Epidemiological studies show high comorbidity between dysmenorrhea and chronic pelvic pain (CPP) disorders such as painful bladder syndrome (PBS). Hormonal suppression of dysmenorrhea using oral contraceptives (OCs) is widely used to treat these conditions, but with variable results; their influence on the mechanisms involved in pelvic nociception remains unclear. Our long-term goal is to develop prevention strategies and effective treatments for CPP. Many female CPP conditions appear linked to repetitive menstrual-induced uterine inflammation and result in pain sensitization of adjacent pelvic organs, or cross organ sensitization (COS). The objective of this proposal is to identify the menstrually-mediated nociceptive, hormonal and psychological mechanisms responsible for COS of the bladder. In turn, we will explore which of these pathways underlie a reduction in experimental bladder pain following administration of OCs. Mechanistically, it is believed chronic pain involves impairments in descending inhibition, the brainstem pathway responsible for inhibiting spinal pain receptors. Clinically, this dysfunction is accompanied by widespread changes in pain sensitivity. We recently identified that women with moderate to severe dysmenorrhea exhibit widespread mechanical pain sensitivity and as well as vulnerability to bladder sensitization. In contrast with existing CPP patients, dysmenorrhea patients are ideal to study COS because of less confounding by anxiety or depression. However, dysmenorrhea patients with silent bladder pain (the D+COS phenotype) on experimental testing also have a key feature of PBS, prolonged pain following mechanical vaginal provocation, suggesting they harbor a high risk of developing chronic pain. Our preliminary data show OC usage is associated with less bladder pain, supporting the idea that hormonal suppression of menstrual pain improves nociceptive mechanisms underlying COS. Therefore, we will test the hypothesis that repeated episodes of menstrual pain reduce descending inhibition and increase vulnerability to COS, while continuous OC administration will reverse this deficit, through two aims.
Aim #1 : To determine if women with dysmenorrhea and concomitant bladder pain sensitivity exhibit neurophysiological features consistent with established CPP. Dysmenorrhea sufferers with and without COS and PBS patients will be compared with controls on experimental pain sensitivity tests, which measure descending inhibition and pelvic and bladder sensitivity.
Aim #2 : To differentiate the individual contributions of circulating sex hormones and repeated sensitizing events (painful menstrual periods) on descending and peripheral mechanisms of bladder pain with a trial of cyclic and continuous OCs. This innovative approach explores a unique pre-clinical phenotype with a battery of novel sensory assessments. This proposal is significant because determining the mechanisms underlying menstrual-mediated COS and their relative hormonal responsiveness is critical to improve CPP treatment. Developing a strategy to reduce early signs of bladder pain has the potential to prevent CPP.

Public Health Relevance

This proposal addresses the NIDDK's mission to advance treatment of urologic diseases that seriously affect public health through examining mechanisms and therapeutics in bladder pain, the most common form of chronic benign urologic pain with poorly understood antecedents. Advancing understanding of the therapeutic mechanisms for preventing and reducing bladder pain through hormonal treatments is essential to improve treatments for millions of American women.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Bavendam, Tamara G
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Northshore University Healthsystem
United States
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Oladosu, Folabomi A; Tu, Frank F; Hellman, Kevin M (2018) Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. Am J Obstet Gynecol 218:390-400
Hellman, Kevin M; Datta, Avisek; Steiner, Nicole D et al. (2018) Identification of experimental bladder sensitivity among dysmenorrhea sufferers. Am J Obstet Gynecol 219:84.e1-84.e8
Zuckerman, Rebecca M; Silton, Rebecca L; Tu, Frank F et al. (2018) Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain. Arch Womens Ment Health 21:533-541
Kutch, Jason J; Tu, Frank F (2016) Altered brain connectivity in dysmenorrhea: pain modulation and the motor cortex. Pain 157:5-6