Barbara Reed, MDNeuroimmunology/Cytokine Alterations In Vulvodynia (2000 – 2003)
Abstract: Hundreds of thousands of women in the United States suffer from vulvodynia a chronic burning vulvar pain of unknown cause. Millions of health care dollars are spent annually for this disorder in the United States alone, not only on management, but also on the large proportion of cases that are misdiagnosed and inadequately treated. This pain, associated with allodynia and hyperpathia, has a strong genetic predelection, with African-American women rarely being affected. The broad, long-term objectives of this proposal are to assess the differences in specific neuroimmunological characteristics between women with vulvodynia and asymptomatic controls. The specific aims include: evaluation of l) the individual cytokine/neurokine production response to stimulation of peripheral blood; 2) local changes in nerve fiber, mast cell, Substance P and serotonin density in vulvar tissue; 3) the interactions of the systemic and local immunologic systems assessed in l) and 2); and 4) the multivariable assessment of these laboratory factors with historical risk factors for vulvodynia to explore potential pathophysiologic mechanisms accounting for the historical risk factors identified. The research design involves a case-control evaluation of 100 women with vulvodynia, 100 controls matched for ethnicity, and 100 African-American control women, using questionnaires, physical examinations, clinical laboratory data, cytokine/neurokine levels in stimulated peripheral blood, and neuroimmunohistological assessment of vulvar biopsy specimens for nerve fiber density, mast cells, Substance P and serotonin. Results from this study will lead to improved understanding of neuroimmunologic alterations in women with vulvodynia which will direct future therapeutic strategies for this disorder.
Midcareer Vulvodynia Research and Mentoring Project (2003 – 2008)
Abstract: This application is in response to the K24 Midcareer Investigator Award in Patient-Oriented Research Program Announcement (PA-00-005), which is designed to provide support for clinicians for protected time to increase their expertise and activities in patient-oriented research and to serve as mentors for beginning clinical investigators. Barbara D. Reed, M.D., M.S.P.H. has developed a research career that focuses on gynecologic disorders of women, with an emphasis on neuroimmunological factors associated with vulvar dysesthesia (vulvodynia). This award would allow her to become increasingly involved with state-of-the-art immunological/neurological technology, to increase multicenter collaborations among vulvodynia researchers, and to further her investigations on the pathogenesis and epidemiology of vulvodynia. Mentoring is also a vital aspect of this award. The award will allow Dr. Reed to augment her own mentoring activities with more junior researchers, while simultaneously developing a program to improve the consistency and accountability of the mentoring of each of the junior investigators throughout her department. Dr. Reed is currently conducting a three-year NICHD-funded project on “Neuroimmunology/cytokine alterations in vulvodynia.” This patient-centered case control project assesses specific cytokine/neurokine responses to lymphocyte stimulation and their association with neurohistochemical changes found in vulvar tissue. Further studies on other aspects of the neuroimmune interactions that clarify differences among women with and without vulvodynia are at various stages of development, including assessing the relationship of cytokine production to local and peripheral psychophysical sensory responses of women with vulvodynia and controls, assessment of the immediate and delayed hypersensitivity reactions and cytokine correlates, evaluation of neuroimmunological changes following treatment, and the use of proteomics for immunological assessment of these women. Support from this award would allow further development, pursuit of funding, and implementation of these projects. Dr. Reed’s research experience, ongoing investigations, and mentoring experience provide the context for this expanded program of study, vulvodynia research, and personal and departmental mentoring.
Longitudinal Population-Based Study of Vulvodynia (2008 – 2013)
Abstract:Vulvodynia is a chronic, painful disorder of the vulvar region that affects 3-18 percent of women in the United States. Most research on this disease has been cross-sectional in design, and has focused on women referred to vulvodynia specialty clinics. Hence, little is known about the natural history of this disorder or the risk factors associated with its occurrence, persistence, or resolution in a general population. A number of genetic characteristics have been found to be associated with chronic pain syndromes in general [Catechol-O-Methyltransferase (COMT) and Nerve Growth Factor receptors (NGF-r)], and vulvodynia in particular [Interleukin-1 receptor antagonist (IL1RN) and melanocortin-1 receptor (MC1R)]. Similarly, hormonal exposures of women have been associated with the presence of vulvodynia and with pain sensitivity of the vulva, but results have been inconsistent. Assessment of genetic susceptibility in conjunction with hormonal factors, in order to assess gene-environment interaction, is imperative to further clarify the impact of these factors on the incidence, persistence, and remission of this morbid disorder. We hypothesize that an increased prevalence of one or more of the pain-associated genetic polymorphisms mentioned above will be present in women with vulvodynia, and that the risk of the onset, persistence, and remission of vulvodynia in these women will be influenced by previous and current exogenous hormone use, such as oral contraceptive and hormone therapy. Using a longitudinal prospective population-based study design, we propose to evaluate the prevalence, incidence, persistence, and remission rates of vulvodynia among a population-based, geographically defined group of 2500 women. Our specific aims are 1) to assess the prevalence, incidence, persistence, and remission rates of vulvodynia among these women, with clinical confirmation and DNA analysis in all women reporting current or past vulvodynia, in a representative subset of asymptomatic controls, and in all women reporting new or resolved vulvar symptoms during the study, and 2) to determine the association between pain-related genetic polymorphisms and exogenous hormone use, singly and in combination, with the incidence, persistence, and remission of vulvodynia via 2a) determining the prevalence of specific polymorphisms of candidate genes related to neuropathic pain (COMT, NGF-r, IL1RN, and MC1R) among these groups of women, 2b) assessing the associations between exogenous hormone use and the natural history of vulvodynia, and 2c) assessing gene-environment interactions between hormone exposure and genetic polymorphisms and their impact on the incidence, persistence, and remission of vulvodynia. Results from this study will substantially augment our understanding of the combined role of genetics and hormone exposure in the onset, maintenance, and remission of vulvodynia, facilitating future studies on pathophysiology, treatment, and prevention. PUBLIC HEALTH RELEVANCE: Results from this study will substantially augment our understanding of the combined role of genetics and hormone exposure in the onset, maintenance, and remission of vulvodynia, and will further direct our studies on pathophysiology, treatment, and prevention.
