
      clinical mimic.
  downstream:
  - target: Basalis Invagination and Myometrial Infiltration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - invagination_tiar_model
    intermediate_mechanisms:
    - KRAS-driven survival and proliferation of displaced endometrial epithelium.
    description: >-
      Mutant clones possess the survival and growth capability needed to
      establish and expand within the myometrium.
- name: Basalis Invagination and Myometrial Infiltration
  biological_scale: TISSUE
  description: >-
    Endometrial basalis glands and stroma invaginate into and infiltrate the
    myometrial wall. Invasion is not driven by a single migratory program:
    epithelial-mesenchymal transition is implicated in the early stages of
    progression and spread, while collective cell migration appears to mediate
    the later invasive events, making invasiveness a time-dependent combination
    of two processes. Lesions develop predominantly in the median region of the
    upper two-thirds of the uterine wall.
  locations:
  - preferred_term: myometrium
    term:
      id: UBERON:0001296
      label: myometrium
  cell_types:
  - preferred_term: glandular epithelial cell of endometrium
    term:
      id: CL:0009084
      label: glandular epithelial cell of endometrium
  - preferred_term: endometrial stromal cell
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  - preferred_term: cell migration
    term:
      id: GO:0016477
      label: cell migration
    modifier: INCREASED
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous investigations performed in human adenomyotic lesions and
      corroborated by studies in mice supported the involvement of the
      epithelial-mesenchymal transition process in the early stages of
      progression and spread of adenomyosis.
    explanation: >-
      Establishes EMT as the early invasive mechanism in human lesions with
      mouse corroboration.
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      studies conducted in a recently developed baboon model indicate that
      collective cell migration may be implicated in the later events of
      invasion
    explanation: >-
      Baboon model evidence that a second, collective-migration mechanism
      operates in later invasion, distinct from EMT.
  - reference: PMID:19644696
    reference_title: "The pathophysiology of endometriosis and adenomyosis: tissue injury and repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overt auto-traumatization of the uterus with dislocation of fragments of
      basal endometrium into the peritoneal cavity and infiltration of basal
      endometrium into the depth of the myometrial wall ensues.
    explanation: >-
      Describes myometrial infiltration of basalis endometrium as the
      consequence of sustained auto-traumatization.
  downstream:
  - target: Myometrial Hypertrophy and Uterine Enlargement
    causal_link_type: DIRECT
    description: >-
      Ectopic endometrial islands provoke hypertrophy and hyperplasia of the
      surrounding smooth muscle.
  - target: Lesional Fibrosis and Myofibroblast Transdifferentiation
    causal_link_type: DIRECT
    hypothesis_groups:
    - invagination_tiar_model
    description: >-
      Because adenomyotic lesions are wounds subjected to repeated injury and
      repair, the same EMT that drives invasion also feeds a
      fibroblast-to-myofibroblast programme that progressively fibroses the
      lesion.
- name: Lesional Fibrosis and Myofibroblast Transdifferentiation
  biological_scale: TISSUE
  conforms_to: fibrotic_response#Mesenchymal Cell Activation
  description: >-
    Adenomyotic lesions behave as wounds undergoing repeated tissue injury and
    repair, and their natural history is progressive fibrosis via three linked
    routes: epithelial-mesenchymal transition, fibroblast-to-myofibroblast
    transdifferentiation, and smooth muscle metaplasia. This is the same
    central-effector step conserved across organs in the fibrotic_response
    module, with the uterine specialization that smooth muscle metaplasia
    contributes alongside classical myofibroblast conversion. Fibrosis is not
    confined to the lesion: it propagates into the neighbouring
    endometrial-myometrial interface and endometrium, which is what converts a
    focal lesion into the diffuse uterine phenotype and links the lesion
    directly to heavy menstrual bleeding.
  locations:
  - preferred_term: myometrium
    term:
      id: UBERON:0001296
      label: myometrium
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: uterine smooth muscle cell
    term:
      id: CL:0002601
      label: uterine smooth muscle cell
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36099328
    reference_title: "Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      adenomyotic lesions are fundamentally wounds undergoing repeated tissue
      injury and repair (ReTIAR), which progress to fibrosis through
      epithelial-mesenchymal transition, fibroblast-to-myofibroblast
      transdifferentiation, and smooth muscle metaplasia
    explanation: >-
      States the three-route fibrotic programme and frames adenomyotic lesions
      as repeatedly injured wounds, the basis for conformance to the
      fibrotic_response module.
  - reference: PMID:36099328
    reference_title: "Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increasing lesional fibrosis propagates into the neighboring EMI and
      endometrium.
    explanation: >-
      Establishes spread of fibrosis beyond the lesion into the interface and
      endometrium, the step that couples lesional fibrosis to the endometrial
      bleeding phenotype.
  downstream:
  - target: Myometrial Hypertrophy and Uterine Enlargement
    causal_link_type: DIRECT
    description: >-
      Myofibroblast-driven matrix deposition and smooth muscle metaplasia
      together generate the stiff, hypertrophic myometrium around lesions.
- name: Aromatase-Driven Estrogen Signaling and Progesterone Resistance
  biological_scale: MOLECULAR
  description: >-
    Epigenetic abnormalities in lesional stromal cells produce an abnormal
    nuclear receptor expression pattern. The consequences are excessive local
    estrogen biosynthesis by aromatase, abnormal estrogen action routed through
    estrogen receptor beta, and deficient progesterone receptor expression
    yielding progesterone resistance. This receptor lesion is shared with
    endometriosis and is clinically consequential: it is the mechanistic reason
    progestin-based therapy is variably effective, and the rationale for
    combining or substituting agents that lower estrogen exposure.
  cell_types:
  - preferred_term: endometrial stromal cell
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  biological_processes:
  - preferred_term: estrogen biosynthetic process
    term:
      id: GO:0006703
      label: estrogen biosynthetic process
    modifier: INCREASED
  - preferred_term: response to progesterone
    term:
      id: GO:0032570
      label: response to progesterone
    modifier: DECREASED
  evidence:
  - reference: PMID:36925057
    reference_title: "Endometriosis and adenomyosis: shared pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These epigenetic defects give rise to excessive local estrogen
      biosynthesis by aromatase and abnormal estrogen action via estrogen
      receptor-β.
    explanation: >-
      Specifies aromatase-driven local estrogen excess and ER-beta-routed
      signaling as the downstream consequence of stromal epigenetic defects.
  - reference: PMID:36925057
    reference_title: "Endometriosis and adenomyosis: shared pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deficient progesterone receptor expression results in progesterone
      resistance in both endometriosis and adenomyosis.
    explanation: >-
      Establishes progesterone resistance and its receptor-level basis, shared
      with endometriosis.
  downstream:
  - target: Myometrial Hypertrophy and Uterine Enlargement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Estrogen-driven smooth muscle proliferation in myometrium adjacent to lesions.
    description: >-
      Sustained local estrogen excess drives the smooth muscle response around
      ectopic endometrial islands.
- name: Myometrial Hypertrophy and Uterine Enlargement
  biological_scale: TISSUE
  description: >-
    Islands of ectopic endometrial tissue within the myometrium are surrounded
    by hypertrophic smooth muscle. The resulting globular uterine enlargement,
    distorted architecture, and disrupted junctional zone produce the clinical
    syndrome: dysmenorrhea, excessive uterine bleeding with consequent anemia,
    and impaired implantation. Lesional neuroangiogenesis and chronic
    inflammation contribute to the pain phenotype.
  locations:
  - preferred_term: myometrium
    term:
      id: UBERON:0001296
      label: myometrium
  cell_types:
  - preferred_term: uterine smooth muscle cell
    term:
      id: CL:0002601
      label: uterine smooth muscle cell
  biological_processes:
  - preferred_term: uterine smooth muscle cell proliferation
    term:
      id: GO:0048659
      label: smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis, characterized by the presence of islands of endometrial
      tissue surrounded by hypertrophic smooth muscle cells within the
      myometrium, is one of the most challenging uterine disorders in terms of
      diagnosis and management.
    explanation: >-
      Defines the characteristic histopathology of endometrial islands ringed by
      hypertrophic smooth muscle.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia
      and infertility.
    explanation: >-
      Links the structural lesion to the four cardinal clinical manifestations.
histopathology:
- name: Endometrial glands and stroma within the myometrium
  description: >-
    The defining histological finding is islands of endometrial glands and
    accompanying stroma located within the myometrium, beyond the normal
    endometrial-myometrial interface, encircled by hypertrophic and hyperplastic
    smooth muscle. Diagnosis was historically made only on hysterectomy
    specimens, which is the principal reason prevalence estimates vary so widely;
    MRI and transvaginal ultrasound now permit non-invasive diagnosis based on
    junctional zone thickening and myometrial architecture.
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis, characterized by the presence of islands of endometrial
      tissue surrounded by hypertrophic smooth muscle cells within the
      myometrium
    explanation: >-
      States the defining histopathological criterion for adenomyosis.
imaging_findings:
- name: Junctional zone thickening on MRI
  description: >-
    Thickening of the junctional zone — the inner myometrium adjacent to the
    endometrium — is the principal MRI criterion for adenomyosis. Careful
    multiplanar visualization is required to distinguish true adenomyotic
    lesions from transient junctional zone enlargement caused by peristaltic
    waves or sporadic myometrial contractions, which otherwise mimic the
    diagnosis.
  evidence:
  - reference: PMID:25241270
    reference_title: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By this method of "visualization" all transient enlargement of the JZ,
      such as peristaltic waves of the archimyometrium and sporadic neometral
      contractions that might mimic adenomyotic lesions could be excluded.
    explanation: >-
      Documents the imaging pitfall — transient peristaltic junctional zone
      enlargement mimicking adenomyosis — and the visualization method used to
      avoid it.
  - reference: PMID:25241270
    reference_title: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As concluded from their localization within the uterine wall, the
      adenomyotic lesions predominantly developed in the median region of the
      upper two-thirds of the uterine wall.
    explanation: >-
      Establishes the characteristic anatomical distribution of adenomyotic
      lesions on MRI.
phenotypes:
- category: Clinical
  name: Dysmenorrhea
  description: >-
    Progressively severe menstrual pain is a cardinal symptom. In the MRI
    series, cystic cornual angle adenomyosis was observed only in patients with
    extreme primary dysmenorrhea, linking a specific lesion morphology to pain
    severity.
  phenotype_term:
    preferred_term: Dysmenorrhea
    term:
      id: HP:0100607
      label: Dysmenorrhea
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis is a commonly diagnosed estrogen-dependent gynecological
      disorder that causes pelvic pain, abnormal uterine bleeding, and
      infertility.
    explanation: >-
      Confirms pain as a cardinal manifestation of adenomyosis.
  - reference: PMID:25241270
    reference_title: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic cornual angle adenomyosis was a distinct phenomenon that was only
      observed in patients suffering from extreme primary dysmenorrhea.
    explanation: >-
      Associates a specific adenomyotic lesion subtype with the most severe
      dysmenorrhea phenotype.
- category: Clinical
  name: Heavy menstrual bleeding
  description: >-
    Excessive uterine bleeding results from the enlarged, architecturally
    distorted uterine cavity and impaired myometrial contractility, and is a
    principal driver of hysterectomy in adenomyosis.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia
      and infertility.
    explanation: >-
      Lists excessive uterine bleeding among the cardinal presenting features.
  - reference: PMID:36099328
    reference_title: "Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increased endometrial fibrosis, with ensuing greater tissue stiffness,
      results in attenuated prostaglandin E2, hypoxia signaling and glycolysis,
      impairing endometrial repair and causing HMB.
    explanation: >-
      Supplies the mechanism linking lesional fibrosis to heavy menstrual
      bleeding — stiffness-driven failure of endometrial repair rather than
      simple surface-area or contractility effects.
- category: Clinical
  name: Pelvic pain
  description: >-
    Chronic pelvic pain extends beyond menstruation in many patients and is the
    endpoint targeted by the hormonal therapies compared in network
    meta-analysis.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis is a commonly diagnosed estrogen-dependent gynecological
      disorder that causes pelvic pain, abnormal uterine bleeding, and
      infertility.
    explanation: >-
      Confirms pelvic pain as a defining clinical feature.
- category: Clinical
  name: Dyspareunia
  description: >-
    Pain with intercourse is one of the three pain domains the SOGC guideline
    treats as an outcome of interest in adenomyosis management, alongside
    dysmenorrhea and chronic pelvic pain.
  phenotype_term:
    preferred_term: Dyspareunia
    term:
      id: HP:0030016
      label: Dyspareunia
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reduction in pelvic pain (dysmenorrhea, dyspareunia, chronic pelvic pain)
    explanation: >-
      National guideline lists dyspareunia among the pain outcomes targeted in
      adenomyosis, establishing it as a recognized component of the phenotype.
- category: Clinical
  name: Anemia
  description: >-
    Iron deficiency anemia is a frequent consequence of chronic heavy menstrual
    bleeding in adenomyosis.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia
      and infertility.
    explanation: >-
      Lists anemia as a recognized manifestation, consequent on heavy bleeding.
- category: Clinical
  name: Infertility and impaired IVF outcomes
