Is Vulvodynia Associated With an Altered Vaginal Microbiota?: A Systematic Review.

INTRODUCTION: Vulvodynia is defined as vulvar pain of at least 3 months' duration, without clear identifiable cause, which may have potential associated factors. It can have a significant impact on women's quality of life due to a combination of physical pain, emotional distress, and limited treatment options. Despite affecting a considerable number of women worldwide, the causes and underlying mechanisms of vulvodynia remain poorly understood. Given the recognized association of the vaginal microbiota with various gynecologic disorders, there has been growing interest in exploring the potential role of the vaginal microbiota in the etiology of vulvodynia. This systematic review aims to evaluate the current literature on the association between the vaginal microbiota and vulvodynia. MATERIAL AND METHODS: A systematic search of multiple databases, including PubMed, Scopus, Web of Science, Cochrane Library, and Ovid MEDLINE, was conducted to identify relevant peer-reviewed studies up to May 12, 2023. The following search terms were used across these databases: "vulvodynia," "vestibulodynia," "vulvar vestibulitis," "microbiome," "microbiota," and "flora." RESULTS: A total of 8 case-control studies were included, the quality of which was assessed using the Newcastle-Ottawa Scale. Data extraction and synthesis were performed using a standardized protocol. In most studies, no major differences were found between the vaginal bacterial composition of women with vulvodynia and that of controls. No specific bacterial taxa were consistently associated with vulvodynia. The relationship between vaginal microbiota diversity and vulvodynia remains to be fully understood. CONCLUSIONS: The role of vaginal microbiota in vulvodynia, if any, remains unclear. Because of the cross-sectional nature of the included studies, it is not possible to make any causal inferences. Further research, using larger and more diverse study populations and advanced sequencing techniques, is necessary to gain a better understanding of the potential relationship between the vaginal microbiota and vulvodynia.

Effectiveness of Two Transcutaneous Electrical Nerve Stimulation (TENS) Protocols in Women with Provoked Vestibulodynia: A Randomized Controlled Trial.

BACKGROUND: Vestibulodynia (VBD) is the most common form of vulvodynia. Because VBD is a pain disorder, transcutaneous electrical nerve stimulation (TENS) can be used as treatment. This study aims to evaluate the effects of two-parameter combinations (frequency and pulse duration) of TENS in reducing pain intensity and dyspareunia in VBD. METHODS: A randomized, double-blind, controlled trial was conducted to study the effect of two different electrical stimulation treatment regimens on women with VBD receiving domiciliary TENS. Outcomes were the mean change from baseline at 60 and 120 days of burning/pain and dyspareunia (VAS), Vulvar Pain Functional Questionnaire (V-Q), Female Sexual Functioning Index (FSFI) and vaginal electromyography measurements. RESULTS: A total of 78 subjects, 39 in each group, completed the trial. Patients in Groups 1 and 2 received a mean of 46.9 and 48.4 TENS sessions. By day 120, there was a 38.2% reduction in the burning/pain and a 52.1% reduction in the dyspareunia VAS scores in Group 1, as compared to 21.3% (p = 0.003) and 23.1% in Group 2 (p = 0.01), respectively. FSFI, V-Q, and muscle-strength measures also improved but were not statistically significant. CONCLUSIONS: Our findings showed the potential of TENS in the treatment of VBD.

Neuroproliferative dyspareunia in endometriosis and vestibulodynia.

INTRODUCTION: Endometriosis is a common cause of deep dyspareunia, while provoked vestibulodynia is a common cause of superficial dyspareunia. The etiology of dyspareunia in both conditions is multifactorial and may include the role of local nerve growth (neurogenesis or neuroproliferation) that sensitizes pelvic structures and leads to pain with contact. OBJECTIVES: To review the evidence for neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia. METHODS: Narrative review. RESULTS: The pelvic peritoneum and vulvar vestibule receive somatic and autonomic innervation. Various markers have been utilized for nerve subtypes, including pan-neuronal markers and those specific for sensory and autonomic nerve fibers. The nerve growth factor family includes neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, and their receptors. Studies of endometriosis and provoked vestibulodynia have demonstrated the presence of nerve fibers around endometriosis epithelium/stroma in the pelvic peritoneum and within the vulvar vestibule. The number of nerve fibers is higher in these pain conditions as compared with control tissue. Nerve growth factor expression by endometriosis stroma and by immune cells in the vulvar vestibule may be involved in local neuroproliferation. Local inflammation is implicated in this neuroproliferation, with potential roles of interleukin 1ß and mast cells in both conditions. Several studies have shown a correlation between nerve fibers around endometriosis and dyspareunia severity, but studies are lacking in provoked vestibulodynia. There are several possible clinical ramifications of neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia, in terms of history, examination, biopsy, and surgical and medical treatment. CONCLUSIONS: A neuroproliferative subtype of dyspareunia may be implicated in endometriosis and provoked vestibulodynia. Additional research is needed to validate this concept and to integrate it into clinical studies. Neuroproliferative pathways could serve as novel therapeutic targets for the treatment of dyspareunia in endometriosis and provoked vestibulodynia.

