Mechanistic Characterization of Uterine Pain (M-CUP) to improve diagnosis and treatment for dysmenorrhea

由于缺乏研究子宫生理的非侵入性工具，月经痉挛疼痛的根本原因 在原发痛经和继发性痛经(子宫肌瘤、子宫内膜异位症、子宫腺肌症)中仍然存在 未知。在15%的女性中，这种疼痛对典型的非处方药消炎药没有反应，是一种 导致慢性盆腔疼痛障碍的主要危险因素。为了指导药物发现 并创造个性化的治疗方法，至关重要的是揭示其潜在机制 痛经。我们的研究计划侧重于我们在子宫生理学知识方面的关键空白，如 子宫收缩、血液灌流和氧合对月经疼痛的影响。尽管这些 这种令人衰弱的疼痛障碍与各种因素有很大的关联，仍然需要确凿的人类数据。是这样的 研究将是非常及时的，因为许多候选药物已经瞄准了这些潜在的机制 是存在的。我们的协作团队开发了基于MRI的工具，以非侵入性和动态测量 子宫收缩、血流灌注、相对组织氧合，以及无氧呼吸的代谢物。 我们还首创了将自发疼痛报告与同时发生的子宫事件联系起来的方法。一起， 这些方法将使我们能够评估收缩、灌流或低氧血症对月经的影响。 疼痛。值得注意的是，我们的初步数据支持了我们的中心假设，即月经疼痛与 不同的表型，包括子宫肌层收缩过度，子宫血流灌注受损，子宫低氧血症，或 非子宫来源。自从了解了当前的抗炎药物是如何缓解或预防疼痛 (以及它们失败的原因)对于改进治疗策略的开发是有价值的，我们还将进行调查 萘普生对月经痛妇女子宫生理的影响。来检验我们的假设 子宫肌肉活动、灌流和氧合改变对疼痛的贡献，我们建议：目标1： 确定与子宫肌层活动受损相关的月经疼痛表型， 灌流和/或充氧。子宫的连续MRI序列将在 同时测量健康女性和经痛患者的自我报告疼痛。一个 还将分析患有子宫肌瘤和子宫内膜异位症的女性队列，以评估 具有结构可识别条件的妇女的子宫肌层活动、灌流和氧合。目标2： 评估萘普生对子宫肌层活性、灌流和/或氧合的影响 止痛药。初步数据显示，未解决的子宫肌层活动和萘普生吸收不足 与疼痛缓解不足有关。评价萘普生对子宫生理学的依赖作用 为诊断测试提供基础，为失败的患者提供相关的个性化治疗 常规治疗。这些研究的进一步翻译可能会促进在其他领域的发现机制 慢性盆腔疼痛和子宫疾病，如特发性早产和原因不明的不孕症。

Due to a lack of noninvasive tools to study uterine physiology, the root causes of menstrual cramping pain within primary dysmenorrhea and secondary dysmenorrhea (leiomyoma, endometriosis, adenomyosis) remain unknown. This pain does not respond to typical over-the-counter anti-inflammatories in 15% of women and is a leading risk factor for developing challenging chronic pelvic pain disorders. In order to guide drug discoveries and create personalized treatment approaches, it is essential to unveil the underlying mechanisms of dysmenorrhea. Our research program has focused on key gaps in our knowledge of uterine physiology, such as the contributions of uterine contractions, perfusion, and oxygenation to menstrual pain. Although these factors are strongly implicated in this debilitating pain disorder, confirmatory human data is still needed. Such research would be quite timely, as numerous drug candidates targeting these potential mechanisms already exist. Our collaborative team has developed MRI-based tools to noninvasively and dynamically measure uterine contractions, perfusion, relative tissue oxygenation, and metabolites indicative of anaerobic respiration. We have also pioneered methods that link spontaneous pain report to simultaneous uterine events. Together, these methods will allow us to evaluate the contribution of contractility, perfusion, or hypoxemia to menstrual pain. Notably, our preliminary data supports our central hypothesis that menstrual pain is associated with different phenotypes involving myometrial hypercontractility, impaired uterine perfusion, uterine hypoxemia, or a non-uterine source. Since understanding how current anti-inflammatory medications relieve or prevent pain (and why they fail) is valuable for the development of improved treatment strategies, we will also investigate the effects of naproxen on uterine physiology in women with menstrual pain. To test our hypothesized contributions of altered uterine muscle activity, perfusion, and oxygenation on pain, we propose: Aim 1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI sequences of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. A cohort of women with leiomyoma and endometriosis will also be analyzed to evaluate the contribution of myometrial activity, perfusion, and oxygenation in women with structurally identifiable conditions. Aim 2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. Preliminary data suggests unresolved myometrial activity and inadequate naproxen absorption are associated with insufficient pain relief. Evaluating the naproxen-dependent effects of uterine physiology will provide a foundation for diagnostic tests to indicate relevant personalized treatment for patients that have failed conventional treatments. Further translation of these studies could advance mechanisms for discovery in other chronic pelvic pain conditions and uterine disorders such as idiopathic preterm labor and unexplained infertility.