Randomized healthservices study of human papillomavirus-based management of low-grade cytological abnormalities.

Human papillomavirus (HPV)-based management of women with borderline atypical squamous cells of undetermined significance (ASCUS) or mildly abnormal cervical intraepithelial neoplasia (CINI) cervical cytology has been extensively studied in the research setting. We wished to assess safety and health care resource use of a real-life health care policy using HPV triaging. All 15 outpatient clinics involved in the organized population-based screening program in Stockholm, Sweden screening program were randomized to either continue with prior policy (colposcopy of all women with ASCUS/CINI) or to implement a policy with HPV triaging and colposcopy only of HPV-positive women. The trial enrolled the 3,319 women who were diagnosed with ASCUS (n = 1,335) or CINI (n = 1,984) in Stockholm during 17th March 2003 to 16th January 2006. Detection of high-grade cervical lesions (CINII+) and health care cost consumption was studied by registry linkages. The proportion of histopathology-verified CINII+ was similar for the two policies (395 of 1,752 women (22.5%; 95% Confidence interval [CI]: 20.6-24.6%) had CINII+ diagnosed with HPV triaging policy, 318 of 1,567 women (20.3%; 95%CI: 18.3-22.4%) had CINII+ with colposcopy policy). Sixty-four percent of women with ASCUS and 77% of women with CINI were HPV positive. HPV-positivity was age-dependent, with 81% of women below 35 years of age and 44% of women above 45 years of age testing HPV-positive. HPV triaging was cost-effective only above 35 years of age. In conclusion, a real-life randomized healthservices study of HPV triaging of women with ASCUS/CINI demonstrated similar detection of CINII+ as colposcopy of all women.

Human papillomavirus and Papanicolaou tests to screen for cervical cancer.

BACKGROUND: Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS: In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS: At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS: The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).

Steroid receptor expression and morphology in provoked vestibulodynia.

OBJECTIVE: This study was undertaken to survey the steroid receptor expression and morphology in the vulvar vestibular mucosa in women with provoked vestibulodynia. STUDY DESIGN: Fourteen patients and 25 controls without oral contraceptives were included. Vestibular biopsy specimens were obtained and analyzed by using immunohistochemistry, followed by computerized image analysis of estrogen receptors alpha and beta, progesterone receptors A and B, glucocorticoid receptor, androgen receptor, and the proliferation marker Ki67. The morphology was estimated by measuring 4 parameters in the epithelium. RESULTS: There was a significantly higher expression of estrogen receptor alpha in both the epithelium (P = .04) and the stroma (P = .02) in the patient specimens compared with the controls. There were no significant differences in the other analyses performed. CONCLUSION: There is an increased expression of estrogen receptor alpha in the vestibular mucosa but the epithelial morphology seems unaffected in women with provoked vestibulodynia. Further studies regarding plausible associations to neurogenic inflammation are needed.

Surgery for localized, provoked vestibulodynia: a long-term follow-up study.

OBJECTIVE: To evaluate the long-term results of vestibulectomy in women with localized, provoked vestibulodynia. STUDY DESIGN: A retrospective questionnaire survey was filled out by 67 Swedish women who underwent surgery for localized, provoked vestibulodynia during 1992-2003. The questionnaire was completed a minimum of 12 months after the operation. Coital pain, quality of sexual life and psychologic well-being were evaluated. RESULTS: The mean age at the time of surgery was 27 years (18-56) and the median follow-up time 41 months (12-120). Coital pain, rated with Visual Analogue Scales (VAS(neg)) (0-10), was 8.0 (median) before surgery, 5.0 (p < 0.001) 6 months after surgery and 2.0 (p < 0.001) at follow-up. Quality of sexual life, using VAS(pos) (10-0), was 6.5 (median) before dyspareunia, 0.5 (p < 0.001) prior to surgery and 6.5 (p < 0.001) at followup. Complete or major improvement was reported by 56% of women with secondary vestibulodynia and 17% of women with primary vestibulodynia (p = 0.03). Improved psychologic well-being was reported by 79%. CONCLUSION: Women with secondary localized provoked vestibulodynia will often benefit from surgery when other treatments fail. Surgical outcome should include both pain relief and psychosexual well-being. In this study women with primary vestibulodynia were less likely to benefit from surgery.

Steroid receptor expression in the vulvar vestibular mucosa--effects of oral contraceptives and menstrual cycle.

