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.
