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7
Pathophys.
7
Phenotypes
4
Genes
8
Treatments
4
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
ENDOCRINOLOGY_METABOLISM

Pathophysiology

7
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 link
Cell Proliferation link
Show evidence (1 reference)
PMID:16166933 PARTIAL
"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.
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
Chronic Inflammation
Ectopic lesions trigger chronic pelvic inflammation with elevated cytokines and prostaglandins. Inflammatory milieu contributes to pain and adhesion formation.
Inflammatory Response link
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 link
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
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 link
Show evidence (3 references)
PMID:16166933 NO_EVIDENCE
"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."
Immune cell dysfunction leads to impaired 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.
Response to Hypoxia link Angiogenesis link
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
Adhesion Formation
Chronic inflammation leads to fibrous adhesions distorting pelvic anatomy. Adhesions contribute to pain and infertility.

Phenotypes

7
Blood 1
Heavy Menstrual Bleeding FREQUENT Menorrhagia (HP:0000132)
Genitourinary 3
Pelvic Pain VERY_FREQUENT Dyspareunia (HP:0030016)
Chronic, cyclical
Dyspareunia FREQUENT Dyspareunia (HP:0030016)
Deep dyspareunia
Infertility FREQUENT Infertility (HP:0000789)
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."
Snippet supports inflammatory lesion growth mechanisms but does not directly support infertility frequency.
Constitutional 3
Dysmenorrhea VERY_FREQUENT Dysmenorrhea (HP:0100607)
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
Painful Bowel Movements OCCASIONAL Abdominal pain (HP:0002027)
With rectovaginal disease
Fatigue FREQUENT Fatigue (HP:0012378)
🧬

Genetic Associations

4
WNT4 (Risk Factor)
VEZT (Risk Factor)
GREB1 (Risk Factor)
ID4 (Risk Factor)
💊

Treatments

8
NSAIDs
First-line for pain management.
Combined Oral Contraceptives
Suppress ovulation and reduce menstruation.
Progestins
Create hypoestrogenic state (dienogest, medroxyprogesterone).
GnRH Agonists
Induce medical menopause, add-back therapy needed.
GnRH Antagonists
Elagolix with dose-dependent estrogen suppression.
Aromatase Inhibitors
Reduce local estrogen production in lesions.
Laparoscopic Surgery
Excision or ablation of lesions, adhesiolysis.
Hysterectomy
Definitive surgery for completed childbearing.
🌍

Environmental Factors

4
Early Menarche
Increases lifetime estrogen exposure
Short Menstrual Cycles
More frequent retrograde menstruation
Nulliparity
Risk factor
Low BMI
Associated with increased 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
{ }

Source YAML

click to show
name: Endometriosis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
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.
- 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
- name: Adhesion Formation
  description: >
    Chronic inflammation leads to fibrous adhesions distorting pelvic
    anatomy. Adhesions contribute to pain and infertility.
phenotypes:
- name: Pelvic Pain
  category: Reproductive
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Chronic, cyclical
  phenotype_term:
    preferred_term: Pelvic Pain
    term:
      id: HP:0030016
      label: Dyspareunia
- 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.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
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: []
📚

References & Deep Research

References

4
Targeting the formation of estrogens for treatment of hormone dependent diseases–current status
No top-level findings curated for this source.
Pathogenesis of Endometriosis and Endometriosis-Associated Cancers
No top-level findings curated for this source.
Molecular and cellular landscape of endometriosis
No top-level findings curated for this source.
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.