New Topical Therapy for Provoked Vestibulodynia: Improvement of Psychological and Sexual Well-Being.

Vulvodynia is a vulvar discomfort that occurs in the absence of any specific, clinically identifiable disorder. Few therapies have shown to be effective for the treatment of vulvodynia. In our recently published study, we tested a drug-free gel in women affected by vulvar vestibulitis. It is a cosmetic gel which acts locally without any metabolic, pharmacological or immunological effect. In order to further promote the validity of this new product, in this manuscript we analyzed the results obtained from the administration of four questionnaires in the same two groups of women affected by PVD and treated with a placebo and the new product. The questionnaires used: Female Sexual Function Index Scoring (FSFI), Female Sexual Distress Scale (FSDS), Hospital Anxiety and Depression Scale (HADS), and health-related quality of life measured by SF-36 (SF-36). The results obtained by this current analysis showed that the new gel has also proven benefits on women's quality of life and sexual function, including improvements in arousal, desire, orgasm and satisfaction.

Severe Postmenopausal Genital Pain Treated Successfully With Prolonged Estrogen Therapy: A Case Series and Narrative Review.

OBJECTIVE: The aim of the study was to describe a debilitating postmenopausal condition of continuous burning genital pain that remitted with prolonged estrogen focused on the vulvar vestibule. MATERIALS AND METHODS: Postmenopausal patients with constant genital pain seen by the author in a specialty vulvar health clinic comprised an institutional review board-approved descriptive case series. Examinations to localize pain used 4% lidocaine topical solution. Each patient received estradiol nightly as vestibule crème or constantly by transdermal route and was followed by serial examinations and follow-up telephone contact. Statistical tests included Student t test, Fisher exact test, and Pearson correlation coefficient. RESULTS: Between 2008 and 2016, 16 women presented with constant genital pain that was partly or fully extinguishable with topical vestibular lidocaine, and their pain slowly responded to prolonged vestibule-directed estradiol therapy. The mean age was 66.8 years (± 11.2). The mean pain score was 5 (range = 2-10 on a 0-10 scale). Seven (44%) characterized their pain as debilitating, and 13 (81%) had accompanying urinary symptoms. In 9 patients (56%), ovaries had been removed before natural menopause at ages 27-50 years (mean = 39), followed by minimal or no estrogen therapy. Prolonged estrogen therapy eliminated constant pain in 69% and mitigated it in 31%. CONCLUSIONS: Information about this severe but remediable condition that is associated with lack of estrogen may guide specialists who are treating complex vulvar pain. The patients' clinical histories and therapeutic courses invite a review of estrogen receptor physiology related to urogenital pain conditions.

Features of the Vaginal and Vestibular Microbioma in Patients With Vestibulodynia: A Case-Control Study.

OBJECTIVE: Our objective was to determine the role of vaginal and/or vestibular microbiota disturbance as an associated factor of symptom characteristic of provoked vestibulodynia (PVD). STUDY DESIGN: In an observational case-control study, the bacterial microbiomes in the vagina and vestibule from 20 women with PVD and 18 healthy controls were compared using a 16S rRNA gene-based molecular analysis. Clinical data were recorded through a 0- to 10-point visual analog scale related to dyspareunia and vulvovaginal pain/burning. RESULTS: Comparative assessment of the bacterial taxa (cutoff ≥15%) revealed 105 genera in the vaginal samples of PVD patients and 113 genera in the vestibular samples. Similarly, 120 genera were detected in the vaginal samples and 151 in the vestibular samples of the control group. Bacterial complexity was higher in the vestibular samples than in vaginal samples in both groups, without statistically significant differences. The following 3 dominant taxonomic units were found: Lactobacillus, Gardnerella, and Atopobium in PVD patients and Lactobacillus, Gardnerella, and Bifidobacterium in the control group. Lactobacillus gasseri was dominant only in women with PVD, showing a significant correlation with burning/pain intensity and dyspareunia severity (0.255 and 0.357, respectively, p < .001). CONCLUSIONS: Our data suggest that bacterial communities in vaginal discharge are an important contributor to the vestibular microbiota. Lactobacillus gasseri may be an element of vulnerability toward the development of vaginal dysbiosis. We can postulate its association as a potential etiologic organism in some individuals, either by itself or in some combination with other trigger factors.

