Comparing Vestibule Examination Techniques: Light Touch, Serial Forces, and the Lidocaine Test.

OBJECTIVE: The purpose of this study was to compare techniques and pain scales that assess tenderness in the vulvar vestibule in provoked vestibulodynia, using the cotton swab test and a vulvalgesiometer, and assess topical lidocaine solution with each. MATERIALS AND METHODS: This randomized study at a specialty vulvar clinic evaluated tender vestibules of reproductive-aged women with vestibulodynia using light rolling cotton swab touch at 6 sites and evaluated the vulvalgesiometer at 2 sites, randomizing the order of the initial tool. Participants reported pain using the Numerical Rating Scale 0-10 and the Verbal Pain Scale 0-3. With the vulvalgesiometer, the pain tolerance threshold was measured using forces of 10, 25, 50, 100, 200, and 300 g. After both initial tests, lidocaine 4% topical solution was applied for 3 minutes, and the swab test and vulvalgesiometer were repeated in the order initially performed, constituting the lidocaine test. Data analysis used t tests, Fisher exact tests, Wilcoxon signed rank tests, and Spearman rank correlation. RESULTS: Sixteen patients completed the study, 8 starting with each instrument. Light swab touch evoked significant pain, and lidocaine reduced pain to zero or mild levels. The pain threshold was 25 g, and only 38% could tolerate testing past 100 g without lidocaine. The Verbal Pain Scale correlated well with the Numerical Rating Scale. CONCLUSIONS: Light rolling cotton swab touch using the 4-item verbal scale can map vestibulodynia tenderness that can be extinguished by lidocaine, consistent with distinguishing a mucosal condition. Forces by vulvalgesiometer of greater than 100-200 g may evoke pain other than mucosal allodynia.

Acupuncture Augmentation of Lidocaine for Provoked, Localized Vulvodynia: A Feasibility and Acceptability Study.

OBJECTIVE: The aim of the study was to assess the feasibility and acceptability of acupuncture's augmentation of lidocaine therapy in the treatment of provoked localized vulvodynia (PLV). MATERIALS AND METHODS: For 12 weeks, women with moderate to severe PLV were randomized to either 18 sessions of traditional acupuncture (TA) or non-TA (NTA). All participants applied lidocaine 5% cream 4 times daily to the vestibule. Feasibility was assessed by recruitment, enrollment, assessment completion, and blinding. Acceptability was assessed by study visit attendance and satisfaction. The primary outcome was change in tampon test scores from baseline to week 12 and follow-up at week 24. RESULTS: Nineteen women enrolled and 14 completed the study. Five withdrew because of lidocaine reaction (n = 2), inability to insert tampon (n = 1), starting a new medication (n = 1), or change in vulvar diagnosis (n = 1). Participants in both groups reported pain reduction for 12 weeks. There was no statistically significant difference between groups. Women in the TA group (n = 7) experienced less pain from baseline to 12 weeks (mean difference [MD] = 42.4 ± 19.4 and MD = 35.7 ± 17.8 at week 24). In the non-TA group (n = 7), women experienced a within-group MD of 28.7 ± 28.5 at 12 weeks and an MD of 36.7 ± 17.7. CONCLUSIONS: In this early-phase research, acupuncture augmentation of lidocaine was acceptable. The study procedures, with modifications, may be feasible for future investigation. Both acupuncture techniques showed a favorable effect; however, the contribution to pain relief is undetermined.

Mindfulness-Based Group Cognitive Behavior Therapy for Provoked Localized Vulvodynia: A Randomized Controlled Trial.

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.

Red Rashes of the Vulva.

Red patches and plaques of the vulva may be manifestations of neoplasms, infections, or inflammatory skin diseases. These diseases can mimic one another clinically; features that generally allow the diseases to be identified on most cutaneous surfaces can be altered in the moist, occluded vulvar environment, making clinical diagnosis difficult. A detailed history and thorough physical examination can point to the likely diagnosis, but biopsy and culture may be needed for diagnosis especially in refractory disease. It is not uncommon for several of these processes to be present concomitantly or complicating other vulvar diseases.

