Beyond the pelvis: redefining endometriosis as a systemic inflammatory disorder. A systematic review and...

Endometriosis has traditionally been defined as a disease localized to the pelvis. However, its clinical presentation is often accompanied by systemic comorbidities that extend far beyond the pelvic cavity, a phenomenon that challenges the traditional disease paradigm.

This study aimed to comprehensively assess the associations between endometriosis and autoimmune diseases, allergic conditions, chronic pain syndromes, and endocrine disorders through a systematic review and meta-analysis, thereby providing evidence for redefining endometriosis as a systemic immuno-inflammatory disorder.

To conduct this study, a comprehensive search strategy was employed to identify relevant published studies. Electronic databases, including Web of Science and Medline, were searched from their inception up to December 31, 2025. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through the electronic database searches. Eligible studies were observational in design (cohort, case-control, and cross-sectional) and reported quantitative data on the association between endometriosis and predefined comorbidities in women. Exclusion criteria included non-human studies, non-English publications, secondary literature types (e.g., reviews, case reports), and studies lacking sufficient data for effect size calculation. Quality assessment was conducted based on the GRADE criteria.

The final analysis included 55 studies that met the predefined inclusion criteria and were incorporated into the comprehensive analysis. Of these, 48 studies provided sufficient data for quantitative synthesis (meta-analysis). Specifically, 32 studies investigated the association between endometriosis and autoimmune diseases: 14 on systemic lupus erythematosus (SLE), 8 on Sjögren's syndrome (SS), 10 on rheumatoid arthritis (RA), 5 on multiple sclerosis (MS), 5 on celiac disease (CLD), and 4 on inflammatory bowel disease (IBD). Additionally, 17 studies examined associations with allergic diseases, 13 focused on pain syndromes, and 6 explored associations with endocrine disorders. Meta-analysis showed that women with endometriosis had a significantly higher risk of certain autoimmune diseases in cohort studies, including SLE (RR: 1.81, 95% CI: 1.50-2.18), SS (RR: 1.54, 95% CI: 1.40-1.71), and RA (RR: 1.71, 95% CI: 1.40-2.09), as well as significantly higher odds in case-control and cross-sectional studies for SLE (OR: 3.93, 95% CI: 2.59-5.98), SS (OR: 3.13, 95% CI: 1.10-8.90), RA (OR: 2.27, 95% CI: 1.75-2.95), MS (OR: 2.30, 95% CI: 1.57-3.37), CLD (OR: 4.50, 95% CI: 1.94-10.42), and IBD (OR: 2.82, 95% CI: 0.58-13.61). Significant associations were also observed for allergic conditions-such as asthma (RR: 1.27, 95% CI: 1.14-1.40) and eczema (OR: 1.58, 95% CI: 1.34-1.87)-and for pain syndromes including fibromyalgia (RR: 1.65, 95% CI: 1.42-1.92), chronic fatigue syndrome (RR: 1.41, 95% CI: 1.31-1.51), and irritable bowel syndrome (RR: 2.51, 95% CI: 1.55-4.07; OR: 3.49, 95% CI: 3.21-3.80). In contrast, no statistically significant increase was observed in the odds of endocrine disorders such as hypothyroidism (OR: 1.89, 95% CI: 0.61-5.90) and hyperthyroidism (OR: 0.95, 95% CI: 0.60-1.52) among women with endometriosis compared with women without endometriosis. However, the overall quality of evidence was generally low or very low according to the GRADE approach, largely due to a high risk of bias in most of the included study designs and statistical analyses.

The body of evidence provided by this study supports the reconceptualization of endometriosis as a systemic immuno-inflammatory disease. The associations with various comorbidities are underpinned by shared mechanisms of immune dysregulation and central sensitization. This paradigm shift necessitates a move in clinical practice from a purely gynecological intervention model toward a patient-centered, comprehensive multidisciplinary management approach. It also provides a theoretical foundation for developing novel treatment strategies targeting shared pathological pathways.

CRD420251258716.