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

由于缺乏非侵入性工具来研究子宫生理，月经痉挛疼痛的根本原因 在原发性痛经和继发性痛经（平滑肌瘤，子宫内膜异位症，子宫腺肌病）仍然存在 未知15%的女性对典型的非处方抗炎药没有反应， 导致慢性盆腔疼痛疾病的主要危险因素。为了指导药物发现 并创造个性化的治疗方法，这是至关重要的揭示的潜在机制， 痛经。我们的研究项目集中在我们对子宫生理学的知识中的关键空白，例如 子宫收缩、灌注和氧合对月经痛的作用。虽然这些 尽管这些因素强烈地牵涉到这种使人衰弱的疼痛障碍，但仍然需要证实的人类数据。等 研究将是非常及时的，因为许多针对这些潜在机制的候选药物已经 存在.我们的合作团队开发了基于MRI的工具，可以无创地动态测量 子宫收缩、灌注、相对组织氧合和指示无氧呼吸的代谢物。 我们还开创了将自发性疼痛报告与同时发生的子宫事件联系起来的方法。在一起， 这些方法将使我们能够评估收缩力、灌注或低氧血症对月经的影响。 痛苦值得注意的是，我们的初步数据支持我们的中心假设，即月经疼痛与 不同的表型，包括子宫肌层收缩过度、子宫灌注受损、子宫低氧血症，或 非子宫来源由于了解目前的抗炎药物如何缓解或预防疼痛 (and他们失败的原因）对于改进治疗策略的发展是有价值的，我们还将研究 萘普生对痛经妇女子宫生理的影响。为了验证我们的假设 改变子宫肌肉活动、灌注和氧合对疼痛的贡献，我们提出：目的1： 表征与子宫肌层活动受损相关的月经痛表型， 灌注和/或氧合。将进行子宫的连续MRI序列， 同时测量健康女性和经历月经疼痛的女性自我报告的疼痛。一 还将分析一组患有平滑肌瘤和子宫内膜异位症的妇女， 子宫肌层活性、灌注和氧合。目标二： 评价萘普生对子宫肌层活动、灌注和/或氧合的影响， 缓解疼痛。初步数据表明，未解决的子宫肌层活动和吸收不足， 与疼痛缓解不足有关。评估萘普生对子宫生理学的依赖性影响将 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以推进其他领域的发现机制。 慢性盆腔疼痛和子宫疾病，如特发性早产和不明原因的不孕症。

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.