ABSTRACT. Endometriosis is a chronic inflammatory condition defined by the presence of endometrial-like tissue outside the uterus that often presents with pain and infertility, affecting approximately 10% of reproductive aged women. While some women respond well to hormonal therapy or surgical treatment, others do not and are plagued with continued or worsening pain. Many patients whose lives are substantially impacted by endometriosis associated pelvic pain (EAPP) experienced a transition from acute to persistent pain, often early in life, and subsequent worsening of symptoms. Once pain becomes persistent, it is often refractory to current treatments and may further evolve to include debilitating comorbid symptoms such as back, bladder and bowel pain, as well as widespread pain and fatigue. Identifying prognostic biomarkers associated with persistent and/or refractory EAPP would allow for strategic selection of treatments and interventions in vulnerable patients before pain becomes entrenched. Our overarching hypothesis is that neuroimmune/inflammatory markers can help identify women at risk for developing persistent and/or nociplastic pain. Specifically, we hypothesize that neuroimmune/inflammatory activity contributes to both the emergence and persistence of EAPP during adolescence, as well as the development of nociplastic pain in adults. Our preliminary analyses suggest that inflammatory and neuroimmune pathways are associated with more severe symptoms and may be implicated in the transition to persistent and/or refractory pain. In this proposal, we will leverage existing longitudinal questionnaire data and banked biospecimens (serial blood and peritoneal fluid) collected from females younger than 25 years participating in the Women’s Health Study: From Adolescence to Adulthood (A2A) to evaluate the emergence of EAPP. Further, following harmonized protocols we will collect blood samples, peritoneal fluid, and functional MRIs from a new cohort of adult women with established EAPP that began in adolescence who are undergoing both surgical and non-surgical therapies at the University of Michigan (UM) in order to evaluate markers of nociplastic EAPP. We will apply an innovative proteomics platform (basic science component) that has shown high reproducibility and can simultaneously measure >7,000 proteins. Detailed longitudinal assessment of endometriosis-associated symptoms (clinical/translational component), based on self-reported pain (both studies) and fMRI (UM cohort only), and biomarker quantification will be harmonized between the two cohorts to determine robust associations with persistent EAPP. By leveraging systemic and local biomarkers in combination with detailed pain assessment over time, this project is uniquely poised to identify biomarkers associated with persistent endometriosis-associated pain and emergence of nociplastic pain to advance our understanding of the underlying mechanisms that contribute to pelvic pain.

PROJECT NARRATIVE Endometriosis-associated pelvic pain (EAPP), which often originates during adolescence, evolves into chronic pelvic pain in some women, leading to decreased quality of life and altered life trajectory impacting well into adulthood. The proposed research will leverage unique data from two longitudinal cohorts to identify proteins and pathways that confer increased risk of persistent pain in patients with endometriosis despite receiving current standard treatments. Results from this study will advance our understanding of the underlying mechanisms that contribute to pain and inform strategic selection of treatments and interventions in vulnerable patients before pain becomes entrenched.