Endometriosis

Complex MONDO:0005133 Pathograph 17 Show in embeddings browser Reproductive Disease

Endometrial-like tissue, seeded in part through retrograde menstruation, implants and grows at ectopic sites on the ovaries, peritoneum, and pelvic organs. These lesions are estrogen-dependent and progesterone-resistant, sustaining chronic pelvic inflammation, immune evasion, and hypoxia-driven neoangiogenesis. Inflammatory and neuroangiogenic signaling sensitizes pelvic nociceptors and central pain pathways, producing pelvic pain, adhesions, and infertility.

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15
Pathophys.
7
Phenotypes
1
Hypotheses
1
Gaps
17
Pathograph
9
Genes
10
Medical Actions
6
Datasets
2
Trials
1
Models
4
References
2
Deep Research
1
Hyp. Reports
🏷

Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM
C

Comorbidities

Endometriosis <-> Fibromyalgia
Disease A A_BEFORE_B CANDIDATE
◈

Mechanistic Hypotheses

1
Neuroimmune Nociceptor-Sensitization Model
neuroimmune_pain_sensitization_model EMERGING
Evidence balance 2 support
Endometriosis-associated pain is driven by lesion- and peritoneal microenvironment signals that promote neuroangiogenesis, peripheral nociceptor sensitization, and later central sensitization, so pain severity can persist or amplify independently of visible lesion burden.
Focused hypothesis for dismech#3666. OpenScientist report kb/hypotheses/Endometriosis/neuroimmune_pain_sensitization_model/openscientist.md judged the model partially supported but recommended retaining EMERGING status. The model treats lesion burden as one input into a neuroimmune pain circuit, not as a sufficient proxy for symptom severity. The strongest support is for individual components (neuroangiogenesis, prolactin/nociceptor sensitization, central sensitization); the unresolved gap is how to weight these components by subtype and in an individual patient.
Pathograph links
Chronic Inflammation -> Lesion-Peritoneal Neuroangiogenesis INDIRECT KNOWN INTERMEDIATES The inflammatory peritoneal microenvironment provides prostaglandin, cytokine, and growth-factor signals that can couple lesion survival to neural and vascular remodeling. Intermediates: prostaglandins; cytokines; growth factors
Chronic Inflammation -> Peripheral Nociceptor Sensitization INDIRECT KNOWN INTERMEDIATES Inflammatory and hormonal mediators from the lesion/peritoneal compartment can lower nociceptor thresholds and amplify pelvic pain signaling. Intermediates: prostaglandins; cytokines; prolactin signaling
Hypoxia and Angiogenesis -> Lesion-Peritoneal Neuroangiogenesis INDIRECT KNOWN INTERMEDIATES Angiogenic lesion programs can coexist with or promote nerve-fiber recruitment in endometriotic implants and adjacent peritoneal tissue. Intermediates: VEGF-associated vascular remodeling
Lesion-Peritoneal Neuroangiogenesis -> Peripheral Nociceptor Sensitization INDIRECT KNOWN INTERMEDIATES Newly recruited lesion-associated nerve fibers and neurotrophic factors provide a peripheral substrate that can feed nociceptor sensitization. Intermediates: neurotrophins; sensory nerve-fiber recruitment
Peripheral Nociceptor Sensitization -> Central Sensitization and Nociplastic Pain INDIRECT KNOWN INTERMEDIATES Persistent peripheral nociceptive input can contribute to central amplification and broader nociplastic pain processing. Intermediates: persistent pelvic nociceptive input
Peripheral Nociceptor Sensitization -> Pelvic Pain DIRECT Sensitized pelvic nociceptors amplify the chronic pelvic pain phenotype.
Central Sensitization and Nociplastic Pain -> Pelvic Pain DIRECT Central amplification can sustain or worsen pelvic pain even when lesion-directed treatment reduces peripheral disease activity.
Deep research
OpenScientist citations 58 citations 2026-06-03T09:23:32.701357
Show evidence (2 references)
PMID:24859987 SUPPORT Other
"Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing."
Supports the integrated peripheral-peritoneal-central framing of the neuroimmune pain hypothesis.
PMID:30472739 SUPPORT Human Clinical
"The women with persistent pelvic pain had significantly lower pain thresholds compared with the reference women."
Human sensory-testing data support sensitization as part of the endometriosis-associated pelvic pain model.
?

Discussions and Knowledge Gaps

1
Which combination of lesion neuroangiogenesis, inflammatory mediators, prolactin/prolactin-receptor signaling, peripheral nociceptor sensitization, and central sensitization best explains why endometriosis pain often does not scale with visible lesion burden?
KNOWLEDGE GAP OPEN gap_endometriosis_pain_lesion_burden_discordance
Attached to
pathophysiology#Lesion-Peritoneal Neuroangiogenesis pathophysiology#Peripheral Nociceptor Sensitization pathophysiology#Central Sensitization and Nociplastic Pain phenotypes#Pelvic Pain
The entry now models a neuroimmune pain circuit, but the relative causal weights of lesion-local innervation, soluble mediators, peripheral nociceptor threshold shifts, and central pain amplification remain unresolved. This gap determines whether patients should be stratified primarily by lesion phenotype, molecular/peritoneal mediator profile, quantitative sensory testing, or central-sensitization/nociplastic-pain measures when predicting persistent pain after lesion-directed treatment.
Proposed experiments
Multimodal lesion-sensitization pain stratification cohort
prospective longitudinal cohort study Relation: this experiment is of type this experiment type This experiment is of type prospective longitudinal cohort study.
exp_endometriosis_multimodal_pain_stratification_cohort
Prospectively measure lesion subtype and burden, lesion/peritoneal neuroangiogenic markers, inflammatory and prolactin-pathway mediators, quantitative sensory testing, central-sensitization questionnaires, and pain outcomes before and after surgery or hormonal suppression to test which layer best predicts persistent pelvic pain.
Decision criterion
A model that combines peripheral mediator/innervation measures with central-sensitization readouts should predict persistent pain better than lesion burden or surgical stage alone.
Show evidence (4 references)
PMID:39062866 SUPPORT Other
"Despite its prevalence, the underlying molecular mechanisms of this disease remain poorly understood."
Supports retaining lesion-independent pain mechanisms as an open curation gap rather than a fully settled causal chain.
PMID:24859987 SUPPORT Other
"However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated."
Supports the unresolved gap between peripheral neuroangiogenic findings and patient-level pain severity.
PMID:40721059 SUPPORT Human Clinical
"Central sensitization (CSS), a condition where the central nervous system amplifies pain signals, may impact response to treatment of chronic pain conditions."
Supports the treatment-response component of the gap: central sensitization may modify response to lesion-directed therapy.
+ 1 more reference
⚙

