Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia.

BACKGROUND: The underlying causes of vulvar pain in women with vulvodynia remain poorly understood. Catechol-O-methyltransferase, an enzyme that metabolizes catecholamines, is a neuromodulator that is involved with perception and sensitivity to pain. The catechol-O-methyltransferase gene is polymorphic, and a single nucleotide polymorphism is associated with low activity and heightened pain sensitivity. The variant allele that encodes this polymorphism commonly is called the "L allele" because of its low enzyme activity as opposed to the normal H (high activity) allele. OBJECTIVE: The methionine-containing catechol-O-methyltransferase protein coded by the L allele results in elevated catecholamine levels, reduced inactivation of the dopaminergic and adrenergic systems, and increased sensitivity to pain. This polymorphism not only may decrease the pain threshold in response to acute pain but also may facilitate the development of chronic pain. Therefore, the objective of our study was to assess whether a variation in the catechol-O-methyltransferase genotype is involved in increased pain sensitivity in women with vulvodynia. STUDY DESIGN: We conducted a prospective cohort study. METHODS: Buccal swabs were collected from 167 white women with vulvodynia and 107 control subjects; the DNA was tested for a single nucleotide polymorphism at position 158 (rs4680) in the catechol-O-methyltransferase gene. RESULTS: Women with vulvodynia had a marginally increased, yet not significant, prevalence of the catechol-O-methyltransferase genotype that is associated with high activity of the coded protein: 32.9% in the women with vulvodynia, as opposed to 21.5% in the control subjects (odds ratio, 1.80; 95% confidence interval, 1.02-3.15). Subgrouping the cases based on pain frequency revealed that the elevated occurrence of this catechol-O-methyltransferase genotype was present in 40.6% of the subset of women who experienced pain only with sexual intercourse vs only 21.5% of control subjects (odds ratio, 2.50; 95% confidence interval, 1.27-4.93). Also, women with primary vulvodynia had a significantly higher prevalence of the H allele than did the control subjects (62.9% vs 48.1%; odds ratio, 1.82; 95% confidence interval, 1.05-3.17). CONCLUSION: Increased pain sensitivity in women with vulvodynia is not due to a genetically determined low catechol-O-methyltransferase enzyme activity. Other mechanisms may account for alterations in catechol-O-methyltransferase activity in women with pain that is limited to intercourse or primary vulvodynia that contributes to pain sensitivity.

Vestibulodynia: A Multifactorial Syndrome: A Case Report.

BACKGROUND: Vulvodynia is a difficult-to-treat, chronic, multifactorial malady that drastically lowers the quality of life of afflicted patients. CASE: A 68-year-old woman, who had been treated successfully for vulvodynia years before with medication, returned with a recurrence of vulvodynia symptoms that this time did not respond to treatment. She now had biopsy-confirmed lichen sclerosis and was found to have markedly elevated serum testosterone levels. An imaging study detected an ovarian lesion that, on removal, proved to be afibrothecoma. Postoperatively the testosterone rapidly dropped to normal levels. What was unexpected and unusual was that the vulvar pain disappeared and the lichen sclerosis markedly regressed. CONCLUSION: This case demonstrates a hormonal trigger for the development of vulvodynia.

Decreased concentration of protease inhibitors: possible contributors to allodynia and hyperalgesia in women with vestibulodynia.

OBJECTIVE: Women with vestibulodynia exhibit increased pain sensitivity to contact with the vaginal vestibule as well as with vaginal penetration. The mechanism(s) responsible for this effect remains incompletely defined. Based on reports of a possible role for proteases in induction of pain, we compared levels of proteases and protease inhibitors in vaginal secretions from women with vestibulodynia and controls. STUDY DESIGN: Vaginal secretions from 76 women with vestibulodynia and from 41 control women were assayed by an enzyme-linked immunosorbent assay for the protease inhibitors, secretory leukocyte protease inhibitor (SLPI) and human epididymis protein-4 (HE-4), and the proteases, kallikrein-5 and cathepsins B and S. Concentrations between subjects and controls were compared and levels related to clinical and demographic variables. RESULTS: Concentrations of HE-4 and SLPI were markedly reduced in vaginal samples from women with vestibulodynia compared with controls (P ≤ .006). All other compounds were similar in both groups. HE-4 (P = .0195) and SLPI (P = .0033) were lower in women with secondary, but not primary, vestibulodynia than in controls. Subjects who had constant vulvar pain had lower levels of HE-4 and SLPI than did healthy control women (P ≤ .006) or women who experienced vulvar pain only during sexual intercourse (P ≤ .0191). There were no associations between HE-4 or SLPI levels and event associated with symptom onset, duration of symptoms, age, number of lifetime sexual partners, or age at sex initiation. CONCLUSION: Insufficient vaginal protease inhibitor production may contribute to increased pain sensitivity in an undefined subset of women with secondary vestibulodynia who experience constant vulvar pain.

