The impact of hormonal modulation on systemic inflammation and central sensitization

抽象的。慢性盆腔疼痛仍然是一种具有挑战性的疾病，很大程度上是因为 人们对疾病的机制知之甚少。子宫内膜异位症相关性盆腔疼痛(EAPP)是一种常见的形式 疾病的严重程度仅与所经历的疼痛程度有微弱的关联。而当 盆腔炎是EAPP的一个公认的致病因素，我们认为低度全身炎症 炎症还通过促进中枢神经系统(CNS)敏感化而导致疾病状态。 来自我们小组和其他人的新证据表明，低级别的全身炎症可以促进 中枢神经系统敏化的多个方面，包括临床表现(合并疼痛情况，广泛存在 疼痛)、对实验刺激的高敏感性，以及骨盆疼痛的脑功能连通性改变。而当 激素抑制对许多女性是有效的，部分是通过抑制依赖雌激素的盆腔起作用。 炎症，对低度全身炎症和中枢神经系统的相对作用知之甚少。 对EAPP的敏化。我们建议使用FDA批准的促性腺激素释放激素受体 拮抗剂Elagolix，有两种剂量可用，作为一种机械探针，用于评估盆腔和 EAPP的全身性炎症。强健的剂量依赖效应对EAPP及其共生效应的影响 症状向我们表明，更高的剂量也会降低中枢神经系统的敏感度，这可能是由于减少了 全身炎症。为了研究这一假设，我们将进行一项双盲、安慰剂对照试验 随机临床试验，其中200名患有EAPP的妇女将被随机分配到低剂量(每天150 mg) 或大剂量(每天400毫克)伊拉格利克斯或安慰剂，评估疼痛机制前后的结果 治疗。我们将重点研究两种常见的患者表型--仅患有EAPP的患者和患有EAPP的患者 和广泛的痛苦(1：1招募)。在目标1中，我们将首先定义骨盆之间的关系 炎症、全身性炎症和中枢神经系统敏感化使用经过良好审查的神经生物学措施 中枢神经系统敏化。我们预计全身性炎症将与中枢神经系统敏化有关，而 盆腔炎就不会了。在目标2中，我们也将确定中枢神经系统敏化的剂量依赖性变化。 作为全身和盆腔炎期间激素抑制的EAPP通过上述 临床试验。我们预计这两种剂量都能改善盆腔炎，但全身炎症 高剂量的伊拉格里克斯可提高中枢神经系统的致敏作用。我们还预计，那些拥有 广泛的疼痛将更有可能对大剂量的伊拉格利思有反应。在探索性目标3中，我们将 确定盆腔和/或全身炎症活动的基线水平以及中枢神经系统的敏感度， 预测Elagolix的反应。这些研究对于开发疼痛的替代机制模型至关重要。 促进和缓解这一脆弱的患者群体，并将对理解荷尔蒙产生影响 慢性疼痛综合征以女性为主的贡献。

Abstract. Chronic pelvic pain remains a challenging condition to treat, in large part because underlying disease mechanisms are poorly understood. Endometriosis-associated pelvic pain (EAPP) is a common form of CPP wherein the severity of disease is only weakly associated with the degree of pain experienced. While pelvic inflammation is a well-established contributing factor to EAPP, we propose that low-grade systemic inflammation also contributes to the disease state by promoting central nervous system (CNS) sensitization. Emerging evidence from our group and others suggests that low-grade systemic inflammation can promote multiple aspects of CNS sensitization including clinical manifestations (comorbid pain conditions, widespread pain), hypersensitivity to experimental stimuli, and altered brain functional connectivity in pelvic pain. While hormonal suppression is effective for many women, and acts in part by dampening estradiol-dependent pelvic inflammation, little is known about the relative contributions of low-grade systemic inflammation and CNS sensitization to EAPP. We propose to use the FDA-approved, gonadotropin releasing hormone receptor antagonist, elagolix, available in two dosages, as a mechanistic probe to assess the effects of pelvic and systemic inflammation on EAPP. The presence of robust dose-dependent effects on EAPP and its comorbid symptoms suggests to us that the higher dose also reduces CNS sensitization, possibly due to reduced systemic inflammation. To investigate this hypothesis, we will conduct a double-blind, placebo controlled randomized clinical trial in which 200 women with EAPP will be randomly assigned to low-dose (150mg daily) or high-dose (400mg daily) elagolix or placebo with evaluation of pain mechanism outcomes prior to and after treatment. We will focus on two common patient phenotypes – those with EAPP only and those with EAPP and widespread pain (1:1 recruitment). In Aim 1, we will first define the relationship between pelvic inflammation, systemic inflammation, and CNS sensitization using well-vetted neurobiological measures of CNS sensitization. We anticipate that systemic inflammation will be associated with CNS sensitization, while pelvic inflammation will not be. In Aim 2, we will identify dose-dependent changes in CNS sensitization as well as systemic and pelvic inflammation during hormonal suppression for EAPP through the above-described clinical trial. We anticipate that both dosages will improve pelvic inflammation, but that systemic inflammation and CNS sensitization will be improved on high-dose elagolix. We furthermore anticipate that those with widespread pain will be more likely to respond to high-dose elagolix. In an exploratory Aim 3, we will determine if baseline levels of pelvic and/or systemic inflammatory activity, as well as CNS sensitization, predict the response to elagolix. These studies are critical to develop alternative mechanistic models of pain promotion and relief in this vulnerable group of patients and will have implications for understanding hormonal contributions to the female preponderance of chronic pain syndromes.