Mechanistic Characterization of Uterine Pain

NCT ID: NCT04145518

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 183 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-25
• Study Completion Date: 2025-07-23

Brief Summary

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.

Detailed Description

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. The investigators 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, the investigators 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, The investigators 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.

Conditions

Dysmenorrhea (Disorder); Dysmenorrhea Primary; Dysmenorrhea Secondary; Endometrial Diseases; Leiomyoma; Fibroid Uterus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: QUADRUPLE

Study Groups

Naproxen/Placebo Crossover

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill. Randomization with a block size only known by the statistician, will be programmed to be allocated out of REDcap.

Our clinical research pharmacy will provide naproxen and an identical looking placebo in containers with codes only known to the statistician to provide a double-blinded experimental design.

On a subsequent episode of menstrual pain (1-2 months later), participants will receive the opposite treatment and undergo the exact same assessments.

Group Type: ACTIVE_COMPARATOR

Naproxen Sodium

Intervention Type: DRUG

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill.

Placebo/Naproxen Crossover

Participants will receive placebo first in this arm.

Group Type: PLACEBO_COMPARATOR

Naproxen Sodium

Intervention Type: DRUG

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill.

Interventions

Naproxen Sodium

Participants will be randomized to take either a placebo pill or a single 550 mg naproxen sodium pill.

Intervention Type: DRUG

Other Intervention Names

Placebo

Eligibility Criteria

Exclusion Criteria

Age restrictions for all study participants: Regularly menstruating women (age 18-45) will be identified using our well-tested community-wide recruitment strategy, including approaching our division's busy gynecological disorders clinic, and the departments of Ob/Gyn at NorthShore and the University of Chicago. Although women above the age of 45 can have menstrual pain, irregularities in perimenopause could cause confounding effects on uterine physiology and scheduling difficulty. Similarly, irregularities in menstruation, ovulation, and pain levels in participants under age 18 could potentially detract from meaningful interpretation of phenotypes (Seidman et al., 2018). Additionally, before age 18, the uterus is still developing and substantially increasing in size (Porcu et al., 1989; Verguts et al., 2013). Thus, to limit potential confounding effects, participants under the age of 18 will be investigated in a separate study.

The investigators will exclude participants with criteria that would affect our ability to obtaining meaningful MRI data such as

1. presence of an intrauterine device (IUD). The use of an IUD potentially affects interpretability of MRI because it creates an imaging artifact in the endometrium extending to the myometrium.

2. inability to read or comprehend the informed consent written in English,

3. history of metallic implants,

4. history of metallic injury,

5. any diagnosed condition that would preclude investigation with MRI (e.g., claustrophobia),

6. BMI >40,

7. allergy or inability to tolerate naproxen

1. thyroid dysfunction,

2. adrenal dysfunction,

3. renal disorders,

4. liver disorders,

5. coagulopathy,

6. prolactinoma,

7. von Willebrand disease,

8. platelet disorders,

9. diabetic neuropathy,

10. gastrointestinal conditions or surgeries that would affect naproxen absorption,

11. active genitourinary or sexually transmitted infection

Provisional exclusion for primary analyses for all study participants: Acute or chronic conditions associated with pelvic pain with a defined anatomical cause other than endometriosis or leiomyoma (e.g., pathological ovarian cysts, significant persistent hydro/hematosalpinx, untreated pelvic inflammatory disease, active pelvic or abdominal malignancies, Mullerian anomalies, or stage 3 uterine prolapse), and comorbid diagnosis of significant leiomyoma and endometriosis.

Provisional exclusion for adenomyosis group: Because the frequency of adenomyosis is low or unknown, and may consist of multiple subtypes resulting in heterogeneity and inadequate statistical power, adenomyosis patients are not a planned study group and diagnosed cases will be initially excluded from recruitment. Focal and diffuse adenomyosis will be excluded by guidelines (Chapron et al., 2017) adapted from the Kishi criteria (Kishi et al., 2012): maximal junctional zone thickness exceeding 12 mm, a ratio of junctional zone thickness to myometrium exceeding 40%, or high-intensity foci within the myometrium. If a substantial number of adenomyosis participants participate, as discovered after-the-fact with MRI, results will be analyzed.

Intermediate levels of dysmenorrhea pain exclusion: Participants with mild menstrual pain (between 3 and 5 on a 0-10 scale) will be excluded. Our prior experience with this cohort (Westling et al., 2013) suggests that The investigators may encounter a floor effect when studying the effectiveness of NSAIDs. Also, since this cohort is most likely to respond to NSAIDs, it is imperative The investigators study the mechanisms of the most severe sufferers of refractory menstrual pain.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Endeavor Health

OTHER

Sponsor Role: lead

Responsible Party

Kevin Hellman

Research Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kevin M Hellman, PhD

Role: PRINCIPAL_INVESTIGATOR

Endeavor Health

Locations

NorthShore University HealthSystem

Evanston, Illinois, United States

Countries

United States

Other Identifiers

R01HD098193-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

EH19-040

Identifier Type: -

Identifier Source: org_study_id