DETERMINED TO PREVENT AND REVERSE THE CAUSES OF PELVIC PAIN,
Why are girls still missing so many days because of their menstrual cycle?”
-Michelle Obama tweeting on barriers to girl’s education in 2016
As highlighted by the former First Lady, a hidden, personal, and painful reality of many women is severe, gut-wrenching menstrual cramps occurring every 3-5 minutes for several days each month. This misery is a leading cause of missed school and work. These cramps are hallmarks of dysmenorrhea and are not sufficiently relieved by nonsteroidal anti-inflammatories (NSAIDs) in roughly 15% of reproductive age women. My analysis of over 1000 adult women found that the severity of dysmenorrhea along with self-report of sensory sensitivity predict nearly 75% of the participants who experience high levels of overall pelvic pain. Thus, developing effective treatments for menstrual pain is imperative to reducing gender disparity and chronic pelvic pain.
However, scientific demonstration of the mechanisms responsible for menstrual pain remains limited by in vitro methods, irrelevant models, or failure to use precise methods to assess contractility, perfusion, oxygenation, and pain. Therefore, to address this limitation, we developed novel methods for clarifying the mechanisms responsible for menstrual cramps.
CINE MRI DURING SPONTANEOUS CRAMPS IN WOMEN WITH MENSTRUAL PAIN
We developed novel MRI and pain testing methods for clarifying pathophysiological mechanisms responsible for dysmenorrhea in humans. I recognized a key gap in the dysmenorrhea research field was a lack of attention to the temporal relationship between myometrial activity and pain. Improving on these study design limitations was a key focus, as spontaneous cramps are the primary phenomenon reported by dysmenorrhea sufferers. Discerning the temporal relationship between the perception of pain and uterine physiological changes is also essential for establishing causality. To clarify whether myometrial contractile-induced ischemia is responsible for cramping symptoms, I developed a real-time method for monitoring spontaneous pain with fMRI. In this paradigm, participants were instructed to squeeze a bulb every time they felt a severe menstrual cramp. Simultaneously, acquired pelvic MRI signals demonstrated that decreases in myometrial signal occurred either coincident with pain report or 30-70 seconds before. The location and directionality of signal change and its temporal relationship to pain onset lead me to hypothesize that cramping pain results from a combination of uterine pressure and hemodynamic dysfunction. My study is unique in demonstrating the underlying physiology in an internal pelvic organ, time-locked to the report of spontaneous pain. Thus, as a new technical method it holds promise as a technique for identifying the cause of pelvic pain and other visceral pain disorders that are amenable to fMRI interrogation.
ABDOMINAL SKELETAL MUSCLE ACTIVITY PRECEDES SPONTANEOUS MENSTRUAL CRAMPING PAIN IN PRIMARY DYSMENORRHEA.
We developed a method of studying spontaneous cramping to identify neurological mechanisms responsible for referred pelvic pain, which could allow for clinical phenotyping of dysmenorrhea. By evaluating the relationship between abdominal muscle activity and spontaneous pain, I was able to provide evidence linking distinct abdominal muscle activity to reported spontaneous cramps in primary dysmenorrhea. In contrast, women with chronic pelvic pain were less likely to have abdominal muscle activity preceding cramping pain, had widespread mechanical hypersensitivity and responded poorly to naproxen. The phenotyping methods described in this manuscript provide a strategy for characterizing nociceptive mechanisms in cyclical uterine pain and may ultimately predict treatment responsiveness
THE ASSOCIATION OF DYSMENORRHEA WITH NONCYCLIC PELVIC PAIN ACCOUNTING FOR PSYCHOLOGICAL FACTORS
Our analysis of over 1000 adult women found that the severity of dysmenorrhea along with self-report of sensory sensitivity predict nearly 75% of the participants who experience high levels of overall pelvic pain (odds ratio 13). Depression and anxiety may be secondary effects.
THE EFFECTS OF PLATELET-ACTIVATING FACTOR ON UTERINE CONTRACTILITY, PERFUSION, HYPOXIA, AND PAIN IN MICE
I developed an in vivo mouse model to clarify the pathophysiological mechanisms responsible for dysmenorrhea and to allow for the testing of new therapeutics. My model allowed us to characterize the effects of candidate molecules while simultaneously using novel optical methods to monitor uterine perfusion and oxygenation. Our model demonstrated that prostaglandin and Platelet Activating Factor (PAF) could directly elicit visceral pain and pelvic hyperalgesia via uterine hypercontractility and uterine ischemia. These results challenged the dogma that uterine ischemia never occurs. Furthermore, since PAF is not inhibited by NSAIDS it represents a new potential druggable target for NSAID-resistant dysmenorrhea. This animal model provided the fundamental conceptual foundation for the mechanisms (inflammation, contractility and ischemic pain) underlying menstrual pain that I subsequently tested in humans as described above.
IDENTIFICATION OF EXPERIMENTAL BLADDER SENSITIVITY AMONG DYSMENORRHEA SUFFERERS
Since treatments for chronic pelvic pain have low efficacy, it is critical to develop prevention methods. A first step would be to identify at-risk women for prevention trials. The prior use of invasive visceral tasks (such as colorectal distension) had greatly limited research because it deterred participation and was vulnerable to fear-related factors. Therefore, we developed a noninvasive task in which women are asked to promote diuresis by drinking water, followed by structured measurement of their level of bladder pain as their bladder fills, with serial monitoring of this process with ultrasonography. Together, we performed additional experiments, and I performed the necessary analyses for validation of these findings to confirm my hypothesis that women with dysmenorrhea are more likely to have bladder sensitivity. We have confirmed our original novel finding that a subset of women with severe dysmenorrhea (~25%) have significant bladder pain (even off menses) without having any symptomatology resembling chronic pelvic pain. We have also validated our task and shown that it is less confounded by psychological factors than even questionnaire methods. The development and validation of this bladder task has led to its use as a tool for identifying preventable factors responsible for the transition from episodic menstrual pain to chronic pelvic pain. This task serves as the foundation for our NIH-funded chronic pelvic pain prevention program.