Neural Immune and Genetic Influences on Chronic Pelvic Pain and Endometriosis

慢性盆腔疼痛显著影响多达10%的子宫内膜异位症妇女的健康（Stratton, Fertil Steril 2006;86: 1302）。我们最近发表了一项随机、前瞻性、安慰剂对照试验的结果，该试验使用雷洛昔芬（每日180mg）治疗慢性盆腔疼痛和子宫内膜异位症。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。

Chronic pelvic pain significantly affects the health of up to 10 percent of women with endometriosis (Stratton, Fertil Steril 2006;86: 1302). We have recently published the results of a randomized, prospective, placebo-controlled trial of raloxifene (180 mg daily) used by women with chronic pelvic pain and endometriosis. 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. 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%). In a second study, they 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. Stratton and her team of surgeons have continued to describe other causes of chronic pain in women with endometriosis, such as adenomyosis, appendiceal disease, or obdurator hernia. Of the women surveyed by the Endometriosis Association, 4,334 Endometriosis Association members reported surgically diagnosed endometriosis. In a subset of these women (1,160) reporting primarily having pelvic pain (95%), many women had tried 3+ medical treatments (46%) and had at least 3 surgical procedures (42%). Despite reporting various treatments as helpful, women used many different types and endured symptoms for an average of two decades, indicating the profound effect of endometriosis on womens health. 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. 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 a better experience 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. Sinaii and Stratton have also considered the relationship between disease severity and patient characteristics in endometriosis by analyzing questionnaires from 1,000 women in the Oxford Endometriosis Gene (OXEGENE) Study. Women were assigned to Group I (rAFS Stage I-II, n=423) or Group II (rAFS Stages III-IV, n=517). The most common symptoms leading to a diagnosis were dysmenorrhea and pelvic pain. Dyspareunia and depression were more common in Group I. In Group II, sub-fertility and an ovarian mass more commonly led to a diagnosis. Sub-fertility remained more common in Group II throughout reproductive life, but birth and miscarriage rates were similar. This study shows differences in characteristics of women with different stages of endometriosis, which may aid future clinical and epidemiological studies. Remarkably, the time to diagnosis was similar between women with different stages of disease. 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. In addition, women with chronic pelvic pain may also have other regional pain syndromes like migraine headaches. We have recently hypothesized that these two chronic, debilitating conditions might co-occur. In our preliminary review of patients enrolled in the clinical trial, at least two thirds of women with chronic pelvic pain have migraine headaches that appear to be independent of endometriosis diagnosis. We will examine whether quality-of-life is lowered, beyond that due to pelvic pain alone. If migraine headache is common in women with chronic pelvic pain, regardless of the presence of endometriosis, it may contribute to disability of those with both conditions and may suggest a common pathophysiology. In the coming year, we will continue examining aspects of the health of women with endometriosis by analyzing the Endometriosis Association Survey, continue efforts to define the pain outcomes in endometriosis clinical trials, and 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.