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.
