Chronic pelvic pain significantly affects the health of up to 10 percent of women with endometriosis (Stratton and Berkely, Hum Reprod Update 2011;17: 327). We have published the results of a randomized, prospective, placebo-controlled trial of raloxifene (180 mg daily) used by women with chronic pelvic pain and endometriosis (Stratton, Obstet Gynecol 2008 Jan;111: 88). This study was one of the largest randomized studies of medical therapy for endometriosis and, unlike other studies of endometriosis and pain, adhered to stringent entry criteria, including only those with biopsy-proven disease. Unexpectedly, women treated with the selective estrogen-receptor modulator raloxifene experienced return of chronic pelvic pain sooner than those treated with placebo. As both groups had endometriosis in similar proportions at second surgery, these results suggested that interference with estrogen action was related to pain threshold, lowering it in some such that their pain returned sooner. Importantly, pain location does not correlate with lesions location (Hsu, Fertil Steril, 2011 Aug;118:223). These observations have prompted further research into the relationship between pain and endometriosis in a cohort study. Diagnosis of endometriosis is done at a surgical procedure. One persistent issue in surgical diagnosis is whether histologic confirmation of the disease should be obtained, given the variable appearance of lesions. Stratton and Stegmann have correlated biopsy results with lesion appearance in two different ways. In the first study, we reported on the histologic confirmation given varying lesion characteristics, illustrating that no single color was associated with endometriosis and that surgeons should biopsy any suspicious lesion. Overall, it appears that single color lesions had similar frequencies of biopsy-confirmed endometriosis (59 to 62%). Only lesions with multiple colors had a significantly higher percentage of positive biopsies (76%). Of subtle lesions, 60% who only these type of lesions had endometriosis and of these, 40% of women who had only small, subtle lesions had biopsy-proven endometriosis. Mixed color lesions and endometriomas were the only two lesion types that were more commonly biopsy-proven (78%; Stegmann Fertil Steril, 2008 Jun;89:1632). In a second study, we created a logistic model to predict endometriosis. This model identified characteristics which indicated a high and low probability of biopsy-proven endometriosis. It was useful as a guide in choosing appropriate lesions for biopsy, but should not be used as a substitute for histologic confirmation (Stegmann Fertil Steril, 2009 Jan;91:51) Stratton and her colleagues have continued to describe other contributors to chronic pain in women with endometriosis, such as adenomyosis, appendiceal disease, or obdurator hernia. Stratton with Kennedy of Oxford University co-chaired an international meeting to standardize entry criteria and outcome measures for clinical trials in endometriosis-related pain. Such standardization would facilitate the comparison of trial results and the production of systematic reviews, improving evidence-based practice in this area (Vincent, Kennedy and Stratton Fertil Steril, 2010 Jan;93:62). To better understand endometriosis, chronic pelvic pain and its treatment, we have analyzed a survey of 4,334 Endometriosis Association members reporting surgically diagnosed endometriosis. We have investigated whether the first doctor seen and adolescent onset of symptoms impact the diagnostic process of endometriosis (Greene, Fertil Steril, 2009 Jan; 91:51). Almost all respondents reported pelvic pain with 50% first consulting a gynecologist and 45% a generalist for symptoms of endometriosis. Women and girls who reported seeing a gynecologist first for symptoms of endometriosis were more likely to have a shorter time to diagnosis, see fewer physicians, and report abetterexperience overall with their physicians. The majority reported onset of symptoms during adolescence, who reported a longer time and a worse experience while obtaining a diagnosis. The survey of the Endometriosis Association members was also analyzed to assess the prevalence of patient-reported, physician-diagnosed infectious diseases, cancers, and endocrine diseases in women with endometriosis (Gemmill, Fertil Steril, 2010;94: 1627). Nearly two-thirds of women reported one or more of the assessed conditions. Recurrent upper respiratory infections and recurrent vaginal infections were common and more likely in women responding to the EA survey. Melanoma was reported by 0.7%, breast cancer by 0.4%, and ovarian cancer by 0.2%. While ovarian cancer and melanoma were significantly more common than in the general population, breast cancer was surprisingly less common. Addisons disease and Cushings syndrome were rare (0.2% and 0.1%, respectively). These findings document other potential associations related to the immune system, which may help focus future research into this disease. Women with chronic pelvic pain have other regional pain syndromes like migraine headaches (Karp, Fertil Steril, 2011;95:895). We hypothesized that these two chronic, debilitating conditions co-occur. Of patients enrolled in the clinical trial, at least two thirds of women with chronic pelvic pain had migraine headaches that was independent of endometriosis diagnosis. Quality-of-life was lowered, beyond that due to pelvic pain alone. If migraine headache was common in women with chronic pelvic pain, regardless of the presence of endometriosis, it likely contributed to disability of those with both conditions and suggested a common pathophysiology. We also explored the relationship between central nervous system sensitization and myfascial dysfunction in women with chronic pain and endometriosis (Stratton, Obstet Gynecol 2015;124:719). In our study, all women with chronic pain and endometriosis have myofascial dysfunction. Those with chronic pain with current or a history of endometriosis appear to be more likely to have central nervous system sensitization than those with chronic pain but no history of endometriosis and healthy volunteers. Traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation, as our study illustrates. Thus, women with chronic pelvic pain associated with endometriosis often have an element of spasm of the pelvic floor muscles that may be a strong contributor to the patients pelvic pain. Botulinum toxin, an effective treatment for disorders associated with muscle spasm, has recently been used to treat headache and myofascial pain, where it is believed to act directly on nociceptive pathways as well as on muscle spasm. We have begun a study to determine the effectiveness of botulinum toxin injection in treating pelvic pain in a cohort with pelvic floor spasm, chronic pelvic pain and a history of surgery for endometriosis. Chronic stress and depression blunt the ACTH and cortisol response curves following Corticotropic-Releasing Hormone stimulation. Patients with chronic pelvic pain experience both and are at risk of having an altered response. Duration of pelvic pain, after adjusting for race, may be associated with an altered response in those with chronic pelvic pain and endometriosis. Additionally, difficulty sleeping and body pain may also be associated with an altered response. In the coming year, we will continue to conduct analyses of endocrine responses in women with chronic pelvic pain related to endometriosis to determine whether there may be altered stress responses in chronic pelvic pain, and undertake a study of the interrelationships of various aspects of chronic pain observed in endometriosis.

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Aredo, Jacqueline V; Heyrana, Katrina J; Karp, Barbara I et al. (2017) Relating Chronic Pelvic Pain and Endometriosis to Signs of Sensitization and Myofascial Pain and Dysfunction. Semin Reprod Med 35:88-97
Rogers, Peter A W; Adamson, G David; Al-Jefout, Moamar et al. (2017) Research Priorities for Endometriosis. Reprod Sci 24:202-226