The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications

Abstract

Endometriosis is a complex gynecological disorder characterized by endometrial-like tissue growing outside the uterus, leading to chronic pain, infertility, and reduced quality of life. Its pathophysiology involves genetic, epigenetic, immune, and molecular factors. Theories such as retrograde menstruation, coelomic metaplasia, and stem cell involvement explain lesion formation. Endometrial mesenchymal stem cells (eMSCs) and epithelial progenitors (eEPs) contribute to lesion establishment by adhering to peritoneal surfaces, proliferating, and differentiating into ectopic tissue. Aberrant adhesion molecules, inflammatory cytokines, and molecular pathways like PI3K/Akt and Wnt/β-catenin drive proliferation, angiogenesis, and resistance to apoptosis. Elevated estrogen levels and progesterone resistance further promote lesion growth and immune evasion. Immune dysfunction, including altered macrophage activity and reduced natural killer (NK) cell function, contributes to inflammation and lesion persistence. Pain is linked to prostaglandin E2 (PGE2) and nerve infiltration, emphasizing the need for targeted pain management. Current therapies, such as GnRH agonists, suppress ovarian hormone production but face limitations in long-term efficacy and side effects. Integrating molecular insights into clinical practice may advance diagnostics and treatment, with emerging approaches focusing on molecular pathways, immune modulation, and hormonal regulation for more effective, personalized therapies. Future research should unravel the complex mechanisms driving endometriosis to improve patient outcomes.

Keywords: endometrial mesenchymal stem cells; endometriosis; natural killer cell.

Figure 1

A flowchart of the database search, screening, selection, and inclusion of eligible articles from the literature.

Figure 2

The diagram illustrates the pathophysiological theories of endometriosis proposed in the literature from the past to present.

Figure 3

The cellular mechanisms of endometriosis show that endometrial stem cells shed during retrograde menstruation may adhere to peritoneal surfaces due to altered integrin profiles. eMSCs: endometrial mesenchymal stem cells; eEPs: endometrial epithelial progenitors.

Figure 4

The interaction of cell adhesion molecules (double arrow) between the endometrial cells, extracellular matrix, peritoneal surface, and immune cells. ICAM-1: intercellular adhesion molecule-1; LFA-1: leukocyte function-associated antigen-1; MMP: matrix metalloproteinases; sICAM-1: soluble intercellular adhesion molecule-1.

Figure 5

The proliferation, apoptosis, and dysregulated angiogenesis of endometriotic cells, mediated by the interactions of different hormones, cytokines, and tissue factors. 17β-HSD2: 17-beta-hydroxysteroid dehydrogenase 2; COX-2: cyclooxygenase-2; ILs: interleukins; HGF: hepatocyte growth factor; MCP1: monocyte chemoattractant protein-1; MMP: matrix metalloproteinases; TNFα: tissue necrosis factor alpha; PAR1: protease-activated receptor 1; StAR: steroidogenic acute regulatory protein; TF: tissue factor.

Figure 6

The role of immune and inflammatory response in endometriosis via a variety of mediators and signaling pathways. IL: interleukin; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa B; PDGF: platelet-derived growth factor; ROS: reactive oxygen species; TGF-β: transforming growth factor-beta; TNF-α: tumor necrosis factor-alpha.

Figure 7

The mechanisms of epigenetic regulation involved in the pathogenesis and development of endometriosis. miRNAs: microRNAs.