Grants made through NVA’s Medical Research Fund provide scientists with the opportunity to gather vital pilot data, which they need to secure funding from larger institutions, such as the National Institutes of Health (NIH). Many of our grant recipients have been successful in obtaining multi-million grants from the NIH and other institutions. (To view summaries of NIH-funded studies, click here.) To date, the NVA has awarded over $1 million in research grants. Announcements of funding availability are disseminated by e-mail twice a year. To sign-up for these announcements and/or to obtain an application, please e-mail Michelle Living.
Studies funded through NVA’s Medical Research Fund are summarized below.
Caroline Pukall, PhD-Queen’s University
Caroline Pukall, PhD, a professor and director in the department of psychology and school of rehabilitation therapy, at Queen’s University, was awarded an NVA research grant on spinal cord imaging of women with provoked vestibulodynia (PVD). This study will be cross-sectional and will include a total of 40 participants between the ages of 18 and 30: 20 women with PVD and 20 control women. The main reason for the narrow age range stipulated for this study is due to the novel nature of this initial study; they want to ensure that any changes they find between groups will not be due to age or menopausal status.
Participation in the study will include the following: 1) screening interview over the telephone to assess eligibility; 2) gynecological examination to confirm eligibility; 3) interview/questionnaires and quantitative sensory testing (QST) session; and 4) imaging session. The level of imaging focus in this paradigm will be the cervical cord and brainstem, and not on the whole brain, as is typical for neuroimaging protocols in the vulvodynia literature. The reason for this unique focus is that 1) we know very little about cervical cord and brainstem
function in women with PVD, and 2) we have an existing pain imaging database of these regions in patients with a variety of pain conditions (e.g., fibromyalgia) with which to compare the data obtained from the proposed study—allowing comparisons of neural responses among women with PVD, women
without PVD, and women with other pain conditions.
Elke Jarboe, MD-University of Utah
Elke Jarboe, MD, an assistant professor of pathology and obstetrics and gynecology, at the University of Utah, was awarded an NVA research grant on genetic and immunohistochemical analysis of primary and secondary vestibulodynia. Her group has recently presented the first familiality analysis to test for a heritable contribution to this disease. Employing the Utah Population Database (UPDB), which is a resource linking clinical diagnoses to large genealogy-based family pedigrees, the results support the hypothesis that women treated by vestibulectomy likely have a genetic predisposition. The question now is whether primary and secondary vestibulodynia share the same genetic predisposition.
They propose to use the UPDB to specifically test the relative risk in first-, second-, and third-degree relatives of women specifically diagnosed with either primary or secondary vestibulodynia. They have identified 308 vestibulectomy cases at the University of Utah classified into these two diagnostic subtypes that can now be investigated in the UPDB.
Nina Bohm-Starke, MD, PhD – Karolinska Institutet Danderyd Hospital
Nina Bohm-Starke, MD, PhD, an assistant professor at Karolinska Institutet Danderyd Hospital, was awarded an NVA research grant to evaluate the efficacy and safety of botulinum Toxin A (BTA) as treatment for provoked vestibulodynia (PVD). Recent evidence supports the importance of a pelvic floor muscle (PFM) dysfunction to the etiology of PVD. Women with PVD have been shown to have elevated resting activity, lower maximal strength and poorer control of the PFM compared to healthy controls. The treatment guidelines for PVD recommend a multi-modal treatment including topical anesthetic agents, cognitive behavioral therapy and PFM rehabilitation based on physiotherapy. Injections with BTA in the bulbocavernous muscles bilaterally have been suggested as a second line treatment. Previously published reports on the effects of BTA for PVD are few and the methods of injection (injection sites, use or non-use of an EMG needle for directing injection sites, and doses used (20, 35, 100 IU)) differ as well as methods of measuring treatment results. BTA is starting to be used for PVD in various clinical settings, but the treatments vary and require further evaluation before becoming a regular treatment option for PVD. The aim of this study is to investigate treatment outcomes of BTA injections in the bulbocavernous muscles in women with PVD. The primary outcome is reduction of pelvic floor tension using a vaginal manometer. Secondary outcomes are reduction of dyspareunia (painful sex), safety aspects, duration of BTA effect, quality of life and psychosexual evaluation. The researchers will recruit 140 patients and the study will be a double-blind, randomized and placebo-controlled trial. Patients will be given either a BTA 50 IU or saline injection in the bulbocavernous muscles bilaterally (on both sides) twice; at base-line and at three months. Follow-ups will be in between treatments and at six and 12 months after the first treatment. A diary for reporting side-effects, sexual activity and the result of the at-home tampon test will be completed.
Candace S. Brown, MSN, PharmD – University of Tennessee Health Science Center
Candace S. Brown, MSN, PharmD, a professor at the University of Tennessee Health Science Center in the Departments of Clinical Pharmacy and Psychiatry, was awarded an NVA research award to develop a protocol template for multicenter clinical trials of vulvodynia treatments. Protocol templates serve as the framework for the development of clinical research and have been developed by many institutes at the NIH for use in clinical trials and observational studies. The development of a vulvodynia protocol template, patterned after those developed by NIH institutes, would improve the quality and fundability of NICHD-sponsored clinical research in vulvodynia. A working group of leaders in the field will develop the protocol template, determine core elements, and identify appropriate funding mechanisms. These efforts will lay the framework for a large, multicenter grant and an NIH-sponsored vulvodynia workshop. By increasing the amount of NIH-funded research through the development of a comprehensive template, the etiology and management of vulvodynia will become better defined.
Terry K. Morgan, MD, PhD – Oregon Health & Science University
Terry Morgan, MD, PhD, a pathologist at Oregon Health Sciences University, was awarded an NVA research grant titled, Heritability and Proteomic Pathway Analysis of Vestibulodynia. Prior research, including Morgan’s, has shown that inflammation and nerve growth (neurogenic inflammation) are involved in the pathophysiology of vestibulodynia (aka provoked localized vulvodynia, or PLV). Although PLV is not currently considered to be a genetic disease, Dr. Morgan hypothesizes there is a genetic predisposition that can be tested using the Utah Population Database (UPDB). The UPDB takes advantage of large Mormon families with documented genealogies linked to their diagnostic codes. It has been employed in a number of studies to determine whether a disease runs in families (familiality), by comparing the frequency of the diagnosis in related versus non-related women. If PLV is familial, it will be more common among blood relatives of women with confirmed disease. The goal will be to identify distantly related affected women for subsequent NIH-funded whole genome sequencing and “shared haplotype analysis,” which is a proven method to identify key candidate genes that cause common diseases.
