Enhanced synthesis of proinflammatory cytokines by vulvar vestibular fibroblasts: implications for vulvar vestibulitis.

OBJECTIVE: The objective of the study was to determine whether vestibular fibroblasts from vulvar vestibulitis (VVS) patients produce higher proinflammatory cytokine levels when provoked with Candida albicans (yeast) and alpha-melanocyte-stimulating hormone (alpha-MSH) in vitro. STUDY DESIGN: Twenty anatomically defined fibroblast strains from patients and age-matched controls were stimulated with 5 regimens: no stimulus, alpha-MSH, heat-killed yeast, alpha-MSH plus yeast, and interleukin (IL)-1beta. Supernatant products included the following: granulocyte macrophage colony-stimulating factor, interferon-gamma, IL-10, IL-12, IL-1beta, IL-2, IL-4, IL-6, IL-8, and tumor necrosis factor-alpha were assayed. RESULTS: Coincubation with alpha-MSH plus yeast significantly increased IL-6 (3-fold) and IL-8 (greater than 40-fold) production in patients and controls. Vestibular fibroblast exceeded external vulvar fibroblast production of IL-1beta, IL-6, and IL-8 following yeast alone and alpha-MSH plus yeast stimuli in patients and controls. Substratified by anatomic origin, vestibular fibroblasts from VVS patients produced the highest relative levels of IL-1beta, IL-6, and IL-8 at baseline and following the yeast-alone regimen. CONCLUSION: Localized pain of VVS may results from regionally elevated cytokines produced by vulvar vestibule-specific fibroblasts.

Retrospective histopathologic reevaluation of 18 cases of plasma cell vulvitis.

OBJECTIVE: To determine some common histologic features in a series of plasma cell vulvitis (PCV) cases. STUDY DESIGN: In a retrospective study, 18 histologic sections, previously obtained by vulvar biopsy in women diagnosed as having PCV, were critically reevaluated by the same pathologist. RESULTS: We observed that plasma cells in the dermal infiltrate were frequently present in a high percentage. Hemosiderin deposition and epithelial atrophy were 2 other histologic parameters useful for the diagnosis of PCV. Lozenge-shaped keratinocytes were rarely observed. CONCLUSION: In our series of PCV the percentage of plasma cells seemed to be the most important parameter when making the diagnosis. In particular, when this percentage was > or = 50% it was a sufficient histologic parameter for a diagnosis of PCV. When the percentage was 25-50%, hemosiderin deposition and epithelial atrophy were additional histologic features helpful in diagnosing PCV. Under 25% plasma cells was nonspecific and related to the mucosal site of involvement.

Estrogen receptor expression in vulvar vestibulitis syndrome.

OBJECTIVE: A pilot study was performed to investigate the relationship between vulvar vestibulitis syndrome and estrogen receptor expression. STUDY DESIGN: Women with a diagnosis of vulvar vestibulitis syndrome had tissue samples taken for vulvar estrogen receptor-alpha expression and this was compared with a control group. RESULTS: The study group showed a significant decrease in estrogen receptor expression, and 50% of the samples did not exhibit any receptor expression. CONCLUSION: There appears to be a subgroup of women with vulvar vestibulitis syndrome who exhibit abnormal estrogen receptor-alpha expression. This may be helpful in explaining why some women are resistant to medical treatment and may allow treatment to be prescribed more effectively.

A deficiency in interferon-alpha production in women with vulvar vestibulitis.

