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Background: Neuroproliferative vestibulodynia (NPV), a provoked genital pain characterized by severe allodynia and hyperalgesia, is confirmed in excised vestibular tissue by immunohistochemical staining (>8 CD117-positive immunostained cells/100× microscopic field) rather than by hematoxylin and eosin staining., Aim: In this study we sought to assess immunostaining of tissue samples obtained during vestibulectomy surgery and to correlate results with patient outcomes., Methods: Patients (n = 65) meeting criteria for NPV who underwent vestibulectomy during the period from June 2019 through December 2022 formed the study cohort. We performed assessment of pathology of vestibular tissues by use of immunohistochemical staining, including quantitation of mast cells by CD117 (mast cell marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments., Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement., Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments., Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement., Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the median area of CD117 immunostaining was similar in both regions (0.69% and 0.73%). The median area of PGP9.5 immunostaining was 0.47% and 0.31% in these same regions. Pain scores determined with cotton-tipped swab testing were nominally higher in lifelong vs acquired NPV patients, reaching statistical significance in the 1:00-11:00 o'clock region (P < .001). The median score for the McGill Pain Questionnaire affective subscale dimension was also significantly higher in lifelong vs acquired NPV patients (P = .011). No correlations were observed between hematoxylin and eosin results and density of mast cells or neuronal markers. Of note, 63% of the patient cohort reported having additional conditions associated with aberrant mast cell activity., Clinical Implications: The pathology of NPV is primarily localized to the vestibular epithelial basement membrane and subepithelial stroma with no visible vulvoscopic findings, making clinical diagnosis challenging., Strengths and Limitations: Strengths of this study include the large number of tissues examined with what is to our knowledge the first-ever assessment of the 12:00 vestibule. Major limitations are specimens from a single timepoint within the disease state and lack of control tissues., Conclusions: Performing immunohistochemical staining of excised vestibular tissue with CD117 and PGP9.5 led to histometric confirmation of NPV, indications that NPV is a field disease involving all vestibular regions, validation for patients whose pain had been ignored and who had experienced negative psychosocial impact, and appreciation that such staining can advance knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia's pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as "vulvodynia", "chronic vulvar pain", "vulvodynia induction", and "animal models of vulvodynia" to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

Abstract: Lymphangioma circumscriptum (LC) is a rare benign condition, with marked dilation of surface lymphatic vessels in the deep and subcutaneous layers. Vulvar LC can become a highly disabling condition with vulvar discomfort, itching, burning and lymph seeping being the dominant symptoms. Biopsy is mandatory for the diagnosis. There is no consensus on the standard treatment for vulvar LC and recurrence is frequent. In complex cases with wide disease location, combination of different treatment options, such as abrasive methods and surgery, may lead to the best clinical and aesthetical result, with extended disease-free periods. We present a patient with a long history of Crohn disease with multiple pelvic surgeries who developed an extensive vulvar LC., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023, ASCCP.)

Vulvodynia is a debilitating condition characterized by painful sensitivity to touch and pressure in the vestibular tissue surrounding the vaginal opening. It is often a "diagnosis of exclusion" of idiopathic pain made in the absence of visible inflammation or injury. However, the association between increased vulvodynia risk and a history of yeast infections and skin allergies has led researchers to explore whether immune mechanisms of dysregulated inflammation might underlie the pathophysiology of this chronic pain condition. Here we synthesize epidemiological investigations, clinical biopsies and primary cell culture studies, and mechanistic insights from several pre-clinical models of vulvar pain. Taken together, these findings suggest that altered inflammatory responses of tissue fibroblasts, and other immune changes in the genital tissues, potentially driven by the accumulation of mast cells may be key to the development of chronic vulvar pain. The association of increased numbers and function of mast cells with a wide variety of chronic pain conditions lends credence to their involvement in vulvodynia pathology and underscores their potential as an immune biomarker for chronic pain. Alongside mast cells, neutrophils, macrophages, and numerous inflammatory cytokines and mediators are associated with chronic pain suggesting immune-targeted approaches including the therapeutic administration of endogenous anti-inflammatory compounds could provide much needed new ways to treat, manage, and control the growing global pandemic of chronic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Tonc, Omwanda, Tovar, Golden and Chatterjea.)

Pain of the vulvar vestibule, including provoked vestibulodynia, is prevalent among women, yet challenging to treat due to its multifactorial etiology. Recent evidence indicates a neuroproliferative subtype in which hypersensitivity of the vulvar vestibule is due, in part, to hyperinnervation. Detailed knowledge regarding the innervation of the vulvar vestibule is crucial to understanding and treating pain conditions impacting this region. The purpose of this review is to consolidate the current evidence regarding the innervation of the human vulvar vestibule and discuss the implications of this innervation for pathological conditions affecting this tissue. A comprehensive review of the literature was conducted using keywords including vulvar vestibule, innervation, and vestibulodynia to identify articles concerning the innervation of the vulvar vestibule. Fifteen studies published between 1998 and 2017 were reviewed. Evidence from immunohistochemical investigations support that the vulvar vestibule has nociceptive, mechanosensory, sympathetic, and parasympathetic innervation. In pathological samples, hyperinnervation supports the neuroproliferative etiology of provoked vestibulodynia. Additionally, there is some evidence supporting the role of the pudendal nerve in vulvar vestibule innervation, although no cadaveric studies have been reported to date. Progress has been made in our understanding of the innervation of the vulvar vestibule, though further research into the origin of sensory and autonomic innervation of this region is needed. Advancing the knowledge of vulvar vestibule innervation is crucial towards improving our understanding of the function of this tissue, in addition to informing the etiology and management of pain syndromes impacting this region., (© 2022 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Chronic pelvic pain represents a major public health problem for women and impacts significantly on their quality of life. Yet it is under-researched and a challenge to manage. Women who suffer from chronic pelvic pain frequently describe their healthcare journey as long, via a variety of specialists and frustrating, with their pain often dismissed. Aetiological factors and associations are best conceptualised using the 'three P's' model of predisposing, precipitating and perpetuating factors. This integrates the numerous biological, psychological and social contributors to the complex, multifactorial nature of chronic pelvic pain. Overall management involves analgesia, hormonal therapies, physiotherapy, psychological approaches and lifestyle advice, which like other chronic pain conditions relies on a multidisciplinary team approach delivered by professionals experienced and trained in managing chronic pelvic pain., (© 2021 Association of Anaesthetists.)

Introduction: Localized Provoked Vulvodynia (LPV) is a gynecological disease that is difficult to manage. Despite the wide spectrum of pathophysiological mechanisms and treatment modalities, there is limited success in the management of this disease. Surgical treatment is usually performed as the last resort. We aimed to investigate the histopathological results of 38 women with LPV who underwent surgical vestibulectomy., Methods: of the 55 women that were diagnosed with LPV and underwent vulvar vestibulectomy, 38 patients with complete histopathological results were included in this retrospective study., Results: in 14 patients, the pathological reports revealed Low-Grade Squamous Intraepithelial Lesions (LGSIL) (36.8%) whereas for 21 cases (55.2%), the findings were concordant with vestibulitis. The remaining three patients (7.8%) were diagnosed with lichen simplex chronicus., Conclusion: the presence of LGSIL in the surgical specimens of LPV cases is noteworthy. In this group of patients, surgical excision may contribute to the prevention of progression into high-grade lesions. The relationship between Human Papilloma Virus (HPV) infections and LPV should be further investigated., Competing Interests: The authors declare no competing interests., (Copyright: Suleyman Eserdag et al.)