  description: >-
    Adenomyosis reduces implantation, clinical pregnancy, ongoing pregnancy, and
    live birth rates after IVF, and increases miscarriage rates, relative to
    women without adenomyosis. Impaired implantation is attributed to junctional
    zone dysfunction, altered uterine peristalsis, and a hostile endometrial
    environment.
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  evidence:
  - reference: PMID:28865548
    reference_title: "Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rates of implantation, clinical pregnancy per cycle, clinical
      pregnancy per embryo transfer, ongoing pregnancy, and live birth among
      women with adenomyosis were significantly lower than in those without
      adenomyosis.
    explanation: >-
      Meta-analysis of 11 comparative studies quantifying reduced IVF success
      across every fertility outcome measured.
  - reference: PMID:28865548
    reference_title: "Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The miscarriage rate in women with adenomyosis was higher than in those
      without adenomyosis.
    explanation: >-
      Documents increased pregnancy loss as a distinct component of the
      fertility phenotype.
genetic:
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  relationship_type: SOMATIC_DRIVER
  association: >-
    Activating somatic KRAS mutations are the characteristic genetic lesion of
    adenomyosis, confined to endometrial-type epithelial cells and shared with
    matched eutopic endometrium and with endometriosis, while absent from the
    driver landscape of uterine leiomyoma. They confer survival and
    proliferative advantage and are associated with progesterone resistance.
  evidence:
  - reference: PMID:36925057
    reference_title: "Endometriosis and adenomyosis: shared pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activating mutations of KRAS are the most commonly found genetic variant
      in endometriotic epithelial cells, whereas the adenomyotic epithelial
      cells almost exclusively bear KRAS mutations.
    explanation: >-
      Establishes KRAS as the near-exclusive somatic driver in adenomyotic
      epithelium.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activating mutations of KRAS stimulate specific pathways to increase cell
      survival and proliferation and are associated with progesterone resistance
      in adenomyosis.
    explanation: >-
      Connects the KRAS driver to both the growth advantage and the
      progesterone-resistant treatment phenotype.
  - reference: PMID:31857578
    reference_title: Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multi-regional sequencing reveals oligoclonality in adenomyosis, with some
      mutations also detected in normal endometrium and/or co-occurring
      endometriosis.
    explanation: >-
      Multi-regional sequencing establishes adenomyosis as oligoclonal and finds
      shared mutations in normal endometrium, independently reinforcing the
      invagination origin.
  - reference: PMID:31857578
    reference_title: Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KRAS mutations are more frequent in cases of adenomyosis with co-occurring
      endometriosis, low progesterone receptor (PR) expression, or progestin
      (dienogest; DNG) pretreatment.
    explanation: >-
      Links the KRAS driver directly to low PR expression and to dienogest
      pretreatment — the clinical bridge between this genetic lesion and the
      progesterone-resistance node.
  case_fractions:
  - population: Japanese adenomyosis cohort, multi-regional NGS
    case_fraction_percent: 37.1
    cohort_size: 70
    notes: 26/70 individuals, 192 multi-regional samples.
    evidence:
    - reference: PMID:31857578
      reference_title: Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases
      explanation: >-
        Largest multi-regional sequencing series, giving the most-cited estimate
        of the KRAS-mutant share of adenomyosis cases.
  - population: Taiwanese adenomyosis cohort, 275-gene targeted NGS panel
    case_fraction_percent: 24.0
    cohort_size: 17
    notes: >-
      Smaller targeted-panel series; KRAS was the most frequently mutated gene,
      ARID1A second.
    evidence:
    - reference: PMID:36708516
      reference_title: Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The results revealed that KRAS and AT-rich interactive domain 1A
        (ARID1A) were the two most frequently mutated genes (mutation
        frequencies: 24% and 12%, respectively).
      explanation: >-
        Independent cohort confirming KRAS as the leading somatic driver, at a
        lower frequency than the Japanese series.
- name: ARID1A
  gene_term:
    preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  relationship_type: SOMATIC_DRIVER
  association: >-
    ARID1A, a SWI/SNF chromatin-remodelling subunit, is the second most
    frequently mutated gene in adenomyotic lesions after KRAS. Its loss is a
    recurrent event across endometriosis-associated lesions generally,
    consistent with the shared mutational signature between adenomyosis and
    deep infiltrating endometriosis.
  case_fractions:
  - population: Taiwanese adenomyosis cohort, 275-gene targeted NGS panel
    case_fraction_percent: 12.0
    cohort_size: 17
    evidence:
    - reference: PMID:36708516
      reference_title: Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The results revealed that KRAS and AT-rich interactive domain 1A
        (ARID1A) were the two most frequently mutated genes (mutation
        frequencies: 24% and 12%, respectively).
      explanation: >-
        Establishes ARID1A as the second most frequent somatic driver in
        adenomyosis at 12% of cases.
  evidence:
  - reference: PMID:36708516
    reference_title: Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that mutations in the KRAS, ARID1A, FBXW7 and
      STAG2 genes may play a critical role in the pathogenesis of adenomyosis.
    explanation: >-
      Names ARID1A among the somatic drivers implicated in adenomyosis
      pathogenesis.
prevalence:
- population: Worldwide, general population
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1000.0
  rate_low: 0.0
  rate_high: 2000.0
  notes: >-
    Pooled general-population prevalence 1% (95% CI 0-2%) from 59 adenomyosis
    studies. Note the very wide interval and the contrast with the
    symptom-selected and imaging-selected estimates below — ascertainment, not
    biology, drives most of the spread.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The global prevalence of adenomyosis and endometriosis in the general
      population worldwide is 1% (95%CI, 0%-2%), and 5% (95%CI, 2%-9%),
      respectively.
    explanation: >-
      Meta-analysis of 127 studies covering ~199 million women, giving the
      general-population baseline.
- population: Women with infertility
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 31000.0
  rate_low: 10000.0
  rate_high: 58000.0
  notes: Pooled prevalence 31% (95% CI 10-58%) among women presenting with infertility.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of adenomyosis and endometriosis among women experiencing
      infertility was 31% (95%CI, 10%-58%) and 38% (95%CI, 25%-51%),
      respectively.
    explanation: >-
      Quantifies the strong enrichment of adenomyosis in infertile populations,
      complementing the IVF-outcome data curated under the infertility phenotype.
- population: Worldwide, focal adenomyosis
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 17000.0
  rate_low: 7000.0
  rate_high: 30000.0
  notes: >-
    Pooled prevalence of the focal subtype, 17% (95% CI 7-30%); the diffuse
    subtype was 15% (95% CI 9-23%) in the same analysis.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of focal and diffuse adenomyosis was found to be 17% (95%CI,
      7%-30%) and 15% (95%CI, 9%-23%), respectively.
    explanation: >-
      Subtype-resolved pooled prevalence for focal versus diffuse adenomyosis.
- population: Worldwide, histopathology-diagnosed series
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 35100.0
  rate_low: 30900.0
  rate_high: 39400.0
  notes: >-
    Ascertainment-stratified. Histopathology 35.1% and MRI 35.0% both exceed
    ultrasound at 30.7% — the quantitative anchor for the ascertainment caveat
    recorded under epidemiology, and the reason estimates from surgical series
    are not comparable with imaging-based ones.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      histopathology (35.1%; 95%CI, 30.9%−39.4%) and MRI (35.0%; 95%CI,
      22.6%−48.4%) reveal a greater prevalence of adenomyosis compared to
      ultrasound (30.7%; 95%CI, 25.2%−48.4%)
    explanation: >-
      Modality-stratified subgroup analysis quantifying how much of the spread
      in reported prevalence is attributable to diagnostic method.
- population: Worldwide, ultrasound-diagnosed series
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 30700.0
  rate_low: 25200.0
  rate_high: 48400.0
  notes: Lowest of the three diagnostic modalities in the same subgroup analysis.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      histopathology (35.1%; 95%CI, 30.9%−39.4%) and MRI (35.0%; 95%CI,
      22.6%−48.4%) reveal a greater prevalence of adenomyosis compared to
      ultrasound (30.7%; 95%CI, 25.2%−48.4%)
    explanation: >-
      Same subgroup analysis; ultrasound, the most widely used first-line
      modality, yields the lowest pooled estimate.
- population: Women undergoing hysterectomy for benign indications
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 42300.0
  rate_low: 35800.0
  rate_high: 48900.0
  notes: >-
    42.3% versus 31.9% when the hysterectomy was performed for malignant
    indications — selection bias made numerical, and the clearest single
    illustration of why hysterectomy-series prevalence overstates the
    population figure.
  evidence:
  - reference: PMID:41257733
    reference_title: "Global prevalence of adenomyosis and endometriosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (42.3%; 95%CI, 35.8%−48.9%) than among those who have the procedure for
      malignant conditions (31.9%; 95%CI, 15.1%−51.4%)
    explanation: >-
      Quantifies the surgical-indication selection effect underlying historical
      hysterectomy-based prevalence estimates.
diagnosis:
- name: Transvaginal sonography and MRI
  description: >-
    Adenomyosis is now diagnosed non-invasively. Transvaginal sonography is the
    first-line modality and MRI the adjunct, with junctional zone thickening the
    principal MRI criterion. This replaced the historical position in which
    diagnosis required a hysterectomy specimen — the single biggest reason older
    prevalence estimates are not comparable with modern ones.
  diagnosis_term:
    preferred_term: transvaginal sonography and MRI
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic options include transvaginal sonography and magnetic resonance
      imaging.
    explanation: >-
      National guideline establishing the two accepted non-invasive diagnostic
      modalities for adenomyosis.
environmental:
- name: Ovulatory cycling and cumulative estrogen exposure
  description: >-
    Adenomyosis is estrogen-dependent and its severity tracks with ovarian
    steroid exposure and ovulatory cycles — a feature that distinguishes it from
    many other uterine disorders and underlies both its progression through the
    reproductive years and its regression after menopause or ovarian suppression.
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dependence on ovarian steroids and ovulatory cycles for disease severity
      is a unique feature of adenomyosis.
    explanation: >-
      States the steroid- and cycle-dependence of disease severity, the basis
      for hormonal and surgical treatment strategies.
treatments:
- name: Dienogest
  description: >-
    Dienogest, an oral progestin, ranked as the most effective hormonal option
    for adenomyosis-associated pelvic pain in a network meta-analysis of
    randomized trials, outperforming both placebo and the levonorgestrel
    intrauterine system at 3 months on visual analog scale pain scores.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dienogest
      term:
        id: CHEBI:70708
        label: dienogest
  target_mechanisms:
  - target: Local Estrogen Production and TIAR Self-Perpetuation
    treatment_effect: INHIBITS
    description: >-
      Progestin-induced decidualization and subsequent endometrial atrophy,
      together with suppression of ovulatory estrogen exposure, reduce the
      estrogen drive sustaining the lesion.
  evidence:
  - reference: PMID:40166680
    reference_title: "Efficacy and safety of hormone therapies for treating adenomyosis-associated pelvic pain: a systematic review and network meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 3 months, women who received a placebo or a levonorgestrel-based
      intrauterine system (LNG-IUS) experienced more AAPP than those who
      received dienogest
    explanation: >-
      Network meta-analysis of randomized trials ranking dienogest above both
      placebo and LNG-IUS for adenomyosis-associated pelvic pain at 3 months.
  - reference: PMID:31857578
    reference_title: Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DNG's anti-proliferative effect is diminished via epigenetic silencing of
      PR in immortalized cells with mutant KRAS.
    explanation: >-
      Qualifies the efficacy evidence above: KRAS-mutant lesions may respond
      less well to dienogest because mutant KRAS drives epigenetic PR silencing.
      Shown in immortalized cells, hence IN_VITRO, so this is a mechanistic
      caveat rather than established clinical stratification.
- name: Levonorgestrel-releasing intrauterine system
  description: >-
    The LNG-IUS delivers progestin locally to the endometrium, reducing
    menstrual blood loss and pain while preserving the uterus. It is a mainstay
    of conservative management, though the randomized evidence places it behind
    dienogest for pain control at 3 months.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levonorgestrel
      term:
        id: CHEBI:6443
        label: levonorgestrel
  target_mechanisms:
  - target: Local Estrogen Production and TIAR Self-Perpetuation
    treatment_effect: INHIBITS
    description: >-
      Local progestin exposure induces endometrial atrophy, opposing the
      estrogen-driven proliferative signal at the lesion.
  evidence:
  - reference: PMID:40166680
    reference_title: "Efficacy and safety of hormone therapies for treating adenomyosis-associated pelvic pain: a systematic review and network meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 3 months, women who received a placebo or a levonorgestrel-based
      intrauterine system (LNG-IUS) experienced more AAPP than those who
      received dienogest
    explanation: >-
      Places LNG-IUS behind dienogest for pain control at 3 months in the
      randomized evidence, while remaining a widely used uterus-sparing option.
- name: GnRH agonist therapy
  description: >-
    GnRH agonists induce a hypoestrogenic state that suppresses the estrogen
    drive sustaining the lesion. Beyond symptom control, long-term GnRH agonist
    pretreatment before embryo transfer improves fertility outcomes in women
    with adenomyosis, and appears to increase spontaneous pregnancy rates.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: leuprolide
      term:
        id: CHEBI:6427
        label: leuprolide
  target_mechanisms:
  - target: Aromatase-Driven Estrogen Signaling and Progesterone Resistance
    treatment_effect: INHIBITS
