Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Nervous System Diseases

Neoplasm Metastasis

Leiomyoma

Myofibroma

Pain

Dysmenorrhea

Uterine Diseases

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Menstruation Disturbances

Pelvic Pain

Neurologic Manifestations

Neoplasms, Connective Tissue

Connective Tissue Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Naproxen

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

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.

Participants will receive placebo first in this arm.

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

Naproxen Sodium

Ellen Garrisn, BS RN

Kat Dillane, B.S.

Kevin Hellman, PhD.

Kevin M Hellman, PhD

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.

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.

Participants must have a uterus and must not be undergoing hormone therapy.

Mechanistic Characterization of Uterine Pain

Mechanistic Characterization of Uterine Pain (MCUP) to Improve Diagnosis and Treatment for Dysmenorrhea

The investigators will calculate the change in R2\*, ASL (arterial spin label), HASTE, and BOLD (Blood Oxygen Level Dependent) signal for each menstrual pain phenotype.

Principal component analysis of derived MRI signal variables and subsequent scree plotting will be used to reduce the dataset to 4-6 representative parameters that meaningfully separate potential phenotypes via hierarchical cluster analysis (R cluster library). Cluster dissimilarity metrics will be used to establish the probable number of phenotypes. Thus, our analyses are not entirely dependent on hypothesized phenotypes. A post-hoc ANOVA will be performed on relevant signal intensity variables to validate differences between the phenotypes. A post-hoc ANOVA will also be performed to compare whether there are differences in R2\*, ASL, HASTE, and BOLD signals between primary dysmenorrhea, endometriosis and leiomyoma participants.

Data will be processed similarly to Outcome #1. The investigators will use a repeated measures ANOVA and ANCOVA to examine changes in mean R2\*, ASL, HASTE, or EPI-BOLD signal intensity (4 dependent variables) after naproxen and/or placebo administration in all women with primary dysmenorrhea-regardless of cluster identity or phenotype. The investigators will also use an ANCOVA to examine whether the 4 MRI metrics of uterine physiology are related to changes in pain, using the difference of VAS (Visual Analog Scale) after naproxen minus the VAS before naproxen as a covariate. The investigators will detect for ANCOVA assumptions (e.g., homogeneity of variance, normality) and utilize appropriate corrections (transformation, permutation analysis) when needed.

The investigators will also use a paired X2 (McNemar) test to establish reliability of the repeat scans and examine differences in cluster/phenotype categorization across visits. The combined use of principal component analysis, hierarchical testing, and validation by a repeatability test follows recommended guidelines

Since participants with anatomical anomalies are provisionally excluded, the investigators will perform a sensitivity analysis by measuring the impact of provisional exclusion on linkage distance on clusters from Aim #1. Similarly, the impact of endometriosis and leiomyoma on cluster linkage distance will be calculated using recommended methods. Exploratory posthoc ANOVA/ANCOVAs will be performed within individual phenotypes/clusters identified in Aim #1 including endometriosis and leiomyoma to identify phenotypic-specific effects as a secondary analysis for Aim #2.

The investigators will calculate the correlation coefficient between NSAID resistance (defined as visual analog scale pain at 6 hours minus baseline pain) and age, parity, abuse (SPAQ score), anxiety (PROMIS Tscore), depression (PROMIS T-score), central pain sensitization (pain pressure thresholds). To accommodate differences in dimensionality we will use a combination of spearman, pearson, kendalls regression methods.

The investigators will calculate the correlation coefficient between NSAID resistance (defined as visual analog scale pain at 6 hours minus baseline pain) and absorbed serum Naproxen (90 minutes).

National Institutes of Health (NIH)

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

NorthShore University HealthSystem

Research Associate Professor

Gland and Hormone Related Diseases

Syndrome

Polycystic Ovary Syndrome

Endometriosis

Neoplastic Processes

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Gonadal Disorders

Endocrine System Diseases

Patients in the intervention group will first undergo 3 months of regular care and then 3 months of biweekly yoga classes. Participants will complete surveys at baseline, 3 months (after of control care), 6 months (after 3 months of biweekly yoga classes), and 12 months (after 6 months of observation and optional yoga practice).

The study lasts 12 months for the intervention and 9 months for the control group with an optional 3 month yoga therapy session offered at the end

Iyengar Yoga Therapy

Gwen Derk, PhD

The purpose of this clinical trial is to look at the effectiveness of prescribing yoga classes to patients with dysmenorrhea (irregular or painful periods), or other menstrual disorders on patients' self reported pain and quality of life.