Objectives: Three scientific societies, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) developed the "2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia" (referred to as the "2015 consensus terminology").The terminology included 11 descriptors of vulvodynia. However, the definitions of the descriptors were not included in the 2015 consensus terminology publications. The objective of this article was to provide these definitions., Materials and Methods: The ISSVD led a discussion on the definitions for the 11 vulvodynia descriptors, with participation from the ISSWSH and IPPS. The definitions were created through a consensus process., Results: The definitions are described and the rationale for their choice is elucidated., Conclusions: The definitions of vulvodynia descriptors were determined by a multistaged process of discussion among health care providers with expertise in the pathophysiology, evaluation, and treatment of vulvodynia. The definitions were approved by the ISSVD, ISSWSH, and IPPS. It is recommended that these definitions of vulvodynia descriptors as well as the 2015 consensus terminology be used for the classification of vulvodynia.

Objective: The aim of the study was to compare the effectiveness of mindfulness-based group cognitive behavior therapy (M-gCBT) versus education support group therapy for the pain and distress associated with provoked localized vulvodynia., Materials and Methods: Participants were randomized to M-gCBT or education support group therapy. Mindfulness-based group cognitive behavior participants attended 8 weekly sessions. Education support group participants received 8 weeks of online education with 3 in-person group visits. Vaginal insertion pain (tampon test) was the primary outcome. Secondary outcomes (Generalized Anxiety Disorder 7, Beck's Depression Index, Female Sexual Distress Scale, Female Sexual Function Index, and Pain Catastrophizing) were administered before intervention and at the completion of the study period, 3 months, and 6 months. Sample size was based on the ideal number for group dynamics of 6 to 12 participants per group., Results: Participants were enrolled from August 1, 2016, to January 30, 2017. Thirty-two participants were enrolled and 31 were randomized: 14 to M-gCBT and 17 to education support. Baseline characteristics did not differ significantly. Vaginal insertion pain decreased in both groups but was not statistically different between groups (difference of 1.23; 95% CI = -0.52 to 2.98). At 6 months, participants in the M-gCBT group showed statistically significant improvement in the Female Sexual Function Index, Generalized Anxiety Disorder 7, and Beck's Depression Index compared with the education support group., Conclusions: Mindfulness-based group cognitive behavior and education support group therapy are effective in reducing pain and distress. However, women in the M-gCBT program showed greater improvement in certain secondary outcomes, indicating that M-gCBT may offer some advantages in reducing distress associated with provoked localized vulvodynia.

Background: Previous studies using botulinum toxin type A (BT) to treat provoked vestibulodynia (PVD) reported conflicting findings, possibly attributable to singular injections or low doses. We assessed PVD treatment effectiveness with high-dose single injections of BT (50 or 100 units) versus placebo, and then repeat BT 100 U injections over 6 months., Methods: This was a randomized, double-blind, three-arm, placebo-controlled study with 33 PVD patients. BT 50 U (arm A), 100 U (arm B) or saline (arm C) were injected subcutaneously into the dorsal vulvar vestibulum and pain was assessed after 3 months. The investigation proceeded as an unblinded exploratory analysis, in which symptomatic patients received a BT 100 U injection. Symptomatic patients in arm C received a second BT 100 U injection at the 6-month visit. Symptoms were measured at 3-month cycles using: (1) cotton swab-provoked visual analogue scale (VAS), (2) von Frey filaments, and (3) Marinoff dyspareunia scale., Results: The three groups were comparable in terms of demographics and baseline clinical characteristics. Three months after the initial injection, no significant differences in pain were observed among the study arms, yet significant improvements occurred within all groups using the von Frey filaments test. Results from the exploratory analyses showed repeat injections of 100 U BT over 6 months led to significant pain reduction (VAS and von Frey filaments). Fifty-eight percent (7/12) of patients assessable after repeat injections were symptom-free or had ≥ 2 VAS reduction. Adverse events were minor and no serious adverse events occurred during the RCT or exploratory analysis., Conclusions: PVD symptoms after one subcutaneous injection of BT (50 or 100 units) did not significantly differ compared to placebo, yet all three study arms experienced a reduction in pain 3 months after a single injection. Exploratory analyses indicated that repeat high-dose BT injections may significantly reduce pain over 6 months., Trial Registration: This trial was registered with the Swiss Medical Agency (reference number: 2007DR2102) in 2007.

Localized provoked vulvodynia (LPV) causes introital dyspareunia in up to 14% of premenopausal women. Vaginal infections like candidosis may play a initiating role. The aim of this study was to test a possible association of vaginal microbiota alternations such as Candida vaginitis (CV), aerobic vaginitis (AV) and bacterial vaginosis (BV) with severity of vulvodynia and painful intercourse. In an observational study, Q-tip touch test (score 1 (no pain) to 10 (worst possible pain)) was performed on seven vestibular locations in 231 LPV patients presenting in the Vulvovaginal Disease Clinics in Tienen, Leuven and Antwerp, Belgium. Severity of pain upon attempting sexual intercourse was recorded in a similar scale. Both scales were compared to results from fresh wet mount phase contrast microscopy on vaginal fluid smears tested for abnormal vaginal flora (AVF), BV, AV and CV according the standardized microscopy method (Femicare). Fisher's exact test was used. Average age was 31.3 ± 11.6 years, and 58.8% (n = 132) had secondary vestibulodynia. There was an inverse relation between the presence of Candida in the vaginal smears and pain score (p = 0.03). There was no relation of pain score, nor Q-tip score with BV. LPV patients with Q-tip score above 7 at 5 and/or 7 o'clock or at 1 and/or 11 o'clock had more often AV than women with lower pain scores (30 vs 14.5%, p = 0.01, and 39 vs 14.7%, p < 0.005, respectively). Detailed study of the vaginal microflora in patients demonstrates that the most severe patients suffer more from AV and less from Candida. These abnormalities need to be actively looked for and corrected before considering surgery or other therapies.

Objectives of the Study: To systematically evaluate the literature regarding vulvodynia treatment outcome measures., Methods: A systematic literature search on OVID, PubMed, and PsycINFO databases was conducted from inception until May 2016. Studies were included/excluded based on prespecified criteria. Reported outcome measures were organized into 6 core outcome domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT): pain; physical functioning, emotional functioning, participant ratings of global improvement and satisfaction with treatment, symptoms and adverse events, and participant disposition., Results: Of the 206 articles identified for full-text screening, 33 met our criteria. One study adhered to all IMMPACT recommendations. The number of outcomes measured per study ranged from 1 to greater than 20. Patient-reported pain outcomes were found in the majority (27/33; 82%) of studies. Pain severity with intercourse was reported by 24 (73%) of 33 studies-9 different scales were used to measure this outcome. Clinician-reported outcomes were present in 14 (42%) of 33 studies. Methods of measuring vestibular sensitivity by "cotton swab" test were different in 8 of 10 studies. Other domains reported included; physical function (8/33 studies; 24%), sexual function (23/33 studies; 70%), and emotional function (13/33 studies; 39%). Symptoms and adverse events were reported by 15 (45%) of 33 studies. One study formally reported participant disposition using all the information recommended by CONSORT., Conclusions: Comparison of clinical trial results in vulvodynia is not possible because of a lack of standard treatment outcome measures. Vulvodynia researchers should apply the IMMPACT criteria to guide the development of a minimum core set of standard outcome measures that measure holistic health.