    description: >-
      Ovarian suppression removes the systemic estrogen supply that compounds
      local aromatase-derived estrogen at the lesion.
  evidence:
  - reference: PMID:28865548
    reference_title: "Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pretreatment with the use of long-term GnRHa or long protocol could be
      beneficial.
    explanation: >-
      Meta-analytic conclusion supporting GnRH agonist pretreatment to improve
      IVF outcomes in adenomyosis.
  - reference: PMID:28865548
    reference_title: "Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It appears that surgical treatment or treatment withf GnRHa increases the
      spontaneous pregnancy rate in women with adenomyosis.
    explanation: >-
      Reports improved spontaneous pregnancy rates with GnRH agonist or surgical
      treatment. The quoted sentence contains a typographical error present in
      the published abstract.
- name: Combined oral contraceptives
  description: >-
    Combined oral contraceptives are a first-line medical option for
    adenomyosis-associated heavy menstrual bleeding and pain, suppressing
    ovulatory cycling and inducing endometrial atrophy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: oral contraceptive
      term:
        id: NCIT:C389
        label: Oral Contraceptive
  target_mechanisms:
  - target: Local Estrogen Production and TIAR Self-Perpetuation
    treatment_effect: INHIBITS
    description: >-
      Suppressing ovulatory cycling removes the systemic steroid drive on which
      lesion severity depends.
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      medical options (non-steroidal anti-inflammatory drugs, tranexamic acid,
      combined oral contraceptives, levonorgestrel intrauterine system,
      dienogest, other progestins, gonadotropin-releasing analogues)
    explanation: >-
      National guideline listing combined oral contraceptives among recommended
      medical options for adenomyosis.
- name: Non-steroidal anti-inflammatory drugs
  description: >-
    NSAIDs reduce prostaglandin-mediated dysmenorrhea and menstrual blood loss.
    Like tranexamic acid they act on the symptom endpoint rather than the
    lesion, so they carry no target_mechanisms link.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nonsteroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      medical options (non-steroidal anti-inflammatory drugs, tranexamic acid,
      combined oral contraceptives, levonorgestrel intrauterine system,
      dienogest, other progestins, gonadotropin-releasing analogues)
    explanation: >-
      National guideline listing NSAIDs first among recommended medical options
      for adenomyosis.
- name: Tranexamic acid
  description: >-
    An antifibrinolytic used symptomatically for heavy menstrual bleeding. It
    does not act on the adenomyotic lesion, so it carries no target_mechanisms
    link — it treats the bleeding endpoint rather than the mechanism producing it.
  therapeutic_modality: SMALL_MOLECULE
  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:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      medical options (non-steroidal anti-inflammatory drugs, tranexamic acid,
      combined oral contraceptives, levonorgestrel intrauterine system,
      dienogest, other progestins, gonadotropin-releasing analogues)
    explanation: >-
      National guideline listing tranexamic acid among recommended medical
      options for adenomyosis-associated bleeding.
- name: Uterine artery embolization
  description: >-
    Catheter-directed embolization of the uterine arteries devascularizes
    adenomyotic lesions while preserving the uterus. It is the interventional
    middle ground between medical therapy and hysterectomy, and lesion
    vascularity is itself a predictor of response.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: uterine artery embolization
    term:
      id: NCIT:C15230
      label: Embolization Therapy
  target_mechanisms:
  - target: Myometrial Hypertrophy and Uterine Enlargement
    treatment_effect: INHIBITS
    description: >-
      Devascularization induces infarction and shrinkage of the hypertrophic,
      hypervascular lesional myometrium.
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      interventional options (uterine artery embolization)
    explanation: >-
      National guideline recognizing uterine artery embolization as an
      established interventional option.
- name: Endometrial ablation
  description: >-
    Destruction of the endometrial lining to control heavy menstrual bleeding.
    Because adenomyotic tissue lies within the myometrium beyond the reach of an
    ablation, it addresses the bleeding endpoint rather than the lesion, and
    outcomes are less durable than in bleeding without adenomyosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: endometrial ablation
    term:
      id: NCIT:C157834
      label: Endometrial Ablation
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      surgical options (endometrial ablation, excision of adenomyosis,
      hysterectomy)
    explanation: >-
      National guideline listing endometrial ablation among surgical options.
- name: Hysterectomy
  description: >-
    Hysterectomy is definitive treatment for adenomyosis and remains a common
    endpoint for women with severe symptoms who have completed childbearing. It
    was also historically the only route to a confirmed diagnosis, which is why
    older prevalence estimates are drawn from surgical series and are not
    generalizable.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hysterectomy
    term:
      id: NCIT:C15256
      label: Hysterectomy
  target_mechanisms:
  - target: Basalis Invagination and Myometrial Infiltration
    treatment_effect: INHIBITS
    description: >-
      Removal of the uterus eliminates the diseased organ outright — definitive
      rather than mechanism-modifying, and the reason it remains the endpoint
      for refractory disease.
  evidence:
  - reference: PMID:37244746
    reference_title: "Guideline No. 437: Diagnosis and Management of Adenomyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      surgical options (endometrial ablation, excision of adenomyosis,
      hysterectomy)
    explanation: >-
      National guideline listing hysterectomy among the surgical options for
      adenomyosis.
- name: Uterus-sparing conservative surgery
  description: >-
    Adenomyomectomy and related cytoreductive techniques excise or reduce
    adenomyotic tissue while preserving the uterus, offered to women who wish to
    retain fertility. Surgical treatment appears to increase spontaneous
    pregnancy rates.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Basalis Invagination and Myometrial Infiltration
    treatment_effect: INHIBITS
    description: >-
      Direct excision of infiltrating adenomyotic tissue reduces lesion burden
      while preserving the uterus.
  evidence:
  - reference: PMID:28865548
    reference_title: "Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It appears that surgical treatment or treatment withf GnRHa increases the
      spontaneous pregnancy rate in women with adenomyosis.
    explanation: >-
      Supports conservative surgery as a fertility-directed intervention. The
      quoted sentence contains a typographical error present in the published
      abstract.
differential_diagnoses:
- name: Uterine leiomyoma
  description: >-
    Uterine fibroids are the principal clinical mimic, sharing heavy menstrual
    bleeding, pelvic pain, and uterine enlargement. The two are separable
    molecularly: the driver mutations of uterine fibroid smooth muscle are
    absent from adenomyosis, whose driver (KRAS) is confined to endometrial-type
    epithelium. Imaging distinguishes the diffuse, ill-defined junctional zone
    thickening of adenomyosis from the discrete, well-circumscribed leiomyoma.
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Driver mutations found in smooth muscle cells of uterine fibroids are
      absent in adenomyosis.
    explanation: >-
      Molecular basis for distinguishing adenomyosis from its principal
      differential diagnosis.
- name: Endometriosis
  description: >-
    Endometriosis is not so much a differential as a frequent co-diagnosis with
    shared pathophysiology; in one MRI series the prevalence of endometriosis in
    adenomyosis was 80.6% and of adenomyosis in endometriosis 91.1%. Both arise
    from eutopic endometrium, both carry KRAS-mutant epithelial clones, and both
    show the same stromal epigenetic lesion producing local estrogen excess and
    progesterone resistance. They differ in destination: peritoneal or ovarian
    surfaces via retrograde menstruation versus entrapment in the myometrium.
  evidence:
  - reference: PMID:36925057
    reference_title: "Endometriosis and adenomyosis: shared pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oligoclones of endometrial glandular epithelial cells with somatic
      mutations and attached stromal cells may give rise to endometriosis if
      they travel to peritoneal surfaces or the ovary via retrograde
      menstruation and/or may be entrapped in the myometrium to give rise to
      adenomyosis.
    explanation: >-
      States the common origin and the single branch point that separates
      endometriosis from adenomyosis.
  - reference: PMID:25241270
    reference_title: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of endometriosis in adenomyosis was 80.6% and the
      prevalence of adenomyosis in endometriosis was 91.1%.
    explanation: >-
      Quantifies the near-universal co-occurrence of the two conditions in an
      MRI-based series, supporting shared pathogenesis.
epidemiology:
- name: Diagnostic ascertainment and prevalence uncertainty
  description: >-
    Adenomyosis prevalence estimates vary widely because the diagnosis was
    historically confined to hysterectomy specimens, biasing series toward
    severe symptomatic disease in older parous women. Imaging-based diagnosis
    has broadened ascertainment but introduced its own variability, since
    junctional zone criteria differ between studies and transient peristaltic
    junctional zone enlargement can mimic disease. Adenomyosis remains, on the
    authors' assessment, among the most challenging uterine disorders to
    diagnose.
  evidence:
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is one of the most challenging uterine disorders in terms of diagnosis and
      management
    explanation: >-
      Characterizes the diagnostic difficulty that underlies the wide spread of
      published prevalence estimates.
  - reference: PMID:25241270
    reference_title: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this method allowed to lower the limit of detection in terms of thickness
      of the JZ for assured diagnosis of adenomyosis
    explanation: >-
      Shows that the detection threshold used for the junctional zone directly
      determines how many cases are ascertained, a methodological driver of
      prevalence variation.
discussions:
- discussion_id: adenomyosis_invagination_vs_metaplasia
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Basalis Invagination and Myometrial Infiltration
  prompt: >-
    Does adenomyosis arise by invagination of basalis endometrium through an
    injured junctional zone, or by metaplasia of Müllerian remnants and resident
    stem cells already within the myometrium?
  rationale: >-
    The two theories predict different origins for the lesional epithelium and
    therefore different prevention strategies: reducing junctional zone
    microtrauma versus targeting a resident progenitor population.
    Next-generation sequencing has moved the field substantially toward
    invagination, because KRAS mutations map to both adenomyotic lesions and the
    matched intracavitary endometrium — hard to reconcile with an independent
    in-situ origin. The debate is nonetheless recorded as live rather than
    settled: deep lesions without demonstrable continuity with the basalis, and
    adenomyosis in women without evident junctional zone disruption, are not
    fully explained by invagination alone. The two mechanisms are not mutually
    exclusive and may account for different lesion subsets.
  proposed_experiments:
  - experiment_id: exp_adenomyosis_clonal_lineage_mapping
    name: Spatially resolved clonal lineage mapping from cavity to deep lesion
    description: >-
      Perform spatially resolved single-cell sequencing along a continuous
      transect from intracavitary endometrium through the junctional zone into
      deep adenomyotic lesions in hysterectomy specimens, testing whether
      lesional clones form a contiguous mutational gradient with the eutopic
      endometrium (invagination) or constitute independent clones lacking shared
      ancestry (metaplasia). Deep lesions without junctional zone continuity are
      the informative cases.
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two main theories have been proposed to explain the origin of adenomyosis.
    explanation: >-
      Frames the controversy as the central unresolved question in adenomyosis
      pathogenesis.
  - reference: PMID:34131719
    reference_title: "Adenomyosis pathogenesis: insights from next-generation sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of KRAS map to both intracavitary endometrial tissue and
      proximally located adenomyotic samples, supporting the invagination theory
      of pathogenesis.
    explanation: >-
      The strongest current evidence favoring invagination over metaplasia.
- discussion_id: adenomyosis_two_phase_invasion
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Basalis Invagination and Myometrial Infiltration
  prompt: >-
    Are epithelial-mesenchymal transition and collective cell migration
    sequential phases of a single invasive program in adenomyosis, or
    alternative programs operating in different lesions?
  rationale: >-
    EMT evidence comes from human lesions with mouse corroboration and is
    assigned to early progression; collective migration evidence comes from a
    baboon model and is assigned to later invasion. The temporal assignment
    rests on comparing findings across different species and model systems
    rather than on a single longitudinal series, so the ordering is an inference
    rather than an observation. Whether invasiveness is genuinely
    time-dependent — and if so, when the switch occurs — matters for whether an
    anti-EMT strategy would help established disease or only prevent early
    spread.
  evidence:
  - reference: PMID:29566849
    reference_title: "Pathogenesis of uterine adenomyosis: invagination or metaplasia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that the invasiveness of this complex uterine disorder is
      not driven by a single mechanism of migration but by a time-dependent
      combination of two processes.
    explanation: >-
      States the two-process, time-dependent invasion model whose temporal
      structure remains to be demonstrated within a single system.
notes: >-
  Curated in response to the obstetric and benign-gynecology coverage gap
  documented in monarch-initiative/dismech#7837, which singled out adenomyosis
  as the conspicuous absence in benign gynecology given that both its siblings —
  Endometriosis and Uterine_Leiomyoma — are already curated. This entry is
  written to interlock with them: the shared-pathophysiology relationship with
  Endometriosis and the molecular separation from Uterine_Leiomyoma are both
  curated explicitly under differential_diagnoses.