Dr. Morgan will also screen fresh frozen vestibular biopsies for expression differences that may be involved in inflammation and nerve growth. For this pilot experiment, Dr. Morgan will use pooled samples from each diagnostic group: case-control matched samples from negative controls (n=12), primary PLV (n=6), and secondary PLV (n=6). He will use protein expression analysis (proteomics) to test for differences in key regulators like the JAK-STAT pathway that is known to play a role in neurogenic inflammation. Analysis of pooled samples from multiple women within each of the three diagnostic groups will washout natural differences between individuals and amplify shared molecular pathways. It improves the signal:noise result without candidate gene selection bias. Future studies will compare expression levels in individuals within and between groups to validate reproducible differences. The hope is to provide more objective tests to better diagnose PLV and to develop more effective patient-based treatments.
Andrea Nackley, PhD and Denniz Zolnoun, MD – University of North Carolina
Vestibulodynia (VBD) represents a significant healthcare problem that is ineffectively treated due to its unclear etiology and heterogeneous clinical presentation. To reduce the complexity of VBD and improve standards of care, the identification of unique biological signatures and pathways that map onto distinguishing clinical features is required. Emerging evidence implicates that microRNAs, non-coding molecules that regulate gene expression, control molecular pathways linked to pain, mood, and inflammation. Yet little is known about their role in chronic pain conditions such as VBD. In a recent case-control study, the investigators evaluated the relationship between pain, psychological traits, inflammatory cytokines and microRNAs in women with VBD alone and those with VBD and chronic overlapping pain conditions (COPCs). Women with VBD had localized pain, normal self-reported pain and psychological profiles, and increased levels of anti- as well as pro-inflammatory cytokines. Those with VBD+COPCs had pain at remote bodily sites, enhanced self-reported pain and somatization, and no compensatory increase in anti-inflammatory cytokines. Women with VBD and VBD+COPCs displayed a dysregulation of 10 and 11 microRNAs, respectively, that were correlated with pain-relevant phenotypes and cytokine levels. These results suggest microRNAs represent a valuable tool for differentiating VBD subtypes (localized pain with apparent peripheral neurosensory disruption versus widespread pain with a central sensory contribution) that may require different treatment approaches.
Investigators will perform in silico pathway analysis to generate a list of predicted targets for the 21 microRNAs dysregulated in women with VBD and VBD+COPCs. Next, they will measure expression levels of the proteins corresponding to the predicted targets in banked blood samples from VBD, VBD+COPCs, and controls using custom protein microarrays. Finally, protein expression levels will be correlated with previously collected data on case status, intermediate phenotypes, and patient-reported outcomes. Results from the proposed aims will inform the design of a larger population-based study to determine the utility of microRNAs and microRNA targets as screening tools for diagnosis and treatment of VBD subtypes.
Valerie Dernetz, RN – University of Maryland School of Nursing
As with other chronic pain conditions, vulvodynia may involve a complex interaction of physiological and other factors. In recent years, studies have indicated that underlying mechanisms and treatment response vary among clinical presentations of vulvodynia. Thus, the purpose of this study is to investigate neurological differences between women with vulvodynia and controls. We will focus on how these mechanisms differ in women with distinct disease onset, specifically primary versus secondary vulvodynia. In primary vulvodynia, pain is experienced since the first sexual intercourse attempt, and in secondary vulvodynia, symptoms begin after a period of pain-free intercourse. The first aim of the study is to assess neurosensory processing using a comprehensive battery of sensory testing in 20 women with primary vulvodynia, 20 women with secondary vulvodynia, and 20 age- and race-matched controls. The second aim of this study is to assess psychological factors that appear to be associated with other chronic pain syndromes and determine whether they are more prevalent in primary versus secondary vulvodynia patients. Specifically, we will investigate cognitions such as (i) fear of pain and (ii) catastrophizing, i.e., negative cognitive-affective responses to anticipated or actual pain. If a difference exists, targeted treatment strategies may be developed for each subtype.
Terry K. Morgan, MD, PhD and Catherine M. Leclair, MD – Oregon Health & Science University
The cause of provoked localized vulvodynia (PLV) is unknown. It has been shown by using vestibular tissue biopsies, however, that affected women have significantly more nerve branches and chronic inflammation than unaffected women. This so-called “neurogenic inflammation” is known to be painful, especially when touched. The objective of this study is to understand why there is neurogenic inflammation in PLV patients. Drs. Leclair and Morgan will complete a prospective matched case-control analysis of fresh vestibular biopsies from at least 10 women with primary PLV (i.e., always had PLV), 10 women with secondary PLV (i.e., symptoms usually start postpartum or after menopause), and 10-20 matched unaffected controls. The researchers hypothesize that PLV may be triggered by an infection, allergy, or autoimmune process. Their group has recently shown that the CD4 type of lymphocytes (certain white blood cells that help the body fight disease) that mediates the reaction to these triggers is more common in vestibular biopsies from women with PLV. CD4 cells may be further subtyped into Th1, Th2, and Th17 using molecular labeling of the lymphocytes and flow cytometric analysis. To further test for CD4 subtype polarization in vestibular biopsies, expression analysis of markers including γIFN (Th1), IL-4 (Th2), and IL-17 (Th17) will be used in this study. If PLV has an infectious trigger, either past or current, the researchers anticipate Th1 dominance. If it is an allergic trigger, Th2 cells should predominate; and, if PLV has an underlying autoimmune etiology, Th17 cells will be more common. The results will lead to a better understanding of the role of CD4 lymphocytes in PLV and may provide a new method for individualized diagnoses and targeted therapies.
