Endometriosis risk factors and comorbidities by endometriosis lesion macrophenotypes: an analysis from the What is...

While endometriosis is thought to be a heterogeneous disease, the pathophysiologic heterogeneity across the 3 visualized lesion macrophenotypes (ie, superficial peritoneal endometriosis lesions, endometriomas, and deep lesions) remains unclear.

This study aimed to investigate associations between known and putative risk factors and coexisting comorbidities with odds of endometriosis lesion macrophenotypes.

We conducted a pooled, cross-sectional analysis using data from 1244 participants surgically diagnosed with endometriosis and 1271 without endometriosis who participated in 3 World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project compliant population-based studies from North America and Europe. Multivariable logistic regression models adjusting for age at questionnaire completion and studies were used to calculate odds ratios and 95% confidence intervals for the associations between participant characteristics of known and putative risk factors and coexisting comorbidities and surgically-confirmed endometriosis. Polytomous logistic regression was used to examine the associations among case groups defined by endometriosis macrophenotype, with likelihood ratio tests used to evaluate statistically significant differences between macrophenotypes presented as p-heterogeneity.

Among endometriosis cases, 834 (71%) had superficial peritoneal endometriosis only, 92 (8%) had at least one endometrioma, 129 (11%) had deep lesions, and 111 (10%) had both endometrioma and deep lesions. Younger age at menarche was associated with significantly higher odds for having superficial peritoneal endometriosis only and deep + endometrioma macrophenotypes (≤11 vs 12 years-old, odds ratio = 1.29, confidence interval = 1.01-1.65 and odds ratio = 2.07, confidence interval = 1.11-3.86, respectively), but not associated with endometrioma or deep lesions alone (P-heterogeneity = .05). Presence of chronic overlapping pain conditions was associated with greater odds of endometriosis overall (odds ratio = 1.66, confidence interval = 1.49-1.85 per condition) and of superficial peritoneal endometriosis only (odds ratio = 1.80, confidence interval = 1.59-2.04 per condition) and deep lesions (odds ratio = 1.76, confidence interval = 1.44-2.15 per condition), but not with macrophenotypes including endometrioma (P-heterogeneity = .0001). Unsupervised clustering by risk factors and coexisting conditions showed distinct associative patterns by surgically-visualized lesion macrophenotypes.

These results showing heterogeneity of individual risk factors and coexisting conditions across endometriosis macrophenotypes support the concept that endometriosis macrophenotypes may have different etiologies and underscores the importance of evaluating risk factors and biomarkers by endometriosis lesion macrophenotypes.