  Terminology note: cell types are bound to the uterine/endometrial-specific CL
  classes — CL:0002255 stromal cell of endometrium, CL:0002601 uterine smooth
  muscle cell, and CL:0009084 glandular epithelial cell of endometrium. An
  earlier revision of this entry used their generic parents (CL:0000499,
  CL:0000192, CL:0002149) and asserted in this note that no dedicated
  endometrial stromal class existed. That was wrong: the search that produced it
  used the adjective form "endometrial stromal cell", whereas CL names these
  classes in the of-form ("stromal cell of endometrium"), so none of the three
  specific terms were found. Curators searching CL for a tissue-specific cell
  type should try both orderings before concluding a term is absent.

  A second search lesson, from the same review round: the modality-stratified
  prevalence figures (histopathology 35.1%, MRI 35.0%, ultrasound 30.7%) were
  initially reported as not quotable, on the grounds that they do not appear in
  the PMID:41257733 abstract. True but irrelevant — that cached reference holds
  the full text, and the figures sit well past the abstract. Before declaring a
  claim unquotable, search the whole cached file rather than the abstract
  section; many references_cache entries are full text and the reference
  validator matches against the entire body.

  Evidence note: two snippets quoted from PMID:28865548 contain a typographical
  error ("treatment withf GnRHa") that is present in the published abstract.
  The snippets are exact quotes and validate against the cached reference; the
  typo has been left uncorrected rather than silently repaired, since altering
  quoted text would break snippet verification.

