Immunological Factors and Risk of Vulvodynia

外阴疼痛（VVD）是一种使人衰弱的慢性外阴疼痛，发生在没有可见的发现或临床可识别的神经系统疾病。在2000年至2005年期间，我们估计了外阴痛的患病率，并检查了与其主要未知病因相关的因素（NIH-ROI-HD 38428）。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史持续>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，VVD女性具有a）更高水平的神经源性炎症标志物，B）更多的心理创伤和外阴疼痛症状前的精神病发病率，c）作用于免疫炎症反应（IIR）的环境暴露史更普遍，d）阴道微生物菌群特征显著异常。此外，最近的研究表明，女性VVD可能有一个基因的改变，调节细胞因子的表达。总的来说，这些研究结果表明，VVD是由于生殖、妇科、环境或心理暴露而发生的IIR机制改变的结果，异常的阴道微生物区系和遗传多态性是潜在的影响因素。为了检验这一病因学假设，我们建议筛选一个多种族的样本，约24,000名妇女从行政数据库的4个社区卫生诊所，非常类似于周围的一般人群。通过筛查程序，我们预计将确定325名患有VVD的妇女，这些妇女以前可能没有被诊断出来。临床确认后，这些病例将与325例随机抽样的对照组进行频率匹配。数据收集和分析将确定I）生殖、妇科和环境暴露是否影响VVD的几率，2）心理创伤和精神病发病率是否影响VVD的几率，和3）免疫炎症和神经纤维增殖的标志物是否与VVD的几率直接相关，以及遗传和微生物标志物改变上述I和2中的关联的程度。最近的一份国会报告指出，需要新的教育计划来提高对VVD的认识，但报告也指出，实施改进的治疗和预防策略的能力取决于我们对VVD病因的理解。我们提出的研究是独特的，因为它使用了一种流行病学方法，具有足够的统计能力，以确认特定的前因风险因素之间的不同样本的妇女在风险ofVVD（谁市长可能没有寻求照顾他们的条件），同时也测量生物标志物和相关的心理过程，告知潜在的病因途径的可行性。我们还将复杂的分析技术融入我们的研究中，以解决观察性病例对照研究中固有的偏倚可能影响我们的关联的程度。在本研究的前2年，增加了三个重要的增强研究目标。我们将确定I）通过社区诊所行政数据库确定的妇女人口统计学特征是否与社区诊所周围一般人口的普查数据具有可比性，2）是否在来自社区诊所的妇女样本中外阴疼痛症状的患病率-包括投保和未投保受试者的基于行政数据库的数据与通过真实人口抽样的年龄相仿的妇女的数据相当，在波士顿大都会区进行的基于评估，以及3）在涉及外阴痛等污名化疾病的研究中，哪些因素有助于女性选择或不选择palticipate。这些增强的研究目标对所有参与基于人口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，现在不再适用于识别基于人口的主题。它还将有助于确定哪些因素有助于成功招募受试者，以进行关于在妇女中极为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.