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

子宫疼痛 (M-CUP) 的机制表征可改善痛经的诊断和治疗

• 批准号: 10011893
• 负责人: Kevin Hellman
• 金额: $ 60万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011893
• 关键词: Address; Affect; Age; Algorithms; Anaerobic Bacteria; Anti-Inflammatory Agents; Biological Availability; Blood; Categories; Child; Contrast Media; Crossover Design; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dysmenorrhea; Ensure; Event; Failure; Foundations; Generations; Goals; Health; High Pressure Liquid Chromatography; Hypoxemia; Image; Imaging Techniques; Impairment; Ischemia; Knowledge; Leiomyoma; Link; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Menstruation; Methods; Modality; Muscle Cramp; Myometrial; Naproxen; National Institute of Child Health and Human Development; Operative Surgical Procedures; Pain; Pain Disorder; Participant; Pathology; Patient Self-Report; Patients; Pelvis; Perfusion; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Physiological Processes; Physiology; Placebo Control Effect; Placebos; Plant Roots; Premature Labor; Productivity; Prostaglandin Inhibition; Quality of life; Randomized; Reporting; Reproductive Process; Research; Resistance; Respiration; Risk; Risk Factors; Serum; Source; Spectrum Analysis; Structure; Testing; Therapeutic; Time; Translations; Uterine Contraction; Uterine Diseases; Uterine Monitoring; Uterus; Woman; absorption; base; chronic pelvic pain; clinically significant; cohort; conventional therapy; disability; drug candidate; drug discovery; endometriosis; experience; human data; idiopathic infertility; improved; myometrium; non-invasive imaging; pain perception; pain relief; personalized medicine; prevent; programs; reproductive; response; spontaneous pain; targeted treatment; tissue oxygenation; tool; treatment strategy; uterine contractility; uterus endometriosis

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.

由于缺乏无创工具来研究子宫生理学，痛经的根本原因