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs., Perspective: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Vestibulodynia is characterized by perivaginal mechanical hypersensitivity, hyperinnervation, and abundant inflammatory cells expressing renin-angiotensin system proteins. We developed a tractable rat model of vestibulodynia to further assess the contributions of the renin-angiotensin system. Complete Freund's adjuvant injected into the posterior vestibule induced marked vestibular hypersensitivity throughout a 7-day test period. Numbers of axons immunoreactive for PGP9.5, calcitonin gene-related peptide, and GFRα2 were increased. Numbers of macrophages and T cells were also increased whereas B cells were not. Renin-angiotensin-associated proteins were abundant, with T cells as well as macrophages contributing to increased renin and angiotensinogen. Media conditioned with inflamed vestibular tissue promoted neurite sprouting by rat dorsal root ganglion neurons in vitro, and this was blocked by the angiotensin II receptor type 2 receptor antagonist PD123319 or by an angiotensin II function blocking antibody. Sensory axon sprouting induced by inflamed tissue was dependent on activity of angiotensin-converting enzyme or chymase, but not cathepsin G. Thus, vestibular Complete Freund's adjuvant injection substantially recapitulates changes seen in patients with provoked vestibulodynia, and shows that manipulation of the local inflammatory renin-angiotensin system may be a useful therapeutic strategy., Perspective: This study provides evidence that inflammation of the rat vestibule induces a phenotype recapitulating behavioral and cytological features of human vestibulodynia. The model confirms a crucial role of the local inflammatory renin-angiotensin system in hypersensitivity and hyperinnervation. Targeting this system holds promise for developing new nonopioid analgesic treatment strategies., (Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Localized provoked vulvodynia (LPV) afflicts approximately 8% of women in the United States and represents a huge financial, physical, and psychological burden. Women with LPV experience intense pain localized to the vulvar vestibule (area immediately surrounding vaginal opening). We have identified mechanisms involved in the development of LPV whereby vulvar fibroblasts respond to proinflammatory stimuli to perpetuate an inflammatory response that causes pain. However, these mechanisms are not fully elucidated. Therefore, we explored the role of toll-like receptors (TLRs), a class of innate immune receptors that rapidly respond to microbial assaults., Materials and Methods: To determine whether TLRs are expressed by vulvar fibroblasts and whether these contribute to proinflammatory mediator production and pain in LPV, we examined TLR expression and innate immune responses in fibroblasts derived from painful vestibular regions compared with nonpainful external vulvar regions., Results: Human vulvar fibroblasts express functional TLRs that trigger production of inflammatory mediators associated with chronic pain. We focused on the TLR-7-imiquimod proinflammatory interaction, because imiquimod, a ligand of TLR-7, may exacerbate pain in women during treatment of human papillomavirus-associated disease., Conclusions: Human vulvar fibroblasts express a broad spectrum of TLRs (a new finding). A significantly higher TLR-mediated proinflammatory response was observed in LPV case vestibular fibroblasts, and with respect to the imiquimod-TLR 7 interaction, development of chronic vestibular pain and inflammation may be a possible sequelae of treatment of vulvar human papillomavirus-associated disease. Suppressing enhanced TLR-associated innate immune responses to a spectrum of pathogen-associated molecular patterns may represent a new/effective therapeutic approach for vulvodynia.

Objective: To evaluate the histologic features of vestibular biopsies from patients affected by fibro myalgia (FM), or vulvodynia (VD), or the their association (FM-VD) in order to facilitate differential diagnosis among conditions that present sexual pain with similar clinical characteristics., Study Design: Fourty-four women already diagnosed with FM were recruited to evaluate the presence of sexual pain not owing to FM. Fourteen women affected by sexual pain of unknown origin who came to our department requesting treatment were also recruited. All subjects were interviewed regarding their history of pain and examined in order to exclude vaginal conditions. Sexual pain did not show the characteristics of VD in 18 FM women; in the remaining 22 women VD resulted as associated with FM. All fourteen self-referred women were diagnosed with VD. All subjects underwent a posterior vestibular biopsy at the fourchette under local anesthesia. Tissue specimens were processed for histologic examination and immunostained for S-100protein and CD34. Statistical analysis was performed with the Pearson's Chisquare test., Results: Data analysis showed a statistically significant prevalence of inflammation in the VD group. Analysis of the histologic features showed that the concomitant presence of inflammation, nerve bundles, and fibrosis (often mild) is prevalent in VD. Fibrosis is highly frequent and often moderate/severe in FM and it is rarely associated to inflammation and nerve bundles. FM-VD women show intermediate grading., Conclusions: Our findings show different histologic characteristics in vestibular biopsy in patients affected by Fibro Myalgia, by Vulvodynia or by their association that could be useful to facilitate the differential diagnosis between conditions of sexual pain with similar clinical characteristics., (© Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Provoked vestibulodynia manifests as allodynia of the vulvar vestibular mucosa. The exact mechanisms that result in altered pain sensation are unknown. Recently, we demonstrated the presence of secondary lymphoid tissue, which is the vestibule-associated lymphoid tissue in the vestibular mucosa, and showed that this tissue becomes activated in provoked vestibulodynia., Objective: The purpose of this study was to examine whether expression of intraepithelial nerve fibers and nerve growth factor are related to immune activation in provoked vestibulodynia., Study Design: Vestibular mucosal specimens were obtained from 27 patients with severe provoked vestibulodynia that was treated by vestibulectomy and from 15 control subjects. We used antibodies against the protein gene product 9.5, the neuron specific neurofilament, and nerve growth factor for immunohistochemistry to detect intraepithelial nerve fibers and nerve growth factor expressing immune cells in the vestibular mucosa. For intraepithelial nerve fibers, we determined their linear density (fiber counts per millimeter of the outer epithelial surface, protein gene product 9.5) or presence (neuron specific neurofilament). Nerve growth factor was analyzed by counting the staining-positive immune cells. Antibodies against CD20 (B lymphocytes) and CD3 (T lymphocytes) were used to identify and locate mucosal areas with increased density of lymphocytes and the presence of germinal centers (ie, signs of immune activation). B-cell activation index was used to describe the overall intensity of B-cell infiltration., Results: We found more protein gene product 9.5-positive intraepithelial fibers in vestibulodynia than in the control samples (6.3/mm [range, 0.0-15.8] vs 2.0/mm [range, 0.0-12.0]; P=.006). Neuron specific neurofilament -positive intraepithelial fibers were found in 17 of 27 vestibulodynia cases (63.0%) and in none of the control cases. Protein gene product 9.5-positive intraepithelial fibers were more common in samples with more pronounced immune activation. The density of these fibers was higher in samples with than without germinal centers (6.1/mm [range, 4.3-15.8] vs 3.0/mm [range, 0.0-13.4]; P=.020). A positive correlation between the fiber density and B-cell activation index score of the sample was found (Spearman's Rho, 0.400; P=.004; R 2 =0.128). No significant difference, however, was found in the density or presence of nerve fibers between samples with high and low T-cell densities. We identified areas of minor and major vestibular glands in 16 of the patient samples and in 1 control sample. Protein gene product 9.5-positive nerve fibers were found more often in glandular epithelium surrounded by B-cell infiltration than in glands without B cells (P=.013). Also, the presence of neuron specific neurofilament-positive fibers in glandular epithelium was associated with B-cell infiltrates (P=.053). Nerve growth factor-positive immune cells were more common in mucosal areas with than without B-cell infiltration and intraepithelial nerve fibers., Conclusion: Excessive epithelial nerve growth in provoked vestibulodynia is associated with increased B-cell infiltration and the presence of germinal centers. This supports the fundamental role of immune activation in provoked vestibulodynia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To synthesize and critically evaluate all available evidence investigating whether localized, provoked vestibulodynia is associated with a specific inflammatory profile at both a local and a systemic level., Data Sources: Comprehensive electronic searches were performed in MEDLINE, EMBASE, Scopus, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Collaboration databases, and ClinicalTrials.gov. The search strategy was developed using MeSH terms related to localized, provoked vestibulodynia, and inflammatory markers., Methods of Study Selection: Two independent investigators screened titles and abstracts and performed data extraction and risk of bias assessments. Studies were included if they reported at least one baseline inflammatory marker in women with localized, provoked vestibulodynia and compared them with healthy women. Reference lists from published reviews on localized, provoked vestibulodynia were screened for additional studies., Tabulation, Integration, and Results: There were 1,619 studies identified. Eighteen studies met the inclusion criteria, including 400 women with localized, provoked vestibulodynia and 212 healthy women in a control group. Risk of bias assessment revealed that the methodologic quality was generally low. Fifteen studies investigated local inflammation and three studies investigated systemic inflammation. On a local level, the number of mast cells expressed in vestibular tissues was greater in women with localized, provoked vestibulodynia expressed than in women in the control group. Several studies reported undefined inflammatory infiltrate in vestibular tissues to a greater level in women with localized, provoked vestibulodynia than in women in the control group. Systemically, levels of natural killer cells were lower in women with localized, provoked vestibulodynia than in women in the control group. There were no systemic differences in systemic interferon-α and interferon-υ levels between groups., Conclusion: There is limited and contradictory evidence regarding the characteristics of local and systemic inflammation in women with localized, provoked vestibulodynia.

