Mechanistic Characterization of Uterine Pain

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 (\<15%) in this population. Participants with dysmenorrhea that rate their bowel pain, dyspareunia, or non-menstrual pelvic pain equal to or greater than 40 on 0-100 visual analog pain scale on the McGill Pain Questionnaire will be given the option to participate in an additional clinical exam visit. To reduce the likelihood of comorbid endometriosis, primary dysmenorrhea participants with symptoms of endometriosis described above, will be required to have a negative clinical exam and no immediate family history of endometriosis to qualify for final analyses.

Inclusion Criteria for Leiomyomata Group: The investigators will also study participants with leiomyomata (n=20) because it is a frequent cause of menstrual pain and will often be identified in disqualified primary dysmenorrhea participants. Leiomyomata (nondegenerated) will be diagnosed by foci homogeneously hypointense on T2, but isointense relative to myometrium on T1 according to standard definitions (Kubik-Huch et al., 2018). To reduce variability within this category, the investigators will restrict enrollment to small to medium sized intramural leiomyomata (30 to 150 cm3 combined volume). The investigators anticipate 10 participants with leiomyomata will be identified from incidental MRI during this study, while 10 more will be recruited from advertisements and our clinic. A smaller cohort is studied here because the main purpose of this group is to establish whether the physiological basis for menstrual pain in women with leiomyomata is significantly different than women with primary dysmenorrhea. Participants with leiomyomata, who are also symptomatic with surgically diagnosed endometriosis will be excluded.

Inclusion Criteria for Endometriosis Group: Participants without leiomyomata, but symptomatic for endometriosis (n=20) will be enrolled before planned surgical excision (follow-up surgery from an earlier diagnosis). The investigators will confirm a diagnosis of Stage 2, 3, or 4 endometriosis following surgery. For the patients without confirmed abnormal surgical findings for endometriosis with dysmenorrhea will be considered as primary dysmenorrhea cases. Dr. Tu's pelvic pain division performs over 100 laparoscopic pain evaluations annually (many with deep infiltrating disease) enabling us to characterize MRI signals in surgically confirmed endometriosis patients. A smaller cohort is studied here because the main purpose of this group is to establish whether the physiological basis for menstrual pain in women with endometriosis is significantly different than women with primary dysmenorrhea.

Inclusion Criteria for Healthy Controls: Healthy control cases (n=20) must rate their average menstrual pain \< =2/10 over that past 6 months (without NSAID use) and have no other concurrent pain diagnoses or leiomyomata. Their lack of concurrent pain diagnoses will be confirmed with questionnaires (NIH PROMIS scales, Rome Foundation IBS criteria (Palsson et al., 2016), AUA bladder pain syndrome criteria (Hanno et. al. 2012), and the Complex Medical Symptom Inventory (Williams and Schilling, 2009) and a medical exam screen. Healthy controls and participants with primary dysmenorrhea will be ratio-metrically age-matched with comparable pregnancy history to ensure similar demographics between groups.

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.

Menstruation-related exclusion criteria for all study participants: The investigators will exclude certain participants with conditions associated with the absence of regular menses such as polycystic ovarian syndrome, pregnancy, current use of any continuous hormonal medication or contraceptive, or Asherman's syndrome.

MRI-related or participation related exclusion criteria for all study participants:

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

Exclusion criteria for known factors that affect the interpretability of the data for all study participants:

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.

Note: these exclusion criteria may be incidentally discovered after the MRI scan and confirmed with a radiologist's or Dr. Tu's diagnosis.

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.