Lee Hullender Rubin, DAOM, LAc, FABORM – Oregon College of Oriental Medicine
Provoked, localized vulvodynia (PLV) is a poorly understood and treated female sexual pain disorder 1,2 for which there is limited evidence on acupuncture’s effectiveness. They aim to investigate the feasibility and acceptability of adjuvant acupuncture to lidocaine as a treatment for PLV pain. This study will determine acceptability, feasibility of acupuncture and lidocaine therapy, and estimate effect size to prepare for a larger randomized, controlled trial. Thirty subjects with PLV, as diagnosed by physicians in the OHSU Program for Vulvar Health, will be recruited and randomized into two arms. Fifteen subjects will be allocated to the classical acupuncture and lidocaine 5% cream group and fifteen to the non-classical acupuncture and lidocaine 5% cream group. The duration of treatment for both arms is twelve weeks. The primary outcome measure is pain reduction assessed by the Tampon Test. Their secondary goals are to assess pain reduction assessed by the cotton swab test, patient satisfaction, and changes as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires on global health, vaginal discomfort, pain intensity, sexual function, anxiety, depression, pain behavior and interference, and patient characteristics of the Traditional Chinese Medicine (TCM) diagnosis. They expect acupuncture will be feasible and acceptable to PLV patients and significantly decrease pain and improve quality of life. This study will generate the preliminary evidence required to estimate the effect size for an adequately powered efficacy study
Devavani Chatterjea, PhD – Macalester College
Epidemiological evidence points to a history of seasonal allergies as a risk factor for vulvodynia. Clinical studies indicate that mast cells are potentially critical mediators of vulvodynia in conjunction with observed hyper innervation in the vestibular tissue of patients. Mast cell-mediated mechanisms underlying skin allergies have been extensively studied in rodent models using exposures to chemical allergens such as oxazolone. They have successfully established a model of both acute and lasting vulvar mechanical pain in response to one or three challenges with oxazolone in the labiar skin of female mice that have been previously exposed to oxazolone. They also found that oxazolone-induced vulvar pain is accompanied by persistent hyper innervation of the labiar tissue. Here they propose to characterize nerve mast cell connections in the hyper innervated tissue by identifying key molecular players that maintain these connections and regulate the contributions of both nerves and mast cells to pain pathways. Vulvodynia is a complex syndrome with likely a diversity of causes underlying different sub-types. Two of many challenges faced in vulvodynia are 1) lack of biomarkers to indicate which subtype of vulvodynia a patient may be experiencing and 2) lack of specific, targeted therapies that may be most efficacious for specific sub-types of vulvar pain. Through these studies, they aim to identify biomarkers and therapeutic targets that can be used to develop better classification, management and treatment strategies for patients suffering from allergy-associate vulvodynia.
Gerard Ahern, PhD – Georgetown University
Vulvar pain disorders are common and often undiagnosed. A major impediment to better treatment is our poor understanding of “pain” (nociceptive) nerves and receptors in the vulva/vagina. The goal of this project is two- fold. First, they plan to precisely map nociceptive nerves that project to the vulva and distal vagina. They will exploit mice engineered to selectively express a fluorescent, tomato reporter in pain nerves. The exceptionally bright tomato fluorescence will allow them to directly image these nerves in the vulva/vagina to monitor how the localization and density of these nerves change under pathological conditions. Second they aim to measure expression of two pivotal pain receptors, TRPV1 and TRPA1, in the vulva/vagina. These proteins are key pain detectors found throughout the body, but they are yet to be characterized in the vulva/vagina. They will use mice engineered to selectively label TRPV1 and TRPA1 to readily visualize their localization in neuronal and non- neuronal tissue. As there is evidence that ovarian hormones are a potential contributing factor to vulvar pain they propose to study both reproductive aged mice and mice at several time points post-ovariectomy to determine changes associated with ovarian hormone deprivation. The results will reveal fundamental knowledge regarding nociceptive signaling pathways in the vulva/vagina needed to expand our understanding of unexplained vulvar pain.
Steven Witkin, PhD- Weill Cornell Medical College
The mechanisms leading to allodynia and hyperalgesia in women with vestibulodynia remain incompletely defined. Recent evidence from the cancer field implicates the activity of serine proteases as a key intermediate in a previously unidentified mechanism for the induction of allodynia and hyperalgesia. Based on these findings they have initiated an investigation of proteases and serine protease inhibitors in vaginal secretions of women with vestibulodynia and matched controls. Their initial results indicate that the concentrations of two serine protease inhibitors, secretory leukocyte protease inhibitor (SLPI) and human epididymal protein-4 (HE-4) are markedly reduced in women with vestibulodynia. They propose to test the hypothesis that a decrease in serine protease inhibitor concentrations in the vagina leads to an elevation in unopposed serine protease activity and an increased sensitivity of local peripheral nerves to pro-inflammatory signals. This results in an elevated susceptibility to develop vestibulodynia. Their specific study objectives are to determine whether decreases in vaginal levels of SLPI and HE-4 and/or increases in the vaginal serine protease, kallikrein, or the cysteine protease, cathepsin, are associated with primary and/or secondary vestibulodynia, whether this deficit is present in a specific subset(s) of patients and whether successful treatment is associated with an increase in SLPI and/or HE-4 concentrations and/or a decrease in kallikrein or cathepsin levels. They expect that the successful diminution of vestibulodynia-related symptoms will be associated with local elevations in SLPI and/or HE-4 levels and/or decreases in kallikrein or cathepsin. This is an initial study of a novel, biologically plausible and previously unexplored mechanism that may be involved in development and perpetuation of vestibulodynia.
