The impact of hormonal modulation on systemic inflammation and central sensitization

激素调节对全身炎症和中枢敏化的影响

• 批准号: 10584701
• 负责人: Sawsan As-Sanie
• 金额: $ 66.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584701
• 关键词: Affect; Aftercare; Analgesics; Attenuated; Biology; Brain; Central Nervous System; Clinical; Clinical Trials; Complex; Data; Disease; Disease model; Dose; Double-Blind Method; Economics; Estradiol; Estrogens; Evaluation; FDA approved; Fatigue; Female; Functional Magnetic Resonance Imaging; Gonadotropin-Releasing Hormone Receptor; Gynecologic; Hormonal; Hormones; Hypersensitivity; Hysterectomy; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Irritable Bowel Syndrome; Lesion; Measures; Mediating; Medical; Migraine; Neurobiology; Outcome; Pain; Pathway interactions; Patients; Pelvic Pain; Pelvis; Peripheral; Pharmaceutical Preparations; Phenotype; Placebos; Positioning Attribute; Randomized; Reproductive Biology; Research Personnel; Risk Factors; Severities; Severity of illness; Stimulus; Symptoms; Syndrome; Testing; Treatment outcome; United States; Vulnerable Populations; Woman; Work; antagonist; associated symptom; central sensitization; chronic pain; chronic pelvic pain; clinical phenotype; clinical practice; comorbidity; cost; dosage; endometriosis; experience; improved; neurobiological mechanism; pain model; pain relief; predicting response; randomized placebo-controlled clinical trial; randomized, clinical trials; recruit; response; systemic inflammatory response; treatment effect; treatment strategy

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.

摘要：慢性盆腔疼痛仍然是一种具有挑战性的疾病，很大程度上是因为其潜在的原因。 子宫内膜异位症相关盆腔疼痛（EAPP）是一种常见的疾病机制，但人们对此知之甚少。 对于 CPP，疾病的严重程度与所经历的疼痛程度只有微弱的相关性。 盆腔炎症是 EAPP 的一个公认的促成因素，我们认为低度全身性炎症 炎症还通过促进中枢神经系统（CNS）致敏而导致疾病状态。 我们小组和其他人的新证据表明，低度全身炎症可以促进 中枢神经系统致敏的多个方面，包括临床表现（共病疼痛、广泛 疼痛）、对实验刺激的过敏以及骨盆疼痛时大脑功能连接的改变。 荷尔蒙抑制对许多女性来说是有效的，部分是通过抑制雌二醇依赖性盆腔来发挥作用的。 炎症，但对于低度全身炎症和中枢神经系统的相对贡献知之甚少 我们建议使用 FDA 批准的促性腺激素释放激素受体。 拮抗剂恶拉戈利，有两种剂量，作为评估骨盆和骨盆影响的机制探针 EAPP 的全身性炎症对 EAPP 及其共病存在强烈的剂量依赖性影响。 症状向我们表明，较高的剂量也会降低中枢神经系统的敏感性，这可能是由于减少了 为了研究这一假设，我们将进行双盲、安慰剂对照的研究。 随机临床试验，其中 200 名患有 EAPP 的女性将被随机分配接受低剂量（每天 150 毫克） 或高剂量（每天 400 毫克）恶拉戈利或安慰剂，并评估治疗前后的疼痛机制结果 我们将重点关注两种常见的患者表型——仅患有 EAPP 的患者和患有 EAPP 的患者。 和广泛的疼痛（1:1 复张） 在目标 1 中，我们将首先定义骨盆之间的关系。 使用经过严格审查的神经生物学措施来评估炎症、全身炎症和中枢神经系统敏化 我们预计全身炎症与中枢神经系统致敏有关，而 在目标 2 中，我们还将确定中枢神经系统敏化的剂量依赖性变化。 作为 EAPP 激素抑制过程中的全身性和盆腔炎症，通过上述方法 我们预计这两种剂量都会改善盆腔炎症，但会改善全身炎症。 我们还预计，高剂量恶拉戈利的中枢神经系统敏感性将得到改善。 在探索性目标 3 中，我们将更有可能对大剂量恶拉戈利产生反应。 确定盆腔和/或全身炎症活动以及中枢神经系统敏化的基线水平， 预测对恶拉戈利的反应对于开发替代性疼痛机制模型至关重要。 对这一弱势患者群体的缓解和促进，将对了解荷尔蒙产生影响 慢性疼痛综合征女性占多数的原因。