Objectives: To identify whether mast cell densities in vulvar biopsies from the vestibule are associated with vulvodynia., Methods: We enrolled 100 women aged 19 to 59 years with confirmed vulvodynia cases, 100 racially matched controls, and 100 black control women. All had vulvar biopsies performed at the 7 o'clock position of the vestibule, which were then immunostained to detect c-KIT protein. The numbers of c-KIT positive mast cells per ×400 magnification field were manually counted, and t tests and logistic regression were used to assess the association with case-control status., Results: Of the biopsies, 235 were adequate samples for c-KIT testing for mast cells. The mast cell density was substantially lower in black control women (13.9 ± 10.9) in comparison to white control women (22.5 ± 13.2 p < 0.001): hence the analysis was confined to white cases and racially matched control women. Compared with racially matched controls, cases were younger, more likely to be married, and reported a higher household income. The average number of mast cells per ×400 magnification field overall was 19.1 ± 13.2 (range, 0-62). There was no difference in the mast cell count between racially matched cases (22.4 ± 13.9 per ×400 field) and controls (22.5 ± 13.2) in either the univariate or multivariable analyses. Within the group of cases, there was no difference in mast cell density based on the presence or absence of a variety of urogenital symptoms., Conclusions: No difference in mast cell density in biopsies of the vestibule was found between white cases and racially matched controls. Black control women have a lower mast cell density compared with white control women.

Introduction: Pelvic floor muscle (PFM) involvement is suspected in the pathophysiology of provoked vestibulodynia (PVD); however, the underlying mechanisms are unclear. PFM morphology can be inferred from the biometry of the levator hiatus determined through dynamic ultrasound imaging., Aims: The aim of this study was to determine the nature of PFM involvement in women with PVD via an evaluation of the biometry of the levator hiatus at rest, upon maximal voluntary contraction (MVC) of the PFMs, and upon maximal Valsalva maneuver (MVM)., Methods: Thirty-eight women with PVD and 39 asymptomatic controls were imaged using 3D transperineal ultrasound. Levator hiatal dimensions (area; left-right [LR] and anteroposterior [AP] diameters) were measured at rest, on MVC, and on MVM. Differences in hiatal dimensions and in relative changes in dimensions from rest to MVC and from rest to MVM were compared between groups using separate 1-way analyses of variance for each measure and task. Analysis of covariance models were used to investigate the impact of levator hiatal dimensions at rest on the relative changes in the levator hiatal dimensions during MVC and MVM., Main Outcome Measures: Levator hiatal area, LR, and AP diameters, at rest, on MVC, and on MVM were the main outcome measures. Relative changes in hiatal dimensions were assessed as the percent change in hiatal area, LR diameter, and AP diameter., Results: In comparison with controls, women with PVD had smaller hiatal areas at rest, on MVC, and on MVM, concurrent with smaller LR diameters on MVM. Women with PVD had a significantly smaller change in hiatal area on MVM than controls, but no differences were evident on MVC. In both groups, smaller levator hiatal dimensions at rest were associated with smaller relative decreases in dimensions on MVC and larger relative increases in dimensions on MVM., Conclusion: In comparison to controls, women with PVD appear to have narrower levator hiatus' and less capacity to distend their hiatus on Valsalva. The state of the PFMs at rest appears to significantly influence biometric changes in the PFMs during contraction and Valsalva., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Objective: The aims of the study were to define the heterogeneity of vulvodynia by determining data-driven subgroups within the vulvodynia diagnosis using exploratory cluster analysis and to characterize the subgroups identified., Materials and Methods: Included were participants in the longitudinal population-based study of vulvodynia in southeast Michigan who screened positive for vulvodynia at least once during the study. A cluster analysis using variables reflecting vulvar pain characteristics and comorbid pain conditions was conducted. Variables reflecting best separation of clusters were used to assign participants to subgroup categories. Demographic, psychiatric, general health, and other vulvar pain characteristics were summarized for each subgroup, followed by multinomial regression and pairwise comparisons of subgroups on these factors., Results: Of 441 women screening positive for vulvodynia during the course of the study, 393 were eligible on the basis of data requirements. Cluster analysis suggested that best subgroup separation was based on the following 2 variables: (1) presence or absence of spontaneous vulvar pain and (2) presence or absence of other comorbid pain conditions. Subgroups did not differ by age or ethnicity. The subgroup having spontaneous pain and other comorbid conditions demonstrated greatest morbidity in general health measures, psychiatric disorders, and other vulvar pain measures. Primary versus secondary vulvodynia did not vary between subgroups and did not assist in subgroup separation in the cluster analysis., Discussion: Subgroups based on exploratory cluster analysis demonstrated that presence of spontaneous pain and the presence of comorbid pain conditions resulted in best separation of groups. Presence of both spontaneous pain and other comorbid pain conditions identified the group with greatest morbidity.

Aim: Pelvic floor muscle (PFM) dysfunctions, especially elevated tone or tension, are suggested to play an important role in the pathophysiology of provoked vestibulodynia (PVD). However, the involvement of the PFMs remains misunderstood as the assessment of muscle tone is complex and requires a thorough understanding of muscle physiology in relation to the characteristics and limitations of current PFM assessment tools. The aim of this review was to describe the structures and mechanisms involved in muscle tone in normally innervated muscle, and to discuss and relate these concepts to the PFM findings in women with PVD., Methods: A narrative overview of the literature retrieved from searches of electronic databases and hand searches., Results: Muscle tone in a normally innervated muscle comprises both active (contractile) and passive (viscoelastic) components. Current methods for evaluating PFM tone such as digital palpation, ultrasound imaging, pressure perineometry, dynamometry, and electromyography may evaluate different components. Research findings suggestive of PFM hypertonicity in women with PVD include elevated general PFM tone, changes in viscoelastic properties, and at least in some women, abnormal increases in electrogenic activity., Conclusion: There is a growing body of evidence to support the involvement of PFM hypertonicity in the pathophysiology of PVD. Limitations of the instruments as well as their properties should be considered when evaluating PFM tone in order to obtain better insight into which component of PFM tone is assessed. Future research is required for further investigating the underlying mechanisms of PFM hypertonicity, and studying the specific effects of physiotherapeutic interventions on PFM tone in women with PVD., (© 2015 International Society for Sexual Medicine.)

