Neural Immune and Genetic Influences on Chronic Pelvic Pain and Endometriosis

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Chronic pelvic pain significantly affects the health of up to 10 percent of women with endometriosis (Stratton and Berkley, Hum Reprod Update 2011;17: 327). We studied women with chronic pelvic pain and biopsy-proven endometriosis in a randomized, prospective, placebo-controlled trial of raloxifene (180 mg daily). At study surgery, pain location did not correlate with lesion location (Hsu, Fertil Steril, 2011 Aug;118:223). Importantly, at least two thirds of women with chronic pelvic pain enrolled in the clinical trial had migraine headaches, another regional pain syndrome (Karp, Fertil Steril, 2011;95:895). In those subjects, quality-of-life was lowered, beyond that due to pelvic pain alone. As migraine headache was common in women with chronic pelvic pain, regardless of endometriosis lesions, headaches likely contributed to disability of those with both conditions and suggested a common pathophysiology. Unexpectedly, women treated with the selective estrogen-receptor modulator raloxifene experienced return of chronic pelvic pain sooner than those treated with placebo (Stratton, Obstet Gynecol 2008 Jan;111: 88). As both groups had endometriosis in similar proportions at second surgery, these results suggested that interference with estrogen action was related to pain threshold. This cohort study builds on these findings to explore the relationship between chronic pelvic pain and endometriosis. To date, we explored the relationship between central nervous system sensitization and myofascial dysfunction in the study cohort (Stratton, Obstet Gynecol 2015;124:719). All women with chronic pain and endometriosis had myofascial dysfunction. Those with chronic pain with any history of endometriosis were more likely to have central nervous system sensitization than those with chronic pain but no history of endometriosis and healthy volunteers. As our study illustrates traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation. Some chronic pain conditions and comorbidities like chronic stress and depression suppress the hypothalamic-pituitary-adrenal (HPA) axis and may suppress the response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis (Ortiz, Reprod Sci: 2020 Oct;27:1839). HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta, ACTH AUC, and cortisol delta were significantly higher in black than predominately white (non-black) subjects. In analyses among white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions. These neuroendocrine abnormalities suggest that future investigations of the HPA axis response in women with pelvic pain merits stratification by race. In the coming year, we will continue to conduct analyses of the interrelationships of various aspects of chronic pain observed in endometriosis.