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Endometriosis

Pathophysiology description (narrative synthesis)

2025-12-17
Falcon MONDO:0005133 Model: Edison Scientific Literature 12 citations

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).

Table (click to expand)
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

2. Key Molecular Players

3. Biological Processes (GO annotation, representative)

4. Cellular Components (where processes occur)

5. Disease Progression

6. Phenotypic Manifestations and links to mechanisms

Gene/protein annotations with ontology terms (examples)

Cell type involvement (CL terms)

Anatomical locations (UBERON terms)

Chemical entities (CHEBI)

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

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

Direct quotes (recent)

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)

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.