Patients will be recruited from primary care clinics around Illinois, including Carle Hospital. This is a randomized trial in which patients will first be randomized into the control or intervention group. Patients in the control group will undergo usual care and be surveyed at baseline, 3 months, 6 months and 9 months. Patients in the control group will be offered the 3 months of yoga therapy complimentary after completing the 9 month control. Control patients who choose to participate in the yoga therapy will be asked to also complete the surveys at the end of the 3 month yoga intervention. Patients in the intervention group will first undergo 3 months of regular care and then 3 months of biweekly yoga classes. Participants will complete surveys at baseline, 3 months (after of control care), 6 months (after 3 months of biweekly yoga classes), 9 months, and 12 months (after 6 months of observation and optional yoga practice).

Participants will contact the research team with the information on the flyer. Participants will be asked to come to the Iyengar Yoga Center (407 W Springfield Ave, Urbana, IL 61801) to receive more information. Participants will need to disclose their diagnosis to the research staff. If they are not aware of what their diagnosis is, they will need to contact their physician to get their official diagnosis. For example, a woman with dysmenorrhea may be diagnosed with poly cystic ovarian disease or endometriosis or idiopathic dysmenorrhea, or another reproductive disease; participants will need to know their specific diagnosis or find out their specific diagnosis and report it to the research staff. Participants can do this by calling their physicians. For participants that are unaware of their diagnosis, they may also request a copy of their medical records. These records may be shared with the research staff to help determine diagnosis. The research staff will not keep these medical records, but return them to the participants. Participants can then either consent on the first visit or choose to take time as much time as they need and return to the yoga center when they are ready to sign the consent form. Participants will complete the first round of surveys at the yoga center after they sign the consent form (20 minutes). Participants will receive an email or phone call from the study team to inform them of their randomization results.

A blind third party statistician will complete the randomization for all participants at the beginning of the study for all 90 participants and will email the study coordinator with the randomization results. Randomization will be done through a free online software called graphpad. (https://www.graphpad.com/quickcalcs/randomize1.cfm).

The study lasts 12 months for the intervention and 9 months for the control group with an optional 3 month yoga therapy session offered at the end: Once consented, participants will fill out baseline surveys, and then undergo 3 months of usual care (no intervention), the same baseline surveys will be filled out again, then participants will get biweekly free yoga therapy classes for 3 months, and surveys will again be completed at the end of the intervention. Patients will then have a 6 month follow up and will fill out the surveys one last time. Recruitment will occur on a rolling basis so patients may join the study at anytime and not have to wait for a batched group.

Must menstruate or be of menstruating age

Iyengar Yoga Therapy for Dysmenorrhea and Endometriosis

Iyengar Yoga for Treatment of Endometriosis and Secondary Dysmenorrhea: A Randomized Controlled Clinical Trial

This survey is a 4 question short form. The PROMIS(r) Pain Interference instruments (adult and child) measure the self-reported consequences of pain on relevant aspects of a person's life and may include the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities.

This survey is a 3 question short form. The PROMIS Pain Intensity instrument assesses how much a person hurts.

This survey is a 4 question short form. The PROMIS Fatigue instruments evaluate a range of self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles.

This survey is a 4 question short form. Physical Function measures self-reported capability rather than actual performance of physical activities. This includes the functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, such as running errands.

This survey is a 7 question short form. The PROMIS Global Health measures assess an individual's physical, mental, and social health.

This survey is a 10 question survey about participants home yoga practice.

The Menstrual Distress Questionnaire (MDQ) is a standard method for measuring cyclical perimenstrual symptoms. It is used to help clinicians and researchers make systematic, empirical evaluations of a woman's symptoms, of treatments, and of etiological theories.

The MDQ is a 46-item self-report inventory for use in the assessment and treatment of premenstrual and menstrual symptoms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Mechanistic Characterization of Uterine Pain	NCT04145518	Dysmenorrhea (D... Dysmenorrhea Pr... Dysmenorrhea Se... Endometrial Dis... Leiomyoma Fibroid Uterus	Naproxen Sodium	18 Years - 45 Years	NorthShore University HealthSystem
Iyengar Yoga Therapy for Dysmenorrhea and Endometriosis	NCT03784976	Secondary Dysme... Dysmenorrhea Dysmenorrhea Se... Polycystic Ovar... Endometriosis Fibroid Menstrual Pain Menstrual Disor... Menstrual Disco...	Iyengar Yoga Th...	12 Years - 65 Years	University of Illinois at Urbana-Champaign

Spots Global Cancer Trial Database for dysmenorrhea secondary