Assessing menstrual tampon irritation using the "Behind-The-Knee" test.

INTRODUCTION: Colposcopic inspection of the vagina is a routine component of the safety assessment of intravaginal products. However, colposcopic findings occur frequently in healthy women, raising questions about their relevance to intravaginal product safety. Practical disadvantages limit the utility of colposcopy for evaluating menstrual tampons, among them the presence of background microtrauma, the inability to assess effects during menstruation, and, importantly, the question of whether post hoc assessments are sufficiently sensitive to detect small inflammatory changes. The Behind-The-Knee (BTK) test is an alternative for evaluating inflammatory and tissue dryness effects of physical articles by their repeated application to the popliteal fossa under an elastic bandage. It enables concurrent parallel comparisons of experimental and control articles over time and substantially increases the sensitivity of detecting small changes in tissue inflammation. MATERIAL AND METHODS: With the protocol, uncompressed experimental and control tampons yielded comparable relative and absolute erythema scores (after overnight recovery) as did colposcopic assessment of the lower genital tract 3-48 h after menstrual use. Scoring erythema in the BTK test immediately after product removal increased the level of visually discernible inflammation sixfold. In a study of commercial menstrual pads, subclinical inflammation visualized with cross-polarized light correlated with the frequency of subjective reports of discomfort during the test and discriminated the relative tolerability of the two products determined by market surveillance, providing added confidence in the predictive value of the test. CONCLUSION: We believe the BTK test can be a valuable alternative to colposcopy for assessing inflammation and dryness associated with menstrual tampons.

Investigation of the sensitivity of a cross-polarized light visualization system to detect subclinical erythema and dryness in women with vulvovaginitis.

OBJECTIVE: An enhanced visualization technique using polarized light (Syris v600 enhanced visualization system; Syris Scientific LLC, Gray, ME) detects surface and subsurface ( approximately 1 mm depth) inflammation. We sought to compare the Syris v600 system with unaided visual inspection and colposcopy of the female genitalia. STUDY DESIGN: Erythema and dryness of the vulva, introitus, vagina, and cervix were visualized and scored by each method in patients with and without vulvitis. RESULTS: Subsurface visualization was more sensitive in detecting genital erythema and dryness at all sites whether or not symptoms were present. Subsurface inflammation of the introitus, vagina, and cervix only was detected uniquely in women with vulvar vestibulitis syndrome (VVS). A subset of women presenting with VVS exhibited subclinical inflammation of the vulva vestibule and vagina (designated VVS/lichen sclerosus subgroup). CONCLUSION: Enhanced visualization of the genital epithelial subsurface with cross-polarized light may assist in diagnosing subclinical inflammation in vulvar conditions heretofore characterized as sensory syndromes.

Enterobius vermicularis infestation of a hysterectomy specimen in a patient with a colonic reservoir.

A 43-year-old woman (gravida 2, para 1011) with a history of uterine leiomyomata and a Barnett colonic reservoir underwent a supracervical hysterectomy. Final pathology revealed Enterobius vermicularis within the myometrium and adnexal vasculature. Infection may have occurred through a modified mode given the presence of a Barnett colonic reservoir and absence of an anus.

Polymorphism in a gene coding for the inflammasome component NALP3 and recurrent vulvovaginal candidiasis in women with vulvar vestibulitis syndrome.