  Deep research: a `claude_code` provider run was performed via
  `just research-disorder claude_code Adenomyosis`
  (research/Adenomyosis-deep-research-claude_code.md; 21 web searches, 24
  citations, 266 s). It corroborated the TIAR-invagination chain, the KRAS
  driver, and the aromatase/progesterone-resistance arm as curated, and drove
  three additions: the lesional-fibrosis node (which conforms to the
  `fibrotic_response` module — the entry previously had no fibrotic arm at all),
  the fibrosis-stiffness mechanism for heavy menstrual bleeding, and the EMID
  hypothesis group as a third, EMERGING pathogenesis model alongside
  invagination and metaplasia. A subsequent PR-review round closed several
  further gaps from the same run: prevalence, diagnosis, the ARID1A somatic
  driver, per-gene case fractions, dyspareunia, and the medical/interventional
  treatment options.

  Findings from the run still NOT curated: the detailed inflammatory cascade
  (TLR4/NF-kB, cGAS-STING, NLRP3-driven macrophage pyroptosis), the
  HIF-1alpha/VEGF neuroangiogenesis arm, hyperinnervation and central
  sensitization as pain mechanisms, and impaired decidualization (HOXA10/FOXO1)
  as the mechanism of subfertility — the last of these would give the currently
  mechanism-free infertility phenotype a pathophysiology anchor and is the most
  worthwhile remaining follow-up. High-intensity focused ultrasound is also
  omitted: it is an established uterus-sparing option, but the local NCIT
  adapter has no HIFU clinical-action term, so it was left out rather than bound
  to a term that does not fit.

  One DR-reported identifier was not used: the report cited "PMID:34252159
  (approx.)" for the Human Reproduction Update NGS paper, self-flagging the
  uncertainty. The correct identifier for that paper is PMID:34131719, which
  this entry already cited independently.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
Adenomyosis — Comprehensive Disease Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 24 citations 2026-08-02T09:58:58.496883

Adenomyosis — Comprehensive Disease Research Report

1. Disease Information

Overview: Adenomyosis is a benign but often symptomatic gynecologic disorder defined by the ectopic presence of endometrial glands and stroma within the myometrium (the uterine smooth-muscle wall), accompanied by reactive myometrial smooth-muscle hyperplasia and hypertrophy surrounding the ectopic tissue. It was historically termed "endometriosis interna" to contrast with pelvic ("external") endometriosis, though the two are now understood as related but distinct disease entities sharing overlapping pathophysiology. Adenomyosis classically presents with heavy menstrual bleeding (HMB), dysmenorrhea, chronic pelvic pain, and subfertility, and is increasingly recognized as a distinct clinical entity that can occur with or without co-existing pelvic endometriosis or uterine leiomyomas (fibroids).

Key identifiers: - MONDO: MONDO:0010888 - OMIM: 600458 (Adenomyosis) - ICD-11: GA11 (Adenomyosis) - ICD-10: N80.0 - Synonyms: Endometriosis interna; uterine adenomyosis; adenomyosis of the uterus/uterine corpus; adenomyoma (localized form)

Nature of evidence base: The literature is predominantly aggregated disease-level evidence — cross-sectional and retrospective cohort studies, systematic reviews/meta-analyses, hysterectomy-specimen histopathology series, imaging (MRI/TVUS) cohorts, and a growing body of single-cell/spatial transcriptomic and Mendelian-randomization studies using population biobank summary statistics (FinnGen, GTEx). Individual-patient EHR-level data exist (e.g., U.S. claims-based incidence/prevalence studies) but most mechanistic evidence derives from surgical-specimen molecular studies and small mouse models rather than large prospective clinical trials.

Sources: OMIM 600458; StatPearls – Adenomyosis; AAFP – Adenomyosis: Diagnosis and Management

2. Etiology

Disease causal factors: Adenomyosis has no single monogenic cause; it is a complex, multifactorial, estrogen-dependent disease. Three canonical (non-mutually-exclusive) pathogenic theories exist: 1. Invagination/Tissue Injury and Repair (TIAR) theory — mechanical disruption of the endometrial-myometrial interface (EMI) from uterine hyperperistalsis, parturition, or iatrogenic trauma triggers local micro-injury, downward endometrial basalis invagination into the myometrium, and local estradiol biosynthesis that perpetuates the lesion (Leyendecker et al., PMID: 25961248). 2. Metaplasia of embryonic Müllerian remnants theory — de novo lesions arise from misplaced Müllerian-derived tissue. 3. Stem/progenitor cell origin theory — aberrant migration and differentiation of endometrial or bone-marrow-derived multipotent progenitor cells into the myometrium.

A unifying "endometrial-myometrial interface disruption (EMID)" framework integrates these: tissue injury/repair, stem-cell recruitment, and epithelial-mesenchymal transition (EMT) converge to disrupt the archimetra and establish the adenomyotic microenvironment (PMC13070875; PMID: 41968335).

Genetic risk factors: - No Mendelian causal gene is established; adenomyosis is polygenic/multifactorial. - Somatic KRAS mutations are recurrent in adenomyotic glandular epithelium — found in 26/70 (37.1%) of cases in a next-generation-sequencing study of 192 multiregional samples, restricted to the epithelial (not stromal) compartment, and enriched in cases with co-existing endometriosis, low progesterone receptor (PR) expression, or prior progestin treatment (Nat Commun, "Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations"). Mutant KRAS hyperactivates downstream MAPK signaling and induces PGR gene hypermethylation, silencing PR-A/PR-B expression and driving progesterone resistance. - ARID1A somatic mutations activate PI3K signaling, promoting EMT, migration, and invasion. - A 2025 summary-data-based Mendelian randomization study using FinnGen GWAS (4,267 cases / 107,564 controls) plus GTEx v8 whole-blood and uterine cis-eQTLs identified 39 candidate causal genes (24 protein-coding), with ARHGEF35, AMT, RCVRN, GMPPB, and INTS1 as top candidates; differential expression validation nominated DNA2, INTS1, EFCAB2, HLA-DQA2, and RPS26 (combined ROC AUC 0.8) (Medicine (Baltimore), PMID: 40527793). - HOXA10 endometrial expression is decreased in adenomyosis, impairing endometrial receptivity (PMID: [21353411]; PMC3053130). - No large adenomyosis-specific GWAS with genome-wide-significant loci has yet been published at the scale seen for endometriosis (42+ loci) or uterine fibroids; adenomyosis GWAS remain comparatively underpowered (FinnGen-scale only).

Environmental/mechanistic risk factors (all associated with estrogen excess or uterine mechanical trauma): - Early menarche, short menstrual cycles, elevated BMI, multiparity (adjusted OR 1.8 for one birth, 3.1 for ≥2 births vs. nulliparous), oral contraceptive use, tamoxifen therapy (adenomyosis reported in up to 60% of long-term tamoxifen users, supporting estrogen dependence). - Prior uterine surgery — dilation and curettage, cesarean delivery, myomectomy — associated with EMI disruption, though evidence is inconsistent across studies. - Higher CA-125 levels, shorter menstrual cycle length, and earlier menarche were confirmed in a 2024 risk-factor cohort of MRI-diagnosed adenomyosis (PMC11981308).

Protective factors: Cigarette smoking is paradoxically associated with decreased adenomyosis risk in a dose-dependent manner (anti-estrogenic mechanism proposed, similar to endometriosis literature), though this is not a recommended intervention given smoking's broader harms.

Gene-environment interaction: The dominant model is that mechanical/hormonal environmental insults (parturition, surgery, hyperperistalsis) act on a genetically/epigenetically susceptible endometrial-myometrial interface (e.g., KRAS-mutant clones, altered METTL3/m6A epigenetic regulation) to trigger local estrogen biosynthesis (via aromatase upregulation and 17β-HSD2 downregulation) that sustains lesion growth — i.e., environmental injury unmasks and amplifies an underlying estrogen-dependent, epigenetically primed tissue.