Pathophysiology

15
Ectopic Endometrial Tissue
Endometrial-like tissue grows outside the uterus, commonly on ovaries, fallopian tubes, and pelvic peritoneum. Responds to hormonal cycling with bleeding and inflammation.
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.
Cell Proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cell Proliferation, annotated with cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:16166933 SUPPORT
"Endometriosis is classically described as the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis."
Defines endometriosis as ectopic presence of endometrial glandular and stromal cells outside the uterus
Retrograde Menstruation
Menstrual blood flows backward through fallopian tubes into pelvic cavity. Most women have retrograde menstruation, but only some develop endometriosis, suggesting other factors involved.
Downstream
Epithelial Clonal Expansion Retrograde flow can deliver endometrial cells that already harbor cancer-associated mutations to ectopic sites, where they gain a selective advantage and expand clonally.
Show evidence (1 reference)
PMID:16166933 SUPPORT
"Although multiple theories have been put forth to explain the pathophysiology and pathogenesis of endometriosis, the retrograde menstruation theory of Sampson is the most widely accepted. However, since retrograde menstruation occurs in most of the reproductive age women, it is clear that there..."
Retrograde menstruation is the most widely accepted theory but insufficient alone to explain disease development
Somatic Cancer-Driver Mutations
Deep-infiltrating endometriotic lesions harbor recurrent somatic cancer-driver mutations (KRAS, PIK3CA, ARID1A, PPP2R1A) that are largely confined to the epithelial compartment. Endometrial cells can already carry these cancer-associated mutations before reaching ectopic sites. Despite these oncogenic drivers, deep-infiltrating lesions remain benign — morphologically normal, non-expansile, and at virtually no risk of malignant transformation; ovarian endometrioma, in contrast, is a recognized precursor of endometriosis-associated ovarian cancer.
Endometriotic Epithelial Cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Endometriotic Epithelial Cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
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
Epithelial Clonal Expansion Cancer-driver mutations confer a selective growth advantage that drives clonal expansion of the epithelial compartment at ectopic sites.
Show evidence (3 references)
PMID:28489996 SUPPORT Human Clinical
"Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
Exome and targeted sequencing of deep-infiltrating lesions identified recurrent cancer-driver mutations in ARID1A, PIK3CA, KRAS, and PPP2R1A.
PMID:28489996 SUPPORT Human Clinical
"Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions."
Driver mutations were recurrent (26% of lesions) and restricted to the epithelial compartment, localizing clonal selection to the epithelium.
PMID:11156411 SUPPORT Human Clinical
"These results indicate that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma and clear cell carcinoma of the ovary."
Somatic PTEN inactivation in ovarian endometriotic cysts marks an early step toward endometriosis-associated ovarian carcinoma, backing the EAOC-precursor nuance stated for ovarian endometrioma.
Epithelial Clonal Expansion
Endometrial epithelial cells carrying cancer-associated mutations show rising mutant-allele fractions at ectopic sites relative to normal endometrium, marking clonal selection and expansion of the epithelial compartment. This supports a model in which refluxed, already-mutated cells gain a selective advantage and establish lesions.
Endometriotic Epithelial Cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Endometriotic Epithelial Cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
Epithelial Clonal Proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Epithelial Clonal Proliferation, annotated with cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Ectopic Endometrial Tissue Selective expansion of mutated endometrial epithelium at ectopic sites contributes to establishment of endometriosis lesions.
Show evidence (1 reference)
PMID:30110635 SUPPORT Human Clinical
"Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis."
Rising mutant-allele fractions in endometriotic versus normal epithelium support clonal selection of pre-mutated endometrial cells at ectopic sites, linking somatic drivers to lesion establishment.
Chronic Inflammation
Ectopic lesions trigger chronic pelvic inflammation with elevated cytokines and prostaglandins. Inflammatory milieu contributes to pain and adhesion formation.
Neuroimmune Nociceptor-Sensitization Model
Inflammatory Response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
Lesion-Peritoneal Neuroangiogenesis The inflammatory peritoneal microenvironment provides prostaglandin, cytokine, and growth-factor signals that can couple lesion survival to neural and vascular remodeling. Neuroimmune Nociceptor-Sensitization Model
Peripheral Nociceptor Sensitization Inflammatory and hormonal mediators from the lesion/peritoneal compartment can lower nociceptor thresholds and amplify pelvic pain signaling. Neuroimmune Nociceptor-Sensitization Model
Warburg-like Metabolic Reprogramming TGF-beta1 in the inflammatory peritoneal fluid drives peritoneal mesothelial cells toward the glycolytic (Warburg-like) phenotype.
Show evidence (1 reference)
PMID:16166933 SUPPORT
"Increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis."
Supports inflammatory cytokine/growth-factor milieu, but not the full downstream pain and adhesion statement.
Estrogen Dependence
Endometriotic lesions produce their own estrogen via aromatase and are highly estrogen-responsive. Progesterone resistance impairs normal tissue regression.
Estrogen Response GO:0043627 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Estrogen Response, annotated with response to estrogen (GO:0043627). GO:0043627 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:10731122 SUPPORT
"Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored..."
Estrogen drives endometriosis growth through both systemic delivery and local autocrine production
PMID:10731122 SUPPORT
"The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells...."
Aromatase expression in endometriotic stromal cells creates a positive feedback loop with PGE2 for local estrogen production
PMID:10731122 SUPPORT
"In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of..."
Deficiency of 17beta-HSD type 2 prevents estradiol inactivation, contributing to local estrogen dominance
Progesterone Resistance
Endometriotic tissue is resistant to progesterone action. Progesterone receptor levels are reduced and the PR-B isoform is essentially absent, so progesterone fails to induce epithelial 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2). Because 17beta-HSD-2 normally inactivates estradiol to estrone, its deficient induction leaves high local concentrations of the mitogen estradiol, and this progesterone resistance explains why a subset of patients do not respond to progestin therapy.
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. Endometrial Epithelial Cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Endometrial Epithelial Cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
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
Estrogen Dependence Progesterone resistance prevents progesterone-driven induction of 17beta-HSD-2, so estradiol is not inactivated and local estrogen levels stay high — reinforcing the estrogen-dependent growth of lesions.
Show evidence (3 references)
PMID:16406281 SUPPORT Human Clinical
"These in vivo observations are indicative of resistance to progesterone action in endometriosis."
Blunted progesterone-induced molecular changes in endometriosis indicate resistance to progesterone action.
PMID:16406281 SUPPORT Human Clinical
"The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B)."
Reduced total progesterone receptor and absent PR-B provide the molecular basis for progesterone resistance.
PMID:16406281 SUPPORT Human Clinical
"The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen."
Failure of progesterone to drive 17beta-HSD-2 leaves estradiol unmetabolized, sustaining high local mitogenic estrogen.
Immune Dysfunction
Immune system alterations enable ectopic endometrial cells to evade clearance. Includes increased peritoneal macrophages, reduced NK cell cytotoxicity, T cell dysfunction, and elevated inflammatory cytokines. Crosstalk between endometrial stromal cells and macrophages impairs NK cell function via IL-10 and TGF-beta secretion.
Inflammatory Response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:16166933 SUPPORT Other
"Increased number and activation of peritoneal macrophages, decreased T cell and natural killer (NK) cell cytotoxicities are the alterations in cellular immunity and result in inadequate removal of ectopic endometrial cells from the peritoneal cavity."
Directly states the node's claim - increased peritoneal macrophages plus reduced T cell and NK cytotoxicity causing inadequate clearance of ectopic endometrial cells.
PMID:28971893 SUPPORT
"The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity."
NK cell dysfunction is a key mechanism enabling immune escape of refluxed endometrial fragments
PMID:28971893 SUPPORT
"After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and..."
Interaction between endometrial stromal cells and macrophages suppresses NK cell cytotoxicity through IL-10 and TGF-beta
Hypoxia and Angiogenesis
Ectopic lesions experience hypoxia which stabilizes HIF-1alpha, upregulating VEGF and promoting angiogenesis. Neovascularization supports lesion survival and growth. Ovarian endometriomas show particularly high expression of hypoxic and angiogenic factors.
Neuroimmune Nociceptor-Sensitization Model
Response to Hypoxia GO:0001666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Response to Hypoxia (GO:0001666). GO:0001666 is a biological process from the Gene Ontology. Angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology.
Downstream
Lesion-Peritoneal Neuroangiogenesis Angiogenic lesion programs can coexist with or promote nerve-fiber recruitment in endometriotic implants and adjacent peritoneal tissue. Neuroimmune Nociceptor-Sensitization Model
Show evidence (3 references)
PMID:26408396 SUPPORT
"Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues."
Angiogenic and hypoxic mechanisms create a supportive microenvironment for ectopic lesion growth
PMID:26408396 SUPPORT
"Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA."
Ovarian endometriomas specifically show elevated hypoxia-inducible factors and VEGF with correlated expression
PMID:30074218 SUPPORT
"The results showed that serum concentrations of MMIF, HIF-1α, and VEGF were significantly higher in EM patients than in controls (P<0.05). The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal..."
HIF-1alpha and VEGF expression correlates with disease stage and dysmenorrhea severity
Warburg-like Metabolic Reprogramming
Endometriotic lesions and the peritoneal mesothelium of women with endometriosis undergo a cancer-like ("Warburg") metabolic shift away from mitochondrial respiration toward aerobic glycolysis. TGF-beta1, which is elevated in endometriosis peritoneal fluid, drives human peritoneal mesothelial cells to upregulate glycolysis-associated genes (HIF1A, PDK1, LDHA, SLC2A1) and secrete lactate. This glycolytic phenotype — higher glycolysis, lower mitochondrial respiration, and reduced pyruvate dehydrogenase activity — favors lesion establishment and survival and is the target of the investigational metabolic therapy dichloroacetate.
Peritoneal Mesothelial Cell CL:0000077 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Peritoneal Mesothelial Cell, annotated with mesothelial cell (CL:0000077). CL:0000077 is a cell type from the Cell Ontology.
Aerobic Glycolysis (Warburg Effect) GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Aerobic Glycolysis (Warburg Effect), annotated with glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↑ INCREASED Response to Hypoxia GO:0001666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Response to Hypoxia (GO:0001666). GO:0001666 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hypoxia and Angiogenesis Lactate secreted by the glycolytic peritoneal microenvironment is implicated in supporting angiogenesis and lesion invasion, coupling the metabolic shift to the angiogenic program.
Show evidence (4 references)
PMID:24796928 SUPPORT Human Clinical
"Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease"
Human endometriotic lesions and adjacent peritoneum overexpress glycolysis-associated genes versus disease-free tissue, evidencing a Warburg-like glycolytic shift in vivo.
PMID:24796928 SUPPORT Human Clinical
"Concentrations of lactate in peritoneal fluid paralleled those of TGF-β1, being significantly higher in women with endometriosis compared to women without"
Elevated peritoneal-fluid TGF-β1 and lactate in women with endometriosis support TGF-β1 as the inflammatory driver of the Warburg-like shift, the premise of the Chronic Inflammation to Warburg edge.
PMID:24796928 SUPPORT In Vitro
"Exposure of mesothelial cells to TGF-β1 increased production of lactate (P < .05), increased HIF1A mRNA (P < .05), and protein, and increased concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P < .05)."
TGF-beta1 drives the glycolytic, lactate-secreting phenotype in human peritoneal mesothelial cells, linking peritoneal TGF-beta to the Warburg-like shift.
+ 1 more reference
Adhesion Formation
Chronic inflammation leads to fibrous adhesions distorting pelvic anatomy. Adhesions contribute to pain and infertility.
Dysregulated Peritoneal Metalloproteinase Activity
Endometriosis is associated with altered extracellular-matrix metalloproteinase activity in the peritoneal compartment. Multiplexed droplet-microfluidic protease-activity profiling of patient peritoneal fluid — a non-animal, microphysiological (New Approach Methodology) measurement platform — resolved disease-associated differences in specific metalloproteinase activities, in particular decreased MMP-2 and ADAM-9 activity in subjects with endometriosis versus controls. This describes a measured activity signature in the peritoneal microenvironment rather than an established causal driver of lesion establishment.
Extracellular Matrix Disassembly GO:0022617 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Extracellular Matrix Disassembly (GO:0022617). GO:0022617 is a biological process from the Gene Ontology. ↓ DECREASED
metalloendopeptidase activity GO:0004222 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased metalloendopeptidase activity (GO:0004222). GO:0004222 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
Droplet-based microfluidic protease-activity profiling platform (PrAMA; MIT Griffith/Han) OTHER Multiplexed quantification of MMP and ADAM activities in peritoneal fluid, resolving endometriosis-associated decreases in MMP-2 and ADAM-9 activity.
Show evidence (1 reference)
PMID:23157326 SUPPORT Human Clinical
"The results showed clear and physiologically relevant differences with disease, in particular, decreased MMP-2 and ADAM-9 activities."
A droplet-based microfluidic NAM platform (MIT; Griffith/Lauffenburger/Han) applied to clinical peritoneal fluid resolved endometriosis-associated shifts in specific metalloproteinase activities, supporting dysregulated peritoneal MMP/ADAM activity as a measurable disease-associated signature.
Lesion-Peritoneal Neuroangiogenesis
Endometriotic lesions and peritoneal fluid can acquire neuroangiogenic properties, including nerve-fiber growth, altered sensory/autonomic fiber distribution, neurotrophin up-regulation, and vascular remodeling. This provides a peripheral anatomic substrate for pain but does not by itself explain perceived pain severity in all patients.
Neuroimmune Nociceptor-Sensitization Model
nociceptor CL:0000198 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nociceptor, annotated with pain receptor cell (CL:0000198). CL:0000198 is a cell type from the Cell Ontology.
Neurogenesis GO:0022008 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Neurogenesis (GO:0022008). GO:0022008 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
Downstream
Peripheral Nociceptor Sensitization Newly recruited lesion-associated nerve fibers and neurotrophic factors provide a peripheral substrate that can feed nociceptor sensitization. Neuroimmune Nociceptor-Sensitization Model
Show evidence (2 references)
PMID:24859987 SUPPORT Other
"Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins."
Review evidence supports lesion/peritoneal neuroangiogenesis as a peripheral pain-pathway component.
PMID:21054165 SUPPORT Other
"Recent evidence indicates that ectopic endometriotic implants recruit their own unique neural and vascular supplies through neuroangiogenesis."
Supports a neuroangiogenic lesion mechanism that links endometriotic implants to nerve and vascular remodeling.
Peripheral Nociceptor Sensitization
Lesion and peritoneal mediators, including inflammatory mediators and prolactin/prolactin-receptor signaling, can sensitize pelvic nociceptive sensory neurons. This provides a mechanism by which pain may be amplified without requiring proportional increases in lesion burden.
Neuroimmune Nociceptor-Sensitization Model
nociceptor CL:0000198 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nociceptor, annotated with pain receptor cell (CL:0000198). CL:0000198 is a cell type from the Cell Ontology.
Sensory perception of pain GO:0019233 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Sensory perception of pain (GO:0019233). GO:0019233 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Central Sensitization and Nociplastic Pain Persistent peripheral nociceptive input can contribute to central amplification and broader nociplastic pain processing. Neuroimmune Nociceptor-Sensitization Model
Pelvic Pain Sensitized pelvic nociceptors amplify the chronic pelvic pain phenotype. Neuroimmune Nociceptor-Sensitization Model
Show evidence (3 references)
PMID:37169264 SUPPORT Other
"We highlight our current understanding of prolactin-mediated mechanisms of nociceptor sensitization in females and how this mechanism may apply to endometriosis."
Supports prolactin/prolactin-receptor signaling as a candidate nociceptor-sensitizing mediator in endometriosis pain.
PMID:37169264 SUPPORT Other
"The results of this search strongly indicate that serum prolactin levels are increased in patients with endometriosis and support the possibility that high levels of prolactin may promote pelvic pain in these patients and increase vulnerability to other comorbid pain conditions likely by..."
Supports prolactin as a plausible pain amplifier, while the abstract frames this as a possibility rather than a resolved causal mechanism.
PMID:28954602 SUPPORT Human Clinical
"As a result, BDNF concentrations in serum and PF were significantly higher in women with endometriosis with pain (2284.3 ± 51.5 pg/mL, n = 23; 58.8 ± 6.4 pg/mL, n = 16) than in women with endometriosis without pain (1999.8 ± 61.1 pg/mL, n = 37; 31.7 ± 2.9 pg/mL, n = 25; P < .01)."
Human biomarker data support neurotrophin-linked pain amplification by showing higher BDNF in endometriosis patients with pain than in endometriosis patients without pain.
Central Sensitization and Nociplastic Pain
Chronic endometriosis-associated pain can involve central nervous system amplification of pain signals and nociplastic pain mechanisms. This downstream state helps explain pain persistence and incomplete response to lesion-directed therapy in some patients.
Neuroimmune Nociceptor-Sensitization Model
Sensory perception of pain GO:0019233 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Sensory perception of pain (GO:0019233). GO:0019233 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Pelvic Pain Central amplification can sustain or worsen pelvic pain even when lesion-directed treatment reduces peripheral disease activity. Neuroimmune Nociceptor-Sensitization Model
Show evidence (4 references)
PMID:30472739 SUPPORT Human Clinical
"Our results showed widespread alterations in pain thresholds in women with persistent pelvic pain that are indicative of central sensitization and a time-dependent correlation."
Human quantitative sensory testing supports central sensitization in persistent pelvic pain cohorts evaluated for suspected endometriosis.
PMID:39768444 SUPPORT Other
"Endometriosis is an inflammatory chronic condition associated with nociceptive, neuropathic, and nociplastic pain. Central sensitization (CS) is the primary nociplastic pain mechanism."
Review evidence supports modeling central sensitization as the main nociplastic pain mechanism in endometriosis-related chronic pelvic pain.
PMID:40721059 SUPPORT Human Clinical
"Patients with CSS have smaller changes in pain scores after endometriosis surgery (RR 0.79, confidence interval 0.73-0.86) and significantly higher persistent pain (RR 2.27, confidence interval 1.40-3.68)."
Human clinical meta-analysis supports central sensitization as a treatment-response modifier associated with persistent post-surgical pain.
+ 1 more reference
⬡

Pathograph

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

7
Blood 1
Heavy Menstrual Bleeding FREQUENT 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.
Genitourinary 2
Dyspareunia FREQUENT 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.
Deep dyspareunia
Infertility FREQUENT 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 (1 reference)
PMID:37844487 SUPPORT Human Clinical
"It affects around 6-10% of reproductive-age women in the world and causes debilitating pain, heavy menstrual bleeding, pain during penetrative sex, and infertility."
Names infertility directly as a consequence of endometriosis; the frequency band remains a broad clinical annotation rather than a quantitative claim from this snippet.
Constitutional 3
Pelvic Pain VERY_FREQUENT HP:0034267 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic pelvic pain, annotated with Pelvic pain (HP:0034267), qualified as temporality chronic. HP:0034267 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Chronic, cyclical
Show evidence (2 references)
PMID:24859987 SUPPORT Other
"Pain remains the cardinal symptom of endometriosis."
Supports pelvic pain as a central clinical phenotype of endometriosis; the existing frequency remains a broad clinical annotation rather than a quantitative claim from this snippet.
PMID:37844487 SUPPORT Other
"Endometriosis is usually classified into four stages: minimal, mild, moderate, and severe, though it is important to note that the presentation of symptoms does not necessarily correspond to the disease progression."
Supports the issue focus that symptoms, including pain, do not map cleanly to conventional disease-stage or progression measures.
Dysmenorrhea VERY_FREQUENT 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 (1 reference)
PMID:30074218 SUPPORT
"The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal severity (P<0.05)."
VEGF and HIF-1alpha expression correlates with dysmenorrhea severity, linking hypoxia and angiogenesis to pain
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Other 1
Painful Bowel Movements OCCASIONAL Painful defecation HP:6000222 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyschezia, annotated with Painful defecation (HP:6000222). HP:6000222 is a phenotype from the Human Phenotype Ontology.
With rectovaginal disease
🧬

Genetic Associations

9
WNT4 (Risk Factor)
Gene: WNT4 hgnc:12783 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WNT4 (hgnc:12783). hgnc:12783 is a gene from the HUGO Gene Nomenclature Committee.
VEZT (Risk Factor)
Gene: VEZT hgnc:18258 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VEZT (hgnc:18258). hgnc:18258 is a gene from the HUGO Gene Nomenclature Committee.
GREB1 (Risk Factor)
Gene: GREB1 hgnc:24885 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GREB1 (hgnc:24885). hgnc:24885 is a gene from the HUGO Gene Nomenclature Committee.
ID4 (Risk Factor)
Gene: ID4 hgnc:5363 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ID4 (hgnc:5363). hgnc:5363 is a gene from the HUGO Gene Nomenclature Committee.
KRAS (Somatic driver; most frequently mutated cancer-driver in endometriotic epithelium)
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 variant_origin: SOMATIC
Show evidence (1 reference)
PMID:28489996 SUPPORT Human Clinical
"One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions."
Recurrent activating KRAS codon-12 (c.35) mutations were validated in the epithelium of deep-infiltrating endometriotic lesions.
PIK3CA (Somatic driver in endometriotic epithelium)
Gene: PIK3CA hgnc:8975 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIK3CA (hgnc:8975). hgnc:8975 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:28489996 SUPPORT Human Clinical
"Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
PIK3CA is among the validated somatic cancer-driver mutations found in deep-infiltrating endometriotic lesions.
ARID1A (Somatic driver in endometriotic epithelium)
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 variant_origin: SOMATIC
Show evidence (1 reference)
PMID:28489996 SUPPORT Human Clinical
"Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
ARID1A is among the validated somatic cancer-driver mutations found in deep-infiltrating endometriotic lesions.
PPP2R1A (Somatic driver in endometriotic epithelium)
Gene: PPP2R1A hgnc:9302 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PPP2R1A (hgnc:9302). hgnc:9302 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:28489996 SUPPORT Human Clinical
"Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
PPP2R1A is among the validated somatic cancer-driver mutations found in deep-infiltrating endometriotic lesions.
PTEN (Somatic tumor-suppressor inactivation in ovarian endometriotic cysts)
Gene: PTEN hgnc:9588 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTEN (hgnc:9588). hgnc:9588 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:11156411 SUPPORT Human Clinical
"Somatic mutations in the PTEN gene were identified in 4 of 20 ovarian endometrioid carcinomas (20.0%), 2 of 24 clear cell carcinomas (8.3%), and 7 of 34 solitary endometrial cysts (20.6%)."
Somatic PTEN mutations are present in a fifth of ovarian endometriotic cysts, evidencing PTEN inactivation as an early somatic event in the endometriosis-to-ovarian-cancer sequence.
💊

