Endometriosis risk factors and comorbidities by endometriosis lesion macrophenotypes: An analysis from the What is Endometriosis (WisE) study

BACKGROUND: While endometriosis is thought to be a heterogeneous disease, the pathophysiologic heterogeneity across the three visualized lesion macrophenotypes (i.e., superficial peritoneal endometriosis(SPE) lesions, endometriomas, and deep lesions) remains unclear. OBJECTIVES: This study aimed to investigate associations between known and putative risk factors and co-existing comorbidities with odds of endometriosis lesion macrophenotypes. STUDY DESIGN: We conducted a pooled, cross-sectional analysis using data from 1,244 participants surgically diagnosed with endometriosis and 1,271 without endometriosis who participated in three 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 (OR) and 95% confidence intervals (CI) for the associations between participant characteristics of known and putative risk factors and co-existing 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 (p-het). RESULTS: Among endometriosis cases, 834(71%) had SPE 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 SPE only and deep+endometrioma macrophenotypes (≤11 vs. 12 years-old, OR=1.29, CI=1.01-1.65 and OR=2.07, CI=1.11-3.86, respectively), but not associated with endometrioma or deep lesions alone (p-heterogeneity=0.05). Presence of chronic overlapping pain conditions was associated with greater odds of endometriosis overall (OR=1.66, CI=1.49-1.85 per condition) and of SPE only(OR=1.80, CI=1.59-2.04 per condition) and deep lesions(OR=1.76, CI=1.44-2.15 per condition), but not with macrophenotypes including endometrioma(p-het=0.0001). Unsupervised clustering by risk factors and co-existing conditions showed distinct associative patterns by surgically-visualized lesion macrophenotypes. CONCLUSIONS: These results showing heterogeneity of individual risk factors and co-existing 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.