Mechanistic Characterization of Uterine Pain

There are limited treatment options for management of dysmenorrhea, and the physiological processes they affect are not completely understood. For example, NSAIDs are effective in reducing menstrual pain in some women by inhibition of prostaglandin synthesis, but whether those effects are mediated by affecting contractility, perfusion, or hypoxemia is unknown. Understanding how these drugs relieve menstrual pain (and why they fail) would be of substantial clinical significance. Given the foregoing, Two Specific Aims are proposed: Aim #1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI scans of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. The investigators will include cohorts of women with imaging diagnosed leiomyoma and surgically-confirmed endometriosis to evaluate the contribution of structurally identifiable factors. Based on preliminary data, the investigators anticipate finding four phenotypes with menstrual pain related to: 1) myometrial activity, 2) inadequate perfusion and/or oxygenation, 3) a combination of phenotypes 1 \& 2, and 4) a non-uterine source. Aim #2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. In women with primary dysmenorrhea, the investigators will acquire pelvic MRI scans and evaluate self-reported menstrual cramping pain before and after administration of randomized naproxen or placebo. Naproxen could principally affect one or more potential sources of uterine pain such as myometrial activity, perfusion, and/or oxygenation. The investigators will corroborate preliminary data findings, which suggest menstrual phenotypes with myometrial activity will be more likely to respond. Conversely, Aim 2 will also elucidate the mechanisms responsible for inadequate pain relief from naproxen. Bioavailability of naproxen levels and other molecules associated with NSAID-resistance will be evaluated from the serum of participants after taking naproxen using HPLC-MS.

Inclusion Criteria: Inclusion Criteria for Primary Dysmenorrhea Group: All cases (n=70) will have pain in the region between the umbilicus and the perineum, above the level of the inguinal ligament, and rate their average pain greater than or equal to 6/10 (0 = no pain; 10 = worst imaginable pain) during menses when not using NSAIDs. The investigators will use strict inclusion criteria and verification with structural MRI to ensure patients with primary dysmenorrhea most likely do not have endometriosis, leiomyoma, or adenomyosis as described below. It is not possible to reliably evaluate superficial endometriosis with MRI (Nisenblat et al., 2016), but suspicious cases for deep infiltrating endometriosis will be confirmed by the radiologists who routinely evaluate MRIs for our gynecological surgical service. Although it is impossible to rule out endometriosis without surgery, in select cases The investigators will use clinical exams and criteria supported by decision trees (Eskenazi et al., 2001; Chapron et al., 2005, 2011; Vercellini et al., 2007) that suggest the detection of endometriosis stage 2 or higher would be unlikely (\