Andrea Rapkin, MD & Emeran Mayer, MD – David Geffen School of Medicine at UCLA
Efforts to identify effective treatment for vulvodynia have been hampered by our limited understanding of the condition’s causes and underlying mechanisms. To remedy this situation, Drs. Rapkin and Mayer will use their NVA grant, An MRI Study to Investigate Differences in the Brain’s Structure and Function, which was matched with an impressive amount of funding from UCLA, to identify novel biological markers, i.e., “biomarkers,” of two vulvodynia subtypes: Generalized Vulvodynia and Provoked Vestibulodynia. Women will undergo functional resting state MRI to evaluate patterns of structure and activity in the brain at rest, as well as structural MRI to obtain various measures of the brain’s grey matter (e.g., cortical thickness, volume, shape). Because Dr. Mayer participates in the $40 million NIH-funded Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network, an added benefit of this study is that imaging data from women with vulvodynia will be compared to data from hundreds of women with irritable bowel syndrome, interstitial cystitis/painful bladder syndrome and controls collected through the MAPP study. The data will be used to determine whether symptom-based pain syndromes share certain characteristics, as well as identify vulvodynia subtypes associated with specific biomarkers. Further, they will correlate findings of brain scans with known genetic and early environmental risk factors for chronic pain. The long-term goal of this study is to identify biomarkers for different vulvodynia subtypes that can serve as novel treatment targets, and to use this information in developing large controlled trials to test the effectiveness of various treatments for vulvodynia.
Ruby Nguyen, PhD – University of Minnesota School of Public Health
Although dozens of studies have reported on the frequent co-occurrence of vulvodynia and other pain disorders, such as fibromyalgia and irritable bowel syndrome, we don’t know whether the disorders share a common underlying biological mechanism(s). With her NVA grant, Dr. Nguyen will analyze complex data sets from the NVA’s Coexisting Conditions Survey. She will first determine whether women with vulvodynia are more or less likely to have specific clusters of coexisting conditions, e.g., endometriosis, fibromyalgia and headache versus temporomandibular disorders (aka TMJ) and chronic fatigue syndrome. Second, she will delineate the disorders’ temporal relationship, i.e., whether vulvodynia typically precedes or follows the development of other conditions, providing invaluable first-of-its-kind data. This new knowledge will provide evidence to guide future research efforts; for example, whether studies should focus on individual comorbid disorders, certain disorder clusters or both. Collectively, information gleaned from the analyses will aid in our understanding of vulvodynia’s natural history, and provide clues about the etiology and underlying mechanisms of disease in different vulvodynia subgroups, with the overall goal of improving our ability to intervene through successful treatment and/or by stopping the disorder’s progression.
Alice Rickard, MS – St. Louis University School of Medicine
The epithelium covers the exterior surfaces of the body, lines the closed internal cavities and forms the secretory glands. The epithelium can provide an impervious barrier, as in the bladder, and can also form a continuous cellular layer that separates the underlying connective tissue from the external environment, as in the vulva. Whereas the bladder epithelium has been widely researched, only one study on vulvar epithelial tissue has been conducted to date. In order to understand the underlying mechanisms of vulvodynia, it’s essential to obtain this basic information on the make-up of vulvar tissue. With her NVA grant, Characterizing Vulvar Epithelial Tissue in Women with Vulvodynia, Rickard will study the composition of vulvar epithelial tissue taken from women with vulvodynia and compare it to control tissue, as well as bladder epithelium from women with interstitial cystitis. Results will determine whether vulvar epithelium is defective in women with vulvodynia, identifying a new avenue for therapeutic intervention.
Irving Binik, PhD – McGill University
Dr. Binik is investigating brain activity and anatomy in women with primary and secondary provoked vestibulodynia (PVD). According to Dr. Binik, the study of PVD has been focused on peripheral mechanisms underlying chronic vulvar pain (e.g., dysfunction of peripheral vulvar nerves, tissue inflammation), with little attention paid to abnormal pain processing in the spinal cord and brain. Using functional magnetic resonance imaging (fMRI), Dr. Binik is comparing brain activity during the application of painful and nonpainful stimuli to the vestibule of women with PVD and pain-free controls. Brain imaging techniques are being used to correlate clinical PVD pain characteristics with vulvar pain-related brain activity, grey matter density, and axonal (white matter) organization. In addition to adding to our understanding of pathological pain processing in PVD, Dr. Binik proposes that a detailed analysis of brain activity and anatomy will aid in the identification of imaging biomarkers, which could be used to identify PVD subtypes, as well as novel therapeutic targets based on specific structural and anatomical abnormalities.
Joanna Floros, PhD and Colin MacNeill, MD – Pennsylvania State University College of Medicine
Dr. Floros and MacNeill are using their NVA grant, along with matching funds from their institution, to conduct the first proteomics study of vulvodynia. The study goals are two-fold. First, the doctors are comparing vestibular fluid samples from healthy control women and women with vulvodynia to identify protein types and concentrations that may be abnormal in affected women. Next, the doctors are using this information to identify the underlying pathways and mechanisms that may be involved in the pathogenesis of vulvodynia. Data derived from this study will help to identify women who may be at risk of developing the condition as well as new therapeutic targets and biomarkers that could be useful in the diagnosis and/or subtyping of women with vulvodynia.
Devavani Chatterjea, PhD – Macalester College
Dr. Chatterjea is developing an animal model of chronic vulvar pain. Previous studies show that mast cells, which play a critical role in the body’s immunological response, may contribute to the initiation and/or maintenance of vulvodynia in a subgroup of women. To determine the role of mast cells in the disorder’s pathophysiology, Dr. Chatterjea and her group are establishing a mast cell-specific mouse model of inflammatory pain. This model will add to our understanding of specific mast cell-related mechanisms responsible for triggering/maintaining vulvar pain, and also aid in the discovery of novel treatments.
Eric Bair, PhD – University of North Carolina, Chapel Hill
Dr. Bair is conducting cluster analyses and advanced statistical methods on one of the largest patient datasets in the country to identify vulvodynia subgroups that differ in their underlying pathophysiology. Differential contribution of central and peripheral factors may partially explain the large variation in clinical course and treatment response among women with similar vulvar pain symptoms. For example, peripheral factors (e.g., vulvar inflammation) may be the primary generator of pain in some women, whereas in others, vulvar pain may result from a heightened state of pain sensitivity in the central nervous system. The same treatment is therefore unlikely to be equally effective in both groups. The ultimate goal of this research team is to use the results of these advanced analyses to develop clinical criteria for classifying patients into appropriate mechanism-based subgroups, enabling the selection of appropriate effective treatment for each.