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia.

Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on angiotensin II receptor type 2 (AT2) receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients' nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages, and B-cells, whereas mast cells were unchanged. RAS proteins were increased because of greater numbers of T cells and B cells expressing angiotensinogen, and increased renin-expressing T cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, whereas those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechanonociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. PERSPECTIVE: This study provides evidence that local inflammation leads to angiotensin II formation, which acts on the AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition.

BACKGROUND: Provoked vestibulodynia is a poorly understood disease that affects 8-15% of women in their lifetime. There is significant inflammation and nerve growth in vestibular biopsies from affected women treated by vestibulectomy compared with matched female population controls without vestibulodynia. The triggers leading to this neurogenic inflammation are unknown, but they are likely multifactorial. OBJECTIVE: Our objective was to determine whether vestibulodynia is more common in close and distantly related female relatives of women diagnosed with the disease and those specifically treated by vestibulectomy. Excess familial clustering would support a potential genetic predisposition for vestibulodynia and warrant further studies to isolate risk alleles. STUDY DESIGN: Using population-based genealogy linked to University of Utah Hospital CPT coded data, we estimated the relative risk of vestibulectomy in female relatives of affected women. We also compared the average pairwise relatedness of cases to the expected relatedness of the population and identified high-disease-burden pedigrees. RESULTS: A total of 183 potential vestibulectomy probands were identified using CPT codes. The relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P < .00001), second-degree (4.5 [0.5-16], P = .07), and third-degree female relatives (3.4 [1.2-8.8], P = .03). Seventy of these 183 CPT-based probands had available clinical history to confirm a diagnosis of moderate to severe vestibulodynia. Notably, this smaller group of confirmed probands (n = 70) revealed a similar familiality in first-degree (54 [17.5-126], P < .00001), second-degree (19.7 [2.4-71], P = .005), and third-degree relatives (12 [3.3-31], P = .0004), despite less statistical power for analysis. Overall, the average pairwise relatedness of affected women was significantly higher than expected (P < .001) and a number of high-disease-burden Utah families were identified. CONCLUSION: Our data suggest that vestibulodynia treated by vestibulectomy has a genetic predisposition. Future studies will identify candidate genes by linkage analysis in affected families and sequencing of distantly related probands.

CD4-positive T-cell recruitment in primary-provoked localized vulvodynia: potential insights into disease triggers.

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.

Histopathologic characteristics of menopausal vestibulodynia.

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.

Dyspareunia and sexual dysfunction in women seeking fertility treatment.

OBJECTIVE: To compare rates of dyspareunia in infertile women and healthy controls. Secondary aims are to determine whether demographic characteristics, rates of sexual dysfunction, and baseline depression status differ between the two groups. DESIGN: A case-control study. SETTING: University-based faculty fertility and OB/GYN generalist clinics. PATIENT(S): Seventy-five infertile female subjects presenting to the infertility clinic and 210 women presenting to the generalist clinic for their annual exam. INTERVENTION(S): Completion of an anonymous survey including demographic information, the Female Sexual Function Index (FSFI), Patient-Health Questionnaire-9 (PHQ-9), and original questions regarding sexual pain. MAIN OUTCOME MEASURE(S): Rate of dyspareunia and sexual dysfunction. RESULT(S): There were no significant differences in rates of dyspareunia (37.6% controls vs. 30.7% study) or the rate of sexual dysfunction (31.9% controls vs. 37.3% study). Infertile women had more frequent intercourse than controls and were more likely to be married. There were otherwise no differences in baseline rates of depression, demographic characteristics, or individual domain scores of the FSFI. CONCLUSION(S): Women seeking fertility treatment had similar rates of dyspareunia and sexual dysfunction compared with controls.

Benign vulvar dermatoses.

