Immunological Factors and Risk of Vulvodynia

外阴痛（VVD）是一种在没有明显表现或临床可识别的神经系统疾病的情况下发生的使人衰弱的慢性外阴疼痛。在2000年至2005年间，我们估计了外阴痛的患病率，并检查了与其大部分未知病因相关的因素（NIH-ROI-HD38428）。我们了解到，近16%的育龄妇女自我报告目前或过去的外阴疼痛病史，持续50 - 3个月（估计每年有1400万美国妇女），不到50%的人寻求治疗，很少有人得到充分的诊断，西班牙裔妇女更有可能报告外阴疼痛。关于病因学，我们了解到，与对照组相比，患有VVD的女性有a)更高水平的神经源性炎症标志物，b)在外阴疼痛症状之前有更多的心理创伤和精神疾病，c)影响免疫炎症反应（IIR）的环境暴露史更普遍，d)阴道微生物群特征明显异常。此外，最近的研究表明，患有VVD的女性可能在调节细胞因子表达的基因上有改变。总的来说，这些发现表明VVD是由于生殖、妇科、环境或心理暴露导致IIR机制改变的结果，阴道微生物群异常和遗传多态性是潜在的改变因素。为了验证这一病原学假设，我们建议从4个社区卫生诊所的管理数据库中筛选约24,000名多种族女性样本，这些样本与周围的普通人群非常相似。通过筛查程序，我们期望确定325名以前可能没有诊断过的VVD妇女。在临床确诊后，这些病例将与325个随机抽样的对照组进行频率匹配。数据收集和分析将确定1)生殖、妇科和环境暴露是否影响vvd的几率，2)心理创伤和精神疾病是否影响vvd的几率，3)免疫炎症和神经纤维增殖标志物是否与vvd的几率直接相关，以及遗传和微生物标志物在多大程度上改变了上述1和2中的关联。最近的一份国会报告指出，需要新的教育举措来提高人们对VVD的认识，但该报告也指出，实施改进的治疗和预防策略的能力取决于我们对VVD病因学的理解。我们提出的研究的独特之处在于，它使用了具有足够统计能力的流行病学方法，在具有vvd风险的不同女性样本中确认了特定的先前风险因素（这些女性可能没有为自己的病情寻求过治疗），同时还测量了生物标记物和相关的心理过程，这些生物标记物和相关的心理过程告知了潜在病因途径的合理性。我们还在研究中引入了复杂的分析技术，以解决观察性病例对照研究中固有的偏差在多大程度上可能影响我们的关联。在本研究的前两年，增加了三个重要的增强研究目标。我们将确定I)通过基于社区诊所的行政数据库确定的妇女的人口统计学特征是否与从社区诊所周围的一般人群中提取的人口普查数据相比较；2)来自社区诊所管理数据库（包括参保和未参保对象）的女性样本外阴疼痛症状的患病率是否与在波士顿大都会区进行的真正基于人群的评估取样的类似年龄女性的患病率相当；3)哪些因素导致女性选择或不选择参与涉及污名化条件（如外阴痛）的研究。这些增强的研究目标对所有参与以人口为基础的研究的科学家产生了巨大的影响，这些研究以前使用的方法，如随机数字拨号和机动车登记目录，现在已不再适用于确定以人口为基础的研究对象。它还将有助于确定哪些因素有助于成功招募受试者进行对妇女中可能极其普遍的污名化状况的重要研究。

Vulvodynia (VVD) is debilitating chronic vulvar pain that occurs in the absence of visible findings or clinically identifiable neurological disease. Between 2000 and 2005, we estimated the prevalence ofvulvodynia and examined factors associated with its largely unknown etiology (NIH-ROI-HD38428). We learned that nearly 16% of reproductive aged women self-report current or past history of vulvar pain lasting >3 months (an estimated 14 million U.S. women annually), less than 50% seek treatment, few receive an adequate diagnosis, and Hispanic women are more likely to report vulvar pain. Regarding etiology, we learned that women with VVD compared to controls have a) higher levels of neurogenic inflammation markers, b) more psychological trauma and psychiatric morbidity antecedent to vulvar pain symptoms, c) a more prevalent history of environmental exposures that act on immuno-inflammatory response (IIR), and d) significant abnormalities in the characteristics of their vaginal microflora. Furthermore, recent studies have suggested that women with VVD may have an alteration in genes that regulate cytokine expression. Collectively, these findings suggest that VVD is the result oran altered IIR mechanism that occurs as a consequence orreproductive, gynecologic, environmental, or psychological exposures, with abnormal vaginal microflora and genetic polymorphisms as potential modifiers o[the effects o{interest. To test this etiological hypothesis we propose to screen a multiracial sample of approximately 24,000 women from the administrative databases of 4 community health clinics that closely resembles the surrounding general population. Through screening procedures, we expect to identify 325 women with VVD who mayor may not have been previously diagnosed. After clinicalconfirmation, these cases will be frequency-matched to 325 randomly-sampled controls. Data collection and analyses will determine I) whether reproductive, gynecological and environmental exposures influence the odds ofVVD, 2) whether psychological trauma and psychiatric morbidity influence the odds ofVVD, and 3) whether markers of immuno-inflammation and nerve fiber proliferation are directly associated with the odds ofVVD, and the extent to which genetic and microbiological markers modify associations in I and 2 above. A recent congressional report has cited the need for new educational initiatives to create more awareness of VVD, but the repolt also indicates that the ability to implement improved treatment and prevention strategies hinges on our understanding ofVVD etiology. Our proposed study is unique in that it uses an epidemiological approach with adequate statistical power to confirm specific antecedent risk factors among a diverse sample of women at risk ofVVD (who mayor may not have sought care for their condition), while also measuring biological markers and related psychological processes that inform the plausibility of potential etiological pathways. We have also built into our study sophisticated analytical techniques to address the extent to which biases inherent in observational case-control studies could potentially influence our associations. Three important enhanced research goals have been added to be accomplished during the first 2 years of this study. We will determine I) whether demographic characteristics of women identified through community clinic-based administrative databases are comparable to that of census data drawn from the general population surrounding the community clinic, 2) whether the prevalence of vulvar pain symptoms in a sample of women derived from community clinic-based administrative databases that includes insured and uninsured subjects is comparable to that of similarly aged women sampled through a true population-based assessment done in the Boston Metropolitan Area, and 3) what factors contribute toward women choosing to or not choosing to palticipate in studies that involved stigmatizing conditions such as vulvodynia. These enhanced research aims have enormous impact on all scientists involved in population-based studies that previously used approaches such as random digit dialing and motor vehicle registration directories that are now no long viable for identifying population-based subjects. It will also help determine what factors contribute toward successful recruitment of subjects for important studies of stigmatizing conditions which can be extremely prevalent among women.