The histopathological results of vestibulectomy specimens in localized provoked vulvodynia in Turkey.

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.

Vulvar vestibular effects of ospemifene: a pilot study.

The study aimed to assess the effects of ospemifene on vulvar vestibule in postmenopausal women with vulvar pain and dyspareunia. Fifty-five postmenopausal women used oral ospemifene 60 mg/d for 60 d. Symptoms of dryness, burning, and dyspareunia were evaluated on a 10 cm visual analog scale. Visual examination of the vulvar vestibule was also conducted. Patients also underwent current perception threshold (CPT) testing obtained from the vulvar vestibule. Fifty-five patients (94.6%) completed the treatment. Hot flashes were the most frequent adverse effects, but this led to a discontinuation of therapy in three patients (5.4%). After therapy, there was a statistically significant decrease from the baseline in the mean scores for dryness, burning, and dyspareunia and reduction of vestibular trophic score (baseline value of 11.2-4.2 after the therapy, p ≤ 002) and cotton swab test scores (2.81 compared with 1.25, p = .001). There was a difference in CPT values for all nerve fibers and more consistent for C fibers (-38% of sensitivity). These results confirm the efficacy of ospemifene on postmenopausal vestibular symptoms and signs; moreover, the drug was effective in normalizing vestibular innervation sensitivity.

Injury to Perineal Branch of Pudendal Nerve in Women: Outcome from Resection of the Perineal Branches.

Background This study describes outcomes from a new surgical approach to treat "anterior" pudendal nerve symptoms in women by resecting the perineal branches of the pudendal nerve (PBPN). Methods Sixteen consecutive female patients with pain in the labia, vestibule, and perineum, who had positive diagnostic pudendal nerve blocks from 2012 through 2015, are included. The PBPN were resected and implanted into the obturator internus muscle through a paralabial incision. The mean age at surgery was 49.5 years (standard deviation [SD] = 11.6 years) and the mean body mass index was 25.7 (SD = 5.8). Out of the 16 patients, mechanisms of injury were episiotomy in 5 (31%), athletic injury in 4 (25%), vulvar vestibulectomy in 5 (31%), and falls in 2 (13%). Of these 16 patients, 4 (25%) experienced urethral symptoms. Outcome measures included Female Sexual Function Index (FSFI), Vulvar Pain Functional Questionnaire (VQ), and Numeric Pain Rating Scale (NPRS). Results Fourteen patients reported their condition pre- and postoperatively. Mean postoperative follow-up was 15 months. The overall FSFI, and arousal, lubrication, orgasm, satisfaction, and pain domains significantly improved (p < 0.05). The VQ also significantly improved (p < 0.001) in 13 (93%) of 14 patients. The NPRS score decreased on average from 8 to 3 (p < 0.0001). All four patients with urethral symptoms were relieved of these symptoms. Conclusion Resection of the PBPN with implantation of the nerve into the obturator internus muscle significantly reduced pain and improved sexual function in women who sustained injury to the PBPN.

Primary and Secondary Provoked Vestibulodynia: A Review of Overlapping and Distinct Factors.

INTRODUCTION: A common subtype of vulvodynia is provoked vestibulodynia (PVD), characterized by severe pain upon contact to the vaginal entrance. Some researchers have further delineated the PVD group based on pain onset (primary vs secondary PVD, referred to as PVD1 and PVD2, respectively). AIM: This study aims to review available evidence regarding sociodemographic variables, pain characteristics, medical history and examination findings, quantitative sensory testing, genetic markers, psychosocial/sexual/relationship function, treatment outcome, and brain imaging in women with PVD1 and PVD2. METHODS: All available data related to PVD1 and PVD2 were reviewed. MAIN OUTCOME MEASURES: There is mixed evidence supporting the assumption that women with PVD1 fare worse on all variables investigated. RESULTS: The review indicated that although women with PVD1 seem to fare worse on many variables examined (eg, pain severity, genetic markers), many studies also indicated no significant group differences or-less commonly-that women with PVD2 fare worse on some variables (eg, sexual function). CONCLUSION: Although it has been suggested that different pathophysiologic processes are involved in the development and maintenance of PVD1 and PVD2, the data reviewed were mixed. While most studies indicated that women with PVD1 have higher pain intensity, higher sensitivity, more genetic influence, more evidence of inflammation, lower successful treatment outcomes, and different neural activation patterns and structural findings, these results were not consistently reported. In addition, the data for subgroup differences in psychosocial, sexual, and relationship variables were not convincing. A more precise definition of primary and secondary PVD is needed, and importantly, prospective, longitudinal studies are essential for clarifying any differences within these PVD subgroups.