Ontology suggestions: HP:0000009 (functional abnormality of the female internal genitalia — broad); risk-factor genes HGNC:6407 (KRAS), HGNC:713 (ARID1A), HGNC:5085 (HOXA10).

3. Phenotypes

Phenotype Type Frequency HPO suggestion
Heavy menstrual bleeding / menorrhagia Symptom ~60% of symptomatic cases; pooled 42% in AUB cohorts HP:0008946 (Menorrhagia) / HP:0000132 (Menorrhagia — check exact label)
Dysmenorrhea (secondary, often progressive/worsening) Symptom 25–41% (pooled) HP:0100608 (Dysmenorrhea)
Chronic pelvic pain Symptom Pooled 49% in symptomatic cohorts HP:0012648 (Chronic pain) or pelvic-pain-specific term
Dyspareunia Symptom Pooled 46% HP:0032389 (Dyspareunia, if present in HPO)
Infertility / subfertility Clinical finding 31% prevalence among infertility populations HP:0000789 (Infertility)
Enlarged, globular uterus Physical/imaging sign Common on exam and imaging HP:0000138 (Uterine neoplasm — not exact; better: descriptive) / consider "Uterine enlargement"
Elevated serum CA-125 Laboratory abnormality Variable, poorly sensitive/specific Non-HPO lab marker
Chronic/recurrent pelvic pain with central sensitization Symptom/mechanistic Emerging area of study (2026 trial NCT07455721) —
Abnormal uterine bleeding (irregular menses) Symptom Common, FIGO AUB structural category "A" (Adenomyosis) HP:0000140 (Abnormal uterine bleeding, if present)

Onset: Adenomyosis is a disease of reproductive-age and (increasingly, on imaging) even nulliparous younger women, classically diagnosed in the 4th–5th decade of life (peri- or late-reproductive years) at hysterectomy, but improved imaging has shifted diagnosis earlier, including in women in their 20s–30s presenting with dysmenorrhea/infertility. Symptoms typically resolve with menopause given estrogen dependence.

Progression: Generally a chronic, slowly progressive condition; dysmenorrhea and HMB often worsen over years, with severity, extent (focal vs. diffuse), and junctional-zone thickening correlating with symptom burden. Central sensitization to pelvic pain may develop with disease chronicity.

Quality of life: Multiple SF-36-based studies show significantly lower scores across all quality-of-life domains in women with adenomyosis compared to unaffected women, with the psychological impact and negative effect on work productivity exceeding that reported for pelvic endometriosis in some comparative studies (Alcalde et al., J Womens Health 2021). Pain interference and low self-efficacy are correlated with worse HRQoL.

4. Genetic/Molecular Information

  • Causal genes: None Mendelian; disease is driven by somatic mosaicism/oligoclonality plus polygenic susceptibility.
  • Somatic pathogenic variants:
  • KRAS (HGNC:6407) hotspot mutations in glandular epithelium — 37.1% of cases in NGS cohorts; gain-of-function, MAPK-pathway-activating; drives PGR hypermethylation → progesterone resistance and enhanced invasive capacity. Adenomyosis is described as an "oligoclonal disorder" with multiple independent KRAS-mutant clones across lesion regions.
  • ARID1A (HGNC:11110) mutations activate PI3K signaling.
  • Somatic mutation burden and clonality overlap substantially with deep infiltrating endometriosis, supporting a shared "endometriotic epithelium" mutational signature.
  • Germline candidate genes (MR-nominated): ARHGEF35, AMT, RCVRN, GMPPB, INTS1, DNA2, EFCAB2, HLA-DQA2, RPS26 (PMID: 40527793) — associative/candidate-causal, not clinically validated; not yet ClinVar-classified for adenomyosis.
  • Allele frequency: Not applicable in the germline-Mendelian sense; somatic KRAS variant allele fractions are lesion-specific and not captured in population databases (gnomAD/1000G not informative for this somatic-driven disease).
  • Epigenetics:
  • Global and locus-specific DNA methylation changes at the PGR promoter (hypermethylation → PR silencing).
  • N6-methyladenosine (m6A) RNA methylation dysregulation: decreased METTL3 reduces m6A levels, altering IGF1/DDT expression, disturbing estrogen–progesterone balance, and activating Wnt/EMT/angiogenesis programs.
  • Reduced histone deacetylase 3 (HDAC3) impairs resolution of NF-κB-driven inflammation.
  • Chromosomal abnormalities: Not a recognized feature; adenomyosis is not classically associated with aneuploidy/CNV syndromes.
  • Transcriptomics: Single-cell RNA-seq + spatial transcriptomics atlases (Protein & Cell 2024, PMC11214835; medRxiv 2025) have mapped cellular heterogeneity across the endometrial-myometrial junction, identifying unique epithelial/stromal/immune subpopulations, developmental trajectories, and altered cell-cell communication (notably involving macrophages and fibroblasts) specific to adenomyotic lesions versus eutopic endometrium and normal myometrium.

Ontology suggestions: HGNC:6407 (KRAS), HGNC:11110 (ARID1A), HGNC:5085 (HOXA10); GO:0007173 (EGF receptor signaling), GO:0004707 (MAP kinase activity).

5. Environmental Information

  • Environmental/toxicant factors: Endocrine-disrupting chemicals (EDCs) — bisphenol A, dioxins/dioxin-like compounds, organochlorine pesticides, PCBs — are well studied in endometriosis (71% of reviewed studies show significant associations, PMID: 32903210) but only sparsely studied specifically in adenomyosis; the biological plausibility (estrogen-mimicry, aromatase upregulation) is shared given the common estrogen-dependent pathophysiology.
  • Lifestyle factors: Elevated BMI is an established risk factor (adipose-tissue aromatization increases circulating/local estrogen). Smoking is inversely associated (protective, dose-dependent), an unusual and mechanistically debated finding.
  • Iatrogenic/mechanical exposures: Cesarean section, dilation and curettage, myomectomy, and other intrauterine instrumentation are implicated as EMI-disrupting triggers under the TIAR model, though epidemiologic confirmation is inconsistent.
  • Infectious agents: No established infectious etiology, though chronic endometritis co-occurs at increased frequency in adenomyosis/infertility cohorts (PMC11251133), raising a possible inflammatory-cofactor (not causal-pathogen) relationship.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Trigger: Mechanical/hormonal injury at the endometrial-myometrial interface (uterine hyperperistalsis, parturition, instrumentation) or aberrant stem-cell/metaplastic seeding → local tissue injury.
  2. Tissue Injury and Repair (TIAR): Injury activates local wound-healing programs that paradoxically include de novo estradiol biosynthesis (via aromatase upregulation and 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) downregulation), producing sustained local hyperestrogenism (Leyendecker, PMID: 25961248).
  3. EMT and invasion: Elevated local estrogen and COX-2/PGE2 signaling activate ERK, RhoA/ROCK, TGF-β/Smad→β-catenin, and JAK2/STAT3 pathways, driving epithelial-mesenchymal transition (loss of E-cadherin, gain of α-SMA/vimentin) and endometrial-cell invasion into the myometrium.
  4. Progesterone resistance: Somatic KRAS mutation and epigenetic PGR silencing (methylation, METTL3/m6A loss) blunt progesterone signaling, removing the physiological brake on proliferation and inflammation and driving MIG-6 loss → ErbB2-ERK activation.
  5. Chronic inflammation: TLR4/MyD88/NF-κB and cGAS-STING (mtDNA-sensing) activation drive cytokine dysregulation (↑IL-6, IL-1β, TNF-α, TGF-β1, CXCL8/IL-8, CXCL12; ↓IL-10, IL-22, IL-33). NLRP3 inflammasome activation (via GRIM19 downregulation) triggers macrophage pyroptosis and IL-1β release.
  6. Fibrosis/smooth-muscle metaplasia: Fibroblast-to-myofibroblast transdifferentiation (FMT) and smooth-muscle metaplasia (SMM), mediated by GSK-3β/AKT and sphingosine-1-phosphate (S1P)/S1PR signaling, deposit excess extracellular matrix and generate the reactive myometrial hypertrophy characteristic of adenomyotic lesions.
  7. Angiogenesis: Hypoxia (HIF-1α) and NF-κB drive VEGF/VEGFR-2 upregulation (amplified by an E2-Slug-VEGF axis), correlating with MMP-2/MMP-9 activity and lesion vascularity — vascularity is itself a prognostic factor for response to uterine artery embolization.
  8. Clinical manifestation: The combination of ectopic endometrial tissue bleeding within a hypertrophic, poorly contractile, hypervascular myometrium produces heavy menstrual bleeding (impaired local hemostasis, increased endometrial surface area, dysregulated prostaglandins/eicosanoids) and dysmenorrhea/chronic pelvic pain (uterine hypercontractility from oxytocin/oxytocin-receptor upregulation, hyperperistalsis, and local inflammatory mediator release). Impaired decidualization (via HOXA10/FOXO1 downregulation, driven partly by low endometrial IL-10) and adverse endometrial receptivity, plus macrophage/NK-cell-mediated embryotoxic inflammation, underlie the associated subfertility and elevated miscarriage rate.

Cell types involved: endometrial epithelial cells, endometrial stromal cells, myometrial smooth muscle cells (CL:0000192), fibroblasts/myofibroblasts, macrophages (CL:0000235, including pyroptotic and polarized subtypes), endothelial cells (CL:0000115), and (proposed) bone-marrow-derived multipotent stem/progenitor cells.

Molecular targets under therapeutic investigation: COX-2 (celecoxib), NLRP3 inflammasome inhibitors, YAP1/Hippo modulators, JAK2/STAT3 inhibitors, GSK-3β inhibitors, sphingosine kinase (SphK) inhibitors, TrkB/TGF-β-Smad inhibitors, and epigallocatechin gallate (EGCG, multi-target).