Linda McLean, PhD – Queen’s University
Building on the findings of her prior NVA research grant, and with matching funds from her institution, Dr. McLean is studying the nature of pelvic floor muscle (PFM) involvement in women with vulvodynia, and will use this information to enhance physical therapy approaches to treatment. In addition to being one of the first research studies to examine PFM dysfunction in women with generalized vulvodynia, this study is examining the validity and utility of three-dimensional ultrasound imaging (USI) in assessing PFM dysfunction before, during and after physical therapy treatment aimed at relaxing the pelvic floor. The results of this study may demonstrate a novel, non-invasive approach to assess PFM involvement in women with all vulvodynia subtypes, as well as provide evidence of the benefits of visual biofeedback training using USI, rather than a vaginal probe, to promote relaxation of the pelvic floor muscles.
Lori Brotto, PhD – University of British Columbia, Vancouver
Dr. Brotto is using her NVA grant to study pregnancy and childbirth in women with all vulvodynia subtypes. In the first phase of the study, Dr. Brotto is comparing self-reported data on vulvodynia patients’ past pregnancy, childbirth and vulvar pain experiences to that of healthy controls. In the second phase, she is prospectively following women with vulvodynia throughout their pregnancies and into the postpartum period to determine how pregnancy and childbirth affect the severity and constancy of vulvar pain symptoms (and vice versa). In the final phase, her research group is querying local doctors and midwives who care for pregnant women to determine how frequently they encounter women with vulvodynia. Additionally, they are collecting information on the strategies clinicians use to examine this patient population, as well as delineate the clinicians’ pain management, childbirth and postpartum recommendations for vulvodynia patients. Due to the paucity of information available on this topic and in an effort to improve clinical care provided to pregnant women with vulvodynia, upon conclusion of the study, Dr. Brotto’s research team will develop a document summarizing the study’s significant findings and disseminate it to local health care providers who care for pregnant women.
Mark Tommerdahl, PhD and Denniz Zolnoun, MD, MPH – University of North Carolina, Chapel Hill
Drs. Mark Tommerdahl (right) and Denniz Zolnoun (left) used their 2010 NVA grant to conduct the first large-scale study investigating the underlying mechanisms of generalized vulvodynia. They compared peripheral and central nervous system pain processing in three groups: (1) women with generalized vulvodynia, (2) women with provoked vestibulodynia (PVD, aka vulvar vestibulitis), and (3) women with both vulvodynia subtypes. Understanding the mechanisms that initiate and maintain abnormal pain processing at all levels of the nervous system – the brain, spinal cord and peripheral nerves – will help to determine which therapeutic agents are likely to be effective in the treatment of women with generalized vulvodynia.
Additional clinically-focused grants have been awarded to:
Irving Binik, PhD – McGill University (2006 – 2008)
Dr. Binik was awarded an NVA grant in 2006 to investigate the relationship between chronic Candida infection and vulvar vestibulitis syndrome (VVS) in an animal model. Many women with VVS report previous recurrent episodes of vulvovaginal Candida infection. This association has led some researchers to propose that chronic Candida infection, in which there is continued irritation of the vulvovaginal mucosa, may lead to the abnormal pain transmission experienced by women with VVS. In the present study, Dr. Binik will evaluate whether chronic Candida infection results in lowered vulvar pain thresholds and reduced mating behavior in mice. In addition, he will determine if the immunological profile associated with chronic Candida infection is similar to the immunological profile in VVS. Dr. Binik’s goal is to use an animal model to pursue novel therapeutic interventions for women with vulvar pain.
Nina Bohm-Starke, PhD – Danderyd Hospital (Sweden) (2009 – 2013)
Dr. Bohm-Starke will use her 2009 NVA grant, matched by her institution, to investigate whether certain genetic variations are associated with general pain hypersensitivity in women with VVS. Recent studies have found that women with VVS also have lower pain thresholds than controls in non-vulvar body sites (e.g., arm, leg), suggesting altered pain processing in the brain and/or spinal cord. Furthermore, some studies show a significant percentage of women with VVS suffer from more than one pain condition, i.e., they also have fibromyalgia, interstitial cystitis, temporomandibular joint and muscle disorders, and/or irritable bowel syndrome. This has led researchers to propose that some women with VVS may be genetically predisposed to develop pain conditions. In VVS patients and controls, Dr. Bohm-Starke will investigate alterations in several genes that are involved in pain modulation and inflammation. This study aims to: (i) increase our knowledge of the underlying mechanisms in VVS, and (ii) identify a subgroup of women with VVS at risk of developing other pain conditions.
Jacob Bornstein, MD and Tzipora Falik, MD – Western Galilee Hospital (Israel) (2007 – 2010)
Dr. Bornstein (left photo) and Falik (right photo) were awarded a grant in 2007 to investigate possible associations between VVS and genes that transcribe proteins found or hypothesized to be involved in the abnormal tissue changes seen in VVS. Specifically, they will study a number of polymorphisms, or variations, of three genes coding for molecules involved in the break down, or degradation, of vestibular mast cells and increased vestibular nerve fiber growth: heparanase, vanilloid receptor-1 (TRPV1), and nerve growth factor (NGF). The subjects for this pilot study will be women suffering from severe vulvar vestibulitis who have experienced pain since their first episode of sexual intercourse. This study is an important exploratory part of a larger-scale study that will help delineate genetic susceptibility to the condition and pave the way for individualized treatment.
Theodore Fellenbaum, MD – Mid-Michigan Vulvar Care & Colposcopy Center (2006, 2009 – 2010)
Dr. Fellenbaum will use his 2009 NVA grant, matched by Genesys Medical Regional Center, Grand Blanc, Michigan, to test the effectiveness of a potential new treatment for VVS. Dr. Fellenbaum will clinically test the proposed link between mast cells, which play a key role in the inflammatory process, and the development of VVS. When triggered, mast cells degranulate, releasing toxic substances, such as histamine and cytokines, into the surrounding tissue. Mast cell degranulation may lead to an increase in nerve growth factor (a molecule that stimulates the growth of certain sensory nerves) and excessive hypersensitivity of the nerve fibers in the vestibule. This hypersensitivity may account for the pain of vulvar vestibulitis. In this study, Dr. Fellenbaum is investigating the action of an oral medication that reduces mast cell degranulation to see whether it alleviates VVS pain. He will compare the degree of pain relief reported by women taking this oral medication to that of two other groups of women being treated with topical medications.