OBJECTIVE: Previous studies have suggested that interferon-alpha may be an effective treatment for some women with vulvar vestibulitis. We evaluated whether women with this syndrome had a deficiency in endogenous and induced interferon-alpha production. STUDY DESIGN: Blood was collected in heparinized tubes from 62 women with vulvar vestibulitis and 47 control women of similar age and ethnicity. Whole blood cultures were incubated in the presence of 0.1 ng/mL lipopolysaccharide (induced) or culture medium (uninduced) for 18 to 20 hours. Aliquots were tested for interferon-alpha levels by enzyme-linked immunosorbent assay. Vestibular samples were tested for human papillomavirus by polymerase chain reaction. Aliquots were also characterized for alleles of the polymorphic gene, interleukin-1 receptor antagonist, by polymerase chain reaction. RESULTS: In uninduced cultures, interferon-gamma was present in 68.1% of control subjects as opposed to 33.9% of vulvar vestibulitis patients ( P =.0005). Similarly, after lipopolysaccharide stimulation, 70.2% of control subjects and only 48.4% of patients produced interferon-alpha ( P =.03). Among the positive samples, however, there were no differences in the interferon-alpha levels between patients and control subjects. In contrast, induction of interferon gamma in response to lipopolysaccharide was similar in control subjects (78.0%) and vulvar vestibulitis patients (82.1%). Women who have a deficiency in interferon-alpha production did not have an increased prevalence of human papillomavirus infection. There was no relation between interleukin-1 receptor antagonist genotype and interferon-alpha production. CONCLUSION: An inability to produce interferon-alpha may contribute to chronic vestibular inflammation in some women.

Localization of chromogranin, synaptophysin, serotonin, and CXCR2 in neuroendocrine cells of the minor vestibular glands: an immunohistochemical study.

Sections of vulvar tissue containing minor vestibular glands (15 sections from 14 women with vulvar vestibulitis syndrome and six control sections from five asymptomatic women) were immunohistochemically stained with antibodies against chromogranin, synaptophysin, serotonin, and CXCR2. The degree of inflammation in vestibular tissue from women with and without vulvar vestibulitis syndrome was not significantly different. All vulvar minor vestibular glands contained neuroendocrine cells that expressed chromogranin to some degree. Only one case failed to express synaptophysin. The number of cells expressing chromogranin and synaptophysin was the same regardless of the degree of inflammation. However, moderate to severe inflammation was associated with a statistically significant increase in the number of cells expressing serotonin (p < 0.001) and CXCR2 (p < 0.02). It is concluded that neuroendocrine cells are present within minor vestibular glands of the vulva. The number of cells expressing the inflammatory mediator serotonin and CXCR2, the shared interleukin-8 receptor, are upregulated with inflammation. Chronic inflammation is a normal finding in vestibular tissue and does not serve as a histologic marker for vulvar vestibulitis.

Elevated tissue levels of interleukin-1 beta and tumor necrosis factor-alpha in vulvar vestibulitis.

OBJECTIVE: To compare levels of two inflammatory cytokines, interleukin-1 beta(IL-1 beta) and tumor necrosis factor-alpha(TNF-alpha), in selected regions of the vulva, vestibule, and vagina in women with vulvar vestibulitis and in asymptomatic controls. METHODS: Selective samplings of surgical specimens from 12 women undergoing perineoplasty for vulvar vestibulitis and ten pain-free subjects undergoing posterior vaginal repair were prepared into tissue homogenates and analyzed for concentrations of IL-1 beta and TNF-alpha. Interleukin-1 beta and TNF-alpha concentrations were measured by sandwich enzyme-linked immunosorbent assay. The results were reported after adjustment for total tissue protein concentration. RESULTS: Median tissue levels of IL-1 beta and TNF-alpha were elevated 2.3-fold and 1.8-fold, respectively, in women with vulvar vestibulitis relative to pain-free women. Median IL-1 beta tissue levels were increased significantly from 1.3 pg/mg to 3.0 pg/mg total protein in women with vulvar vestibulitis compared to pain-free women. Median TNF-alpha tissue levels were increased from 83 pg/mg to 148 pg/mg total protein in women with vulvar vestibulitis compared to pain-free women. Analysis by selected anatomic site of women with vulvar vestibulitis revealed a significant 2.2-fold higher median level of TNF alpha at the vulvar site compared to the vestibule. CONCLUSION: Concentrations of IL-1 beta and TNF-alpha were elevated in women with vulvar vestibulitis relative to those in asymptomatic controls. This elevation in inflammatory cytokines with vulvar vestibulitis varied according to anatomic site and was, paradoxically, lowest in the area of highest hyperalgesia, the vulvar vestibule. Inflammatory cytokine elevation may contribute to the pathophysiology of mucocutaneous hyperalgesia.