Neural Immune and Genetic Influences on Chronic Pelvic Pain and Endometriosis

神经免疫和遗传对慢性盆腔疼痛和子宫内膜异位症的影响

• 批准号: 10018700
• 负责人: Pamela Stratton
• 金额: $ 16.36万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10018700
• 关键词: Addison' s disease; Adolescence; Adolescent; Affect; Anatomy; Anxiety; Appearance; Area; Biopsy; Blood; Botulinum Toxins; Characteristics; Chronic; Chronic stress; Clinical Trials; Cohort Studies; Color; Consult; Corticotropin; Cushing Syndrome; Diagnosis; Diagnostic; Disease; Effectiveness; Elements; Endocrine; Endocrine System Diseases; Endometriomas; Endometrium; Enrollment; Estrogens; Evaluation; Evidence based practice; Frequencies; Functional disorder; General Population; General Practitioners; Genetic; Goals; Growth Factor; Gynecologist; Headache; Health; Hernia; Histologic; Hormones; Hydrocortisone; Immune; Immune system; Injections; International; Lesion; Location; Logistic Models; Malignant Neoplasms; Malignant neoplasm of ovary; Medical; Mental Depression; Methods; Migraine; Modeling; Myofascial Pain Syndromes; Nerve; Neuraxis; Nociception; Operative Surgical Procedures; Outcome Measure; Pain; Pain Threshold; Pathway interactions; Patients; Pelvic Floor Muscle; Pelvic Pain; Pelvic floor structure; Physicians; Placebos; Predictive Factor; Prevalence; Probability; Process; Production; Publishing; Quality of life; Race; Raloxifene; Randomized; Recording of previous events; Recurrence; Reporting; Research; Respondent; Risk; Selective Estrogen Receptor Modulators; Sleep; Spasm; Standardization; Surgeon; Surveys; Symptoms; Syndrome; Time; Tissues; Universities; Update; Upper Respiratory Infections; Urine; Woman; angiogenesis; base; biological adaptation to stress; chronic depression; chronic pain; chronic pelvic pain; cohort; communicable disease diagnosis; disability; effective therapy; endometriosis; experience; girls; healthy volunteer; illness length; improved; malignant breast neoplasm; meetings; melanoma; member; placebo controlled study; prospective; relating to nervous system; response; systematic review; uterus endometriosis; vaginal infection

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.

慢性盆腔疼痛显著影响多达10%的子宫内膜异位症女性的健康（Stratton和berkeley， Hum rebd Update 2011; 17:3 27）。我们发表了一项随机、前瞻性、安慰剂对照试验的结果，雷洛昔芬（180mg /天）用于慢性盆腔疼痛和子宫内膜异位症的妇女（Stratton, journal of obstetrics gynecology， 2008年1月；111:88）。该研究是子宫内膜异位症药物治疗的最大随机研究之一，与其他子宫内膜异位症和疼痛的研究不同，该研究遵循严格的进入标准，仅包括活检证实的疾病。出乎意料的是，接受选择性雌激素受体调节剂雷洛昔芬治疗的女性比接受安慰剂治疗的女性更早地恢复了慢性盆腔疼痛。由于两组患者在第二次手术中出现子宫内膜异位症的比例相似，这些结果表明，干扰雌激素的作用与疼痛阈值有关，降低了一些人的疼痛阈值，从而使他们的疼痛恢复得更快。重要的是，疼痛位置与病变位置无关（Hsu, Fertil Steril, 2011 Aug;118:223）。这些观察结果促使在一项队列研究中进一步研究疼痛和子宫内膜异位症之间的关系。