OBJECTIVE: Patients with vulvar vestibulitis syndrome (VVS) and control subjects were tested for a polymorphism in the gene coding for the NALP3 component of inflammasomes, cytoplasmic structures regulating interleukin (IL)-1beta production. STUDY DESIGN: DNA from 143 women with VVS and 182 control women were tested for a length polymorphism in intron 4 of the gene (CIAS1) that codes for NALP3. Vestibular tissue was examined for NALP3 expression. Whole blood cultures were tested for Candida albicans-induced IL-1beta production. RESULTS: The allele 12 frequency was higher in control subjects than in the patients with VVS (P = .02). Among patients with VVS and a self-reported history of recurrent vulvovaginal candidiasis (RVVC), the allele 7 frequency was 43.9% as compared with 30.8% in patients with no history of RVVC and 26.9% in control women (P = .035 vs other patients and .001 vs control subjects). NALP3 was identified in vestibular tissue. C albicans-induced IL-1beta production was reduced in samples from women with the 7,7 genotype (P = .030). CONCLUSION: Polymorphism in the CIAS1 gene may play a central role in the triggering of VVS in a subset of patients.

Hyaluronan in vaginal secretions: association with recurrent vulvovaginal candidiasis.

OBJECTIVE: We evaluated whether vaginal concentrations of hyaluronan were altered in women with recurrent vulvovaginal candidiasis (RVVC). STUDY DESIGN: Lavage samples from 17 women with acute RVVC, 27 women who were receiving a maintenance antifungal regimen, and 24 control women were tested for hyaluronan and interleukin (IL)-6, IL-12, and IL-23 by enzyme-linked immunosorbent assay. RESULTS: Median vaginal hyaluronan concentrations were 33.8 ng/mL (range, 21.6-66.3 ng/mL) in women with acute RVVC, 15.0 ng/mL (range, 11.2-50.6 ng/mL) in women who were receiving maintenance therapy, and 4.2 ng/mL (range, 3.6-12.0 ng/mL) in control subjects (P

Association between primary vulvar vestibulitis syndrome, defective induction of tumor necrosis factor-alpha, and carriage of the mannose-binding lectin codon 54 gene polymorphism.

OBJECTIVE: We evaluated whether women with vulvar vestibulitis syndrome (VVS) could be subdivided on the basis of genotyping the polymorphic mannose-binding lectin (MBL) gene. STUDY DESIGN: DNA from 123 women with VVS was tested for a single nucleotide polymorphism at codon 54 of the MBL gene. Blood samples from 86 of the women were evaluated for ex vivo tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 receptor antagonist (IL-1ra) production in response to Candida albicans, gram-positive peptidoglycan, and gram-negative lipopolysaccharide. Associations between laboratory findings and clinical characteristics were analyzed. RESULTS: The variant MBL*B allele was identified in 33 subjects (26.8%). This polymorphism was more prevalent in women whose symptoms developed at their first act of sexual intercourse (primary VVS, 40.9%), as opposed to women with secondary VVS (16.3%; P = .01). Ex vivo TNF-alpha production, but not IL-1ra production, was reduced in MBL*B carriers as compared with MBL*A homozygotes (P < or = .03). CONCLUSION: The MBL gene polymorphism is associated with the development of primary VVS and a reduced capacity for TNF-alpha production in response to microbial components.

Determining the cause of vulvovaginal symptoms.

Both patients and clinicians may incorrectly diagnose vulvovaginitis symptoms. Patients often self-treat with over-the-counter antifungals or home remedies, although they are unable to distinguish among the possible causes of their symptoms. Telephone triage practices and time constraints on office visits may also hamper effective diagnosis. This review is a guide to distinguish potential causes of vulvovaginal symptoms. The first section describes both common and uncommon conditions associated with vulvovaginitis, including infectious vulvovaginitis, allergic contact dermatitis, systemic dermatoses, rare autoimmune diseases, and neuropathic vulvar pain syndromes. The focus is on the clinical presentation, specifically 1) the absence or presence and characteristics of vaginal discharge; 2) the nature of sensory symptoms (itch and/or pain, localized or generalized, provoked, intermittent, or chronic); and 3) the absence or presence of mucocutaneous changes, including the types of lesions observed and the affected tissue. Additionally, this review describes how such features of the clinical presentation can help identify various causes of vulvovaginitis.

An altered immunity hypothesis for the development of symptomatic bacterial vaginosis.

The hypothesis is advanced that the transition from a Lactobacillus-dominated vaginal microflora to a microflora characteristic of bacterial vaginosis (BV), as well as development of the adverse consequences of BV in some women but not in others, are due to alterations in innate immunity. A microbial-induced inhibition of Toll-like receptor expression and/or activity may block induction of proinflammatory immunity and lead to the proliferation of atypical vaginal bacteria. A lack of 70-kDa heat-shock protein production and release in response to abnormal flora would compound this failure to activate antimicrobial immune responses. A deficit in vaginal mannose-binding lectin concentrations would further decrease the capacity for microbial killing and increase the likelihood of bacterial migration from the vagina to the upper genital tract.

