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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name: Endometriosis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-06-03T15:44:34Z'
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
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: PARTIAL
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
- 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
- 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: 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: NO_EVIDENCE
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: Immune cell dysfunction leads to impaired 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: 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: PARTIAL
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:0012532
label: Chronic pain
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: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: Snippet supports inflammatory lesion growth mechanisms but does not directly support infertility frequency.
- 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:0002027
label: Abdominal pain
- 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
- name: VEZT
association: Risk Factor
- name: GREB1
association: Risk Factor
- name: ID4
association: Risk Factor
environmental:
- name: Early Menarche
notes: Increases lifetime estrogen exposure
- name: Short Menstrual Cycles
notes: More frequent retrograde menstruation
- name: Nulliparity
notes: Risk factor
- name: Low BMI
notes: Associated with increased risk
treatments:
- name: NSAIDs
description: First-line for pain management.
- name: Combined Oral Contraceptives
description: Suppress ovulation and reduce menstruation.
- name: Progestins
description: Create hypoestrogenic state (dienogest, medroxyprogesterone).
- name: GnRH Agonists
description: Induce medical menopause, add-back therapy needed.
- name: GnRH Antagonists
description: Elagolix with dose-dependent estrogen suppression.
- name: Aromatase Inhibitors
description: Reduce local estrogen production in lesions.
- name: Laparoscopic Surgery
description: Excision or ablation of lesions, adhesiolysis.
- name: Hysterectomy
description: Definitive surgery for completed childbearing.
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
- phenotype#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: PARTIAL
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.
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:
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: []
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.
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).
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).
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
(papandreouUnknownyearinterinstitutionalinterdepartmentalmasterof pages 7-15): P PAPANDREOU. Interinstitutional/interdepartmental master of science<< application of endoscopic surgical techniques in. Unknown journal, Unknown year.
(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.
(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.
(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.
(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.