UNLABELLED: Vulvar pruritus and pain are common indications for consultation with a gynecologist. Contact dermatitis, lichen sclerosus, lichen planus, and vulvar intraepithelial neoplasia are vulvar dermatoses that are often associated with both pruritus and pain. Because these skin conditions are frequently misdiagnosed by providers and incorrectly self-treated by patients, vulvar biopsy is considered the gold standard for diagnosis. The etiology of these vulvar skin conditions is multifactorial; therefore, patient education, behavior modification, and regular follow-up with an experienced clinician are essential to ensure effective control of patient symptoms and management of the skin condition. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVES: After completing this CME activity physicians should be better able to evaluate common vulvar skin conditions and identify these conditions as a source of significant morbidity for women, diagnose vulvar dermatoses using vulvar biopsy as the gold standard, create a differential diagnosis of vulvar skin disorders.

Differences in primary compared with secondary vestibulodynia by immunohistochemistry.

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.

Pain experienced using two different methods of endometrial biopsy: a randomized controlled trial.

OBJECTIVE: To compare patient-reported pain, provider- reported ease of use, and tissue sampling adequacy between endometrial biopsy instruments. METHODS: Women presenting for endometrial biopsy were randomized to either Pipelle or Explora curette. The primary outcome was patient-reported pain with biopsy as measured by a 100-mm visual analog scale. Secondary outcomes included the adequacy of biopsy sample and provider-reported ease of instrument use. RESULTS: Groups were similar in respect to age, parity, ethnicity, level of dysmenorrhea, menopausal status, and biopsy indication. The most common indication for biopsy was abnormal uterine bleeding. Subject reported pain with biopsy was similar between groups (Pipelle, 6.21 ± 2.41 cm; Explora, 6.91 ± 2.88 cm; P=.14), as was provider-reported ease of use. Although procedure length was significantly shorter for patients in the Pipelle group (4.05 ± 1.48 minutes compared with 5.27 ± 2.53 minutes; P=.007), 38% of Pipelle procedures required two or more passes to obtain a sample compared with only 9% using the Explora (P=.004). The Explora group had a higher proportion of adequate samples (97% compared with 91%; P=.33). CONCLUSION: Women's pain during endometrial biopsy does not differ by type of biopsy instrument used. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov NCT00613925.

Group B streptococcus: prevalence in a non-obstetric population.

OBJECTIVE: To establish and compare the prevalence of group B streptococcus (GBS) colonization in the vaginas of nonobstetric women with and without vaginitis. MATERIALS AND METHODS: Cross-sectional analysis GBS vaginal culture status of nonpregnant, estrogen-replete women 18 years or older presenting for annual gynecological examinations or vaginal infection. Subjects were classified into 3 groups: no vaginitis if symptoms were absent and examination results was normal; common vaginitis (CV) if microscopic examination revealed yeast, bacterial vaginosis, or trichomonads; or inflammatory vaginitis (IV) if examination revealed inflammation and immature squamous cells but no pathogens. RESULTS: Of the 215 women recruited, 147 (68.4%) showed no evidence of vaginitis, 41 (19.1%) had CV, and 27 (12.6%) showed evidence of IV. The overall prevalence rate of GBS was 22.8%. Vaginitis was associated with a significantly increased risk of GBS colonization (adjusted odds ratio: CV = 2.7, 95% CI = 1.1-6.2; IV = 2.9, 95% CI = 1.1-8.0). Logistic regression revealed pH higher than 4.5, presence of abnormal discharge on examination, and a women's complaint of current symptoms as significant predicators of the presence of GBS. CONCLUSIONS: Group B streptococcus colonization occurs more commonly in women with vaginitis. This suggests that disruption of the normal vaginal bacterial environment is an important predictor for GBS colonization.

Histologic and receptor analysis of primary and secondary vestibulodynia and controls: a prospective study.

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.

KTP-nd:YAG laser therapy for the treatment of vestibulodynia: a follow-up study.