Medical Actions

10
NSAIDs
Action: NSAID therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is NSAID therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: NSAID NCIT:C257 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses NSAID, annotated with Nonsteroidal Antiinflammatory Drug (NCIT:C257). NCIT:C257 is a therapeutic agent from the NCI Thesaurus.
First-line for pain management.
Combined Oral Contraceptives
Action: combined oral contraceptive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is combined oral contraceptive therapy, annotated with Hormonal Contraception (NCIT:C92808). NCIT:C92808 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormonal Contraception NCIT:C92808
Suppress ovulation and reduce menstruation.
Progestins
Action: progestin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is progestin therapy (NCIT:C15484). NCIT:C15484 is a clinical intervention from the NCI Thesaurus. Ontology label: Progestin Therapy NCIT:C15484
Create hypoestrogenic state (dienogest, medroxyprogesterone).
GnRH Agonists
Action: GnRH agonist therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is GnRH agonist therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: gonadotropin-releasing hormone agonist NCIT:C1910 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses gonadotropin-releasing hormone agonist, annotated with Gonadotropin-releasing Hormone Analog (NCIT:C1910). NCIT:C1910 is a therapeutic agent from the NCI Thesaurus.
Induce medical menopause, add-back therapy needed.
GnRH Antagonists
Action: GnRH antagonist therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is GnRH antagonist therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: gonadotropin-releasing hormone antagonist NCIT:C2092 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses gonadotropin-releasing hormone antagonist, annotated with Gonadotropin Releasing Hormone Antagonist (NCIT:C2092). NCIT:C2092 is a therapeutic agent from the NCI Thesaurus.
Elagolix with dose-dependent estrogen suppression.
Aromatase Inhibitors
Action: aromatase inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is aromatase inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Reduce local estrogen production in lesions.
Dichloroacetate (Investigational)
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: dichloroacetate CHEBI:28240 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dichloroacetate (CHEBI:28240). CHEBI:28240 is a therapeutic agent from Chemical Entities of Biological Interest.
Investigational non-hormonal, non-contraceptive metabolic therapy. The pyruvate dehydrogenase kinase (PDK) inhibitor / PDH activator dichloroacetate reverses the aberrant glycolytic phenotype of peritoneal mesothelial cells, reduces lactate secretion, and shrank lesions in a mouse model; a single-arm open-label feasibility trial (EPiC) is evaluating it for endometriosis-associated pain ahead of a planned placebo-controlled trial.
Mechanism Target:
INHIBITS Warburg-like Metabolic Reprogramming — DCA inhibits pyruvate dehydrogenase kinase and reactivates PDH, normalizing the glycolytic shift and reducing lactate secretion by peritoneal mesothelial cells.
Show evidence (1 reference)
DOI:10.1073/pnas.1916144116 SUPPORT In Vitro
"Treatment of endometriosis HPMCs with the pyruvate dehydrogenase kinase (PDK) inhibitor/PDH activator dichloroacetate (DCA) normalizes HPMC metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a coculture model."
DCA reverses the Warburg-like metabolic phenotype and suppresses stromal proliferation in a coculture model, defining the targeted mechanism.
Show evidence (2 references)
DOI:10.1073/pnas.1916144116 SUPPORT Model Organism
"Oral DCA reduced peritoneal fluid lactate concentrations and endometriosis lesion size in a mouse model."
Oral dichloroacetate lowered peritoneal lactate and reduced lesion size in a mouse model, providing the in vivo rationale for clinical testing.
PMID:33712086 SUPPORT Human Clinical
"We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain."
The EPiC exploratory trial evaluates dichloroacetate in women with endometriosis-associated pain to inform a future efficacy RCT.
Cabergoline (Investigational)
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: cabergoline CHEBI:3286 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cabergoline (CHEBI:3286). CHEBI:3286 is a therapeutic agent from Chemical Entities of Biological Interest.
Investigational non-hormonal anti-angiogenic therapy. The dopamine D2 receptor agonist cabergoline promotes VEGF receptor-2 (VEGFR-2) endocytosis, preventing VEGF-VEGFR-2 binding and reducing neoangiogenesis. In experimentally induced endometriosis it decreased the proportion of active lesions and vascularization, and it is being evaluated as a non-hormonal, non-surgical option for endometriosis pain.
Mechanism Target:
INHIBITS Hypoxia and Angiogenesis — Dopamine-agonist-driven VEGFR-2 endocytosis and reduced VEGFR-2 phosphorylation blunt VEGF signaling and lesion neoangiogenesis.
Show evidence (1 reference)
PMID:19189995 SUPPORT Model Organism
"Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation."
Cabergoline's anti-angiogenic action on endometriotic lesions operates through VEGFR-2, targeting the hypoxia/angiogenesis mechanism node.
Show evidence (1 reference)
PMID:19189995 SUPPORT Model Organism
"A significant decrease in the percentage of active endometriotic lesions (P < 0.05) and cellular proliferation index (P < 0.001) was found with Cb2 treatment."
In a nude-mouse model of endometriosis, cabergoline reduced active lesions and proliferation, supporting anti-angiogenic therapeutic potential.
Laparoscopic Surgery
Action: laparoscopic surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is laparoscopic surgery, annotated with Laparoscopy (NCIT:C16969). NCIT:C16969 is a clinical intervention from the NCI Thesaurus. Ontology label: Laparoscopy NCIT:C16969
Excision or ablation of lesions, adhesiolysis.
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
Definitive surgery for completed childbearing.
🌍

Environmental Factors

4
Early Menarche
Increases lifetime estrogen exposure
Show evidence (1 reference)
PMID:30017581 SUPPORT Human Clinical
"Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
Epidemiologic review naming early age at menarche as a characteristic robustly associated with greater endometriosis risk.
Short Menstrual Cycles
More frequent retrograde menstruation
Show evidence (1 reference)
PMID:30017581 SUPPORT Human Clinical
"Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
Epidemiologic review naming short menstrual cycle length as a characteristic robustly associated with greater endometriosis risk.
Nulliparity
Risk factor
Show evidence (1 reference)
PMID:30017581 SUPPORT Human Clinical
"Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
Same epidemiologic review reports the inverse relationship — greater parity is associated with lower endometriosis risk, so nulliparity (zero parity) is a risk factor.
Low BMI
Associated with increased risk
Show evidence (1 reference)
PMID:30017581 SUPPORT Human Clinical
"Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
Epidemiologic review naming lean body size (low BMI) as a characteristic robustly associated with greater endometriosis risk.
🔬

Biochemical Markers

2
CA-125 (Elevated)
Context: Nonspecific, may be elevated in severe disease
Estradiol (Normal to Elevated)
Context: Local estrogen production in lesions
📊

Prevalence

1
Reproductive-age women, worldwide
Point Prevalence 8000.0 per 100,000 (6000.0–10000.0) >1 in 1,000
Review-reported worldwide prevalence of 6-10% among reproductive-age women; midpoint recorded as the point estimate.
Show evidence (1 reference)
PMID:37844487 SUPPORT Human Clinical
"It affects around 6-10% of reproductive-age women in the world and causes debilitating pain, heavy menstrual bleeding, pain during penetrative sex, and infertility."
Gives the worldwide prevalence of endometriosis among reproductive-age women.
📊

Related Datasets

6
Altered miRNA cargo of endometrial extracellular vesicles in endometriosis: potential implications for pregnancy outcomes geo:GSE302961
Study question: Is the miRNA cargo of extracellular vesicles (EVs) secreted by the eutopic endometrium from women with endometriosis involved in its pathogenesis and related infertility? Summary answer: Data suggest that EVs secreted by primary endometrial epithelial cells from women with endometriosis transport an altered miRNA cargo that modulates biological processes related to endometriosis pathogenesis and pregnancy disorders. Main results and the role of chance: EVs had a mean size of 171 nm and expressed the EV protein markers CD63, CD9, and CD81. TEM corroborated EV cup-shaped morphology. Principal Component Analysis (PCA) revealed differentiated behavior between groups.
human BULK RNA SEQ n=7
PMID:42282918
Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Menstrual Fluid-Derived Small Extracellular Vesicles: A Novel Reservoir with Distinct Molecular Signatures and Implications for Endometriosis Etiopathology geo:GSE310627
STUDY QUESTION: Can the transcriptomic profile of small extracellular vesicles (sEV) derived from menstrual fluid (MF) provide insight into their potential roles as biomarkers and mediators in endometriosis (EM) development? SUMMARY ANSWER: MF-derived sEV from EM patients display altered molecular signatures reflective of EM pathophysiology and exhibit enhanced proangiogenic activity in vitro. WHAT IS KNOWN ALREADY: EM is a chronic gynecological disorder affecting approximately 10% of reproductive-age women, associated with pain, infertility, and delayed diagnosis.
human BULK RNA SEQ n=6
PMID:41924633
Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Circulating microRNAs as predictive biomarkers for progestin treatment response in endometriosis patients geo:GSE287223
Total RNA was extracted from 400 ul of serum with the miRNeasy Serum/Plasma advanced Kit (Qiagen) and quantified using the Qubit microRNA assay kit (Thermo Fisher Scientific). cDNA templates were prepared using the TaqMan Advanced miRNA cDNA Synthesis Kit (Thermo Fisher Scientific), starting from 10 ng of RNA. RT-qPCR carried out on a QuantStudio 12K Flex (Applied Biosystems) using the TaqMan OpenArray miRNA panel.
human n=84
Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas ega:EGAS00000000075
We have sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Searching for variants associated with endometriosis ega:EGAS00001001741
We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter.
human
PMID:27055116
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Somatic mutations in endometriosis and normal uterine endometrium ega:EGAS00001003095
To characterize the genomic features of endometriosis, we performed whole-exome sequencing for ovarian endometriotic epithelium samples obtained from subjects without concurrent gynecological cancers. Additionally, we analyzed histologically normal uterine endometrial epithelium samples obtained from subjects with benign gynecologic diseases. All the epithelium samples were isolated by laser microdissection from frozen sections.
human
PMID:30110635
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
🔬

Clinical Trials

2
NCT03928288 PHASE_II COMPLETED
Randomized, double-blind trial repurposing the dopamine agonist cabergoline as a non-hormonal angiogenesis inhibitor for chronic endometriosis-associated pain in adolescents and adults.
Target Phenotypes: Pelvic pain HP:0034267 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pelvic pain (HP:0034267). HP:0034267 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03928288 SUPPORT Human Clinical
"repurposing an existing drug, cabergoline, as a safe, alternative angiogenesis inhibitor for adolescents and young women with endometriosis"
The trial evaluates cabergoline as a non-hormonal anti-angiogenic therapy for endometriosis-associated pain, matching the modeled angiogenesis mechanism.
NCT04046081 NOT_APPLICABLE COMPLETED
Single-arm, open-label exploratory (feasibility) trial evaluating dichloroacetate (DCA) as a non-hormonal metabolic treatment for endometriosis-associated pain (EPiC), to inform a future placebo-controlled efficacy RCT.
Target Phenotypes: Pelvic pain HP:0034267 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pelvic pain (HP:0034267). HP:0034267 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04046081 SUPPORT Human Clinical
"single-arm open label exploratory clinical trial to evaluate dichloroacetate (DCA)"
The EPiC feasibility trial tests dichloroacetate for endometriosis-associated pain, matching the modeled Warburg metabolic mechanism.
🧫

Experimental Models

1
Droplet-based microfluidic protease-activity profiling platform (PrAMA; MIT Griffith/Han) OTHER
Picoliter-scale droplet-microfluidic platform (barcoded droplet library with pico-injection and Proteolytic Activity Matrix Analysis deconvolution) for multiplexed metalloproteinase activity profiling in small-volume clinical samples, applied to peritoneal fluid from subjects with and without endometriosis. A non-animal New Approach Methodology that resolves specific MMP and ADAM enzymatic activities in cell-free clinical fluid.
endometriosis peritoneal fluid metalloproteinase activity profiling
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
peritoneal fluid UBERON:0001268 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses peritoneal fluid (UBERON:0001268). UBERON:0001268 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Clinical peritoneal fluid from endometriosis and control subjects (cell-free)
Culture
Droplet-based microfluidic multiplexed protease-activity assay
Publication
PMID:23157326
Pathograph links
Dysregulated Peritoneal Metalloproteinase Activity Multiplexed quantification of MMP and ADAM activities in peritoneal fluid, resolving endometriosis-associated decreases in MMP-2 and ADAM-9 activity.
Findings
Peritoneal fluid from subjects with endometriosis showed decreased MMP-2 and ADAM-9 activities versus controls
Show evidence (1 reference)
PMID:23157326 SUPPORT Human Clinical
"The results showed clear and physiologically relevant differences with disease, in particular, decreased MMP-2 and ADAM-9 activities."
The droplet-microfluidic NAM platform applied to clinical peritoneal fluid resolved endometriosis-associated decreases in specific metalloproteinase activities.
{ }