Dr. Fellenbaum was also warded a grant in 2006 to organize a community-based vulvodynia clinic that also promotes resident physician education. The Genesys Medical Center demonstrated its commitment to establishing a vulvar pain clinic by matching the amount of NVA’s grant. Dr. Fellenbaum is collaborating with members of the Genesys obstetric & gynecologic residency program and the Genesys Medical Education Department. The goals of this collaboration are: to screen, diagnose and treat genital pain disorders of unknown etiology, to provide a heretofore absent local rotation in genital pain for Genesys and other hospital Ob/Gyn Resident physicians and medical students, to provide educational lectures to other medical disciplines, and to establish a means for ongoing educational training and academic research on vulvodynia.
David Foster, MD, MPH – University of Rochester (1998 – 1999, 2000 – 2001)
Dr. Foster first received an NVA grant in 1998 to further his work on the neuro-inflammatory mechanisms of Vulvar Vestibulitis Syndrome (VVS). Specifically, Dr. Foster studied the cytokine system that mediates inflammation and the neurokine system that mediates pain. The ultimate goal of this research is to develop a specific therapy that interferes with the cytokine-neurokine pathway, thereby relieving the pain of VVS.
In 2000, NVA awarded a second grant to Dr. Foster to continue his work on the etiology of VVS. Through cell culture, Dr. Foster found that the fibroblast, a type of cell that produces scar tissue, acts in a peculiar way immunologically in VVS patients. Dr. Foster proposed to study this peculiarity by testing for differences in cytokine and melanin genes and relating his genetic findings to his observations of cell culture. Dr. Foster’s ultimate goal was to identify inflammatory substances released by the relevant fibroblast cells, thereby providing a target for drug therapy. Dr. Foster’s NVA grants enabled him to gather enough pilot data to receive a large-scale NIH grant to study a combination treatment for VVS.
Bernard Harlow, PhD – University of Minnesota School of Public Health (2007)
Dr. Harlow was awarded a 5-year grant from the National Institutes of Health in 2000 to study the prevalence of vulvodynia and delineate factors associated with an increased risk of developing the condition. Findings from his ongoing work suggest that vulvodynia may be a consequence of an altered vulvar immuno-inflammatory response that can occur well before menarche. NVA awarded Dr. Harlow a grant in 2007 to continue his work in this area. With NVA funds, Dr. Harlow will complete laboratory assessments of vulvar-obtained specimens to determine whether there is a difference in the presence of neurogenic proinflammatory mediators and cytokines, and bactericidal proteins among women with vulvodynia and controls. These laboratory findings coupled with his previous epidemiological data were submitted in a 2008 grant application to the National Institutes of Health.
Mary Kendell, MS, WHCNP – George Washington University (2006-2007)
Ms. Kendell was awarded a grant in 2006 to develop a curriculum to train and evaluate ob-gyn residents in the treatment of women with chronic vulvar pain. The educational component of the curriculum includes traditional and web-based learning tools, as well as hands-on training in standardized exam techniques and vulvar colposcopy. To evaluate residents’ competency, the George Washington University School of Medicine utilizes a state-of-the-art Standardized Patient Testing center that allows students and residents to hone their skills. In this controlled environment, faculty can observe and record resident/patient interactions and provide real time feedback to residents on their patient care, medical knowledge, interpersonal skills, professionalism and systems based practice. Ms. Kendell’s initial goal was to develop a successful standardized curriculum that will improve medical residents’ competence and level of comfort in evaluating and treating vulvar pain disorders. Her ultimate goal is to establish a vulvar pain clinic at George Washington University School of Medicine.
Catherine Leclair, MD and Terry Morgan, MD – Oregon Health & Science University (2007 – 2008)
Drs. Leclair and Morgan were awarded a grant in 2007 to continue their work investigating the etiology, or underlying mechanism, responsible for increased vestibular nerve fiber density found in women with VVS. They also plan to determine if a mild chronic inflammation involving mast cells plays a role in the initiation and/or perpetuation of the condition. Recent research has shown that women with VVS have a decreased number of estrogen receptors in their vestibular tissue. According to Drs. Leclair and Morgan, one consequence of the reduced level of estrogen receptors may be an up-regulation of epidermal growth factor receptor (EGFR), a mediator of abnormal nerve cell growth and mast cell development. EGFR shows significant cross-signaling with steroid receptors, such as estrogen receptors, and is also up-regulated by androgen receptor (AR). They hypothesize that abnormal ER down-regulation and/or AR up-regulation may lead to an increase in EGFR expression and the cascade of events culminating in VVS. The long term goal of their research is to determine the underlying mechanisms responsible for the initiation of vestibulitis and develop treatment strategies that will eliminate the need for surgery.
Colin MacNeill, MD – The Milton S. Hershey Medical Center (2007)
Dr. MacNeill was awarded a grant in 2007 to investigate the role of surfactant proteins in the initiation of the inflammatory process in VVS. Surfactant proteins are produced locally in the vaginal and vestibular mucosa, and based on numerous studies of other mucosa, may play an important role in the immune response that protects the vulva and vagina from infection. These proteins are found elsewhere in the body, such as the lung. Mice that have been genetically altered not to produce these proteins die of infection unless housed in a sterile environment. Dr. MacNeill hypothesizes that variation in the genes that code for these proteins may be responsible for initiating or maintaining the early inflammatory process in VVS. In this study, he will test this hypothesis by measuring levels of surfactant proteins in vestibular tissue and assess eleven different polymorphisms in VVS patients and controls. Ultimately, he will test a novel therapy that modulates the activity of these proteins. He speculates that if this process can be detected and treated early, the development of VVS could be stopped. In 2007, Dr. MacNeill used the data collected with his NVA grant in an application to the National Institutes of Health.