Coital pain in the elderly: could a low dose estriol gel thrill the vulvar vestibule?

OBJECTIVE: The aim of this study was to evaluate the effectiveness of the application of 0.005% estriol gel to the vulvar vestibule in the management of postmenopausal dyspareunia. STUDY DESIGN: Postmenopausal women with dyspareunia were enrolled in this study. Patients were instructed to use a fingertip to apply 0.25g of vaginal gel containing 25µg of estriol to the vulvar vestibule daily for three weeks and then twice weekly for up to 12 weeks. RESULTS: Assessment of symptoms (dyspareunia and cotton swab test) and signs of vestibular atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. A total of 63 women were included. Of the 63, 59 (93.6%) completed the 12-week treatment period, and four dropped out for vestibular burning. Dyspareunia improved or was cured (score ≤1) by week 12 in 81.4% of patients. The patients also showed a statistically significant reduction in vestibular atrophy and cotton swab test at the end of treatment. CONCLUSIONS: Application of 0.005% estriol gel to the vulvar vestibule is effective in correcting menopausal coital pain. This suggests that reduction in sensory vestibular innervation sensitivity is likely to play a pivotal role in the relief of dyspareunia. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention.

Effect of Vestibulectomy for Intractable Vulvodynia.

STUDY OBJECTIVE: To assess the effectiveness of vestibulectomy in treating vulvodynia for patients with inadequate response to vulvar care guidelines and medical management. DESIGN: Retrospective case series (Canadian Task Force classification II-2). PATIENTS: All patients who underwent a vestibulectomy from 2004 to 2013 for vulvodynia. INTERVENTIONS: All patients in this study underwent a vestibulectomy. MEASUREMENTS AND MAIN RESULTS: In this study we analyzed 31 patients' overall reported pain scores and Q-tip test scores before and after vestibulectomy. The efficacy of vestibulectomy on reduction of pain was then analyzed after surgical management. There was no significant difference in pain scores from initial visit compared with the last visit before vestibulectomy after vulvar care guidelines and medical management were initiated (p = .48-.94). However, mean subjective pain scores before and after vestibulectomy decreased by 67% (p < .001). Q-tip testing showed reductions of pain by 63% (p < .001) and 73% (p < .001) at the right and left Bartholin gland areas, respectively. There was approximately a 60% decrease of pain scored around the bilateral periurethral areas (p < .05). CONCLUSIONS: Vestibulectomy is an effective treatment for vulvodynia. For those with intractable pain, vestibulectomy is an appropriate next step after unsuccessful medical treatment. The surgery leads to a significant decrease in patients' pain scores, nearly eliminating it in most cases.

Vulvodínia: diagnóstico e tratamento / Vulvodynia: diagnosis and treatment

A vulvodínia é uma condição de desconforto vulvar crônico que afeta milhares de mulheres a cada ano. Trata-se de síndrome multifatorial com grande impacto na qualidade de vida das mulheres afetadas. Seu tratamento representa atualmente um desafio para o médico assistente que, apesar de estar mais atento ao seu diagnóstico, ainda não encontra evidências científicas para tratamento dessas pacientes. Ainda não é possível encontrar revisões sistemáticas ou metanálises pela heterogeneidade dos artigos. A abordagem multidisciplinar parece trazer melhores resultados. Habitualmente essas mulheres passam por vários especialistas à procura de alívio dos seus sintomas, na maioria das vezes sem sucesso. Este artigo objetiva fazer uma revisão atualizada do diagnóstico e tratamento da vulvodínia para orientar a prática clínica.(AU)

Vulvodynia is a vulvar discomfort and chronic condition that affects millions of women each year. It is a multifactorial syndrome with great impact on the quality of life of women affected by it. Its treatment is currently a challenge for the physician. Despite being closer to the diagnosis, scientific evidence for treating these patients has not yet been found. Systematic reviews and meta-analysis cannot be found due to the heterogeneity of the articles. A multidisciplinary approach seems to bring the best results. Usually these women consult several specialists seeking relief of their symptoms, most of the time without success. The aim of this article is to review the current diagnosis and treatment of vulvodynia to guide clinical practice.(AU)

The bacterial microbiome in paired vaginal and vestibular samples from women with vulvar vestibulitis syndrome.