Ontology suggestions: - GO: GO:0001525 (angiogenesis), GO:0030198 (extracellular matrix organization), GO:0006954 (inflammatory response), GO:0001837 (epithelial to mesenchymal transition), GO:0038095 (Fc-epsilon/NF-κB — approximate; better GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling), GO:0016477 (cell migration) - CL: CL:0000115 (endothelial cell), CL:0000235 (macrophage), CL:0002145 (ciliated columnar cell of endometrium — check exact), CL:0000499 (stromal cell)

Sources: PMC11591984 (signaling pathways review); PMC13070875 / PMID:41968335 (integrated pathogenesis review); Nature Communications — KRAS oligoclonality; Human Reproduction Update — NGS insights PMID:34252159 (approx.); PMC11214835 (single-cell/spatial atlas).

7. Anatomical Structures Affected

  • Organ level: Primary organ — uterus (corpus), specifically the myometrium and the endometrial-myometrial junctional zone (JZ). Secondary/associated involvement: ovaries and pelvic peritoneum when co-existing endometriosis is present; rarely, deep adenomyoma can involve serosal/subserosal uterine layers.
  • Body systems: Female reproductive system primarily; secondary systemic effects via chronic pain (nervous system sensitization) and chronic bleeding (hematologic — iron-deficiency anemia).
  • Tissue/cell level: Ectopic endometrial glandular epithelium and stroma within myometrial smooth muscle; reactive smooth-muscle hyperplasia/hypertrophy surrounding lesions; increased vascular density.
  • Subcellular: Altered mitochondrial DNA release triggering cGAS-STING (cytosolic DNA-sensing pathway); ER/Golgi involvement in secretory dysregulation of cytokines; nuclear epigenetic machinery (METTL3/m6A writer complex, HDAC3).
  • Localization: UBERON:0000995 (uterus); more specifically UBERON:0001296 (myometrium) and the endometrial-myometrial junctional zone (no dedicated UBERON term for JZ; commonly described radiologically). Adenomyosis can be diffuse (throughout the myometrium) or focal/localized (adenomyoma), and can be classified by depth as internal/intrinsic (inner myometrium, junctional-zone-based) vs. external/extrinsic (outer myometrium, subserosal) per the Kishi MRI classification (subtypes I–IV).
  • Lateralization: Not applicable (single midline organ); lesions may be anterior, posterior, or fundal, and diffuse or asymmetric within the uterine wall.

Ontology suggestions: UBERON:0000995 (uterus), UBERON:0001296 (myometrium), UBERON:0001295 (endometrium).

8. Temporal Development

  • Onset: Classically diagnosed in the 4th–5th decade (peri-/late-reproductive years), historically at hysterectomy in multiparous women in their 40s; with modern imaging (TVUS, MRI), diagnosis increasingly occurs in younger, even nulliparous, symptomatic or infertile women in their 20s–30s.
  • Onset pattern: Insidious/chronic — arises gradually from repeated microtrauma/inflammatory cycles rather than an acute event.
  • Progression: Slowly progressive over years; junctional-zone thickening and lesion extent tend to increase with time and parity; estrogen-dependence means progression is expected to plateau/regress after menopause (endogenous estrogen decline) or with GnRH-agonist-induced hypoestrogenism.
  • Disease course pattern: Chronic, generally stable-to-progressive during reproductive years; can be relapsing in terms of symptom flares tied to the menstrual cycle; recurrence after conservative (uterus-sparing) treatment is common, particularly in diffuse-type, younger, longer-duration-disease patients with thicker JZ and higher CA-125.
  • Remission: Menopause (natural or medically induced via GnRH agonists) produces symptom remission through estrogen withdrawal; add-back therapy is needed for long-term GnRH-agonist use due to hypoestrogenic side effects (bone loss).
  • Critical periods: Postpartum/post-instrumentation periods (cesarean section, D&C) are proposed windows of EMI vulnerability; the perimenopausal transition is a window where declining estrogen may naturally attenuate disease.

9. Inheritance and Population

Epidemiology (from a 2025 systematic review/meta-analysis, PMID: 41257733): - General population point prevalence: ~1% (95% CI 0–2%) by strict criteria, but much higher (17–35%) when focal/diffuse imaging or histopathologic definitions are used across symptomatic/surgical cohorts. - Prevalence by diagnostic method: histopathology 35.1% (95% CI 30.9–39.4%), MRI 35.0% (22.6–48.4%), ultrasound 30.7% (25.2–48.4%) — reflecting selected (mostly hysterectomy or symptomatic) populations rather than the general population. - Infertility populations: 31% (95% CI 10–58%). - Symptomatic subgroup prevalence: abnormal uterine bleeding 42%, pelvic pain 49%, dyspareunia 46%, dysmenorrhea 41%. - Parity association: parous women 38% vs. nulliparous 28%. - Co-occurrence with endometriosis: found in 42% of individuals with coexisting endometriosis. - U.S. population-based claims study (2006–2015): annual incidence ~1.03% (28.9 per 10,000 woman-years); highest incidence in women 41–45 years (69.1/10,000 in 2008); Black women showed higher incidence (up to 44.6/10,000) than White women (up to 27.9/10,000), indicating racial disparity.

Inheritance pattern: Not a single-gene Mendelian disorder — complex/multifactorial (polygenic susceptibility + somatic mosaicism + environmental/mechanical triggers). No penetrance, expressivity, anticipation, mosaicism (germline), or founder-effect data apply in the classic monogenic sense; however, somatic mosaicism of KRAS-mutant epithelial clones is itself a defining molecular feature.

Population demographics: - Affects individuals with a uterus during reproductive years, primarily 35–50; increasing detection in younger women due to improved imaging. - Racial/ethnic disparity noted in U.S. incidence data (higher in Black women). - Sex ratio: not applicable (uterus-specific disease in individuals assigned female at birth). - No strong documented geographic/endemic clustering, though international incidence/prevalence estimates vary by diagnostic practice and access to hysterectomy pathology.

10. Diagnostics

Imaging (first-line, non-invasive): - Transvaginal ultrasound (TVUS) and MRI are the two primary recommended modalities per SOGC Guideline No. 437 (2023) (PMID: 37244746). - MUSA (Morphological Uterus Sonographic Assessment) 2022 Delphi-revised criteria: direct signs (echogenic subendometrial lines/buds, myometrial cysts, hyperechogenic islands, translesional vascularity on color Doppler, interrupted junctional zone — at least one required) and indirect signs (globular/enlarged uterus, asymmetric myometrial thickening, fan-shaped shadowing). Interrupted junctional zone and myometrial cysts show highest specificity (89.0%, 88.5%); hyperechoic islands show highest sensitivity (69.2%). No single sign is sufficiently accurate alone. - MRI: Junctional zone (JZ) thickening >12 mm is the key diagnostic threshold; diagnostic accuracy up to 85%. MRI JZ thickness measurements are systematically larger than TVUS measurements of the same structure. - Classification systems: Kishi 4-subtype MRI classification (I – intrinsic/inner myometrium; II – extrinsic/outer myometrium/subserosal; III – intramural/middle myometrium; IV – indeterminate); Gordts et al. proposed five descriptive parameters (affected area, wall location, diffuse vs. focal pattern, muscular vs. cystic lesion type, lesion volume/extent).

Laboratory/biomarkers: - CA-125: can be markedly elevated (case reports up to 4,400 IU/mL in severe disease, normalizing post-surgery) and correlates with dysmenorrhea severity, but has poor sensitivity/specificity as a standalone diagnostic (elevated in endometriosis, pregnancy, and other benign/malignant conditions) — adjunctive use only. A >7-fold CA-125 decrease after GnRH-agonist treatment is associated with improved live-birth rates in IVF. - No FDA-qualified specific biomarker exists; urinary biomarker panels are an active research area (PMC9025125).

Genetic testing: Not clinically indicated — adenomyosis is not diagnosed via germline genetic testing; somatic KRAS profiling remains a research tool.

Histopathology (gold standard, post-hysterectomy): Presence of endometrial glands/stroma within the myometrium, typically ≥2.5 mm from the endometrial-myometrial junction, with surrounding smooth-muscle hyperplasia.

Differential diagnosis: Uterine leiomyoma (fibroids), endometrial polyps, pelvic endometriosis, endometrial hyperplasia/carcinoma (especially given the CA-125 overlap and increased cancer risk noted below), primary dysmenorrhea, chronic pelvic inflammatory disease.

Screening: No population screening program exists (disease is not amenable to mass screening); case-finding relies on symptom-triggered imaging in reproductive-age individuals with HMB, dysmenorrhea, or infertility.

Ontology suggestions: NCIT terms for MRI (NCIT:C16809 Magnetic Resonance Imaging) and transvaginal ultrasound (NCIT:C113663 or closest match); LOINC for CA-125 assay.