Linda McLean, PhD and Caroline Pukall, PhD – Queen’s University (Canada) (2007 – 2008)
Drs. McLean (left photo) and Pukall (right photo) were awarded a grant in 2007 to study pelvic floor muscle function in women with VVS. Specifically, the study’s objectives are to determine if, as compared to healthy controls, women with VVS demonstrate: (1) heightened activity of the superficial pelvic floor muscles in response to vestibular pressure and/or stretching of the introitus, or vaginal opening; (2) heightened activity of the deep pelvic floor muscles in response to introital pressure; (3) anticipatory reactions of the superficial and/or deep pelvic floor muscles in response to introital pressure or stretching; and (4) heightened activity of remote muscles (biceps and trapezius muscles) in anticipation of, or in response to, introital pressure or stretching. This study will be the first to investigate whether there are differences in the tonic and reactive contractility of pelvic floor muscles in women with VVS as compared to healthy controls, and to differentiate between superficial and deep pelvic floor muscle responses. The outcome of this work will shed light of the etiology of the condition and guide clinical assessment and management, including the development of new physical therapy techniques and utility of medications, such as neuromuscular transmission blocking agents (e.g., Botox).
Robert Moldwin, MD – Long Island Jewish Medical Center (New York) (2009 – 2010)
Dr. Moldwin (left photo) and medical student Amin Herati, (right photo) were awarded an NVA grant in 2009 to investigate myofascial trigger points in women with vulvodynia. Women who have myofascial dysfunction have multiple trigger points, or hyperirritable spots of taut skeletal muscle, throughout their bodies. When active, trigger points cause pain and other symptoms. Although patients with chronic pelvic and urogenital pain can have trigger points in their pelvic floor muscles, very little is known about their prevalence and distribution. The goal of this study is to determine whether the locations or pattern of pelvic trigger points differ among three pelvic pain disorders – vulvodynia, interstitial cystitis (painful bladder syndrome) and chronic prostatitis. If distinct trigger point patterns can be identified for vulvodynia and interstitial cystitis, clinicians could add trigger point evaluation to the diagnostic workup of women presenting with pelvic pain and be better-equipped to differentiate vulvodynia from interstitial cystitis.
Andrea Nackley Neely, PhD and Denniz Zolnoun, MD – University of North Carolina (2009)
Drs. Nackley-Neely (left photo) and Zolnoun (right photo) were awarded an NVA grant in 2009 to investigate possible common mechanisms in vulvodynia and temporomandibular joint/muscle disorders (TMD). Drs. Nackley and Zolnoun note that recent studies have demonstrated that persistent pain conditions occurring in isolation may result from local increases in peripheral nerve activity and proinflammatory cytokines (substances that trigger inflammation). Alternately, pain conditions occurring in concert may result from changes in both the central nervous system’s processing of pain and circulating proinflammatory cytokines. They hypothesize that vulvodynia and TMD share common central pathophysiology and will compare pain sensitivity and circulating cytokines in four groups: women with vulvodynia, women with TMD, women with concurrent vulvodynia/TMD and healthy controls. This study aims to provide: (i) a better understanding of the key mechanisms that drive vulvodynia and TMD, (ii) more accurate differentiation of distinct subgroups of vulvodynia and TMD patients, and (iii) the development of new therapeutic strategies tailored to these subgroups. Their ultimate goal is to uncover the underlying mechanisms and perpetuating factors for each subgroup and utilize treatments that target those factors.
Caroline Pukall, PhD – Queen’s University (2005 – 2007)
Dr. Pukall was awarded a grant in 2005 to examine differences between women with primary and secondary vulvar vestibulitis syndrome (VVS). There is a tendency to view all women with VVS as a homogeneous group; however, it has been suggested that differences in etiology, pain characteristics, and treatment outcome exist between these two groups. This controlled study will investigate multiple dimensions of pain and its functional effects using various methods, such as standardized self-report measures, a standardized gynecological examination, quantitative sensory testing, and functional magnetic resonance imaging. This study will provide much-needed information regarding different aspects of primary and secondary vestibulitis in order to determine what factors are responsible for initiating and maintaining the pain in both subgroups. Findings from this study will shed light on potential etiological factors involved in primary and secondary vestibulitis and may help guide treatment for these women.
Andrea Rapkin, MD and John McDonald, MD – University of California – Los Angeles (2007 – 2010)
Drs. Rapkin and McDonald were awarded a grant in August 2007 to study the efficacy of sequential nerve blocks in women with generalized vulvodynia.
Danielle Tonelli, DO – Aurora Women’s Pavilion, Wisconsin (2010-2011)
Danielle Tonelli, DO, a fellowship-trained women’s health specialist with board certification in family medicine, received an NVA grant in early 2010 to start a vulvar pain clinic in Milwaukee, Wisconsin. Dr. Tonelli currently serves as co-clinical director of the Center for Optimal Health and Wellness at the Aurora Women’s Pavilion (AWP) in Milwaukee. AWP showed its support of her work by matching the NVA’s grant. Dr. Tonelli will develop and implement educational programs for local women with vulvodynia as well as medical professionals. “With the establishment of the AWP Vulvar Pain Clinic, women in our community and their providers will now have a local center with a full range of services, from outreach and education to compassionate patient care,” says Dr. Tonelli.”
Ursula Wesselmann, MD, PhD – Johns Hopkins University School of Medicine (1997 – 1998, 2002 – 2003)
Dr. Wesselmann was awarded a grant in 1997 to develop a basic science model of vulvodynia. Her aim was to advance the knowledge of the neural mechanisms underlying the disorder in order to develop specific treatment modalities. Dr. Wesselmann’s NVA grant enabled her to gather pilot data and receive large-scale funding from the National Institutes of Health in 2002.
NVA awarded a second grant to Dr. Wesselmann in 2002. The aim of this pilot study is to examine sensory mechanisms contributing to dysesthetic vulvodynia in post-menopausal women and to determine how these sensory mechanisms are affected by hormone replacement therapy. To date, there have been almost no studies on dysesthetic vulvodynia in post-menopausal women. Wesselmann’s study could make an important contribution to our understanding of the relationship between hormone status and vulvodynia.