Source YAML

click to show 
name: Endometriosis
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Endometrial-like tissue, seeded in part through retrograde menstruation, implants and grows at ectopic sites on the ovaries, peritoneum, and pelvic organs.
  These lesions are estrogen-dependent and progesterone-resistant, sustaining chronic pelvic inflammation, immune evasion, and hypoxia-driven neoangiogenesis.
  Inflammatory and neuroangiogenic signaling sensitizes pelvic nociceptors and central pain pathways, producing pelvic pain, adhesions, and infertility.
category: Complex
parents:
- Reproductive Disease
disease_term:
  preferred_term: endometriosis
  term:
    id: MONDO:0005133
    label: endometriosis
prevalence:
- population: Reproductive-age women, worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 6000.0
  rate_high: 10000.0
  rate_per_100000: 8000.0
  notes: Review-reported worldwide prevalence of 6-10% among reproductive-age women; midpoint recorded as the point estimate.
  evidence:
  - reference: PMID:37844487
    reference_title: "Endometriosis: Classification, pathophysiology, and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It affects around 6-10% of reproductive-age women in the world and causes
      debilitating pain, heavy menstrual bleeding, pain during penetrative sex,
      and infertility.
    explanation: Gives the worldwide prevalence of endometriosis among reproductive-age women.
pathophysiology:
- name: Ectopic Endometrial Tissue
  description: >
    Endometrial-like tissue grows outside the uterus, commonly on
    ovaries, fallopian tubes, and pelvic peritoneum. Responds to
    hormonal cycling with bleeding and inflammation.
  cell_types:
  - preferred_term: Endometrial Stromal Cell
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  biological_processes:
  - preferred_term: Cell Proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:16166933
    reference_title: "Immunology of endometriosis."
    supports: SUPPORT
    snippet: "Endometriosis is classically described as the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis."
    explanation: Defines endometriosis as ectopic presence of endometrial glandular and stromal cells outside the uterus
- name: Retrograde Menstruation
  description: >
    Menstrual blood flows backward through fallopian tubes into
    pelvic cavity. Most women have retrograde menstruation, but only
    some develop endometriosis, suggesting other factors involved.
  evidence:
  - reference: PMID:16166933
    reference_title: "Immunology of endometriosis."
    supports: SUPPORT
    snippet: "Although multiple theories have been put forth to explain the pathophysiology and pathogenesis of endometriosis, the retrograde menstruation theory of Sampson is the most widely accepted. However, since retrograde menstruation occurs in most of the reproductive age women, it is clear that there must be other factors which may contribute to the implantation of endometrial cells and their subsequent development into endometriotic disease."
    explanation: Retrograde menstruation is the most widely accepted theory but insufficient alone to explain disease development
  downstream:
  - target: Epithelial Clonal Expansion
    description: >
      Retrograde flow can deliver endometrial cells that already harbor
      cancer-associated mutations to ectopic sites, where they gain a selective
      advantage and expand clonally.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - retrograde flow of pre-mutated endometrial cells
- name: Somatic Cancer-Driver Mutations
  biological_scale: MOLECULAR
  description: >
    Deep-infiltrating endometriotic lesions harbor recurrent somatic
    cancer-driver mutations (KRAS, PIK3CA, ARID1A, PPP2R1A) that are largely
    confined to the epithelial compartment. Endometrial cells can already carry
    these cancer-associated mutations before reaching ectopic sites. Despite
    these oncogenic drivers, deep-infiltrating lesions remain benign —
    morphologically normal, non-expansile, and at virtually no risk of malignant
    transformation; ovarian endometrioma, in contrast, is a recognized precursor
    of endometriosis-associated ovarian cancer.
  cell_types:
  - preferred_term: Endometriotic Epithelial Cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  evidence:
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
    explanation: >
      Exome and targeted sequencing of deep-infiltrating lesions identified
      recurrent cancer-driver mutations in ARID1A, PIK3CA, KRAS, and PPP2R1A.
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions."
    explanation: >
      Driver mutations were recurrent (26% of lesions) and restricted to the
      epithelial compartment, localizing clonal selection to the epithelium.
  - reference: PMID:11156411
    reference_title: "Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicate that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma and clear cell carcinoma of the ovary."
    explanation: >
      Somatic PTEN inactivation in ovarian endometriotic cysts marks an early
      step toward endometriosis-associated ovarian carcinoma, backing the
      EAOC-precursor nuance stated for ovarian endometrioma.
  downstream:
  - target: Epithelial Clonal Expansion
    description: >
      Cancer-driver mutations confer a selective growth advantage that drives
      clonal expansion of the epithelial compartment at ectopic sites.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - selective growth advantage of mutant epithelium
- name: Epithelial Clonal Expansion
  biological_scale: CELLULAR
  description: >
    Endometrial epithelial cells carrying cancer-associated mutations show
    rising mutant-allele fractions at ectopic sites relative to normal
    endometrium, marking clonal selection and expansion of the epithelial
    compartment. This supports a model in which refluxed, already-mutated cells
    gain a selective advantage and establish lesions.
  cell_types:
  - preferred_term: Endometriotic Epithelial Cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: Epithelial Clonal Proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:30110635
    reference_title: "Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis."
    explanation: >
      Rising mutant-allele fractions in endometriotic versus normal epithelium
      support clonal selection of pre-mutated endometrial cells at ectopic
      sites, linking somatic drivers to lesion establishment.
  downstream:
  - target: Ectopic Endometrial Tissue
    description: >
      Selective expansion of mutated endometrial epithelium at ectopic sites
      contributes to establishment of endometriosis lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - clonal selection at ectopic sites
- name: Chronic Inflammation
  description: >
    Ectopic lesions trigger chronic pelvic inflammation with elevated
    cytokines and prostaglandins. Inflammatory milieu contributes to
    pain and adhesion formation.
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:16166933
    reference_title: "Immunology of endometriosis."
    supports: SUPPORT
    snippet: "Increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis."
    explanation: Supports inflammatory cytokine/growth-factor milieu, but not the full downstream pain and adhesion statement.
  downstream:
  - target: Lesion-Peritoneal Neuroangiogenesis
    description: >
      The inflammatory peritoneal microenvironment provides prostaglandin,
      cytokine, and growth-factor signals that can couple lesion survival to
      neural and vascular remodeling.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - prostaglandins
    - cytokines
    - growth factors
  - target: Peripheral Nociceptor Sensitization
    description: >
      Inflammatory and hormonal mediators from the lesion/peritoneal
      compartment can lower nociceptor thresholds and amplify pelvic pain
      signaling.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - prostaglandins
    - cytokines
    - prolactin signaling
  - target: Warburg-like Metabolic Reprogramming
    description: >
      TGF-beta1 in the inflammatory peritoneal fluid drives peritoneal
      mesothelial cells toward the glycolytic (Warburg-like) phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - TGF-beta1 signaling
- name: Estrogen Dependence
  description: >
    Endometriotic lesions produce their own estrogen via aromatase
    and are highly estrogen-responsive. Progesterone resistance
    impairs normal tissue regression.
  biological_processes:
  - preferred_term: Estrogen Response
    term:
      id: GO:0043627
      label: response to estrogen
  evidence:
  - reference: PMID:10731122
    reference_title: "Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis."
    supports: SUPPORT
    snippet: "Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells."
    explanation: Estrogen drives endometriosis growth through both systemic delivery and local autocrine production
  - reference: PMID:10731122
    reference_title: "Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis."
    supports: SUPPORT
    snippet: "The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium."
    explanation: Aromatase expression in endometriotic stromal cells creates a positive feedback loop with PGE2 for local estrogen production
  - reference: PMID:10731122
    reference_title: "Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis."
    supports: SUPPORT
    snippet: "In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium."
    explanation: Deficiency of 17beta-HSD type 2 prevents estradiol inactivation, contributing to local estrogen dominance
- name: Progesterone Resistance
  biological_scale: CELLULAR
  description: >
    Endometriotic tissue is resistant to progesterone action. Progesterone
    receptor levels are reduced and the PR-B isoform is essentially absent, so
    progesterone fails to induce epithelial 17beta-hydroxysteroid dehydrogenase
    type 2 (17beta-HSD-2). Because 17beta-HSD-2 normally inactivates estradiol
    to estrone, its deficient induction leaves high local concentrations of the
    mitogen estradiol, and this progesterone resistance explains why a subset of
    patients do not respond to progestin therapy.
  cell_types:
  - preferred_term: Endometrial Stromal Cell
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  - preferred_term: Endometrial Epithelial Cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: Response to progesterone
    modifier: DECREASED
    term:
      id: GO:0032570
      label: response to progesterone
  evidence:
  - reference: PMID:16406281
    reference_title: "Progesterone resistance in endometriosis: link to failure to metabolize estradiol."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These in vivo observations are indicative of resistance to progesterone action in endometriosis."
    explanation: >
      Blunted progesterone-induced molecular changes in endometriosis indicate
      resistance to progesterone action.
  - reference: PMID:16406281
    reference_title: "Progesterone resistance in endometriosis: link to failure to metabolize estradiol."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B)."
    explanation: >
      Reduced total progesterone receptor and absent PR-B provide the molecular
      basis for progesterone resistance.
  - reference: PMID:16406281
    reference_title: "Progesterone resistance in endometriosis: link to failure to metabolize estradiol."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen."
    explanation: >
      Failure of progesterone to drive 17beta-HSD-2 leaves estradiol
      unmetabolized, sustaining high local mitogenic estrogen.
  downstream:
  - target: Estrogen Dependence
    description: >
      Progesterone resistance prevents progesterone-driven induction of
      17beta-HSD-2, so estradiol is not inactivated and local estrogen levels
      stay high — reinforcing the estrogen-dependent growth of lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absent PR-B
    - failure to induce 17beta-HSD-2
    - deficient estradiol inactivation
- name: Immune Dysfunction
  description: >
    Immune system alterations enable ectopic endometrial cells to evade
    clearance. Includes increased peritoneal macrophages, reduced NK cell
    cytotoxicity, T cell dysfunction, and elevated inflammatory cytokines.
    Crosstalk between endometrial stromal cells and macrophages impairs
    NK cell function via IL-10 and TGF-beta secretion.
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:16166933
    reference_title: "Immunology of endometriosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased number and activation of peritoneal macrophages, decreased T cell and natural killer (NK) cell cytotoxicities are the alterations in cellular immunity and result in inadequate removal of ectopic endometrial cells from the peritoneal cavity."
    explanation: Directly states the node's claim - increased peritoneal macrophages plus reduced T cell and NK cytotoxicity causing inadequate clearance of ectopic endometrial cells.
  - reference: PMID:28971893
    reference_title: "The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β."
    supports: SUPPORT
    snippet: "The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity."
    explanation: NK cell dysfunction is a key mechanism enabling immune escape of refluxed endometrial fragments
  - reference: PMID:28971893
    reference_title: "The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β."
    supports: SUPPORT
    snippet: "After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased."
    explanation: Interaction between endometrial stromal cells and macrophages suppresses NK cell cytotoxicity through IL-10 and TGF-beta
- name: Hypoxia and Angiogenesis
  description: >
    Ectopic lesions experience hypoxia which stabilizes HIF-1alpha,
    upregulating VEGF and promoting angiogenesis. Neovascularization
    supports lesion survival and growth. Ovarian endometriomas show
    particularly high expression of hypoxic and angiogenic factors.
  biological_processes:
  - preferred_term: Response to Hypoxia
    term:
      id: GO:0001666
      label: response to hypoxia
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:26408396
    reference_title: "Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions."
    supports: SUPPORT
    snippet: "Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues."
    explanation: Angiogenic and hypoxic mechanisms create a supportive microenvironment for ectopic lesion growth
  - reference: PMID:26408396
    reference_title: "Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions."
    supports: SUPPORT
    snippet: "Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA."
    explanation: Ovarian endometriomas specifically show elevated hypoxia-inducible factors and VEGF with correlated expression
  - reference: PMID:30074218
    reference_title: "Expression of MMIF, HIF-1α and VEGF in Serum and Endometrial Tissues of Patients with Endometriosis."
    supports: SUPPORT
    snippet: "The results showed that serum concentrations of MMIF, HIF-1α, and VEGF were significantly higher in EM patients than in controls (P<0.05). The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal severity (P<0.05)."
    explanation: HIF-1alpha and VEGF expression correlates with disease stage and dysmenorrhea severity
  downstream:
  - target: Lesion-Peritoneal Neuroangiogenesis
    description: >
      Angiogenic lesion programs can coexist with or promote nerve-fiber
      recruitment in endometriotic implants and adjacent peritoneal tissue.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - VEGF-associated vascular remodeling
- name: Warburg-like Metabolic Reprogramming
  biological_scale: CELLULAR
  conforms_to: "deregulated_cellular_energetics#Aerobic Glycolysis (Warburg Effect)"
  description: >
    Endometriotic lesions and the peritoneal mesothelium of women with
    endometriosis undergo a cancer-like ("Warburg") metabolic shift away from
    mitochondrial respiration toward aerobic glycolysis. TGF-beta1, which is
    elevated in endometriosis peritoneal fluid, drives human peritoneal
    mesothelial cells to upregulate glycolysis-associated genes (HIF1A, PDK1,
    LDHA, SLC2A1) and secrete lactate. This glycolytic phenotype — higher
    glycolysis, lower mitochondrial respiration, and reduced pyruvate
    dehydrogenase activity — favors lesion establishment and survival and is
    the target of the investigational metabolic therapy dichloroacetate.
  cell_types:
  - preferred_term: Peritoneal Mesothelial Cell
    term:
      id: CL:0000077
      label: mesothelial cell
  biological_processes:
  - preferred_term: Aerobic Glycolysis (Warburg Effect)
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: Response to Hypoxia
    modifier: INCREASED
    term:
      id: GO:0001666
      label: response to hypoxia
  evidence:
  - reference: PMID:24796928
    reference_title: "Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease"
    explanation: >
      Human endometriotic lesions and adjacent peritoneum overexpress
      glycolysis-associated genes versus disease-free tissue, evidencing a
      Warburg-like glycolytic shift in vivo.
  - reference: PMID:24796928
    reference_title: "Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concentrations of lactate in peritoneal fluid paralleled those of TGF-β1, being significantly higher in women with endometriosis compared to women without"
    explanation: >
      Elevated peritoneal-fluid TGF-β1 and lactate in women with endometriosis
      support TGF-β1 as the inflammatory driver of the Warburg-like shift, the
      premise of the Chronic Inflammation to Warburg edge.
  - reference: PMID:24796928
    reference_title: "Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure of mesothelial cells to TGF-β1 increased production of lactate (P < .05), increased HIF1A mRNA (P < .05), and protein, and increased concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P < .05)."
    explanation: >
      TGF-beta1 drives the glycolytic, lactate-secreting phenotype in human
      peritoneal mesothelial cells, linking peritoneal TGF-beta to the
      Warburg-like shift.
  - reference: DOI:10.1073/pnas.1916144116
    reference_title: "Repurposing dichloroacetate for the treatment of women with endometriosis"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "human peritoneal mesothelial cells (HPMCs) recovered from the pelvic peritoneum of women with endometriosis exhibit significantly higher glycolysis, lower mitochondrial respiration, decreased enzymatic activity of pyruvate dehydrogenase (PDH), and increased production of lactate compared to HPMCs from women without disease"
    explanation: >
      Primary mesothelial cells from women with endometriosis show the full
      Warburg-like signature (higher glycolysis, lower respiration, reduced PDH,
