Cyclic and non-menstrual pain in the pelvis and lower abdomen is associated with significant morbidity among women worldwide. The heterogeneity observed in the clinical presentation of pelvic pain and its associated disorders is not well understood. Endometriosis is among the most common disorders diagnosed in those presenting with pelvic pain. At the population level, there is great uncertainty regarding the true prevalence and incidence of endometriosis. At the individual level, pelvic endometriosis staging based on lesion type, location, or volume does not correlate well with pelvic pain symptoms. The overarching purpose of this dissertation was to describe and delineate the ways in which populations with pelvic pain - with and without endometriosis can be meaningfully partitioned.The first aim was to characterize the population-level heterogeneity in the global distribution of endometriosis. We summarized and critically assessed studies of endometriosis frequency, distribution, and stage estimates between 1989-2019. We identified 69 studies describing the prevalence and/or incidence of endometriosis and examined stratification by population type and by indication for diagnosis, finding endometriosis prevalence ranging from 15.4% to 71.4% among women presenting with chronic pelvic pain. We did not find a change in frequency or distribution of endometriosis across the 30-year period.The second aim was to identify subgroups of pelvic pain symptoms based on clustering patterns and investigate their association with comorbidities related to inflammation and chronic pain. Cross-sectional baseline data were analyzed from 1255 participants in the Women's Health Study: from Adolescence to Adulthood (A2A) cohort, an ongoing longitudinal cohort study oversampled for adolescents and individuals with surgically confirmed endometriosis. We derived subgroups using latent class analysis (LCA) consisting of six variables: menstruation associated (cyclic; dysmenorrhea) and non-menstruation associated (acyclic) pelvic pain severity, frequency, and impact on daily activities. We identified five subgroups defined by pelvic pain characteristics and found distinct associations of comorbidity patterns, including endometriosis, differentially associated with these subgroups.The third aim was to, again, utilize these identified five subgroups defined by pelvic pain characteristics and investigate their association with seven plasma-based inflammatory biomarkers selected for their previously observed associations with pelvic pain. We performed a three-step approach to examine these associations, accounting for non-linearity and classification uncertainty in the relationship between biomarkers and subgroup assignment, as well as adjusting for confounding by age and body mass index. We found that the most significant associations of pro-inflammatory cytokines were with the subgroup defined by those reporting both severe cyclic and severe acyclic pelvic pain compared to the subgroup inclusive of those reporting no pelvic pain. This severe multifactorial pelvic pain subgroup was the same group found in our second aim to be associated with the highest number of inflammatory and pain comorbidities.Overall, this work contributes to understanding of the heterogeneity and patterning of symptomology in pelvic pain, with a lens on endometriosis. Considering the strengths and limitations of each study, subgroup associations with comorbid inflammatory and pain conditions and inflammatory biomarkers may suggest both distinct biologic pathways and shared underlying etiologies that warrant investigation in future research.
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