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

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

(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

• Research Advances in Adenomyosis-Related Signaling Pathways and Promising Targets (PMC11591984)
• Pathogenesis of Adenomyosis: An Integrated Review of Cellular Origins, Molecular Mechanisms, and Intersecting Diseases (PMC13070875 / PMID:41968335)
• A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR) — PMID:25961248
• Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations — Nature Communications
• Adenomyosis pathogenesis: insights from next-generation sequencing — Human Reproduction Update
• Identification of novel causally related genes in adenomyosis: MR study — PMID:40527793
• Global prevalence of adenomyosis and endometriosis: systematic review and meta-analysis — PMID:41257733
• Adenomyosis incidence, prevalence and treatment: US population-based study 2006–2015 — AJOG
• SOGC Guideline No. 437: Diagnosis and Management of Adenomyosis — PMID:37244746
• Innovative Ultrasound Criteria for the Diagnosis of Adenomyosis (MUSA) — PMC10886873
• MRI and Adenomyosis: What Can Radiologists Evaluate? — PMC9140978
• Comprehensive transcriptional atlas of human adenomyosis — single-cell + spatial transcriptomics (PMC11214835)
• Establishment of a novel mouse model of adenomyosis (EMI puncture) — Scientific Reports / PMC9585053
• Neonatal ERβ agonist adenomyosis-like mouse model — Reprod Dev Med
• Women with adenomyosis are at higher risks of endometrial and thyroid cancers — PMC5844548
• The Risks for Ovarian, Endometrial, Breast, Colorectal, and Other Cancers in Women With Newly Diagnosed Endometriosis or Adenomyosis
• Impact of Adenomyosis on Women's Psychological Health and Work Productivity
• Outcomes in Adenomyosis Treated with Uterine Artery Embolization Are Associated with Lesion Vascularity — PMC5091759
• Risk factors for uterine adenomyosis diagnosed by MRI in women of reproductive age — PMC11981308
• OMIM Entry 600458 — Adenomyosis
• StatPearls — Adenomyosis
• AAFP — Adenomyosis: Diagnosis and Management