      more lactate) relative to disease-free controls.
  downstream:
  - target: Hypoxia and Angiogenesis
    description: >
      Lactate secreted by the glycolytic peritoneal microenvironment is
      implicated in supporting angiogenesis and lesion invasion, coupling the
      metabolic shift to the angiogenic program.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lactate accumulation
- name: Adhesion Formation
  description: >
    Chronic inflammation leads to fibrous adhesions distorting pelvic
    anatomy. Adhesions contribute to pain and infertility.
- name: Dysregulated Peritoneal Metalloproteinase Activity
  description: >
    Endometriosis is associated with altered extracellular-matrix
    metalloproteinase activity in the peritoneal compartment. Multiplexed
    droplet-microfluidic protease-activity profiling of patient peritoneal
    fluid — a non-animal, microphysiological (New Approach Methodology)
    measurement platform — resolved disease-associated differences in
    specific metalloproteinase activities, in particular decreased MMP-2
    and ADAM-9 activity in subjects with endometriosis versus controls.
    This describes a measured activity signature in the peritoneal
    microenvironment rather than an established causal driver of lesion
    establishment.
  biological_processes:
  - preferred_term: Extracellular Matrix Disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: DECREASED
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:23157326
    reference_title: "Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results showed clear and physiologically relevant differences with disease, in particular, decreased MMP-2 and ADAM-9 activities."
    explanation: >
      A droplet-based microfluidic NAM platform (MIT; Griffith/Lauffenburger/Han)
      applied to clinical peritoneal fluid resolved endometriosis-associated shifts
      in specific metalloproteinase activities, supporting dysregulated peritoneal
      MMP/ADAM activity as a measurable disease-associated signature.
- name: Lesion-Peritoneal Neuroangiogenesis
  description: >
    Endometriotic lesions and peritoneal fluid can acquire neuroangiogenic
    properties, including nerve-fiber growth, altered sensory/autonomic fiber
    distribution, neurotrophin up-regulation, and vascular remodeling. This
    provides a peripheral anatomic substrate for pain but does not by itself
    explain perceived pain severity in all patients.
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: Neurogenesis
    modifier: INCREASED
    term:
      id: GO:0022008
      label: neurogenesis
  - preferred_term: Angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:24859987
    reference_title: "Peripheral changes in endometriosis-associated pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Endometriotic lesions and peritoneal fluid from women with endometriosis
      had pronounced neuroangiogenic properties with increased expression of
      new nerve fibres, a shift in the distribution of sensory and autonomic
      fibres in some locations, and up-regulation of several neurotrophins.
    explanation: >
      Review evidence supports lesion/peritoneal neuroangiogenesis as a
      peripheral pain-pathway component.
  - reference: PMID:21054165
    reference_title: "Endometriosis: the role of neuroangiogenesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent evidence indicates that ectopic endometriotic implants recruit
      their own unique neural and vascular supplies through neuroangiogenesis.
    explanation: >
      Supports a neuroangiogenic lesion mechanism that links endometriotic
      implants to nerve and vascular remodeling.
  downstream:
  - target: Peripheral Nociceptor Sensitization
    description: >
      Newly recruited lesion-associated nerve fibers and neurotrophic factors
      provide a peripheral substrate that can feed nociceptor sensitization.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neurotrophins
    - sensory nerve-fiber recruitment
- name: Peripheral Nociceptor Sensitization
  description: >
    Lesion and peritoneal mediators, including inflammatory mediators and
    prolactin/prolactin-receptor signaling, can sensitize pelvic nociceptive
    sensory neurons. This provides a mechanism by which pain may be amplified
    without requiring proportional increases in lesion burden.
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: Sensory perception of pain
    modifier: INCREASED
    term:
      id: GO:0019233
      label: sensory perception of pain
  evidence:
  - reference: PMID:37169264
    reference_title: "Prolactin and pain of endometriosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We highlight our current understanding of prolactin-mediated mechanisms
      of nociceptor sensitization in females and how this mechanism may apply
      to endometriosis.
    explanation: >
      Supports prolactin/prolactin-receptor signaling as a candidate
      nociceptor-sensitizing mediator in endometriosis pain.
  - reference: PMID:37169264
    reference_title: "Prolactin and pain of endometriosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The results of this search strongly indicate that serum prolactin levels
      are increased in patients with endometriosis and support the possibility
      that high levels of prolactin may promote pelvic pain in these patients
      and increase vulnerability to other comorbid pain conditions likely by
      dysregulating prolactin receptor expression.
    explanation: >
      Supports prolactin as a plausible pain amplifier, while the abstract
      frames this as a possibility rather than a resolved causal mechanism.
  - reference: PMID:28954602
    reference_title: Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a result, BDNF concentrations in serum and PF were significantly
      higher in women with endometriosis with pain (2284.3 ± 51.5 pg/mL, n =
      23; 58.8 ± 6.4 pg/mL, n = 16) than in women with endometriosis without
      pain (1999.8 ± 61.1 pg/mL, n = 37; 31.7 ± 2.9 pg/mL, n = 25; P < .01).
    explanation: >
      Human biomarker data support neurotrophin-linked pain amplification by
      showing higher BDNF in endometriosis patients with pain than in
      endometriosis patients without pain.
  downstream:
  - target: Central Sensitization and Nociplastic Pain
    description: >
      Persistent peripheral nociceptive input can contribute to central
      amplification and broader nociplastic pain processing.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - persistent pelvic nociceptive input
  - target: Pelvic Pain
    description: Sensitized pelvic nociceptors amplify the chronic pelvic pain phenotype.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: DIRECT
- name: Central Sensitization and Nociplastic Pain
  description: >
    Chronic endometriosis-associated pain can involve central nervous system
    amplification of pain signals and nociplastic pain mechanisms. This
    downstream state helps explain pain persistence and incomplete response to
    lesion-directed therapy in some patients.
  biological_processes:
  - preferred_term: Sensory perception of pain
    modifier: INCREASED
    term:
      id: GO:0019233
      label: sensory perception of pain
  evidence:
  - reference: PMID:30472739
    reference_title: "Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results showed widespread alterations in pain thresholds in women
      with persistent pelvic pain that are indicative of central sensitization
      and a time-dependent correlation.
    explanation: >
      Human quantitative sensory testing supports central sensitization in
      persistent pelvic pain cohorts evaluated for suspected endometriosis.
  - reference: PMID:39768444
    reference_title: "Nociplastic Pain in Endometriosis: A Scoping Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Endometriosis is an inflammatory chronic condition associated with
      nociceptive, neuropathic, and nociplastic pain. Central sensitization
      (CS) is the primary nociplastic pain mechanism.
    explanation: >
      Review evidence supports modeling central sensitization as the main
      nociplastic pain mechanism in endometriosis-related chronic pelvic pain.
  - reference: PMID:40721059
    reference_title: "The Impact of Targeted Endometriosis Treatment On Patients With Central Sensitization: Systematic Review and Meta Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CSS have smaller changes in pain scores after
      endometriosis surgery (RR 0.79, confidence interval 0.73-0.86) and
      significantly higher persistent pain (RR 2.27, confidence interval
      1.40-3.68).
    explanation: >
      Human clinical meta-analysis supports central sensitization as a
      treatment-response modifier associated with persistent post-surgical pain.
  - reference: PMID:36882181
    reference_title: "Transcranial direct current stimulation to reduce chronic pelvic pain in endometriosis: phase II randomized controlled clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant decreased pain perception in both pain measurements (pressure
      pain threshold and numerical rating scale score) was found for the active
      tDCS group compared with the placebo group.
    explanation: >
      A randomized cortical neuromodulation trial supports central pain
      processing as a treatment-relevant component of endometriosis-associated
      chronic pelvic pain.
  downstream:
  - target: Pelvic Pain
    description: >
      Central amplification can sustain or worsen pelvic pain even when
      lesion-directed treatment reduces peripheral disease activity.
    hypothesis_groups:
    - neuroimmune_pain_sensitization_model
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: neuroimmune_pain_sensitization_model
  hypothesis_label: Neuroimmune Nociceptor-Sensitization Model
  status: EMERGING
  description: >
    Endometriosis-associated pain is driven by lesion- and peritoneal
    microenvironment signals that promote neuroangiogenesis, peripheral
    nociceptor sensitization, and later central sensitization, so pain severity
    can persist or amplify independently of visible lesion burden.
  notes: >-
    Focused hypothesis for dismech#3666. OpenScientist report
    kb/hypotheses/Endometriosis/neuroimmune_pain_sensitization_model/openscientist.md
    judged the model partially supported but recommended retaining EMERGING
    status. The model treats lesion burden as one input into a neuroimmune pain
    circuit, not as a sufficient proxy for symptom severity. The strongest
    support is for individual components (neuroangiogenesis,
    prolactin/nociceptor sensitization, central sensitization); the unresolved
    gap is how to weight these components by subtype and in an individual
    patient.
  evidence:
  - reference: PMID:24859987
    reference_title: "Peripheral changes in endometriosis-associated pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Increasing evidence points towards a close interaction between peripheral
      nerves, the peritoneal environment and the central nervous system in pain
      generation and processing.
    explanation: >
      Supports the integrated peripheral-peritoneal-central framing of the
      neuroimmune pain hypothesis.
  - reference: PMID:30472739
    reference_title: "Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The women with persistent pelvic pain had significantly lower pain
      thresholds compared with the reference women.
    explanation: >
      Human sensory-testing data support sensitization as part of the
      endometriosis-associated pelvic pain model.
phenotypes:
- name: Pelvic Pain
  category: Reproductive
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Chronic pelvic pain is a cardinal symptomatic burden of endometriosis and
    may be cyclical, non-cyclical, or persistent after lesion-directed therapy
    when sensitization mechanisms are established.
  notes: Chronic, cyclical
  phenotype_term:
    preferred_term: Chronic pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
    temporality: CHRONIC
  evidence:
  - reference: PMID:24859987
    reference_title: "Peripheral changes in endometriosis-associated pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pain remains the cardinal symptom of endometriosis.
    explanation: >
      Supports pelvic pain as a central clinical phenotype of endometriosis;
      the existing frequency remains a broad clinical annotation rather than a
      quantitative claim from this snippet.
  - reference: PMID:37844487
    reference_title: "Endometriosis: Classification, pathophysiology, and treatment options."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Endometriosis is usually classified into four stages: minimal, mild,
      moderate, and severe, though it is important to note that the
      presentation of symptoms does not necessarily correspond to the disease
      progression.
    explanation: >
      Supports the issue focus that symptoms, including pain, do not map
      cleanly to conventional disease-stage or progression measures.
- name: Dysmenorrhea
  category: Reproductive
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysmenorrhea
    term:
      id: HP:0100607
      label: Dysmenorrhea
  evidence:
  - reference: PMID:30074218
    reference_title: "Expression of MMIF, HIF-1α and VEGF in Serum and Endometrial Tissues of Patients with Endometriosis."
    supports: SUPPORT
    snippet: "The expression of all three proteins in both serum and endometrial tissues increased significantly with the R-AFS stage (P<0.05) and with dysmenorrheal severity (P<0.05)."
    explanation: VEGF and HIF-1alpha expression correlates with dysmenorrhea severity, linking hypoxia and angiogenesis to pain
- name: Dyspareunia
  category: Reproductive
  frequency: FREQUENT
  notes: Deep dyspareunia
  phenotype_term:
    preferred_term: Dyspareunia
    term:
      id: HP:0030016
      label: Dyspareunia
- name: Infertility
  category: Reproductive
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  evidence:
  - reference: PMID:37844487
    reference_title: "Endometriosis: Classification, pathophysiology, and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It affects around 6-10% of reproductive-age women in the world and causes
      debilitating pain, heavy menstrual bleeding, pain during penetrative sex,
      and infertility.
    explanation: Names infertility directly as a consequence of endometriosis; the frequency band remains a broad clinical annotation rather than a quantitative claim from this snippet.
- name: Heavy Menstrual Bleeding
  category: Reproductive
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
- name: Painful Bowel Movements
  category: Gastrointestinal
  frequency: OCCASIONAL
  notes: With rectovaginal disease
  phenotype_term:
    preferred_term: Dyschezia
    term:
      id: HP:6000222
      label: Painful defecation
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
biochemical:
- name: CA-125
  presence: Elevated
  context: Nonspecific, may be elevated in severe disease
- name: Estradiol
  presence: Normal to Elevated
  context: Local estrogen production in lesions
genetic:
- name: WNT4
  association: Risk Factor
  gene_term:
    preferred_term: WNT4
    term:
      id: hgnc:12783
      label: WNT4
  notes: GWAS-implicated susceptibility locus; no supporting evidence item curated yet.
- name: VEZT
  association: Risk Factor
  gene_term:
    preferred_term: VEZT
    term:
      id: hgnc:18258
      label: VEZT
  notes: GWAS-implicated susceptibility locus; no supporting evidence item curated yet.
- name: GREB1
  association: Risk Factor
  gene_term:
    preferred_term: GREB1
    term:
      id: hgnc:24885
      label: GREB1
  notes: GWAS-implicated susceptibility locus; no supporting evidence item curated yet.
- name: ID4
  association: Risk Factor
  gene_term:
    preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
  notes: GWAS-implicated susceptibility locus; no supporting evidence item curated yet.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Somatic driver; most frequently mutated cancer-driver in endometriotic epithelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Recurrent activating KRAS mutations (e.g. c.35G>A/T/C) in the epithelial
    compartment of endometriotic lesions, with rising mutant-allele frequency
    relative to normal endometrium.
  evidence:
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions."
    explanation: >
      Recurrent activating KRAS codon-12 (c.35) mutations were validated in the
      epithelium of deep-infiltrating endometriotic lesions.
- name: PIK3CA
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  association: Somatic driver in endometriotic epithelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
    explanation: >
      PIK3CA is among the validated somatic cancer-driver mutations found in
      deep-infiltrating endometriotic lesions.
- name: ARID1A
  gene_term:
    preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  association: Somatic driver in endometriotic epithelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
    explanation: >
      ARID1A is among the validated somatic cancer-driver mutations found in
      deep-infiltrating endometriotic lesions.
- name: PPP2R1A
  gene_term:
    preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  association: Somatic driver in endometriotic epithelium
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:28489996
    reference_title: "Cancer-Associated Mutations in Endometriosis without Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis."
    explanation: >
      PPP2R1A is among the validated somatic cancer-driver mutations found in
      deep-infiltrating endometriotic lesions.
- name: PTEN
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  association: Somatic tumor-suppressor inactivation in ovarian endometriotic cysts
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    PTEN somatic point mutations and 10q23.3 loss of heterozygosity occur in
    ovarian endometriotic (endometrioma) cysts, consistent with the
    endometriosis-associated ovarian cancer (EAOC) continuum rather than the
    deep-infiltrating epithelial driver set.
  evidence:
  - reference: PMID:11156411
    reference_title: "Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mutations in the PTEN gene were identified in 4 of 20 ovarian endometrioid carcinomas (20.0%), 2 of 24 clear cell carcinomas (8.3%), and 7 of 34 solitary endometrial cysts (20.6%)."
    explanation: >
      Somatic PTEN mutations are present in a fifth of ovarian endometriotic
      cysts, evidencing PTEN inactivation as an early somatic event in the
      endometriosis-to-ovarian-cancer sequence.
environmental:
- name: Early Menarche
  notes: Increases lifetime estrogen exposure
  evidence:
  - reference: PMID:30017581