Background: The prevalence of vulvodynia has been reported to be lower in black compared to white and Latina women. Use of different terminology to describe vulvar pain symptoms may play a role in lower prevalence. The objectives were to compare pain descriptors used by black and white women with provoked vulvodynia (PVD) to determine the effect of race on symptom reporting., Methods: Ninety-two women, self-identified as black (n = 55) and white (n = 37) with clinically confirmed PVD completed a questionnaire containing demographic information and vulvar pain characteristics. Variables that were significant with race retained in the logistic regression model were included in multivariate analysis to determine the effect of race on reporting of vulvar pain symptoms., Results: Of statistical significance, white women more often described their pain as burning as compared with black women (84% vs. 22%, p ≤ 0.0001). White women more frequently reported their pain as stinging (51% vs. 29%, p = 0.03) and itching (32% vs. 15%, p = 0.04) as well, whereas there was a trend for black women to more often describe their pain as aching (67% vs. 49%, p = 0.07). Overall, white women were 19 times as likely to report their pain as burning (adjusted odds ratio [aOR] 18.51, 99% confidence interval [CI] 4.46-76.86)., Conclusions: These data suggest that black women are less likely to self-report their vulvar pain as burning, the classic symptom of PVD. Cultural influences and different underlying pain mechanisms may contribute to differences in symptom reporting by race.

Vulvar pain affecting the vestibule (vestibulodynia) is an enigmatic pain disorder that greatly affects quality of life and sexual functioning. The most common form of the disorder (localized provoked vulvodynia) is initiated by genital contact but is otherwise asymptomatic. Findings on examination are limited to excessive tenderness of the vestibule with light touch with cotton swab but may also include localized erythema and pelvic floor muscle tightness and tenderness. This review will summarize the literature regarding the role of inflammation in the genesis of the disorder. Some evidence exists for altered histology consisting of increased numbers of mast cells and nerve endings. Immunological abnormalities that have been reported include altered cytokines and neurokines. Abnormal inflammatory response and heightened sensitivity of the vaginal opening has been documented in a murine model of vaginal infection with Candida albicans. In vitro studies of fibroblasts from the vestibule of affected women with vestibulodynia demonstrate a proinflammatory response to C albicans that may be important in the initiation of pain. However, thus far none of the findings have led to adequate treatments., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Vuval pathologies manifested by allodynia and burning sensations can be due to infection, inflammatory dermatoses or other causes. Infective as well as certain inflammatory diseases, e.g. drug eruptions, allergic eczemas, irritative dermatitis/vulvitis, Behcet's Syndrome and pemphigus/pemphigoid usually respond well to conservative treatment. The category of inflammatory diseases also contains pathologies that in certain circumstances do require a surgical intervention, e.g. Lichen ruber planus/Lichen sclerosus, Condyloma, scars, premalignant lesions (VIN, genital M. Paget) and cancer. Vulodynia also can cause some stinging to the vulvar skin. The surgical aspects relating to the treatment of the benign and premalignant pathologies indicated above are mentioned in this mini-review.

Mast cell infiltrates in tissues of vulvodynia are common, but they have not been characterized for criteria of neoplastic mast cell disease or correlated with patient's concomitant diseases associated with increased mast cells. Formalin-fixed specimens of 35 patients with vulvodynia were evaluated immunohistochemically with antibodies to CD 3,4,8,20,117c and human mast cell tryptase, and for WHO-criteria of neoplastic mastocytosis (>25% spindled mast cell, CD25 expression, point mutations of the c-kit gene (D816V), and chronically elevated serum tryptase levels). Only 20/35 specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm(2) , 15/35 specimens 40-60 mast cells/mm(2) and 16/35 specimens >60 mast cells/mm(2) (average 80/mm(2) ). Control tissue contained typically <10 mast cells/mm(2) . Spindling, CD25-expression, c-kit gene mutations, or increased serum tryptase levels were not detected. 26/35 (74%) patients had concomitant autoimmune diseases, psoriasis, atopy, various allergies, preceding infections. Independent of the subtype of vulvodynia, the majority of mast cell rich biopsies with >40 mast cells/mm(2) were classified as a secondary mast cell disorder reflecting an activated immune system in 75% of vulvodynia patients. Patients with increased mast cells may benefit from medical therapy targeting mast cells., (© 2015 APMIS. Published by John Wiley & Sons Ltd.)

Objective: Localized provoked vulvodynia (LPV) may have inflammatory etiology. We wanted to find out whether the cell-mediated immune system becomes activated in the vestibular mucosa in LPV., Study Design: This was a controlled cross-sectional study. Vestibular mucosal specimens were obtained from 27 patients with severe LPV and 15 controls. Detailed clinical history of the patients was obtained. For immunohistochemistry, antibodies against CD3 (T cells), CD20 (B cells), IgA (mucosal plasma cells), CD163 (dendritic cells [DCs]), CD68 (macrophages), and CD117 (mast cells) were employed. Mann-Whitney U test and χ(2) test were used for statistical analyses., Results: More B lymphocytes and mature mucosal IgA-plasma cells were found in patients than in controls (P < .001 and P < .001, respectively). In LPV samples, B and T cells were arranged into germinal centers representing local immune activation. Germinal centers were not seen in controls. Antigen-presenting DCs and macrophages were found both in patients and controls with similar densities. DCs were found to extend their dendrites into the luminal space through an intact epithelium. Similar amounts of mast cells were found evenly scattered throughout the stroma of vestibular mucosa of both patients and controls., Conclusion: We demonstrate here local organized vestibule-associated lymphoid tissue analogous to mucosa-associated lymphoid tissue. Vestibule-associated lymphoid tissue may emerge as a response to local infection or inflammation in LPV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fibroblast strains were derived from 2 regions of the lower genital tract of localized provoked vulvodynia (LPV) cases and pain-free controls. Sixteen strains were derived from 4 cases and 4 controls, age and race matched, after presampling mechanical pain threshold assessments. Strains were challenged with 6 separate stimuli: live yeast species (Candida albicans, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae), yeast extract (zymosan), or inactive vehicle. Production of prostaglandin E2 (PGE2) and interleukin 6 (IL-6) were proinflammatory response measures. Highest IL-6 and PGE2 occurred with vestibular strains after C albicans, C glabrata, and zymosan challenges, resulting in the ability to significantly predict IL-6 and PGE2 production by genital tract location. After C albicans and C glabrata challenge of all 16 fibroblast strains, adjusting for dual sampling of subjects, PGE2 and IL-6 production significantly predicted the presampling pain threshold from the genital tract site of sampling. At the same location of pain assessment and fibroblast sampling, in situ immunohistochemical (IHC)(+) fibroblasts for IL-6 and Cox-2 were quantified microscopically. The correlation between IL-6 production and IL-6 IHC(+) was statistically significant; however, biological significance is unknown because of the small number of IHC(+) IL-6 fibroblasts identified. A low fibroblast IL-6 IHC(+) count may result from most IL-6 produced by fibroblasts existing in a secreted extracellular state. Enhanced, site-specific, innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in LPV pathogenesis. Fibroblast strain testing may offer an attractive and objective marker of LPV pathology in women with vulvodynia of inflammatory origin.

