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.

抽象。慢性盆腔疼痛仍然是一个具有挑战性的条件治疗，在很大程度上是因为潜在的 疾病机制知之甚少。子宫内膜异位症相关盆腔疼痛（EAPP）是一种常见的形式， 其中疾病的严重程度与所经历的疼痛程度仅弱相关。而 盆腔炎是EAPP的一个公认的促发因素，我们建议， 炎症还通过促进中枢神经系统（CNS）致敏而促成疾病状态。 来自我们小组和其他人的新证据表明，低度全身性炎症可以促进 中枢神经系统致敏的多个方面，包括临床表现（共病疼痛状况，广泛 疼痛），对实验刺激的超敏反应，以及骨盆疼痛中脑功能连接的改变。而 激素抑制对许多女性有效，部分作用是通过抑制雌二醇依赖性盆腔炎。 炎症，很少有人知道低度全身性炎症和中枢神经系统炎症的相对贡献 宣传EAPP。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，可在两个剂量，作为一种机制探针，以评估骨盆和 EAPP全身炎症。对EAPP及其共病存在稳健的剂量依赖性效应 症状向我们表明，较高剂量也可降低CNS致敏性，可能是由于降低了 全身性炎症为了研究这一假设，我们将进行一项双盲、安慰剂对照的研究。 一项随机临床试验，其中200名EAPP女性将被随机分配到低剂量组（每日150 mg） 或高剂量（每日400 mg）elagolix或安慰剂，在治疗前后评价疼痛机制结局 治疗我们将重点关注两种常见的患者表型-仅EAPP和EAPP 和广泛疼痛（1：1招募）。在目标1中，我们将首先定义骨盆与 炎症、全身性炎症和CNS致敏，使用经过充分审查的神经生物学指标， 中枢神经系统致敏。我们预期全身性炎症将与CNS致敏相关， 盆腔炎不会。在目标2中，我们还将确定CNS致敏的剂量依赖性变化 如通过上述方法对EAPP进行激素抑制期间的全身性和盆腔炎 临床试验我们预计，这两种剂量将改善盆腔炎，但全身炎症， 高剂量elagolix可改善CNS致敏性。我们还预计， 大剂量elagolix更可能对广泛的疼痛产生反应。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CNS致敏， 预测对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 促进和缓解这一弱势群体的患者，并将有影响的理解激素 女性在慢性疼痛综合征中占优势。