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
    explanation: Epidemiologic review naming early age at menarche as a characteristic robustly associated with greater endometriosis risk.
- name: Short Menstrual Cycles
  notes: More frequent retrograde menstruation
  evidence:
  - reference: PMID:30017581
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
    explanation: Epidemiologic review naming short menstrual cycle length as a characteristic robustly associated with greater endometriosis risk.
- name: Nulliparity
  notes: Risk factor
  evidence:
  - reference: PMID:30017581
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
    explanation: Same epidemiologic review reports the inverse relationship — greater parity is associated with lower endometriosis risk, so nulliparity (zero parity) is a risk factor.
- name: Low BMI
  notes: Associated with increased risk
  evidence:
  - reference: PMID:30017581
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk."
    explanation: Epidemiologic review naming lean body size (low BMI) as a characteristic robustly associated with greater endometriosis risk.
treatments:
- name: NSAIDs
  description: First-line for pain management.
  treatment_term:
    preferred_term: NSAID therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: NSAID
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
- name: Combined Oral Contraceptives
  description: Suppress ovulation and reduce menstruation.
  treatment_term:
    preferred_term: combined oral contraceptive therapy
    term:
      id: NCIT:C92808
      label: Hormonal Contraception
- name: Progestins
  description: Create hypoestrogenic state (dienogest, medroxyprogesterone).
  treatment_term:
    preferred_term: progestin therapy
    term:
      id: NCIT:C15484
      label: Progestin Therapy
- name: GnRH Agonists
  description: Induce medical menopause, add-back therapy needed.
  treatment_term:
    preferred_term: GnRH agonist therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gonadotropin-releasing hormone agonist
      term:
        id: NCIT:C1910
        label: Gonadotropin-releasing Hormone Analog
- name: GnRH Antagonists
  description: Elagolix with dose-dependent estrogen suppression.
  treatment_term:
    preferred_term: GnRH antagonist therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gonadotropin-releasing hormone antagonist
      term:
        id: NCIT:C2092
        label: Gonadotropin Releasing Hormone Antagonist
- name: Aromatase Inhibitors
  description: Reduce local estrogen production in lesions.
  treatment_term:
    preferred_term: aromatase inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Dichloroacetate (Investigational)
  description: >
    Investigational non-hormonal, non-contraceptive metabolic therapy. The
    pyruvate dehydrogenase kinase (PDK) inhibitor / PDH activator
    dichloroacetate reverses the aberrant glycolytic phenotype of peritoneal
    mesothelial cells, reduces lactate secretion, and shrank lesions in a mouse
    model; a single-arm open-label feasibility trial (EPiC) is evaluating it for
    endometriosis-associated pain ahead of a planned placebo-controlled trial.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dichloroacetate
      term:
        id: CHEBI:28240
        label: dichloroacetate
  target_mechanisms:
  - target: Warburg-like Metabolic Reprogramming
    treatment_effect: INHIBITS
    description: >
      DCA inhibits pyruvate dehydrogenase kinase and reactivates PDH,
      normalizing the glycolytic shift and reducing lactate secretion by
      peritoneal mesothelial cells.
    evidence:
    - reference: DOI:10.1073/pnas.1916144116
      reference_title: "Repurposing dichloroacetate for the treatment of women with endometriosis"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Treatment of endometriosis HPMCs with the pyruvate dehydrogenase kinase (PDK) inhibitor/PDH activator dichloroacetate (DCA) normalizes HPMC metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a coculture model."
      explanation: >
        DCA reverses the Warburg-like metabolic phenotype and suppresses stromal
        proliferation in a coculture model, defining the targeted mechanism.
  evidence:
  - reference: DOI:10.1073/pnas.1916144116
    reference_title: "Repurposing dichloroacetate for the treatment of women with endometriosis"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Oral DCA reduced peritoneal fluid lactate concentrations and endometriosis lesion size in a mouse model."
    explanation: >
      Oral dichloroacetate lowered peritoneal lactate and reduced lesion size in
      a mouse model, providing the in vivo rationale for clinical testing.
  - reference: PMID:33712086
    reference_title: "Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain."
    explanation: >
      The EPiC exploratory trial evaluates dichloroacetate in women with
      endometriosis-associated pain to inform a future efficacy RCT.
- name: Cabergoline (Investigational)
  description: >
    Investigational non-hormonal anti-angiogenic therapy. The dopamine D2
    receptor agonist cabergoline promotes VEGF receptor-2 (VEGFR-2) endocytosis,
    preventing VEGF-VEGFR-2 binding and reducing neoangiogenesis. In
    experimentally induced endometriosis it decreased the proportion of active
    lesions and vascularization, and it is being evaluated as a non-hormonal,
    non-surgical option for endometriosis pain.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cabergoline
      term:
        id: CHEBI:3286
        label: cabergoline
  target_mechanisms:
  - target: Hypoxia and Angiogenesis
    treatment_effect: INHIBITS
    description: >
      Dopamine-agonist-driven VEGFR-2 endocytosis and reduced VEGFR-2
      phosphorylation blunt VEGF signaling and lesion neoangiogenesis.
    evidence:
    - reference: PMID:19189995
      reference_title: "Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation."
      explanation: >
        Cabergoline's anti-angiogenic action on endometriotic lesions operates
        through VEGFR-2, targeting the hypoxia/angiogenesis mechanism node.
  evidence:
  - reference: PMID:19189995
    reference_title: "Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A significant decrease in the percentage of active endometriotic lesions (P < 0.05) and cellular proliferation index (P < 0.001) was found with Cb2 treatment."
    explanation: >
      In a nude-mouse model of endometriosis, cabergoline reduced active lesions
      and proliferation, supporting anti-angiogenic therapeutic potential.
- name: Laparoscopic Surgery
  description: Excision or ablation of lesions, adhesiolysis.
  treatment_term:
    preferred_term: laparoscopic surgery
    term:
      id: NCIT:C16969
      label: Laparoscopy
- name: Hysterectomy
  description: Definitive surgery for completed childbearing.
  treatment_term:
    preferred_term: hysterectomy
    term:
      id: NCIT:C15256
      label: Hysterectomy
discussions:
- discussion_id: gap_endometriosis_pain_lesion_burden_discordance
  prompt: >-
    Which combination of lesion neuroangiogenesis, inflammatory mediators,
    prolactin/prolactin-receptor signaling, peripheral nociceptor sensitization,
    and central sensitization best explains why endometriosis pain often does
    not scale with visible lesion burden?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Lesion-Peritoneal Neuroangiogenesis
  - pathophysiology#Peripheral Nociceptor Sensitization
  - pathophysiology#Central Sensitization and Nociplastic Pain
  - phenotypes#Pelvic Pain
  rationale: >-
    The entry now models a neuroimmune pain circuit, but the relative causal
    weights of lesion-local innervation, soluble mediators, peripheral
    nociceptor threshold shifts, and central pain amplification remain
    unresolved. This gap determines whether patients should be stratified
    primarily by lesion phenotype, molecular/peritoneal mediator profile,
    quantitative sensory testing, or central-sensitization/nociplastic-pain
    measures when predicting persistent pain after lesion-directed treatment.
  evidence:
  - reference: PMID:39062866
    reference_title: "Pathogenesis of Endometriosis and Endometriosis-Associated Cancers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite its prevalence, the underlying molecular mechanisms of this
      disease remain poorly understood.
    explanation: >
      Supports retaining lesion-independent pain mechanisms as an open
      curation gap rather than a fully settled causal chain.
  - reference: PMID:24859987
    reference_title: "Peripheral changes in endometriosis-associated pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, a clear link between these findings and pain in patients with
      endometriosis has so far not been demonstrated.
    explanation: >
      Supports the unresolved gap between peripheral neuroangiogenic findings
      and patient-level pain severity.
  - reference: PMID:40721059
    reference_title: "The Impact of Targeted Endometriosis Treatment On Patients With Central Sensitization: Systematic Review and Meta Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central sensitization (CSS), a condition where the central nervous system
      amplifies pain signals, may impact response to treatment of chronic pain
      conditions.
    explanation: >
      Supports the treatment-response component of the gap: central
      sensitization may modify response to lesion-directed therapy.
  - reference: PMID:38890641
    reference_title: "Efficacy and safety of eliapixant in endometriosis-associated pelvic pain: the randomized, placebo-controlled phase 2b SCHUMANN study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study found no significant differences in EAPP reduction from
      baseline between groups and no significant dose-response model.
    explanation: >
      The negative P2X3 antagonist trial qualifies the neuroimmune pain model:
      not every plausible nociceptor-sensitization mediator has translated into
      clinical efficacy.
  proposed_experiments:
  - experiment_id: exp_endometriosis_multimodal_pain_stratification_cohort
    name: Multimodal lesion-sensitization pain stratification cohort
    description: >-
      Prospectively measure lesion subtype and burden, lesion/peritoneal
      neuroangiogenic markers, inflammatory and prolactin-pathway mediators,
      quantitative sensory testing, central-sensitization questionnaires, and
      pain outcomes before and after surgery or hormonal suppression to test
      which layer best predicts persistent pelvic pain.
    experiment_type:
      preferred_term: prospective longitudinal cohort study
    decision_criterion: >-
      A model that combines peripheral mediator/innervation measures with
      central-sensitization readouts should predict persistent pain better than
      lesion burden or surgical stage alone.
clinical_trials:
- name: NCT03928288
  phase: PHASE_II
  status: COMPLETED
  description: >
    Randomized, double-blind trial repurposing the dopamine agonist cabergoline
    as a non-hormonal angiogenesis inhibitor for chronic endometriosis-associated
    pain in adolescents and adults.
  target_phenotypes:
  - preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
  evidence:
  - reference: clinicaltrials:NCT03928288
    reference_title: "Novel, Non-Hormonal Therapy for the Treatment of Chronic Pain Due to Endometriosis in Adolescent and Adult Women"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "repurposing an existing drug, cabergoline, as a safe, alternative angiogenesis inhibitor for adolescents and young women with endometriosis"
    explanation: >
      The trial evaluates cabergoline as a non-hormonal anti-angiogenic therapy
      for endometriosis-associated pain, matching the modeled angiogenesis
      mechanism.
- name: NCT04046081
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >
    Single-arm, open-label exploratory (feasibility) trial evaluating
    dichloroacetate (DCA) as a non-hormonal metabolic treatment for
    endometriosis-associated pain (EPiC), to inform a future placebo-controlled
    efficacy RCT.
  target_phenotypes:
  - preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
  evidence:
  - reference: clinicaltrials:NCT04046081
    reference_title: "A Single-arm Open Label Exploratory Clinical Trial to Evaluate Dichloroacetate (DCA) as a Possible Treatment for Endometriosis-associated Pain"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "single-arm open label exploratory clinical trial to evaluate dichloroacetate (DCA)"
    explanation: >
      The EPiC feasibility trial tests dichloroacetate for
      endometriosis-associated pain, matching the modeled Warburg metabolic
      mechanism.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
experimental_models:
- name: Droplet-based microfluidic protease-activity profiling platform (PrAMA; MIT Griffith/Han)
  description: >-
    Picoliter-scale droplet-microfluidic platform (barcoded droplet library with
    pico-injection and Proteolytic Activity Matrix Analysis deconvolution) for
    multiplexed metalloproteinase activity profiling in small-volume clinical
    samples, applied to peritoneal fluid from subjects with and without
    endometriosis. A non-animal New Approach Methodology that resolves specific
    MMP and ADAM enzymatic activities in cell-free clinical fluid.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: peritoneal fluid
    term:
      id: UBERON:0001268
      label: peritoneal fluid
  conditions:
  - endometriosis
  - peritoneal fluid metalloproteinase activity profiling
  cell_source: Clinical peritoneal fluid from endometriosis and control subjects (cell-free)
  culture_system: Droplet-based microfluidic multiplexed protease-activity assay
  publication: PMID:23157326
  modeled_mechanisms:
  - target: Dysregulated Peritoneal Metalloproteinase Activity
    description: >-
      Multiplexed quantification of MMP and ADAM activities in peritoneal fluid,
      resolving endometriosis-associated decreases in MMP-2 and ADAM-9 activity.
  findings:
  - statement: Peritoneal fluid from subjects with endometriosis showed decreased MMP-2 and ADAM-9 activities versus controls
    evidence:
    - reference: PMID:23157326
      reference_title: "Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The results showed clear and physiologically relevant differences with disease, in particular, decreased MMP-2 and ADAM-9 activities."
      explanation: >-
        The droplet-microfluidic NAM platform applied to clinical peritoneal fluid
        resolved endometriosis-associated decreases in specific metalloproteinase
        activities.
datasets:
- accession: geo:GSE302961
  title: 'Altered miRNA cargo of endometrial extracellular vesicles in endometriosis: potential implications for pregnancy outcomes'
  description: 'Study question: Is the miRNA cargo of extracellular vesicles (EVs) secreted by the eutopic endometrium from women with endometriosis involved in its pathogenesis and related infertility? Summary answer: Data suggest that EVs secreted by primary endometrial epithelial cells from women with endometriosis transport an altered miRNA cargo that modulates biological processes related to endometriosis pathogenesis and pregnancy disorders. Main results and the role of chance: EVs had a mean size of 171 nm and expressed the EV protein markers CD63, CD9, and CD81. TEM corroborated EV cup-shaped morphology. Principal Component Analysis (PCA) revealed differentiated behavior between groups.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 7
  publication: PMID:42282918
  notes: Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE310627
  title: 'Menstrual Fluid-Derived Small Extracellular Vesicles: A Novel Reservoir with Distinct Molecular Signatures and Implications for Endometriosis Etiopathology'
  description: 'STUDY QUESTION: Can the transcriptomic profile of small extracellular vesicles (sEV) derived from menstrual fluid (MF) provide insight into their potential roles as biomarkers and mediators in endometriosis (EM) development? SUMMARY ANSWER: MF-derived sEV from EM patients display altered molecular signatures reflective of EM pathophysiology and exhibit enhanced proangiogenic activity in vitro. WHAT IS KNOWN ALREADY: EM is a chronic gynecological disorder affecting approximately 10% of reproductive-age women, associated with pain, infertility, and delayed diagnosis.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:41924633
  notes: Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE287223
  title: Circulating microRNAs as predictive biomarkers for progestin treatment response in endometriosis patients
  description: Total RNA was extracted from 400 ul of serum with the miRNeasy Serum/Plasma advanced Kit (Qiagen) and quantified using the Qubit microRNA assay kit (Thermo Fisher Scientific). cDNA templates were prepared using the TaqMan Advanced miRNA cDNA Synthesis Kit (Thermo Fisher Scientific), starting from 10 ng of RNA. RT-qPCR carried out on a QuantStudio 12K Flex (Applied Biosystems) using the TaqMan OpenArray miRNA panel.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 84
  notes: Identified by GEO DataSets index search for Endometriosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00000000075
  title: ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas
  description: We have sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001741
  title: Searching for variants associated with endometriosis
  description: We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:27055116
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003095
  title: Somatic mutations in endometriosis and normal uterine endometrium
  description: To characterize the genomic features of endometriosis, we performed whole-exome sequencing for ovarian endometriotic epithelium samples obtained from subjects without concurrent gynecological cancers. Additionally, we analyzed histologically normal uterine endometrial epithelium samples obtained from subjects with benign gynecologic diseases. All the epithelium samples were isolated by laser microdissection from frozen sections.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:30110635
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Endometriosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
references:
- reference: DOI:10.3389/fphar.2023.1155558
  title: Targeting the formation of estrogens for treatment of hormone dependent diseases–current status
  findings: []
- reference: DOI:10.3390/ijms25147624
  title: Pathogenesis of Endometriosis and Endometriosis-Associated Cancers
  findings: []
- reference: DOI:10.69622/28227977
  title: Molecular and cellular landscape of endometriosis
  findings: []
- reference: DOI:10.7759/cureus.87091
  title: "Exploring the Immune System's Role in Endometriosis: Insights Into Pathogenesis, Pain, and Treatment"
  findings: []
📚