Steven Witkin, PhD and William Ledger, MD – Cornell University (2001 – 2002, 2005 – 2006, 2007 – 2008, 2009 – 2011)
Drs. Witkin (left photo) and Ledger (right photo) from Cornell University received their first NVA research grant in 2000 and have published the results of seven studies in the past nine years. They have found the following genetic variations in women with VVS, aka provoked vestibulodynia: (i) a reduced capacity to terminate inflammation (IL-1ra gene), (ii) an increased capacity to initiate inflammatory responses (IL-1beta gene), and (iii) a reduced capacity to combat Candida albicans infections (MBL gene). Similarly, they’ve found reduced circulating levels of the anti-microbial compound, interferon-alpha, increased pro-inflammatory cytokine and decreased production of an anti-inflammatory mediator in women with VVS. They have attempted to differentiate patients on the basis of time of symptom onset, factors associated with onset, history of recurrent yeast infections, degree of vestibular pain and associations with an indicator of an allergic response to seminal fluid. Their findings have verified that more than one biological process is responsible for the initiation of VVS.
The finding that many women with VVS have a relative inability to mount an effective anti-microbial immune response, coupled with a low capacity to terminate pro-inflammatory immune response, is the basis for their 2005 study funded by NVA; Drs. Witkin and Ledger tested the hypothesis that the subset of women with VVS who experience constant or intermittent pain, and whose pain is too severe to engage in sexual intercourse, have a diminished capacity to mount an innate immune response to microorganisms. The doctors hypothesize that this relative inability to prevent the colonization and/or proliferation of microorganisms could lead to a persistent induction of pro-inflammatory mediators and a continual stimulation of nerve fibers in the vestibular region, culminating in greatly enhanced sensitivity to touch or pain stimuli. Their long term objective is to uncover the mechanisms that predispose women to develop VVS and to develope a new treatment for the condition.
Dr. Witkin was awarded a third NVA grant in 2007 to continue his work on the etiology of VVS. Because women with VVS report a variety of events that initially trigger their symptoms, including vulvovaginal infection, childbirth, hormonal alteration and chemical and laser treatment, researchers have been unable to identify the exact etiology of the condition. Since 2000, Dr. Witkin has published several studies showing that some women with VVS have gene alterations (polymorphisms) that make them more susceptible to developing the condition. Women with VVS are more likely to exhibit a reduced capacity to ‘turn-off’ inflammation (IL-1ra gene polymorphism), an increased capacity to initiate inflammation (IL-1beta gene polymorphism) and a reduced capacity to combat Candida albicans infections (MBL gene polymorphism). He now proposes that VVS, regardless of the initial trigger, may be due to vestibular peripheral nerve damage caused by prolonged exposure to reactive oxygen species (ROS). ROS are oxygen-containing molecules that can damage other cells and molecules in the body, i.e., nerve cells; they can be induced by a number of different infectious or non-infectious insults. Specifically, he suggests that ROS persistence, which is known to increase susceptibility to nerve damage and maximize regional sensitivity, may be due to the presence of polymorphisms in genes that either directly inactivate ROS or foster a prolongation of ROS production. With this grant, Dr. Witkin will test this novel and unifying hypothesis by comparing the DNA of women with VVS whose symptoms began after a defined event such as childbirth, vulvovaginal infection or surgery, with those whose symptoms were not associated with any specific event. In addition, he will collect blood samples from these two groups to measure immune responses to the yeast and hyphal forms of Candida. Evidence of a unifying mechanism to explain the diverse clinical observations in women with VVS will lead to an improved ability to identify women at risk for development of this syndrome, the testing of more effective preventative strategies and the formulation of novel treatments.
In 2009, Drs. Witkin and Ledger were awarded a grant to (i) analyze the types of bacterial organisms, or endogenous flora, found in the vagina and vulva of women with PVD, and (ii) investigate the relationship between specific organisms and the carriage of genetic polymorphisms or appearance of vestibular inflammation. They hypothesize that it is the interaction between specific bacteria types and a woman’s genetic makeup that determines the extent of vaginal and sub-surface vestibular inflammation and the degree of susceptibility to developing PVD. Specifically, they will analyze the vulvovaginal flora in 40 PVD patients when they are symptomatic, and then eight weeks after treatment, comparing the findings to those of an equal number of controls. They will also use a new instrument to visualize the extent of patients’ vaginal and vestibular inflammation. The researchers will obtain DNA samples to determine whether polymorphisms associated with inflammation, vulvovaginal infection and peripheral nerve damage (IL1RN, CIAS1, MBL2, and MnSOD genes) are more prevalent in women with PVD than controls. Furthermore, they will quantify levels of immune mediators, pro-inflammatory cytokines (IL-1beta, tumor necrosis factor-alpha) and anti-inflammatory cytokines (IL-1ra and IL-4) in vaginal secretions.
Denniz Zolnoun, MD – University of North Carolina (2007)
In 2007, NVA awarded a grant to Dr. Zolnoun to conduct a survey of compounding pharmacies in North Carolina. Given the lack of consensus guidelines for the treatment of vulvodynia and many patients’ reliance on compounded medications, Dr. Zolnoun and others believe it is critical to gain a better understanding of compounding pharmacies’ practice trends, with particular emphasis on vulvodynia. This knowledge will provide insight into both treatment options for vulvodynia and the impact that current legislation, such as the Safe Drug Compounding Act of 2007, could have on the future of compounding pharmacies. These pharmacies often provide the only source of treatment options for marginalized populations suffering from poorly studied illnesses, such as vulvodynia. Dr. Zolnoun’s hypothesis is that many areas of women’s health, specifically vulvovaginal disorders, rely heavily on compounding pharmacies and the services they provide. Though this is a commonly acknowledged fact, this survey will provide the objective data needed to empower lobbyists and affect policy change. To that end, she distributed a questionnaire to approximately 500 compounding pharmacies and will analyze the survey data to: (1) demonstrate the importance of compounding pharmacies in the provision of women’s health services; (2) establish the prevalence of medications compounded for vulvodynia, 3) identify trends in compounding for vulvodynia; and 4) identify the types and combinations of medications used for the treatment of vulvodynia.