Endometriosis as a Systemic and Complex Disease: Toward Phenotype-Based Classification and Personalized Therapy

Abstract

Endometriosis is traditionally conceptualized as a pelvic lesion-centered disease; however, mounting evidence indicates it is a chronic, systemic, and multifactorial inflammatory disorder. This review examines the molecular dialog between ectopic endometrial tissue, the immune system, and peripheral organs, highlighting mechanisms that underlie disease chronicity, symptom variability, and therapeutic resistance. Ectopic endometrium exhibits distinct transcriptomic and epigenetic signatures, disrupted hormonal signaling, and a pro-inflammatory microenvironment characterized by inflammatory mediators, prostaglandins, and matrix metalloproteinases. Immune-endometrial crosstalk fosters immune evasion through altered cytokine profiles, extracellular vesicles, immune checkpoint molecules, and immunomodulatory microRNAs, enabling lesion persistence. Beyond the pelvis, systemic low-grade inflammation, circulating cytokines, and microRNAs reflect a molecular spillover that contributes to chronic pain, fatigue, hypothalamic-pituitary-adrenal axis dysregulation, and emerging gut-endometrium interactions. Furthermore, circulating biomarkers-including microRNAs, lncRNAs, extracellular vesicles, and proteomic signatures-offer potential for early diagnosis, patient stratification, and monitoring of therapeutic responses. Conventional hormonal therapies demonstrate limited efficacy, whereas novel molecular targets and delivery systems, including angiogenesis inhibitors, immune modulators, epigenetic regulators, and nanotherapeutics, show promise for precision intervention. A systems medicine framework, integrating multi-omics analyses and network-based approaches, supports reconceptualizing endometriosis as a systemic inflammatory condition with gynecologic manifestations. This perspective emphasizes the need for interdisciplinary collaboration to advance diagnostics, therapeutics, and individualized patient care, ultimately moving beyond a lesion-centered paradigm toward a molecularly informed, holistic understanding of endometriosis.

Keywords: chronic inflammation; endometriosis; epigenetic regulation; immune crosstalk; molecular biomarkers; precision medicine.

Figure 1

Possible mechanisms underlying the pathophysiology of endometriosis and the primary factors contributing to its development. Since the pathophysiology of endometriosis is not yet fully understood due to its complexity and multifactorial nature, several hypotheses have been proposed to explain its development, including the theories of retrograde menstruation, coelomic metaplasia, embryogenic origin, stem cell implantation, and vascular or lymphatic dissemination of endometrial cells. Factors involved in its progression include hormonal, genetic, immunological, and environmental influences—such as poor nutrition (including processed foods), tobacco use, excessive alcohol consumption, and chronic stress—which act as aggravating elements that may intensify inflammation and promote disease advancement [17,18,19]. Created in BioRender. Reytor, C. (2026) https://BioRender.com/0z5en66 (accessed on 12 January 2026).

Figure 2

Peritoneal–Endometrioma crosstalk driving inflammation, hypoxia, and lesion progression in endometriosis. The bidirectional interaction shown promotes lesion establishment and progression in endometriosis. In the peritoneal compartment, immune cells release pro-inflammatory cytokines and growth factors—including IL-6, IL-8, IL-17, and VEGF—driving oxidative stress and impairing debris clearance. During menstruation, macrophages and neutrophils clearing endometrial debris generate ROS, and ectopic tissue simultaneously exposed to elevated Fe²⁺, hypoxia, and inflammatory cytokines undergoes oxidative damage, thereby intensifying local inflammatory signaling. Immune dysregulation simultaneously fuels angiogenesis, with macrophages, neutrophils, dendritic cells, and T lymphocytes releasing VEGF together with IL-6, IL-8, and IL-17, a pro-angiogenic effect especially prominent in neutrophils, whose secretion is further intensified by estrogen. Among HIF-1α downstream targets, VEGF is central to angiogenesis, acting through VEGFR-1, VEGFR-2, and VEGFR-3 to promote endothelial proliferation, migration, and vascular permeability. Dysregulated estrogen signaling—characterized by increased ERβ expression and altered local estrogen metabolism via 17β-HSD2—enhances E2 availability, fueling angiogenesis, EMT, oxidative stress, and hypoxia-related responses. Hypoxia-induced VEGF expression, together with vasoconstriction, facilitates neovascularization and supports lesion survival. In parallel, macrophage polarization toward an M2 phenotype maintains a pro-angiogenic and pro-fibrotic milieu through NF-κB activation and the secretion of cytokines, growth factors, and MMPs. In parallel, MMP-2 and MMP-9 function as key downstream effectors regulated by estrogen, inflammatory cytokines, oxidative stress, and PGE2, promoting extracellular matrix degradation, EMT, angiogenesis, and fibrosis; additionally, MMP-9 interacts with PGE2 and TNF-α pathways, reinforcing chronic inflammation and lesion expansion. By enabling endothelial migration and releasing ECM-bound growth factors, MMPs further potentiate VEGF-driven angiogenesis. Together, these interrelated processes establish a self-sustaining inflammatory, estrogen-dependent, and hypoxia-adapted niche that underpins endometrioma persistence and progression [60,61,62,63,64,65]. Abbreviations: Th17: T helper 17 cells; IL: interleukin; TNF-α: tumor necrosis factor alpha; ROS: reactive oxygen species; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; ERα: estrogen receptor alpha; ERβ: estrogen receptor beta; E2: estradiol; E1: estrone; 17β-HSD2: 17 beta-hydroxysteroid dehydrogenase type 2; EMT: epithelial–mesenchymal transition; HIF-1α: hypoxia-inducible factor-1 alpha; NF-κB: nuclear factor kappa B; COX-2: cyclooxygenase-2; TGF-β1: transforming growth factor beta 1; MMP: matrix metalloproteinase; PGE2: prostaglandin E2; ECM: extracellular matrix.arrows; (↑) indicate increased levels or overexpression; (↓) indicate reduced levels or functional downregulation Created in BioRender. Reytor, C. (2026) https://BioRender.com/ndwzjhc (accessed on 12 January 2026).