Provoked vestibulodynia, a female pelvic pain syndrome affecting substantial numbers of women, is characterized by genital hypersensitivity and sensory hyperinnervation. Previous studies have shown that the risk of developing provoked vestibulodynia is markedly elevated following adolescent use of oral contraceptives with high progesterone content. We hypothesized that progesterone, a steroid hormone with known neurotropic properties, may alter genital innervation through direct or indirect actions. Female Sprague Dawley rats received progesterone (20 mg/kg subcutaneously) from Days 20-27; tissue was removed for analysis in some rats on Day 28, while others were ovariectomized on Day 43 and infused for 7 days with vehicle or 17beta estradiol. Progesterone resulted in overall increases in vaginal innervation at both Day 28 and 50 due to proliferation of peptidergic sensory and sympathetic (but not parasympathetic) axons. Estradiol reduced innervation in progesterone-treated and untreated groups. To assess the mechanisms of sensory hyperinnervation, we cultured dissociated dorsal root ganglion neurons and found that progesterone increases neurite outgrowth by small unmyelinated (but not myelinated) sensory neurons, it was receptor mediated, and it was nonadditive with NGF. Pretreatment of ganglion with progesterone also increased neurite outgrowth in response to vaginal target explants. However, pretreatment of vaginal target with progesterone did not improve outgrowth. We conclude that adolescent progesterone exposure may contribute to provoked vestibulodynia by eliciting persistent genital hyperinnervation via a direct effect on unmyelinated sensory nociceptor neurons and that estradiol, a well-documented therapeutic, may alleviate symptoms in part by reducing progesterone-induced sensory hyperinnervation., (© 2014 by the Society for the Study of Reproduction, Inc.)

Objective: To better understand the potential disease triggers of neurogenic inflammation in provoked localized vulvodynia (PLV), our objective was to determine whether the types of infiltrating lymphocytes were different in vestibular biopsies from women with primary PLV, secondary PLV, and unaffected controls., Methods: Secondary retrospective analysis of archived vestibular biopsies from a series of adult premenopausal women with primary PLV (n = 10), secondary PLV (n = 10), and unaffected controls (n = 4) was performed. All study patients had severe entry dyspareunia for more than 1 year. Subjects were excluded if pregnant, or they had a known infection, or history of generalized vulvodynia. Biopsies were performed during the midfollicular phase. Lymphocyte subtypes were highlighted in histologic sections using antibodies against CD3, CD4, and CD8 and scored as the mean number of T-cell subtypes per high-power field. Flow cytometry was also used to test fresh biopsies from a de novo prospective series of primary PLV (n = 4) and unaffected controls (n = 2)., Results: Unaffected control biopsies showed more CD8-positive than CD4-positive T cells, similar to previous reports of the gynecologic tract. In contrast, biopsies from women with primary PLV showed significantly more CD4-positive T cells than those from women with secondary PLV and unaffected controls (p = .003). This observation was further supported by flow cytometry., Conclusions: CD4-positive T cells are more numerous in vestibular biopsies from premenopausal women with primary PLV. This may be important because subtypes of CD4-positive T cells are specifically recruited by infectious, allergic, or autoimmune triggers. Future studies distinguishing these subtypes may lead to new insights into this common disease.

Objective: This study aimed to determine whether histology can predict response to vestibulectomy in the management of provoked vestibulodynia., Materials and Methods: Inflammatory cell, mast cell, and nerve fiber counts were determined in prospectively collected vulvar vestibulectomy specimens from 30 women treated surgically for provoked vestibulodynia., Results: Twenty-three subjects (77%) had a complete early response to surgery. At 3 years of follow-up, this had increased to 28 (93%), with a 29th showing some improvement. No subject had gotten worse after surgery or in the 3 years of follow-up. When comparing patients with an early complete response with those patients who still had symptoms, no difference in lymphocyte counts (27.6 vs. 37.8 per mm), mast cell counts (110.4 vs. 97.8 per mm), or stromal nerve fiber counts (16.4 vs. 16.4 per mm) was found., Conclusions: Vestibulectomy is a very effective treatment option in women with provoked vestibulodynia who have had failed conservative treatment. Histology is unable to predict which patients will respond to surgery.

Introduction: It has been suggested that pelvic floor muscles (PFMs) play an important role in provoked vestibulodynia (PVD) pathophysiology. Controversy in determining their exact contribution may be explained by methodological limitations related to the PFM assessment tools, specifically the pain elicited by the measurement itself, which may trigger a PFM reaction and introduce a strong bias., Aim: The aim of this study was to compare PFM morphometry in women suffering from PVD to asymptomatic healthy control women using a pain-free methodology, transperineal four-dimensional (4D) ultrasound., Methods: Fifty-one asymptomatic women and 49 women suffering from PVD were recruited. Diagnosis of PVD was confirmed by a gynecologist following a standardized examination. All the participants were nulliparous and had no other urogynecological conditions. The women were evaluated in a supine position at rest and during PFM maximal contraction., Main Outcome Measures: Transperineal 4D ultrasound, which consists of a probe applied on the surface of the perineum without any vaginal insertion, was used to assess PFM morphometry. Different parameters were assessed in sagittal and axial planes: anorectal angle, levator plate angle, displacement of the bladder neck, and levator hiatus area. The investigator analyzing the data was blinded to the clinical data., Results: Women with PVD showed a significantly smaller levator hiatus area, a smaller anorectal angle, and a larger levator plate angle at rest compared with asymptomatic women, suggesting an increase in PFM tone. During PFM maximal contraction, smaller changes in levator hiatus area narrowing, displacement of the bladder neck, and changes of the anorectal and of the levator plate angles were found in women with PVD compared with controls, which may indicate poorer PFM strength and control., Conclusion: Using a reliable and pain-free methodology, this research provides sound evidence that women with PVD display differences in PFM morphometry suggesting increased tone and reduced strength., (© 2013 International Society for Sexual Medicine.)

Objective: To assess whether premenopausal and postmenopausal vestibulodynia have different histologic features., Methods: We conducted a retrospective analysis of vestibulectomy specimens from 21 women with postmenopausal vestibulodynia and compared them with 88 premenopausal patients (42 primary, 46 secondary). Women with primary vestibulodynia experienced pain at first introital touch and women with secondary vestibulodynia experienced pain after an interval of painless intercourse. Clinical records established the type of vestibulodynia, duration of symptoms, and hormone status. Tissues were stained for inflammation, nerves, mast cells, estrogen receptor α, and progesterone receptor. Histologic findings in the postmenopausal patients were compared with primary and secondary premenopausal patients using proportional odds logistic regression and analysis of variance., Results: Seventy-one percent (15/21) of postmenopausal women reported vestibular dyspareunia related to a drop in estrogen either with menopause (13/21) or previously, postpartum (2/21). Eighty-six percent (18/21) of postmenopausal patients were using local or systemic estrogen but pain persisted. Compared with premenopausal primary and secondary vestibular biopsies, postmenopausal tissues had more lymphocytes (unadjusted odds ratio [OR] 9.0, 95% confidence interval [CI] 2.8-33.3; adjusted OR for parity and duration of symptoms 9.1, 95% CI 2.6-31.9; unadjusted OR 6.2, 95% CI 1.9-20.0; adjusted OR 6.6, 95% CI 2.0-21.9, respectively) and mast cells (mean 36 compared with 28 and 36 compared with 26, respectively). There was significantly less neural hyperplasia and progesterone receptor expression in postmenopausal biopsies compared with primary cases but less progesterone receptor and similar neural hyperplasia compared with premenopausal secondary cases. Estrogen receptor α did not vary among groups., Conclusion: Premenopausal and postmenopausal vestibulodynia share histologic features of neurogenic inflammation but differ strikingly in degree. When estrogen supplement does not alleviate symptoms of postmenopausal dyspareunia, vestibulodynia should be considered., Level of Evidence: : II.

