Pathogenesis of Endometriosis: An Umbrella Review of Recent Systematic Reviews and Meta-Analyses

Endometriosis is a chronic, estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and remains a major cause of pelvic pain and infertility. Despite its high prevalence and substantial clinical burden, the biological mechanisms underlying endometriosis are still incompletely understood. Although numerous systematic reviews and meta-analyses have addressed individual pathogenic domains, their findings are often fragmented, methodologically heterogeneous, and partially overlapping. This umbrella review aimed to provide a comprehensive synthesis of recent evidence on the pathogenesis of endometriosis while critically appraising methodological quality and overlap of primary studies. An umbrella review was conducted in accordance with the PRISMA 2020 guidelines. PubMed was searched for systematic reviews and meta-analyses published between January 2019 and January 2026. Methodological quality was assessed using the AMSTAR 2 tool, and overlap of primary studies was evaluated using the corrected covered area (CCA). Evidence was synthesized narratively using a predefined domain-based framework. Eighteen systematic reviews and meta-analyses were included, covering seven major pathogenic domains, including genetic and epigenetic susceptibility, immunological dysregulation, oxidative stress, tissue remodeling, microbiota dysbiosis, and systems-level molecular networks. Most reviews demonstrated moderate methodological quality, with limited overlap across most domains, except for microbiota-related evidence (CCA = 20%). Overall, the findings support a multifactorial, network-based model of endometriosis pathogenesis involving interactions between genetic susceptibility, immune dysfunction, hormonal signaling, and environmental modifiers. This umbrella review highlights key pathogenic domains, identifies areas of evidentiary fragility, and underscores the need for integrative, systems-level research to inform future mechanistic studies and targeted clinical interventions.