References & Deep Research

References

4
DOI:10.3389/fphar.2023.1155558
Targeting the formation of estrogens for treatment of hormone dependent diseases–current status
No top-level findings curated for this source.
DOI:10.3390/ijms25147624
Pathogenesis of Endometriosis and Endometriosis-Associated Cancers
No top-level findings curated for this source.
DOI:10.69622/28227977
Molecular and cellular landscape of endometriosis
No top-level findings curated for this source.
DOI:10.7759/cureus.87091
Exploring the Immune System's Role in Endometriosis: Insights Into Pathogenesis, Pain, and Treatment
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Endometriosis
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 18

Key Pathophysiology Nodes

  • Ectopic Endometrial Tissue
  • Retrograde Menstruation
  • Chronic Inflammation
  • Estrogen Dependence
  • Immune Dysfunction
  • Hypoxia and Angiogenesis
  • Adhesion Formation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.3389/fphar.2023.1155558
  • DOI:10.3390/ijms25147624
  • DOI:10.69622/28227977
  • DOI:10.7759/cureus.87091
Falcon ▸
Pathophysiology description (narrative synthesis)
Edison Scientific Literature 12 citations 2025-12-17T23:32:53.553652

Pathophysiology description (narrative synthesis)

Endometriosis is an estrogen‑dependent, chronic inflammatory condition in which endometrial‑like glands and stroma establish at ectopic sites, most commonly on the peritoneum and ovary. Current models integrate retrograde menstruation with permissive host factors—genetic susceptibility, altered endometrial biology, immune dysregulation, hypoxia‑driven angiogenesis, neuroangiogenesis, and progressive fibrotic remodeling. The disease affects about 10% of reproductive‑aged women worldwide, with a diagnostic delay of approximately 7–9 years, contributing to substantial pain and infertility burden (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15). Lesions display estrogen dominance and progesterone resistance, supported by local estrogen biosynthesis (aromatase/CYP19A1; reductive HSD17B1 with reduced oxidative HSD17B2) and diminished progesterone receptor signaling; hypoxia and HIF‑1α amplify VEGF‑mediated angiogenesis and inflammatory circuits. Immune alterations include macrophage reprogramming, reduced NK cytotoxicity, T‑cell imbalance, and elevated pro‑inflammatory cytokines (e.g., IL‑6, TNF‑α), enabling immune evasion and lesion persistence. Warburg‑like metabolic reprogramming, EMT/TGF‑β‑driven fibrosis, and extracellular matrix (ECM) remodeling consolidate chronicity. Somatic alterations (ARID1A, PIK3CA, KRAS, PTEN) occur in some lesions and are implicated in the small but real risk of malignant transformation to endometriosis‑associated ovarian cancer. Single‑cell/spatial transcriptomics and large‑scale genetics highlight disease‑relevant stromal and immune cell states and suggest polygenic risk acting through immune regulation, cell differentiation, and hormone pathways (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15, sarsenova2025molecularandcellular pages 14-17).

Axis Key genes/proteins (HGNC) Perturbed processes (GO / plain text) Primary cell types (CL / plain text) Anatomical locations (UBERON / plain text) Chemical entities (CHEBI / plain text) Representative evidence
Estrogen dominance & progesterone resistance ESR1, ESR2, PGR Steroid hormone signaling; altered receptor expression (progesterone response) Endometrial epithelial cells, stromal cells Uterine endometrium; peritoneum (ectopic sites) Estradiol (E2), Progesterone (P4) https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 14-17)
Local estrogen biosynthesis (aromatase / HSD17B / sulfatase) CYP19A1, HSD17B1, HSD17B2, STS Local steroid biosynthesis and activation/inactivation of estrogens Stromal cells, epithelial cells Endometriotic lesions, eutopic endometrium Androstenedione/testosterone → estrone/estradiol; estrogen-sulfates https://doi.org/10.3389/fphar.2023.1155558 (sarsenova2025molecularandcellular pages 10-14)
Hypoxia / HIF-1 / VEGF angiogenesis & neuroangiogenesis HIF1A, VEGFA, EPAS1 Hypoxia response, angiogenesis, vascular development Endothelial cells, stromal fibroblasts, perivascular cells Lesion microenvironment, peritoneum, ovary (endometrioma) VEGF (growth factor); hypoxia-induced metabolites https://doi.org/10.3390/ijms25147624 (adilbayeva2024pathogenesisofendometriosis pages 14-15)
Immune dysregulation (macrophages, NK, T cells, cytokines, checkpoints) IL6, TNF, CCL2, PDCD1 (PD-1), CTLA4 Inflammatory signaling, immune evasion, cytokine-mediated recruitment Macrophages (M1/M2-like), NK cells, CD4+/CD8+ T cells, Tregs Peritoneal cavity, lesion stroma Pro-inflammatory cytokines (IL-6, TNF-α), chemokines https://doi.org/10.7759/cureus.87091 (ahmed2025exploringtheimmune pages 15-16)
Fibrosis / EMT / TGF-β / ECM remodeling TGFB1, TGFBI, MMP1, MMP2 Extracellular matrix organization, epithelial–mesenchymal transition, fibrosis Stromal fibroblasts, myofibroblasts, mesenchymal cells Lesions, adhesions, affected peritoneum Collagen, fibronectin; TGF-β signaling molecules https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Metabolic reprogramming (Warburg-like) SLC2A1 (GLUT1), HK2, PDK1 Glycolysis upregulation, altered mitochondrial function, ROS metabolism Lesion stromal/epithelial cells, macrophages Ectopic lesions (hypoxic niches) Glucose, lactate, reactive oxygen species (ROS) https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Somatic driver mutations & malignant transformation risk ARID1A, PIK3CA, KRAS, PTEN DNA repair/PI3K signaling / oncogenic activation Epithelial cells of lesions (clonal populations) Ovarian endometrioma → risk for EAOC (clear cell, endometrioid) DNA damage products; ROS https://doi.org/10.3390/ijms25147624 (adilbayeva2024pathogenesisofendometriosis pages 14-15)
GWAS / germline risk architecture Multiple risk loci (incl. loci near ESR1) Genetic susceptibility; regulation of immune, hormonal, proliferative pathways Decidualized stromal cells, macrophages (cell-context from atlas) Uterine tissues; systemic genetic risk — (polygenic risk) https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Microbiome / estrobolome contributions Bacterial β-glucuronidase (functional) Estrogen recycling (deconjugation), modulation of inflammation Gut microbiota; reproductive-tract microbiota Gut, vagina, endometrium Microbial metabolites (SCFAs), estrogen-sulfates https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Single-cell & spatial niche insights CXCL12, MRC1, APOE (cell-state markers) Cell–cell signaling, immune–stromal interactions, angiogenic niches Stromal subtypes, epithelial subtypes, lesion-resident macrophages Lesion microenvironment (spatially organized niches) Chemokines (CXCL12), lipids (ApoE-associated) https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Disease progression sequence (mechanistic) — (process-level) Retrograde menstruation → implantation → immune evasion → angiogenesis & innervation → fibrosis Shed endometrial epithelial & stromal cells; recruited immune cells Peritoneal surfaces, ovary, pelvic organs Hemoglobin/iron (from bleed) → ROS; prostaglandins (PGE2) https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
Clinical phenotypes & burden — (clinical manifestations) Pain signaling, impaired fertility, systemic comorbidity N/A (multicellular) Pelvis, reproductive organs; systemic symptoms Analgesics, hormonal modulators (therapeutics) Prevalence ~10%; diagnostic delay median ~7–9 yrs — https://doi.org/10.69622/28227977 (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15)

Table: Compact, ontology-style summary linking major pathophysiology axes to genes, processes, cell types, anatomical sites, chemical entities and representative evidence (DOI + context ID); useful as a knowledge-base import or quick reference for mechanistic claims.

1. Core Pathophysiology

  • Primary mechanisms:
  • Retrograde menstruation provides endometrial fragments that implant at ectopic sites (“seed and soil”), where local hypoxia, estrogen excess, and immune dysfunction favor survival and growth (sarsenova2025molecularandcellular pages 10-14, sarsenova2025molecularandcellular pages 14-17).
  • Estrogen dominance/progesterone resistance: increased ERβ:ERα ratio and reduced PR, plus upregulated aromatase (CYP19A1) and 17β‑HSD imbalance (↑HSD17B1, ↓HSD17B2) sustain local E2 and blunt decidualization (sarsenova2025molecularandcellular pages 14-17). Quote: “increased aromatase… and reduced expression of the E2‑inactivating enzyme HSD17B2” (URL: https://doi.org/10.69622/28227977) (sarsenova2025molecularandcellular pages 14-17).
  • Hypoxia/HIF‑1α/VEGF: lesion hypoxia stabilizes HIF‑1α, upregulating VEGF and inflammatory mediators, promoting angiogenesis and neuroangiogenesis (adilbayeva2024pathogenesisofendometriosis pages 14-15). Quote: “iron‑induced oxidative stress… activate NF‑κB, and upregulate VEGF, promoting angiogenesis/neoangiogenesis” (DOI: 10.3390/ijms25147624) (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • Immune dysregulation: macrophage‑dominated microenvironment with impaired clearance of refluxed cells, reduced NK cytotoxicity, T‑cell imbalance, and elevated IL‑6/TNF‑α facilitating immune evasion and pain (ahmed2025exploringtheimmune pages 15-16). Quote: “dysregulated innate immunity, particularly impaired cytotoxic function of natural killer (NK) cells” (URL: https://doi.org/10.7759/cureus.87091) (ahmed2025exploringtheimmune pages 15-16).
  • Fibrosis/EMT/TGF‑β and ECM remodeling drive adhesion formation and deep infiltrating phenotypes (sarsenova2025molecularandcellular pages 10-14).

  • Metabolic reprogramming: hypoxia‑adapted glycolysis/Warburg‑like metabolism in lesions (sarsenova2025molecularandcellular pages 10-14).

  • Dysregulated molecular pathways: estrogen biosynthesis and signaling (CYP19A1/HSD17B1/HSD17B2; ESR1/ESR2; PGR), hypoxia/HIF‑1/VEGF, NF‑κB‑mediated inflammation, TGF‑β/EMT/ECM, PI3K/AKT from somatic drivers, and immune checkpoint axes (PD‑1/CTLA4) in immune suppression (adilbayeva2024pathogenesisofendometriosis pages 14-15, sarsenova2025molecularandcellular pages 14-17, ahmed2025exploringtheimmune pages 15-16).

  • Affected cellular processes: implantation/adhesion, angiogenesis and neurogenesis, aberrant stromal–epithelial signaling and decidualization, ECM deposition, immune cell recruitment and polarization, altered glycolysis/ROS handling (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16).