OBJECTIVE: To evaluate the results of KTP-Nd:YAG laser therapy for the treatment of vestibulodynia. STUDY DESIGN: Retrospective review and follow-up mail survey of women with vestibulodynia who underwent laser treatment. Demographics, number of laser treatments and symptom severity prior to laser treatment (100-mm visual analog scale) were obtained from the medical record. The survey included questions regarding current sexual pain, sexual quality of life and satisfaction with treatment. RESULTS: Of41 treated women, 37 women were located and agreed to participate. The mean number of laser sessions was 2.81 (range, 1-8). The mean age was 32.9 years and mean follow-up, 2.8. Following laser treatment, most (24 of 37, 68%) subjects reported less pain with sexual intercourse. One subject reported more pain, while 29% (11 of 37) reported no change. Sixty percent (21 of 37) reported their sex lives to be more satisfying/pleasurable following laser treatment. Thirteen women (13 of 37, 35%) underwent vestibulectomy following laser therapy, and 2 subjects were treated with a laser after failed vestibulectomy. CONCLUSION: Most women with vestibulodynia treated with a KTP-Nd:YAG laser achieve a reduction in sexual pain and improved sexual satisfaction without excisional therapy.

Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation.

Neonates are more susceptible than adults to viral and bacterial diseases. We hypothesized that plasmacytoid dendritic cells, the cells that provide large amounts of IFN-alpha in response to Toll-like receptor 9 (TLR9) agonists, are defective in neonates. To assess the intrinsic functionality of plasmacytoid dendritic cells from neonates we compared IFN-alpha production by plasmacytoid dendritic cells derived from neonates versus adults in both whole blood and in purified plasmacytoid dendritic cells. TLR9-stimulation of whole blood from adults and neonates resulted in comparable amounts of IFN-alpha production. However, we observed small but significant differences in IFN-alpha production from purified CD123+ plasmacytoid dendritic cells from neonates after stimulation with the TLR9 ligand CpG-DNA. Furthermore, we assessed surface expression of co-stimulatory molecules on plasmacytoid dendritic cells after stimulation. While purified CD123+ plasmacytoid dendritic cells from adults up-regulated co-stimulatory molecules CD80 and CD86 with IL-3 alone those from neonates required the addition of CpG-DNA to reach adult levels. Therefore, the intrinsic deficiencies of neonatal plasmacytoid dendritic cells can be mitigated by TLR9 agonists. These results are consistent with the observation that vaccines that effect strong adjuvant activity on dendritic cells can induce protective responses in neonates.

Patient satisfaction after the treatment of vulvovaginal erosive lichen planus with topical clobetasol and tacrolimus: a survey study.

OBJECTIVE: The purpose of this study was to compare patient satisfaction with the topical immune system modulator tacrolimus to topical clobetasol during treatment for vulvovaginal erosive lichen planus. STUDY DESIGN: Subjects who had been diagnosed with vulvovaginal erosive lichen planus between June 2000 and May 2001 received a mail survey regarding clinical satisfaction and response to treatment with clobetasol and tacrolimus. Satisfaction was assessed with a 100-mm visual analogue scale (very unsatisfied, 0; very satisfied, 100). Satisfaction was compared with the use of a paired t-test. RESULTS: Nineteen subjects met the inclusion criteria; 17 subjects (89%) returned completed surveys. Sixteen of the 17 women reported clobetasol therapy, and 11 of the 17 subjects acknowledged the use of tacrolimus therapy. All but 1 of the women who received tacrolimus had been treated previously with clobetasol therapy. All subjects reported experiencing sexual pain before their initial examination. After treatment with clobetasol, 2 of 16 women reported pain-free intercourse. Two additional women reported pain-free intercourse after switching to tacrolimus therapy. Ten subjects who had used both treatments rated tacrolimus therapy as significantly more satisfactory than clobetasol therapy (63 vs 38 mm; P=.03). CONCLUSION: The use of topical tacrolimus improves satisfaction and may result in better clinical outcomes than therapy with clobetasol for the treatment of vulvovaginal erosive lichen planus.