Mannose-binding lectin gene polymorphism, vulvovaginal candidiasis, and bacterial vaginosis.

OBJECTIVE: To evaluate associations between polymorphisms in the gene coding for mannose-binding lectin (MBL) and the diagnosis of acute or recurrent vulvovaginal candidiasis and bacterial vaginosis METHODS: Women at two outpatient clinics in Brazil filled out a questionnaire and were examined for the presence of vulvovaginal candidiasis or bacterial vaginosis. A buccal swab was blindly tested for codons 54 and 57 MBL2 gene polymorphisms by polymerase chain reaction and endonuclease digestion. RESULTS: A total of 177 women were enrolled. Vulvovaginal candidiasis was identified in 78 (44.1%) women, 33 (18.6%) had bacterial vaginosis, and 66 (37.3%) were normal controls. Recurrent vulvovaginal candidiasis was present in 50 (64.1%) of the women with vulvovaginal candidiasis; 20 (60.6%) of the bacterial vaginosis patients had recurrent disease. Vulvovaginal candidiasis was associated with white race (P=.007), bacterial vaginosis was associated with nonwhite race (P=.05), and both were associated with a history of allergy (P< or =.02) and having sexual intercourse at least three times a week (P<.001). Carriage of the variant MBL2 codon 54 allele B was more frequent in women with recurrent vulvovaginal candidiasis (25.0%) than in the women with acute vulvovaginal candidiasis (17.9%) or controls (10.6%) (P=.004). Allele B was also more prevalent in women with recurrent bacterial vaginosis (22.5%) than in those with acute bacterial vaginosis (0%) (P=.009). The MBL2 codon 57 polymorphism was infrequent and not associated with vulvovaginal candidiasis or bacterial vaginosis. CONCLUSION: The incidence of vulvovaginal candidiasis and bacterial vaginosis differs by ethnicity in Brazilian women. The MBL2 codon 54 gene polymorphism is associated with both recurrent vulvovaginal candidiasis and recurrent bacterial vaginosis.

Are you a lumper or a splitter?

The current goal of evidence-based medicine, prospective therapeutic interventions in large numbers of patients, may not always reach an accurate conclusion. Individual variations in genetic characteristics need to be acknowledged and taken into account in the analysis. Some women with recurrent vulvo-vaginal candiosis (RVVC) have polymorphisms in genes that directly contribute to their increased susceptibility to these infections. Similarly, genetic polymorphism analyses of mother and fetus, along with highly sensitive non-culture methods of microbial detection, have identified patients at elevated risk for premature labor and delivery. Utilization of more complete information provides the basis for more specific and individualized therapeutic interventions.

Frequency of interleukin-4 (IL-4) -589 gene polymorphism and vaginal concentrations of IL-4, nitric oxide, and mannose-binding lectin in women with recurrent vulvovaginal candidiasis.

BACKGROUND: A C-->T substitution at position -589 in the interleukin-4 (IL-4) gene is associated with increased production of IL-4. Associations between this polymorphism and recurrent vulvovaginal candidiasis (RVVC), as well as vaginal concentrations of IL-4 and the anticandidal compounds nitric oxide (NO) and mannose binding lectin (MBL), were evaluated. METHODS: Vaginal samples obtained by lavage from 42 women with RVVC during the acute stage of the disease and 43 control samples were assayed by enzyme-linked immunosorbent assay for IL-4 and NO metabolites. The -589 IL-4 gene polymorphism was detected by polymerase chain reaction and endonuclease digestion. Data were analyzed by Fisher's exact test, the nonparametric Mann-Whitney and Kruskal-Wallis tests, and Spearman rank correlation. P < .05 was considered significant. RESULTS: Candida albicans was identified in 38 patients with RVVC; 3 others had infection due to Candida tropicalis, and 1 had infection due to Candida krusei. The IL-4 T,T genotype was detected in 59.5% of patients with RVVC and in 7.0% of control subjects (P < .0001). The frequency of IL-4*T was 76.2% in patients with RVVC and 23.3% in control subjects (P < .0001). The median concentration of vaginal IL-4 was elevated in patients with RVVC, compared with control subjects (P < .0001). Conversely, vaginal concentrations of NO metabolites (P = .02) and MBL (P < .0001) were reduced in patients with RVVC. There was a positive association between IL-4*T homozygosity and vaginal IL-4 levels (P < .0001) and negative associations between this genotype and vaginal NO (P = .01) and MBL (P < .0001) concentrations. CONCLUSIONS: Reduced vaginal levels of anticandidal factors in IL-4*T homozygotes may increase susceptibility to RVVC.