Characterization of Pain Processing in Vulvodynia (2005 – 2007)
Abstract: Vulvodynia is a chronic pain disorder, consisting of vulvar pain (burning, stabbing, irritation) for three months or longer, and lack of an infectious or dermatologic diagnosis consistent with the pain. The clinical characteristics of vulvodynia, and response to pharmacological therapy, are consistent with those of neuropathic pain. However, previous data from our group indicate increased sensitivity to pressure not only at the vulva, but also in the periphery (thumb, deltoid, and shin), suggesting that central mechanisms may be playing a role in women with vulvodynia. Further clarification of central and peripheral pain processing in women with and without vulvodynia has the potential to dramatically increase our understanding of this disorder, and will direct further study of pathophysiologic mechanisms and treatment options in vulvodynia.The specific aims of this study are: 1) to assess multi-modal sensory profiles at the vulva and in the periphery of 100 women with vulvodynia and 50 women without vulvar pain, and to use principal component and cluster analyses to identify novel subgroupings within the groups, and, 2) to further identify underlying mechanisms of vulvar pain in the established subgroupings by identifying, via fMRI, the qualitative and quantitative differences in location and character of supraspinal activity evoked by non-painful and painful sensory provocation at both vulvar and peripheral sites. We expect to find significant differences among the validated groups, and to then be able to use the known functional role of specific activated neural structures in the central nervous system to further refine hypotheses about the mechanisms that initiate and maintain painful vulvar disorders.Information from this research is anticipated to further define vulvodynia and its variants, to define subgroups based on underlying mechanisms, and to further our understanding of the pathophysiology of women with this disorder.
Sensory Sensitivity and Urinary Symptoms in the Female Population (2011 – 2013)
Abstract: Bladder pain and discomfort, as well as urinary urgency and frequency, are common and bothersome symptoms seen in the general population. Clinical diagnostic terms used to describe these symptoms include interstitial cystitis (IC), painful bladder syndrome (PBS), vulvodynia, chronic prostatitis, and overactive bladder (OAB), but there is tremendous overlap between these entities, and the distinction between them is based more on imminence than evidence. Pain and/or sensory sensitivity have been suspected to play a role in the pathogenesis of both bladder pain and urinary urgency/frequency. However, there has never been a study to determine whether entities such as IC/PBS, vulvodynia and OAB might merely represent different points in a continuum of bladder sensory sensitivity. Moreover, we know of no studies that have directly compared whether sensory sensitivity in the bladder is related to global (i.e. CNS-mediated) sensory sensitivity. In the proposed study, a team of investigators with complementary expertise will perform a population-based study assessing bladder and overall sensory sensitivity, in a cohort of women chosen to be representative of the general population with respect to the entire continuum of bladder pain (from none to severe), nonbladder pain (vulvodynia, irritable bowel symptoms, fibromyalgia) and symptoms of urgency/frequency. These individuals will undergo urodynamics to measure sensory sensitivity in the bladder, as well as pressure pain and auditory loudness thresholds. Our Specific Aims are to demonstrate that in the population, 1) sensory sensitivity in the bladder is related to sensory sensitivity elsewhere in the body, suggesting that this is a CNS-driven mechanism, and 2) those individuals in the population that have more pronounced global sensory sensitivity will display: a) more bladder pain, b) more urgency/frequency, and c) more other symptoms of centrally-mediated pain states, such as pain elsewhere, fatigue, and insomnia. We feel that these studies are crucial to better understand the relationship between sensory sensitivity and urinary symptoms, and to add to the evidence necessary to appropriately diagnose and treat these symptoms and individuals. PUBLIC HEALTH RELEVANCE: Pelvic symptoms such as pain and urgency are very common, and treatments are poorly effective. These studies will examine for clinical evidence of global pain hypersensitivity in these patients. If a global pain abnormality is identified, additional studies can be done to examine the etiology of these symptoms and design novel treatments that are focused on central, rather than peripheral pathophysiology.