Unlabelled: Vulvodynia (VVD) is a chronic pain disorder wherein women display sensitivity to evoked stimuli at the vulva and/or spontaneous vulvar pain. Our previous work suggests generalized hyperalgesia in this population; however, little is known about central neurobiological factors that may influence pain in VVD. Here we investigated local (vulvar) and remote (thumb) pressure-evoked pain processing in 24 VVD patients compared to 13 age-matched, pain-free healthy controls (HCs). As a positive control we also examined thumb pressure pain in 24 fibromyalgia patients. The VVD and fibromyalgia patients displayed overlapping insular brain activations that were greater than HCs in response to thumb stimulation (P < .005 corrected). Compared to HCs, VVD participants displayed greater levels of activation during thumb stimulation within the insula, dorsal midcingulate, posterior cingulate, and thalamus (P < .005 corrected). Significant differences between VVD subgroups (primary versus secondary and provoked versus unprovoked) were seen within the posterior cingulate with thumb stimulation and within the precuneus region with vulvar stimulation (provoked versus unprovoked only). The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder. Moreover, differing central activity between VVD subgroups suggests heterogeneous pathologies within this diagnosis., Perspective: The presence of augmented brain responses to pressure stimuli remote from the vulva was observed in vulvodynia patients. These findings may guide treatment decisions for better response, as brain mechanisms may be a factor in some VVD patients., (Copyright © 2013 American Pain Society. All rights reserved.)

Objective: To estimate the effectiveness of enoxaparin-a low-molecular-weight heparin with antiheparanase properties-in treating localized provoked vulvodynia., Methods: Forty women with severe localized provoked vulvodynia were randomly and blindly assigned to self-administer either 40 mg enoxaparin or saline subcutaneously for 90 days. Dyspareunia and local sensitivity were evaluated before, at the end, and 90 days after treatment. The most painful focus was biopsied at the beginning of the study and a parallel site at the end of study for mast cells, PGP 9.5 nerve fiber staining, and heparanase quantification., Results: The enoxaparin-treated women showed a greater reduction in vestibular sensitivity at the end of treatment and 3 months later (29.6% compared with 11.2%, P=.004). Seventy-five percent (15 of 20) of them reported more than 20% pain reduction compared with 27.8% (five of 18) in the placebo group (P=.004). Seven enoxaparin-treated women compared with three in the placebo group had almost painless intercourse at the end of the study. In women who had improvement of sensitivity at the site parallel to the original biopsy site, there was a histologically documented reduction in the number of intraepithelial-free nerve fibers in the enoxaparin group., Conclusion: Enoxaparin reduced the vestibular sensitivity and dyspareunia, concomitant with a reduction in intraepithelial free nerve fibers, in women with localized provoked vulvodynia.

The article is devoted to combined affection of the lower urinary tracts and genitalia in women with human papilloma virus (HPV) infection which manifests with persistent recurrent urethritis, pelvic pain syndrome. The colposcopic and urethrocystoscopic features, disturbed microcirculation of urethral and vaginal mucosa in virus infection promoting recurrences and persistence of HPV are discussed. Immunomodulators (inosin pranobex-groprinosin) are recommended for more effective treatment.

Symptoms and signs of patients with focal vulvodynia or vulvo-vestibulitis syndrome (VVS) are variable in location and severity. It is not known whether the location of the most severe pain in the vestibulum is linked to the complaints and perhaps a different entity. A clinical gut feeling suggests that two distinct varieties of focal vulvodynia may be either focused at 2 points (5 and 7 o' clock) or at 4 points (5, 7, 1 and 11 o' clock). A questionnaire was filled out by 30 women with focal vulvodynia during 147 visits and checked for completeness by an independent study nurse. Another investigator to evaluated the clinical signs of VVS, blinded to the patients history or complaints. The visual analogue score (VAS) of pain experienced upon attempt of sexual contact was used as a marker of severity. Focal vulvar pain was assessed using Q-tip with a score from 1 to 10 on 7 areas of the vestibulum. Besides pain during sexual contact, 47% also had pain on inserting a tampon. More than 40% of women suffer since more than 3 years, 70% had to interrupt the act of sexual intercourse mostly or always due to unbearable pain and 25% never had satisfactory sex due to this pain. Feeling deep pain, burning lasting for 12-24h after sexual contact, and stopping the attempt of intercourse were more prominent in women with high pain scores (VAS): 26% of women with VAS>7 had no sex during the last year versus 6% in the group with low pain score (p=0.004). Patients suffering from para-urethral pain zones at 1 and 11 o' clock, have more often pain upon deep penetration, and experienced more pain when inserting tampons than patients with only painful areas at 5 and 7 o' clock (p=0.001). We conclude that patients with severe disease display a different panel of complaints than women with less pain. Patients with focal pain at 1 and 11 o' clock have more deep pain sensations, but feel less pain during insertion of tampons. Hence disease with bi-focal disease may have a different ethiopathogenesis that 4-focal disease. Glands of Bartholin and Skene may be involved in this pathogenenis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To investigate the clinical correlates of central nervous system alterations among women with vulvodynia. Altered central sensitization has been linked to dysfunction in central nervous system-inhibitory pathways (e.g., γ-aminobutyric acidergic), and metrics of sensory adaptation, a centrally mediated process that is sensitive to this dysfunction, could potentially be used to identify women at risk of treatment failure using conventional approaches., Methods: Twelve women with vulvodynia and 20 age-matched controls participated in this study, which was conducted by sensory testing of the right hand's index and middle fingers. The following sensory precepts were assessed: (1) vibrotactile detection threshold; (2) amplitude discrimination capacity (defined as the ability to detect differences in intensity of simultaneously delivered stimuli to 2 fingers); and (3) a metric of adaptation (determined by the impact that applying conditioning stimuli have on amplitude discriminative capacity)., Results: Participants did not differ on key demographic variables, vibrotactile detection threshold, and amplitude discrimination capacity. However, we found significant differences from controls in adaptation metrics in 1 subgroup of vulvodynia patients. Compared with healthy controls and women with a shorter history of pain [n=5; duration (y) = 3.4 ± 1.3], those with a longer history [n=7; duration (y) = 9.3 ± 1.4)] were found to be less likely to have adaptation metrics similar to control values., Discussion: Chronic pain is thought to lead to altered central sensitization, and adaptation is a centrally mediated process that is sensitive to this condition. This report suggests that similar alterations exist in a subgroup of vulvodynia patients.

Provoked vestibulodynia, the most common form of vulvodynia (unexplained pain of the vulva), is a prevalent, idiopathic pain disorder associated with a history of recurrent candidiasis (yeast infections). It is characterized by vulvar allodynia (painful hypersensitivity to touch) and hyperinnervation. We tested whether repeated, localized exposure of the vulva to a common fungal pathogen can lead to the development of chronic pain. A subset of female mice subjected to recurrent Candida albicans infection developed mechanical allodynia localized to the vulva. The mice with allodynia also exhibited hyperinnervation with peptidergic nociceptor and sympathetic fibers (as indicated by increased protein gene product 9.5, calcitonin gene-related peptide, and vesicular monoamine transporter 2 immunoreactivity in the vaginal epithelium). Long-lasting behavioral allodynia in a subset of mice was also observed after a single, extended Candida infection, as well as after repeated vulvar (but not hind paw) inflammation induced with zymosan, a mixture of fungal antigens. The hypersensitivity and hyperinnervation were both present at least 3 weeks after the resolution of infection and inflammation. Our data show that infection can cause persistent pain long after its resolution and that recurrent yeast infection replicates important features of human provoked vulvodynia in the mouse.

