Genetic Predisposition and Pathogenesis in Endometriosis

Amani Rustemagic, Aida Ombasic
In: International Journal of Preventive Medicine and Health · 2025 · vol. 5(6) , pp. 17–23 · doi:10.54105/ijpmh.e1113.05060925 · W4414570859
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This review synthesizes genetic, epigenetic, and molecular findings to explain how predisposition, somatic alterations, and epigenetic mechanisms interact to drive endometriosis development, persistence, and symptom severity.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This paper is a review of genetic, epigenetic, and molecular evidence on endometriosis, focusing on why only some individuals develop disease despite the predominance of retrograde menstruation as a pathogenesis theory. It reports that heritability estimates suggest roughly 51% of risk is genetically driven and that GWAS have identified more than a dozen risk loci involving reproductive tract development, hormone signaling, immune modulation, and cell adhesion, citing genes such as WNT4, GREB1, FN1, CDKN2B-AS1, and ESR1. The review also summarizes epigenetic alterations (including DNA methylation and microRNA regulation) and somatic mutations/chromosomal instability in lesions, suggesting a neoplastic-like progression in advanced stages, and it mentions additional validated loci in pathways related to vascular remodeling and oxidative stress (e.g., VEGF, MMPs, NAT2). It explicitly frames its synthesis while noting limitations in current diagnosis and treatment and the need for biomarker and personalized approaches, and this paper is centrally about endometriosis — it integrates genetic, epigenetic, and somatic mechanisms to explain lesion development, persistence, and symptom severity.

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Abstract

Endometriosis is a chronic, estrogen-dependent inflammatory disorder defined by the growth of endometrial-like tissue outside the uterus, leading to pain, infertility, and reduced quality of life. Although retrograde menstruation remains the prevailing theory of pathogenesis, it does not fully explain why only some individuals develop the condition. Accumulating evidence highlights a substantial genetic component, with heritability estimates suggesting that approximately 51 percent of the risk of endometriosis is genetically driven. Genome-wide association studies (GWAS) have identified more than a dozen risk loci, including WNT4, GREB1, FN1, CDKN2B-AS1, and ESR1, which are involved in reproductive tract development, hormone signalling, immune modulation, and cell adhesion. This review synthesizes findings from genetic, epigenetic, and molecular studies to provide an updated understanding of the pathophysiology of endometriosis. In addition to inherited variants, recent discoveries have included epigenetic alterations, such as DNA methylation and microRNA regulation, which influence gene expression in key pathways related to cell proliferation and differentiation. Moreover, somatic mutations found in eutopic endometrial cells and chromosomal instability within lesions suggest a neoplastic-like progression, especially in advanced stages of the disease. Newly validated GWAS loci and polymorphisms in vascular remodelling and oxidative stress related genes (e.g., VEGF, MMPs, NAT2) further underscore the multifactorial nature of endometriosis. The purpose of this review is to investigate how genetic predisposition, somatic alterations, and epigenetic mechanisms interact to contribute to lesion development, persistence, and symptom severity. By examining these interconnected pathways, we highlight the current limitations in diagnosis and treatment, and emphasize the urgent need for personalized approaches in clinical care. These insights pave the way for future research to identify biomarkers for earlier diagnosis and to develop individualized therapeutic strategies. A more comprehensive understanding of endometriosis at the molecular level is crucial for advancing precision medicine and enhancing outcomes for women affected worldwide.

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endometriosisinfertility

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