Despite the high prevalence of menstrual pain, the fundamental physiological explanation for dysmenorrhea remains unknown. A subset of these women suffering from dysmenorrhea do not respond to conventional treatments and are often forced to undergo explorative surgery. Additionally, they may be at further risk for developing life-long chronic pelvic pain disorders, resulting in significant disability associated with lost academic time and reduced productivity for working women. Without scientific tools to properly investigate the mechanisms of both normal and pathologic uterine physiology, diagnostic tests that could determine the use of targeted treatments are not attainable. A more salient model of the underlying mechanisms is urgently needed to guide drug application and discovery in dysmenorrhea. Our research program has focused on key knowledge gaps: increased myometrial activity and reduced tissue oxygen levels and their role in menstrual pain symptoms. Although these factors are commonly held as responsible for menstrual pain, confirmatory human data from validated noninvasive tests is missing. Drugs are known to reduce myometrial activity and improve uterine oxygenation, but mechanistic diagnostics to explain their efficacy are still needed, especially for NSAID non-responders. We have collaborated with established MRI investigators to study human uterine physiology in vivo using proven MRI methods to monitor changes in myometrial activity and oxygen levels. Our preliminary data provides compelling demonstration that progressive retrograde changes in myometrial signal intensity (i.e, symmetrically progressing from the cervix to fundus), correlates with menstrual pain and likely represents myometrial activity. Our preliminary data also confirms altered uterine oxygenation using non- invasive MRI, suggestive that we can identify the degree to which tissue hypoxia causes menstrual pain, and also phenotype patients most likely to respond to either pharmacological or surgical treatments. Our preliminary data supports the overall hypotheses that MRI methods can resolve the contribution of myometrial activity and oxygenation to menstrual pain. To verify these preliminary findings requires a larger cohort, which we propose to study with two aims:
Aim #1 : Demonstrate that MRI markers of uterine myometrial activity are specific for painful menstrual cramps. MRI of the uterus plus a contemporaneous self-reported menstrual pain index will evaluate dysmenorrhea patients and controls.
Aim #2 : Demonstrate that MRI markers of uterine blood oxygenation are specific for painful menstrual cramps. Groups in Aim 1 will be assessed using MRI techniques sensitive to oxygenation. The validation of these MRI methods and confirmation of physiological biomarkers for subgroups of dysmenorrhea could inform the design of treatment trials and ultimately provide an alternative to explorative surgery. Additionally, MRI methods used to characterize uterine physiology could be added to diagnostic dysmenorrhea algorithms or other complex and clinically significant idiopathic conditions, including up to 50% of preterm labor cases, a similar proportion of female infertility, and even cervical and uterine malignancies.

Public Health Relevance

By developing diagnostic to mechanistically treat dysmenorrhea this proposal addresses the NICHD goal that women suffer no harmful effects from reproductive processes and that all children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability, and to ensure the health, productivity, independence and wellbeing of all people.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD091502-02
Application #
9538215
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Tingen, Candace M
Project Start
2017-08-02
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northshore University Healthsystem
Department
Type
DUNS #
069490621
City
Evanston
State
IL
Country
United States
Zip Code
60201