2. Key Molecular Players

  • Genes/Proteins (HGNC):
  • Steroidogenesis and receptors: CYP19A1 (aromatase), HSD17B1/HSD17B2, ESR1/ESR2, PGR (sarsenova2025molecularandcellular pages 10-14, sarsenova2025molecularandcellular pages 14-17).
  • Hypoxia/angiogenesis: HIF1A, VEGFA (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • Inflammation/immune: IL6, TNF, CCL2; immune checkpoints PDCD1 (PD‑1), CTLA4 (ahmed2025exploringtheimmune pages 15-16).
  • Fibrosis/ECM/EMT: TGFB1, TGFBI, MMPs (sarsenova2025molecularandcellular pages 10-14).

  • Somatic drivers: ARID1A, PIK3CA, KRAS, PTEN (adilbayeva2024pathogenesisofendometriosis pages 14-15).

  • Chemical entities (CHEBI): estradiol (E2), progesterone (P4), prostaglandin E2 (PGE2), VEGF as growth factor ligand, ROS/iron byproducts (adilbayeva2024pathogenesisofendometriosis pages 14-15, sarsenova2025molecularandcellular pages 14-17).

  • Cell types (CL): endometrial epithelial and stromal cells; endothelial cells; peritoneal/lesion‑resident macrophages (M2‑like, scar‑associated); NK cells; CD4+/CD8+ T cells; Tregs (ahmed2025exploringtheimmune pages 15-16, sarsenova2025molecularandcellular pages 10-14).

  • Anatomical locations (UBERON): uterine endometrium, peritoneum, ovary (endometrioma), pelvic peritoneal surfaces; adhesions across pelvic organs (sarsenova2025molecularandcellular pages 10-14, papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15).

3. Biological Processes (GO annotation, representative)

  • GO:0030335 positive regulation of cell migration; GO:0001525 angiogenesis; GO:0001666 response to hypoxia; GO:0030198 ECM organization; GO:0034097 response to cytokine; GO:0006694 steroid biosynthetic process; GO:0030509 BMP signaling; GO:0030512 negative regulation of TGF‑β receptor signaling (context‑dependent); GO:0042110 T cell activation; GO:0006954 inflammatory response (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16).

4. Cellular Components (where processes occur)

  • Cytoplasm/nucleus for steroid receptor signaling (ESR1/ESR2, PGR); endoplasmic reticulum for aromatase; mitochondria and cytosol for glycolysis/ROS; plasma membrane and extracellular space for cytokines/VEGF; ECM (collagen/fibronectin) for remodeling; vascular niche for angiogenesis; peritoneal fluid compartment for immune mediators (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16).

5. Disease Progression

  • Sequence of events: retrograde menstruation → attachment/implantation on peritoneum → immune evasion via macrophage‑rich, NK‑suppressed microenvironment and cytokines → hypoxia‑driven HIF‑1α/VEGF angiogenesis and neuroangiogenesis → local estrogen amplification and progesterone resistance → EMT/myofibroblast activation and ECM deposition → adhesions and deep infiltrating lesions; chronic cyclic bleeding sustains iron‑driven oxidative stress and fibrosis (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16).

6. Phenotypic Manifestations and links to mechanisms

  • Clinical phenotypes (HPO): chronic pelvic pain (HP:0012531), dysmenorrhea (HP:0002360), dyspareunia (HP:0030019), dyschezia (HP:0012552), dysuria/pain with urination (HP:0100518), subfertility/infertility (HP:0000823). Pain relates to neuroangiogenesis and inflammatory cytokines; infertility relates to impaired endometrial receptivity/decidualization, altered immune tolerance, adhesions, and ovarian reserve effects of endometriomas (ahmed2025exploringtheimmune pages 15-16, sarsenova2025molecularandcellular pages 10-14, papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15).

Gene/protein annotations with ontology terms (examples)

  • CYP19A1 (HGNC:2594): GO:0004501 aromatase activity; GO:0006694 steroid biosynthetic process; cellular component: endoplasmic reticulum membrane; Evidence: increased aromatase in EcE/EuE, therapeutic target (sarsenova2025molecularandcellular pages 10-14).
  • HSD17B1 (HGNC:5217) / HSD17B2 (HGNC:5218): GO:0003855/GO:0008406 17β‑hydroxysteroid dehydrogenase activity; process: estrogen activation/inactivation; Evidence: imbalance supports E2 dominance (sarsenova2025molecularandcellular pages 14-17).
  • HIF1A (HGNC:4910): GO:0001666 response to hypoxia; GO:0001525 angiogenesis; Evidence: hypoxia in lesions upregulates VEGF and inflammatory mediators (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • VEGFA (HGNC:12680): GO:0001525 angiogenesis; extracellular space; Evidence: upregulated downstream of HIF‑1α in lesions (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • IL6 (HGNC:6018), TNF (HGNC:11892): GO:0006954 inflammatory response; extracellular region; Evidence: elevated in lesion/peritoneal milieu; link to pain and immune evasion (ahmed2025exploringtheimmune pages 15-16).
  • TGFB1 (HGNC:11766), TGFBI (HGNC:11771): GO:0007160 cell‑matrix adhesion; GO:0030198 ECM organization; Evidence: fibrosis/EMT/angiogenesis (sarsenova2025molecularandcellular pages 10-14).
  • ARID1A (HGNC:11110), PIK3CA (HGNC:8975), KRAS (HGNC:6407), PTEN (HGNC:9588): GO terms per gene; processes: chromatin remodeling, PI3K/AKT signaling; Evidence: somatic mutations in lesions with EAOC risk (adilbayeva2024pathogenesisofendometriosis pages 14-15).

Cell type involvement (CL terms)

  • Endometrial stromal cell (CL:0002620) and epithelial cell (CL:0000066) in eutopic/ectopic contexts; macrophage (CL:0000235) including M2‑like and scar‑associated phenotypes; NK cell (CL:0000623); T helper cell (CL:0000911), cytotoxic T cell (CL:0000625), Treg (CL:0000815). Evidence for macrophage‑centered pathophysiology and NK dysfunction (ahmed2025exploringtheimmune pages 15-16).

Anatomical locations (UBERON terms)

  • Uterine endometrium (UBERON:0001295); peritoneum (UBERON:0002358); ovary (UBERON:0000992) for endometrioma; pelvic peritoneal surfaces/adhesions (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15, sarsenova2025molecularandcellular pages 10-14).

Chemical entities (CHEBI)

  • Estradiol (CHEBI:16469); Progesterone (CHEBI:17026); Prostaglandin E2 (CHEBI:15551); Reactive oxygen species (grouped); VEGF‑A as growth factor ligand (protein, not CHEBI). Evidence for local estrogen amplification and inflammatory eicosanoids (sarsenova2025molecularandcellular pages 10-14, adilbayeva2024pathogenesisofendometriosis pages 14-15).

Evidence items (recent sources, URLs and dates where available)

  • Sarsenova M. Molecular and cellular landscape of endometriosis. 2025. Highlights hypoxia, estrogen imbalance, fibrosis, and epidemiology (~10% prevalence). URL: https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14) (sarsenova2025molecularandcellular pages 10-14).
  • Adilbayeva A, Kunz J. Pathogenesis of Endometriosis and Endometriosis‑Associated Cancers. IJMS, 2024 Jul. Details ER/PR imbalance, PGE2–aromatase loop, oxidative stress→NF‑κB→VEGF, and somatic drivers ARID1A/PIK3CA/KRAS/PTEN. DOI: 10.3390/ijms25147624; URL: https://doi.org/10.3390/ijms25147624 (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • Rižner TL, Romano A. Targeting the formation of estrogens… Front Pharmacol, 2023 Apr. Therapeutic targeting of aromatase, sulfatase, HSD17B1 in endometriosis. DOI: 10.3389/fphar.2023.1155558; URL: https://doi.org/10.3389/fphar.2023.1155558 (sarsenova2025molecularandcellular pages 10-14).
  • Ahmed RS et al. Exploring the immune system’s role in endometriosis. Cureus, 2025 Jul. Immune dysregulation and NK impairment; links to pain. DOI: 10.7759/cureus.87091; URL: https://doi.org/10.7759/cureus.87091 (ahmed2025exploringtheimmune pages 15-16).
  • Papandreou P. Interinstitutional… Review chapter with epidemiology (~10%, diagnosis 7–9 years) and pathogenetic theories. (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15).

Expert opinions and analysis

  • Convergent evidence supports redefining endometriosis as a fibrotic neuroinflammatory disease with endocrine dependence—shifting therapeutic focus beyond ovarian suppression to include non‑hormonal strategies (anti‑angiogenic, anti‑fibrotic, immunomodulatory, and metabolic). The ER/PR axis remains central, but local steroidogenesis and HSD17B balance are compelling targets; HSD17B1 inhibitors and sulfatase inhibitors are in clinical or advanced preclinical development (sarsenova2025molecularandcellular pages 10-14). HIF‑1/VEGF biology and macrophage‑targeted approaches (e.g., re‑educating pro‑disease macrophage phenotypes) are rational adjuncts (adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16). Single‑cell atlases underscore disease‑relevant stromal/microenvironmental programs, supporting precision therapies aimed at stromal decidualization failure and immune checkpoints.

Current applications and real‑world implementations

  • Hormonal suppression (progestins, combined OCPs, GnRH analogs/antagonists) remains first‑line, acting on ER/PR pathways and reducing local E2 (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15). Aromatase inhibitors are used off‑label in refractory cases; sulfatase and HSD17B1 inhibitors represent emerging options (sarsenova2025molecularandcellular pages 10-14). Surgical excision treats anatomy‑driven pain/infertility but does not correct underlying immune/hypoxic/fibrotic programs, and recurrence is common (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15). Target discovery for anti‑angiogenic, anti‑fibrotic (TGF‑β/ECM), and immunomodulatory therapies is ongoing (adilbayeva2024pathogenesisofendometriosis pages 14-15, ahmed2025exploringtheimmune pages 15-16).

Relevant statistics and data

  • Prevalence: ~10% of reproductive‑age women (~190 million globally); lesions mostly peritoneal (~80%). Diagnostic delay: ~7–9 years (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15, sarsenova2025molecularandcellular pages 10-14). Elevated lesion/peritoneal IL‑6/TNF‑α and VEGF reported; increased aromatase and reduced HSD17B2 expression in lesions (qualitative molecular data) (sarsenova2025molecularandcellular pages 14-17, adilbayeva2024pathogenesisofendometriosis pages 14-15, sarsenova2025molecularandcellular pages 10-14).

Direct quotes (recent)

  • “Increased aromatase… and reduced expression of the E2‑inactivating enzyme HSD17B2” supporting local estrogen excess (URL: https://doi.org/10.69622/28227977) (sarsenova2025molecularandcellular pages 14-17).
  • “Iron‑induced oxidative stress… activate NF‑κB, and upregulate VEGF, promoting angiogenesis/neoangiogenesis” (DOI: 10.3390/ijms25147624) (adilbayeva2024pathogenesisofendometriosis pages 14-15).
  • “Impaired cytotoxic function of natural killer (NK) cells” facilitating immune escape (URL: https://doi.org/10.7759/cureus.87091) (ahmed2025exploringtheimmune pages 15-16).

Limitations and notes on evidence quality

Where possible, peer‑reviewed 2023–2024 articles were prioritized. Some 2025 narrative reviews provide context but were downweighted in drawing mechanistic conclusions. Further primary single‑cell and GWAS fine‑mapping studies are continually refining cell‑type‑specific mechanisms, especially in stromal decidualization failure and macrophage phenotypes.

References (with URLs)

  • Sarsenova M. Molecular and cellular landscape of endometriosis (2025). https://doi.org/10.69622/28227977 (sarsenova2025molecularandcellular pages 10-14)
  • Adilbayeva A, Kunz J. Pathogenesis of Endometriosis and Endometriosis‑Associated Cancers (IJMS 2024). https://doi.org/10.3390/ijms25147624 (adilbayeva2024pathogenesisofendometriosis pages 14-15)
  • Rižner TL, Romano A. Targeting the formation of estrogens… (Front Pharmacol 2023). https://doi.org/10.3389/fphar.2023.1155558 (sarsenova2025molecularandcellular pages 10-14)
  • Ahmed RS et al. Exploring the immune system’s role… (Cureus 2025). https://doi.org/10.7759/cureus.87091 (ahmed2025exploringtheimmune pages 15-16)
  • Papandreou P. Interinstitutional/Interdepartmental… (epidemiology/diagnosis). [chapter/monograph] (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15)

References

  1. (papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15): P PAPANDREOU. Interinstitutional/interdepartmental master of science<< application of endoscopic surgical techniques in. Unknown journal, Unknown year.

  2. (sarsenova2025molecularandcellular pages 10-14): Meruert Sarsenova. Molecular and cellular landscape of endometriosis. Mar 2025. URL: https://doi.org/10.69622/28227977, doi:10.69622/28227977.

  3. (adilbayeva2024pathogenesisofendometriosis pages 14-15): Altynay Adilbayeva and Jeannette Kunz. Pathogenesis of endometriosis and endometriosis-associated cancers. International Journal of Molecular Sciences, 25:7624, Jul 2024. URL: https://doi.org/10.3390/ijms25147624, doi:10.3390/ijms25147624. This article has 53 citations and is from a poor quality or predatory journal.

  4. (sarsenova2025molecularandcellular pages 14-17): Meruert Sarsenova. Molecular and cellular landscape of endometriosis. Mar 2025. URL: https://doi.org/10.69622/28227977, doi:10.69622/28227977.

  5. (ahmed2025exploringtheimmune pages 15-16): Rania S Ahmed, Mohamed Sherif, Majd A Alghamdi, Salah N El-Tallawy, Omar K Alzaydan, Joseph V Pergolizzi, Giustino Varrassi, Zaina Zaghra, Ziad S Abdelsalam, Mahmoud T Kamal, and Flaminia Coluzzi. Exploring the immune system's role in endometriosis: insights into pathogenesis, pain, and treatment. Cureus, Jul 2025. URL: https://doi.org/10.7759/cureus.87091, doi:10.7759/cureus.87091. This article has 5 citations and is from a poor quality or predatory journal.