Objective: To assess whether primary and secondary vestibulodynia represent different pathologic pathways., Methods: This was an analysis of archived vestibulectomy specimens from 88 premenopausal women with vestibulodynia (2002-2008). Patient records were reviewed to classify the type of vestibulodynia, duration of symptoms, and hormone status. Histologic sections were stained for hematoxylin and eosin to grade inflammation, S100 to highlight nerves, CD117 for mast cells, estrogen receptor α, and progesterone receptor. Differences between primary and secondary vestibulodynia were tested by t tests, chi-square analysis, and linear and logistic regression., Results: Primary vestibulodynia showed significant neural hypertrophy and hyperplasia (P=.02, adjusted odds ratio [OR] 3.01, 95% confidence interval [CI] 1.2-7.6) and increased progesterone receptor nuclear immunostaining (P=.004, adjusted OR 3.94, CI 1.6-9.9) compared with secondary vestibulodynia. Estrogen receptor α expression was also greater in primary vestibulodynia when symptom diagnosis was less than 5 years (P=.004, adjusted OR 5.53 CI 1.71-17.91)., Conclusion: Primary and secondary vestibulodynia have significantly different histologic features, suggesting that they may have separate mechanistic pathways. Clinically, this may mean the discovery of distinct conditions.

Introduction: Provoked vestibulodynia (PVD) is a highly prevalent vulvovaginal pain condition that results in significant sexual dysfunction, psychological distress, and reduced quality of life. Although some intra-individual psychological factors have been associated with PVD, studies to date have neglected the interpersonal context of this condition., Aim: We examined whether partner responses to women's pain experience-from the perspective of both the woman and her partner-are associated with pain intensity, sexual function, and sexual satisfaction., Methods: One hundred ninety-one couples (M age for women=33.28, standard deviation [SD]=12.07, M age for men=35.79, SD=12.44) in which the woman suffered from PVD completed the spouse response scale of the Multidimensional Pain Inventory, assessing perceptions of partners' responses to the pain. Women with PVD also completed measures of pain, sexual function, sexual satisfaction, depression, and dyadic adjustment., Main Outcome Measures: Dependent measures were women's responses to: (i) a horizontal analog scale assessing the intensity of their pain during intercourse; (ii) the Female Sexual Function Index; and (iii) the Global Measure of Sexual Satisfaction Scale., Results: Controlling for depression, higher solicitous partner responses were associated with higher levels of women's vulvovaginal pain intensity. This association was significant for partner-perceived responses (β=0.29, P<0.001) and for woman-perceived partner responses (β=0.16, P=0.04). After controlling for sexual function and dyadic adjustment, woman-perceived greater solicitous partner responses (β=0.16, P=0.02) predicted greater sexual satisfaction. Partner-perceived responses did not predict women's sexual satisfaction. Partner responses were not associated with women's sexual function., Conclusions: Findings support the integration of dyadic processes in the conceptualization and treatment of PVD by suggesting that partner responses to pain affect pain intensity and sexual satisfaction in affected women., (© 2010 International Society for Sexual Medicine.)

Objective: The objective of the study was to assess the association between hormone receptor densities, pain nerves, and inflammation in vestibulodynia patients., Study Design: In a prospective study, tender and nontender biopsies from 10 primary and 10 secondary vestibulodynia patients were compared with biopsies in 4 nontender controls. Hormone receptors were evaluated using immunohistochemistry for estrogen receptor-alpha and -beta, androgen, and progesterone receptors. Inflammation, nerves, and mast cells were assessed histologically. Statistical analysis was by Fisher's exact test, analysis of variance, paired Student t test, and Wilcoxon rank test., Results: Tender sites from primary vestibulodynia had increased nerve density compared with secondary and control biopsies (P = .01). Tender sites in secondary vestibulodynia had more lymphocytes than tender primary sites and control biopsies (P < .0001). Mast cells were increased in tender sites compared with nontender and controls. There were no differences in hormone receptor expression., Conclusion: Markers of inflammation differed between primary and secondary vestibulodynia and controls., (Copyright 2010 Mosby, Inc. All rights reserved.)

Introduction: Physical therapy (PT) may reduce the pain associated with provoked vestibulodynia (PVD) based on previous findings that pelvic floor muscle dysfunction (PFMD) is associated with PVD symptoms., Aims: The goals of this study were: (i) to determine whether women with and without PVD differ on measures of pelvic floor muscle (PFM) behavior; and (ii) to assess the impact of PT treatment for women with PVD on these measures., Methods: Eleven women with PVD and 11 control women completed an assessment evaluating PFM behavior using surface electromyography (SEMG) recordings and a digital intravaginal assessment. Women with PVD repeated the assessment after they had undergone eight PT treatment sessions of manual therapy, biofeedback, electrical stimulation, dilator insertions, and home exercises., Main Outcome Measures: Superficial and deep PFM SEMG tonic activity and phasic activity in response to a painful pressure stimulus, PFM digital assessment variables (tone, flexibility, relaxation capacity, and strength)., Results: At pretreatment, women with PVD had higher tonic SEMG activity in their superficial PFMs compared with the control group, whereas no differences were found in the deep PFMs. Both groups demonstrated contractile responses to the painful pressure stimulus that were significantly higher in the superficial as compared with the deep PFMs, with the responses in the PVD group being higher than those in control women. Women with PVD had higher PFM tone, decreased PFM flexibility and lower PFM relaxation capacity compared with control women. Posttreatment improvements included less PFM responsiveness to pain, less PFM tone, improved vaginal flexibility, and improved PFM relaxation capacity, such that women with PVD no longer differed from controls on these measures., Conclusion: Women with PVD demonstrated altered PFM behavior when compared with controls, providing empirical evidence of PFMD, especially at the superficial layer. A PT rehabilitation program specifically targeting PFMD normalized PFM behavior in women with PVD.

Introduction: Intravesical potassium sensitivity has been reported in 82% of vulvodynia patients, suggesting the bladder generates their pain and indicating interstitial cystitis (IC)/painful bladder syndrome deserves greater attention in differential diagnosis of vulvodynia., Aims: The aims of this study were to: (i) determine the prevalence of IC as detected by intravesical potassium sensitivity; and (ii) survey for urinary, pelvic pain, and sexually associated symptoms in patients with vulvodynia., Methods: Consecutive patients with vulvodynia were surveyed for urinary and pelvic pain symptoms using the pelvic pain and urgency/frequency (PUF) questionnaire, and tested for abnormal epithelial permeability using the potassium sensitivity test (PST). Rates of positive PST were determined overall and by PUF score range, and were compared in patients with intermittent vs. constant vulvodynia symptoms., Main Outcome Measures: Results of intravesical PST., Results: Of 122 vulvodynia patients, 102 (84%) had a positive PST and 97 (80%) had urologic symptoms. Of the 87 sexually active patients, 81 (93%) reported pain associated with sex. Patients with constant (72/87, 83%) vs. intermittent symptoms (30/35, 86%) had no significant difference in rates of positive PST. Mean PUF score was 13.2. PUF scores of 3-4 were associated with an 86% rate of positive PST; scores 5-9, 44%; 10-14, 84%; 15-19, 87%; 20-24, 86%; and 25 and above, 100%., Conclusion: Most patients with vulvodynia have a positive PST and urgency/frequency, indicating pain of bladder origin (IC). IC deserves far greater consideration in the differential diagnosis of patients with vulvodynia. This represents a dramatic change for the gynecologic paradigm of vulvodynia, which in many cases appears to be referred pain from the urinary bladder.