Immunological Factors and Risk of Vulvodynia

外阴疼痛(VVD)是一种在没有明显发现或临床可识别的神经疾病的情况下发生的使人虚弱的慢性外阴疼痛。在2000至2005年间，我们评估了外阴疼痛的患病率，并检查了与其基本未知的病因相关的因素(NIH-ROI-HD38428)。我们了解到，近16%的育龄妇女自我报告当前或过去的外阴疼痛病史持续&>3个月(估计每年有1400万美国妇女)，不到50%的人寻求治疗，很少有人得到足够的诊断，而西班牙裔妇女更有可能报告外阴疼痛。在病因方面，我们了解到，与对照组相比，VVD女性有a)更高的神经源性炎症标志物水平，b)在外阴疼痛症状之前更多的心理创伤和精神障碍，c)作用于免疫炎症反应(IIR)的更普遍的环境暴露史，以及d)她们阴道微生物区系特征的显著异常。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发生了变化。总之，这些发现表明，VVD是由于生殖、妇科、环境或心理暴露或生殖、妇科、环境或心理暴露而发生的IIR机制改变的结果，阴道微生物区系异常和基因多态是潜在的影响因素。为了验证这一病因学假设，我们建议从4家社区卫生诊所的行政数据库中筛选出大约24,000名女性的多种族样本，这些数据库与周围的普通人群非常相似。通过筛查程序，我们预计将确定325名患有VVD的女性，她们之前可能没有被诊断为市长。在临床确诊后，这些病例将与随机抽样的325名对照进行频率匹配。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的发病几率；2)心理创伤和精神疾病是否影响VVD的发病几率；3)免疫炎症和神经纤维增殖的标志物是否与VVD的发病几率直接相关，以及上述I和2中遗传和微生物标志物改变关联的程度。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，但该报告也表明，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。我们建议的研究是独一无二的，因为它使用了具有足够统计能力的流行病学方法来确认VVD风险女性(市长可能没有为她们的病情寻求护理)的不同样本中特定的先期风险因素，同时还测量了生物标记物和相关的心理过程，这些过程告知潜在的病因路径的可能性。我们还在我们的研究中内置了复杂的分析技术，以解决观察性病例对照研究中固有的偏见可能潜在影响我们的相关性的程度。在这项研究的头两年中，增加了三个重要的增强研究目标来实现。我们将确定：1)通过社区诊所管理数据库确定的女性的人口统计特征是否与从社区诊所周围普通人口中获得的人口普查数据相比较；2)从社区诊所管理数据库中获得的女性样本中外阴疼痛症状的患病率是否与通过波士顿大都会地区进行的真正的基于人口的评估而抽样的类似年龄女性的外阴疼痛症状患病率相似；以及3)在涉及外阴疼痛等耻辱性疾病的研究中，哪些因素导致女性选择或不选择参与。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辆登记目录，现在不再能够识别基于人口的受试者。它还将有助于确定哪些因素有助于成功地招募受试者，以便对妇女中极为普遍的污名化状况进行重要研究。

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.