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: 9770369
• 负责人: Pamela Stratton
• 金额: $ 2.06万
• 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/9770369
• 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; Infection; 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; Vagina; 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

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.

慢性盆腔疼痛显着影响高达 10% 的子宫内膜异位症女性的健康（Stratton 和 Berkely，Hum Reprod Update 2011；17：327）。我们发表了一项随机、前瞻性、安慰剂对照试验的结果，该试验对患有慢性盆腔疼痛和子宫内膜异位症的女性使用雷洛昔芬（每天 180 毫克）（Stratton，Obstet Gynecol 2008 年 1 月；111：88）。这项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研究不同，该研究遵循严格的进入标准，仅包括那些经活检证实患有疾病的研究。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经历慢性盆腔疼痛的复发。由于两组患者在第二次手术时子宫内膜异位症的比例相似，因此这些结果表明，雌激素作用的干扰与疼痛阈值有关，降低了某些患者的疼痛阈值，从而使疼痛更快恢复。 重要的是，疼痛位置与病变位置无关（Hsu，Fertil Steril，2011 年 8 月；118：223）。这些观察结果促使队列研究进一步研究疼痛与子宫内膜异位症之间的关系。 子宫内膜异位症的诊断是通过外科手术完成的。外科诊断中的一个长期存在的问题是，考虑到病变外观的变化，是否应该获得疾病的组织学确认。斯特拉顿和斯特格曼以两种不同的方式将活检结果与病变外观相关联。在第一项研究中，我们报告了考虑到不同病变特征的组织学确认，表明没有单一颜色与子宫内膜异位症相关，外科医生应对任何可疑病变进行活检。总体而言，单色病变经活检证实的子宫内膜异位症的发生率相似（59% 至 62%）。只有具有多种颜色的病变才有显着更高的阳性活检百分比（76%）。在细微病变中，60% 仅有此类病变的女性患有子宫内膜异位症，其中，40% 仅有小而细微病变的女性患有经活检证实的子宫内膜异位症。混合颜色病变和子宫内膜异位瘤是仅有的两种更常见的活检证实的病变类型（78%；Stegmann Fertil Steril，2008年6月；89:1632）。在第二项研究中，我们创建了一个逻辑模型来预测子宫内膜异位症。该模型确定了表明活检证实的子宫内膜异位症的高概率和低概率的特征。它可作为选择适当活检病变的指南，但不应替代组织学确认（Stegmann Fertil Steril，2009 年 1 月；91:51） 斯特拉顿和她的同事们继续描述了子宫内膜异位症女性慢性疼痛的其他原因，如子宫腺肌病、阑尾疾病或硬疝。 斯特拉顿与牛津大学的肯尼迪共同主持了一次国际会议，旨在标准化子宫内膜异位症相关疼痛临床试验的进入标准和结果测量。这种标准化将有助于试验结果的比较和系统评价的产生，从而改善该领域的循证实践（Vincent、Kennedy 和 Stratton Fertil Steril，2010 年 1 月；93：62）。 为了更好地了解子宫内膜异位症、慢性盆腔疼痛及其治疗，我们分析了一项对 4,334 名子宫内膜异位症协会成员进行的调查，报告了手术诊断的子宫内膜异位症。我们调查了首次就诊的医生和青少年出现的症状是否会影响子宫内膜异位症的诊断过程（Greene, Fertil Steril, 2009 Jan；91:51）。几乎所有受访者都报告了盆腔疼痛，其中 50% 的受访者首先咨询了妇科医生，45% 的受访者咨询了全科医师以了解子宫内膜异位症的症状。因子宫内膜异位症症状而首先去看妇科医生的妇女和女孩更有可能获得更短的诊断时间，更少的医生，并且总体上与医生的体验更好。大多数人报告在青春期出现症状，他们报告获得诊断的时间更长且经历更糟糕。 还对子宫内膜异位症协会成员的调查进行了分析，以评估子宫内膜异位症女性患者报告的、医生诊断的传染病、癌症和内分泌疾病的患病率（Gemmill, Fertil Steril, 2010;94: 1627）。近三分之二的女性报告了一种或多种评估状况。复发性上呼吸道感染和复发性阴道感染很常见，并且在接受 EA 调查的女性中更有可能出现这种情况。据报道，黑色素瘤的发病率为 0.7%，乳腺癌的发病率为 0.4%，卵巢癌的发病率为 0.2%。虽然卵巢癌和黑色素瘤比一般人群更常见，但乳腺癌的常见率却出人意料地少。阿狄森病和库欣综合征很少见（分别为 0.2% 和 0.1%）。这些发现记录了与免疫系统相关的其他潜在关联，这可能有助于将未来的研究重点放在这种疾病上。 患有慢性盆腔疼痛的女性还患有其他区域疼痛综合征，例如偏头痛（Karp, Fertil Steril, 2011;95:895）。我们假设这两种慢性、使人衰弱的疾病同时发生。在参加临床试验的患者中，至少三分之二患有慢性盆腔疼痛的女性患有与子宫内膜异位症诊断无关的偏头痛。生活质量下降，不仅仅是骨盆疼痛造成的。如果偏头痛在患有慢性盆腔疼痛的女性中很常见，那么无论是否存在子宫内膜异位症，它都可能导致患有这两种疾病的女性残疾，并表明存在共同的病理生理学。 我们还探讨了患有慢性疼痛和子宫内膜异位症的女性中枢神经系统敏化与肌筋膜功能障碍之间的关系 (Stratton, Obstet Gynecol 2015;124:719)。在我们的研究中，所有患有慢性疼痛和子宫内膜异位症的女性都患有肌筋膜功能障碍。与患有慢性疼痛但没有子宫内膜异位症病史的人和健康志愿者相比，患有慢性疼痛且患有子宫内膜异位症或有子宫内膜异位症病史的人似乎更有可能出现中枢神经系统过敏。 正如我们的研究所示，根据疾病、持续时间和解剖结构对子宫内膜异位症相关疼痛进行分类的传统方法是不够的，应该被基于机制的评估所取代。 因此，患有与子宫内膜异位症相关的慢性盆腔疼痛的女性通常具有盆底肌肉痉挛的因素，这可能是导致患者盆腔疼痛的主要原因。 肉毒杆菌毒素是治疗肌肉痉挛相关疾病的有效方法，最近已被用于治疗头痛和肌筋膜疼痛，据信它可以直接作用于伤害性通路和肌肉痉挛。我们已经开始一项研究，以确定肉毒杆菌毒素注射治疗盆底痉挛、慢性盆腔疼痛和子宫内膜异位症手术史队列中盆腔疼痛的有效性。 慢性压力和抑郁会减弱促肾上腺皮质激素释放激素刺激后的 ACTH 和皮质醇反应曲线。患有慢性盆腔疼痛的患者会同时经历这两种情况，并且存在反应改变的风险。 调整种族后，盆腔疼痛的持续时间可能与慢性盆腔疼痛和子宫内膜异位症患者的反应改变有关。 此外，睡眠困难和身体疼痛也可能与反应改变有关。 来年，我们将继续对患有与子宫内膜异位症相关的慢性盆腔疼痛的女性的内分泌反应进行分析，以确定慢性盆腔疼痛是否可能改变应激反应，并对子宫内膜异位症中观察到的慢性疼痛各个方面的相互关系进行研究。