Neutrophil Gelatinase-Associated Lipocalin Concentration in Vaginal Fluid: Relation to Bacterial Vaginosis and Vulvovaginal Candidiasis.

OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is a component of innate immunity that prevents iron uptake by microorganisms. We evaluated whether NGAL was present in vaginal fluid and whether concentrations were altered in women with bacterial vaginosis (BV) or vulvovaginal candidiasis (VVC). METHODS: Vaginal secretions from 52 women with VVC, 43 with BV, and 77 healthy controls were assayed by enzyme-linked immunosorbent assay for NGAL and for concentrations of L-lactic acid. RESULTS: The median concentration of NGAL in vaginal fluid was significantly higher in control women (561 pg/mL) than in women with BV (402 pg/mL; P = .0116) and lower in women with VVC (741 pg/mL; P = .0017). Median lactic acid levels were similar in controls (0.11 mmol/L) and women with VVC (0.13 mmol/L) and were lower in women with BV (0.02 mmol/L; P < .0001). The NGAL and lactic acid concentrations were highly correlated (P < .0001). CONCLUSION: A decrease in Lactobacilli and/or lactic acid plus the absence of leukocytes results in lower vaginal NGAL levels that might facilitate the growth of bacteria associated with BV.

Female genital cutting: confronting cultural challenges and health complications across the lifespan.

Female genital cutting affects over 140 million women worldwide. Prevalent in certain countries of Africa and the Middle East, the practice continues among immigrants to industrialized countries. Female genital cutting is a deeply rooted tradition that confers honor on a woman and her family, yet also a traumatic experience that creates significant dermatological, gynecological, obstetric and infectious disease complications. Little is known about postmenopausal health in cut women. The international community views this practice as a human rights violation. In addition to genital health complications, the medical community must confront an understudied concern of what happens as this population ages. These challenges must be addressed to provide optimal care to women affected by female genital cutting.

Influence of interleukin-1 receptor antagonist gene polymorphism on disease.

Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring competitive inhibitor of interleukin-1 (IL-1)-induced proinflammatory activity. The IL-1RA gene is polymorphic, resulting in quantitative differences in both IL-1RA and IL-1beta production. Persons homozygous for allele 2 of the IL-1RA gene (IL1RN*2) have a more prolonged and more severe proinflammatory immune response than persons with other IL-1RA genotypes. Thus, being IL1RN*2 homozygous might be beneficial when combating infectious agents or malignantly transformed cells, but it might be detrimental for those with chronic inflammatory conditions or who are pregnant. The IL1RN*2 phenotype is associated with ulcerative colitis and Crohn's disease, lupus erythematosus, vulvar vestibulitis, and possibly with osteoporosis and coronary artery disease. IL1RN*2 homozygosity may also be associated with recurrent spontaneous abortion, preterm birth, and severity of preeclampsia. Conversely, there are negative associations between IL1RN*2 homozygosity and vaginal colonization with mycoplasmas, infection with human cytomegalovirus and Epstein-Barr virus, human immunodeficiency virus proliferation, and the occurrence of ovarian cancer.

Relation between recurrent vulvovaginal candidiasis, vaginal concentrations of mannose-binding lectin, and a mannose-binding lectin gene polymorphism in Latvian women.

Vaginal concentrations of mannose-binding lectin (MBL) and possession of a polymorphism in codon 54 of the MBL gene were determined in 42 women with recurrent vulvovaginal candidiasis (RVVC) and 43 control subjects. Reduced vaginal MBL levels and an increased occurrence of the polymorphism were present in women with RVVC.

A growing concern: inability to diagnose vulvovaginal infections correctly.

The accurate diagnosis of vulvovaginitis should distinguish obstetrician-gynecologists from the vast majority of primary care physicians. Diagnostic accuracy is lost when physicians are unable to do a microscopic examination of vaginal secretions, as well as a "whiff" test and a pH determination. Structured instruction in the use of a microscope should be a required component of obstetrics and gynecology residency training. Physician compensation for this testing should be commensurate with the time and office expense required to provide this service.