Patient case (clinical description): A 43-year-old woman, gravida 3 para 3, comes to the clinic complaining of recently painful menstrual cycles.  The patient's last menstrual period was 2 weeks ago. Urine β-hCG is negative. Menarche was at age 12, and menstrual periods occur every 28 days and lasts for 5 days.  She is sexually active with her husband and does not have pain with intercourse. BMI is 23 kg/m2 and Vital signs are normal.  On physical examination, the uterus is uniformly enlarged and tender. She is candidate for hysterectomy with the diagnosis of adenomyosis.

Patient's own account: I'm 43, and I paid a visit to my doctor because my last few periods were insanely painful. My last periods were 2 weeks ago. I already had three pregnancies that gave me the three lovely children. I did a urine test to check for potential pregnancy, and it came back negative. I started to have my periods at the age of 12, and I have been pretty regular with periods every 28 days for 5 days. I'm sexually active with my husband and I do not have any pain when we have sex. My BMI is 23 and my vitals were normal. The doctor performed a physical exam and found that my uterus was tender and enlarged. She proposed me a hysterectomy and diagnosed me with adenomyosis.

Clinical trial: Mechanistic Characterization of Uterine Pain

Eligibility criteria:
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.
Female
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 45 Years

Eligibility (NLI label): Contradiction