11. Outcome/Prognosis

  • Not a mortality-associated disease in itself (benign condition); no survival/mortality statistics apply directly, though associated cancer risk (below) has downstream mortality implications.
  • Fertility/reproductive outcomes: Adenomyosis is associated with impaired IVF/ART outcomes — lower implantation rates (25.6% vs 28.6% controls), lower live-birth rates (26% vs 31.5%), and significantly higher miscarriage rates (29.1–35.4% vs 17.2–18.1% in controls) across multiple retrospective cohorts, with effects most pronounced in women ≥38 years. Mechanistically linked to impaired decidualization/receptivity and macrophage/NK-cell-mediated embryotoxicity.
  • Treatment response prognostic factors: For uterine artery embolization (UAE), recurrence is more likely in younger patients, longer disease duration, more severe pretreatment symptoms, higher CA-125, diffuse-type disease, thicker JZ, and sparsely vascularized lesions; conversely, greater lesion vascularity is associated with better UAE response (PMC5091759).
  • Complications: Iron-deficiency anemia from chronic HMB; chronic pelvic pain with risk of central sensitization; infertility/subfertility; in pregnancy, adenomyosis is associated with increased risk of preterm birth, preeclampsia, and other obstetric complications (per multiple cohort studies, not detailed above but consistently reported in the literature).
  • Malignancy risk: Adenomyosis is associated with a 4–5-fold increased risk of subsequent endometrial cancer (aOR 5.13, 95% CI 1.36–19.40) and ovarian cancer (aOR 5.50, 95% CI 1.95–15.50) in population-based cohort studies; increased thyroid cancer risk has also been reported (PMC5844548). Co-existing endometriosis further raises colorectal cancer risk (aOR 13.04). Proposed shared mechanisms include chronic inflammation, hormonal dysregulation, and overlapping somatic mutational landscapes (KRAS, ARID1A) with endometrioid/clear-cell gynecologic cancers.
  • Quality of life prognosis: Significant, sustained reduction across SF-36 domains; treatment (medical, interventional, or surgical) generally improves symptom-specific and global quality-of-life scores, though recurrence is common with conservative management.

12. Treatment

Pharmacotherapy (first-line, per SOGC Guideline No. 437, 2023): - Levonorgestrel-releasing intrauterine system (LNG-IUS, 20 μg/day) — first-line for HMB and pain; reduces menstrual blood loss by 71–95%, efficacy comparable to endometrial ablation. NCIT: consider NCIT:C15986 (Pharmacotherapy) with therapeutic_agent levonorgestrel (CHEBI applicable). - Combined oral contraceptives — first-line for pain/HMB. - Dienogest (progestin) — first-line. - NSAIDs and tranexamic acid — symptomatic HMB/pain management (supportive care, NCIT:C15747). - GnRH agonists — second-line (due to hypoestrogenic adverse effects — bone loss, vasomotor symptoms); add-back hormone therapy required if used >6 months.

Interventional: - Uterine artery embolization (UAE) — minimally invasive, uterus-sparing; short-term (12-month) improvement rates of 70.9–74.0% for dysmenorrhea/menorrhagia, long-term (5–7 year) sustained improvement in a majority of patients (68.8–92.3% depending on cohort); outcomes correlate with lesion vascularity.

Surgical: - Endometrial ablation, hysteroscopic/laparoscopic excision of adenomyoma (adenomyomectomy), high-intensity focused ultrasound (HIFU), and hysterectomy (definitive treatment, reserved for those who have completed childbearing or with refractory symptoms).

Emerging/experimental targets (preclinical, not yet clinical standard): COX-2 inhibitors (celecoxib), NLRP3 inflammasome inhibitors, JAK2/STAT3 inhibitors, YAP1/Hippo pathway modulators, GSK-3β inhibitors, sphingosine kinase inhibitors, TrkB inhibitors, EGCG (green tea catechin).

Treatment strategy: Management is individualized by symptom priority (HMB vs. pain vs. fertility), age, and desire for fertility preservation, following a stepwise algorithm from medical → interventional → surgical management (per SOGC Guideline No. 437 and AAFP 2022 review).

Adverse events: GnRH agonists → hypoestrogenic bone loss, vasomotor symptoms (mitigated by add-back therapy); UAE → post-embolization syndrome, rare ovarian-reserve impact; surgery → standard surgical/anesthetic risks, and hysterectomy is irreversible/fertility-ending.

Ontology suggestions: NCIT:C15986 (Pharmacotherapy), NCIT:C15329 (Surgical Procedure), NCIT:C15313 is not applicable here but UAE could map to an interventional radiology procedure NCIT term; therapeutic_agent CHEBI terms for levonorgestrel, dienogest, tranexamic acid, leuprolide (GnRH agonist).

13. Prevention

  • Primary prevention: No established primary prevention strategy exists given the multifactorial, not-fully-preventable etiology; minimizing unnecessary uterine instrumentation (D&C, non-medically-indicated cesarean) is a plausible but unproven risk-reduction measure under the TIAR mechanical-injury model.
  • Secondary prevention (early detection): Prompt imaging (TVUS/MRI) in reproductive-age patients presenting with HMB, progressive dysmenorrhea, or unexplained infertility enables earlier diagnosis and fertility-preserving management before progression to diffuse disease.
  • Tertiary prevention: Early initiation of LNG-IUS/hormonal therapy in diagnosed patients may reduce complication burden (anemia from chronic HMB, progression of pain/central sensitization) and preserve fertility options before disease progression necessitates surgery.
  • Behavioral/lifestyle interventions: Weight management (given BMI-estrogen association) is a plausible, evidence-adjacent risk-modification strategy, though not a formally validated prevention protocol; lifestyle interventions for pelvic-pain symptom management (exercise, dietary modification) are under active scoping review (PMC12935590) but evidence remains preliminary.
  • Genetic counseling: Not applicable — no Mendelian inheritance pattern to counsel on.
  • Screening programs: None population-based; case-finding is symptom-triggered.

14. Other Species / Natural Disease

  • Taxonomy: Naturally occurring adenomyosis has been documented in dogs (Canis lupus familiaris, NCBITaxon:9615) and cats (Felis catus, NCBITaxon:9685), where it is typically an incidental finding associated with other uterine pathology (endometritis, pyometra, cystic endometrial hyperplasia, and occasionally co-occurring uterine leiomyoma), rather than a primary clinical disease entity.
  • Veterinary relevance: Considered rare and usually asymptomatic/incidental in companion animals; case reports document adenomyosis with severe cervical inflammation in a dog (PMC1082876) and co-existing leiomyoma/adenomyosis/cystic endometrial hyperplasia (Karagiannis 2011, Case Rep Vet Med).
  • Comparative biology: The fundamental mechanism (ectopic endometrial glandular/stromal tissue within myometrium with reactive smooth-muscle change) is conserved across mammals, but naturally-occurring veterinary disease has not been developed as a systematic comparative-pathology model given its rarity and incidental-finding status in animals.
  • Transmission: Not applicable — non-infectious, non-zoonotic condition.
  • No dedicated OMIA (Online Mendelian Inheritance in Animals) entry was identified for adenomyosis, consistent with its non-Mendelian, largely incidental veterinary occurrence.

15. Model Organisms

  • Mouse models (primary experimental system):
  • Mechanical-injury (EMI-puncture) model: Repeated needle puncture disrupting the endometrial-myometrial interface generates persistent glandular epithelium/stroma structures within the myometrium resembling human adenomyosis; this 2022 model (Sci Rep, PMC9585053) is notable for producing durable, quantifiable lesions suitable for longitudinal and perinatal-outcome studies, improving on earlier, slower-developing models.
  • Neonatal estrogen-receptor-β (ERβ) agonist exposure model: Neonatal feeding of an ERβ agonist to ICR mice induces external adenomyosis-like lesions, supporting the estrogen-receptor-dependent mechanistic hypothesis (Reprod Dev Med 2021).
  • Other historical models include tamoxifen-induced and pituitary-isograft-induced hyperprolactinemia/hyperestrogenic mouse models (referenced in the broader animal-model literature but not detailed in current search results); the classically cited Tsp2 (thrombospondin-2) knockout mouse spontaneously develops adenomyosis-like lesions, supporting a role for ECM/anti-angiogenic regulation in disease genesis (cited across review literature, though not independently re-verified in this search pass — flag for confirmation before KB citation).
  • Model characteristics: Mechanical-injury models best recapitulate the TIAR/EMI-disruption theory and are suited to studying lesion initiation, fibrosis, and perinatal/obstetric outcome consequences; hormonal-exposure models best recapitulate the estrogen-dependence and receptor-signaling arm. No single model captures the full human triad of somatic KRAS-driven epithelial clonality + progesterone resistance + chronic pelvic pain phenotype — a noted translational limitation.
  • Applications: Used to study lesion initiation/EMI disruption, fibrosis and smooth-muscle metaplasia, angiogenesis, fertility/perinatal outcomes, and to test candidate therapeutics (e.g., COX-2, NLRP3, JAK/STAT inhibitors) preclinically.
  • In vitro/cell-based models: Primary human endometrial epithelial/stromal cell cultures, endometriotic epithelial cell lines (used to study KRAS/PIK3CA-driven progesterone resistance, PMC11049223), and emerging patient-derived organoids.
  • Resources: MGI (Mouse Genome Informatics) for strain/allele records; no dedicated adenomyosis-specific consortium repository identified (contrast with more established disease-model networks like IMPC for single-gene knockouts).

Summary of Key Ontology Term Suggestions for KB Curation

Category Suggested terms
MONDO MONDO:0010888
Phenotypes (HP) Dysmenorrhea, Menorrhagia/abnormal uterine bleeding, Chronic pelvic pain, Infertility, Dyspareunia
Genes (HGNC) KRAS (hgnc:6407), ARID1A (hgnc:713 — verify), HOXA10 (hgnc:5100 — verify), METTL3 (hgnc — verify)
GO biological processes epithelial to mesenchymal transition, angiogenesis, extracellular matrix organization, inflammatory response, response to estrogen
Cell types (CL) endometrial stromal cell, endometrial epithelial cell, uterine smooth muscle cell, macrophage, endothelial cell
Anatomy (UBERON) uterus (UBERON:0000995), myometrium (UBERON:0001296), endometrium (UBERON:0001295)
Treatments (NCIT) Pharmacotherapy (NCIT:C15986), Surgical Procedure (NCIT:C15329), with therapeutic_agent CHEBI terms for levonorgestrel, dienogest, leuprolide, tranexamic acid

(Note: several HGNC/HPO IDs above are given from memory/search snippets and should be independently verified with OAK before committing to the dismech KB, per the project's anti-hallucination validation workflow — this report is a curation input, not pre-validated YAML.)

Sources