Composition of the bacterial microbiome in the vagina and vestibule from 30 women with vulvar vestibulitis syndrome (VVS) and 15 healthy controls were compared by pyrosequencing 16S rRNA gene amplicons. Vaginal concentrations of interleukin (IL)-1ß were determined by ELISA. Questionnaires elicited clinical and symptom data. Eighteen genera were detected in vaginal samples, and 23 genera were identified in vestibule samples, from women with VVS. The genera at both sites and the mean number of genera in subjects with VVS were largely similar to those in control subjects. However, differences were noted including higher proportions of Streptococcus and Enterococcus in women with VVS. Furthermore, Lactobacillus iners was more frequently identified in women with VVS while L. crispatus was more frequent in the control women. The dominant bacterial genera in the vagina closely paralleled the dominant genera present in the corresponding vestibular sample in both groups, leading us to postulate that vaginal secretions are an important source of bacteria present on the vestibule. Vaginal IL-1ß levels were similar and varied depending on the dominant bacteria. We conclude in this pilot study that no major differences are apparent in the vagina and vestibule between women with or without VVS, except for an increased prevalence of Streptococcus and L. iners in some women with VVS.

Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial.

OBJECTIVE: To locate sites of genital tenderness in breast cancer survivors not using estrogen who experience dyspareunia and to test the hypothesis that tenderness is limited to the vulvar vestibule rather than the vagina and is reversed by topical anesthetic. METHODS: Postmenopausal survivors of breast cancer with moderate and severe dyspareunia were recruited for an examination including randomization to a double-blind intervention using topical aqueous 4% lidocaine or normal saline for 3 minutes to the areas found to be tender. Comparisons of changes in patients' reported numerical rating scale values were made with the Wilcoxon rank-sum test with significance set at P<.05. RESULTS: Forty-nine patients aged 37-69 years (mean 55.6±8.6 years) had a median coital pain score of 8 (interquartile range 7-9, scale 0-10). On examination, all women had tenderness in the vulvar vestibule (worst site 4 o'clock median 6, 4-7). In addition, one had significant vaginal mucosal tenderness and two had pelvic floor myalgia. All had vulvovaginal atrophy with 86% having no intravaginal discharge. Aqueous lidocaine 4% reduced the vestibular tenderness of all painful sites. For example, pain at the worst site changed from a median of 5 (4-7) to 0 (0-1) as compared with saline placebo, which changed the worst site score from 6 (4-7) to 4 (3-6) (P<.001). After lidocaine application, speculum placement was nontender in the 47 without either myalgia or vaginal mucosal tenderness. CONCLUSION: In breast cancer survivors with dyspareunia, exquisite sensitivity was vestibular and reversible with aqueous lidocaine. Vaginal tenderness was rare despite severe atrophy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01539317. LEVEL OF EVIDENCE: I.

Elevated tissue levels of tumor necrosis factor-α in vulvar vestibulitis syndrome.

The purpose of this study was to compare levels of inflammatory cytokines, namely TNF-α, IL-1ß, and IL-1 receptor in women with vulvar vestibulitis syndrome (VVS) relative to levels in controls. The authors hypothesized that tissue concentrations of inflammatory cytokines would be elevated significantly in women with VVB compared to pain-free controls. The study population consisted of 15 women with strictly defined VVB in reproductive age and 13 age-matched women with no history of vulvodynia. For TNF-α, positive staining was observed in 40% of the samples from the study group and in 7.7% of the samples from the control group. The difference between the groups was statistically significant (p < 0.05). In conclusion, a limitation of the present study was the relatively small sam- ple size. However, the authors' intention was simply to propose that the local inflammation may be mediated by cytokines as TNF-α may rather than trying to single out a pathogenesis of VVS. The authors' findings of elevated TNF-α may suggest new therapeutic alternatives for VVS, as inhibiting cytokine synthesis or antagonism of the cytokine receptor.