BACKGROUND: The objective was to evaluate the influence of combined oral contraceptives (COC) and of the menstrual cycle on the steroid receptor expression in the vulvar vestibular mucosa of healthy women. STUDY DESIGN: Forty-five healthy women (20 with COC and 25 without) were included. Vestibular biopsies were obtained during the menstrual cycle. Estrogen receptors (ER) alpha and beta, progesterone receptors (PR) A and B, glucocorticoid receptor and androgen receptor as well as the proliferation marker Ki67 were analyzed using immunohistochemistry followed by computerized image analysis. RESULTS: The vestibular stromal tissue of women using COC expressed more ERbeta (p=.024) than that of women without COC. In the follicular phase, PRB was more abundant in the stromal tissue than in the luteal phase (p=.01). CONCLUSIONS: ERbeta is more abundant in the vulvar vestibular mucosa of women using COC than in that of women without COC. There is a cyclic variation in PRB in the vestibular mucosa in healthy women without COC.

Perceived stress in women with recurrent vulvovaginal candidiasis.

OBJECTIVE: Recurrent vulvovaginal candidiasis (RVVC) has become very common. The aim of this study was to evaluate if women with RVVC perceive more signs of chronic stress than healthy control subjects. STUDY DESIGN: Thirty-three women with RVVC and 28 healthy control subjects completed a questionnaire about perceived stress at work and in private life, and a health questionnaire. A comparison of the results was performed with the one-way ANOVA test. RESULTS: More women with RVVC than control subjects reported signs of burnout (p < 0.001), emotional symptoms of stress (p < 0.005), impaired balance between work and leisure time (p = 0.01), bodily symptoms of stress (p < 0.05), worrying factors at work (p < 0.05), and presented type D-personality (p < 0.05). CONCLUSIONS: The results of this pilot study showed higher degree of perceived stress in women with RVVC compared with healthy controls. These results are in line with our earlier findings of blunted morning rise cortisol and lower mean levels of cortisol in women with RVVC compared with healthy controls.

Glucose in vaginal secretions before and after oral glucose tolerance testing in women with and without recurrent vulvovaginal candidiasis.

OBJECTIVE: To measure the change of glucose in vaginal secretions during glucose tolerance testing in women with recurrent vulvovaginal candidiasis and in healthy control subjects. METHODS: Thirty-eight women with recurrent vulvovaginal candidiasis and 45 healthy, age-matched controls completed a health questionnaire regarding general and gynecologic health and food and alcohol habits. They all underwent an oral glucose tolerance test and a vaginal examination. Vaginal secretion was collected from the proximal part of the vagina. Glucose in plasma and in vaginal secretions were measured at fasting and after 2 hours and analyzed with the hexokinase method. A sample size analysis showed that the number of subjects included in the study was sufficient for a beta value of 0.80, at the significance level of alpha=.05, at a difference in glucose in vaginal secretions of 30% after oral glucose tolerance test. RESULTS: In healthy women, the median level of glucose in vaginal secretions was 5.2 mM before and 3.7 mM after oral glucose tolerance test, and plasma glucose was 5.0 mM before and 5.8 mM after oral glucose tolerance test. No significant difference was seen regarding change of glucose level in vaginal secretions and plasma glucose after testing, compared with before oral glucose tolerance testing. CONCLUSION: There were no differences between women with recurrent vulvovaginal candidiasis and control subjects regarding change in glucose level in vaginal secretions or in plasma during oral glucose tolerance test. LEVEL OF EVIDENCE: II-2.

Signs of chronic stress in women with recurrent candida vulvovaginitis.

OBJECTIVE: The purpose of this study was to determine whether there is an association between recurrent vulvovaginal candida and chronic stress. Chronic stress affects the hypothalamus-pituitary-adrenal axis, which influences the immune function. Recurrent candida vulvovaginitis is increasing. STUDY DESIGN: Women with recurrent vulvovaginal candida (n = 35) and age-matched healthy control subjects (n = 35) collected saliva for the analysis of cortisol. Hormone analyses of blood samples and vulvovaginal examinations were performed. A questionnaire was completed. RESULTS: Morning rise cortisol level was significantly blunted among patients compared with control subjects (P < .002). Mean levels of salivary cortisol were lower the first 45 minutes after awakening in women with recurrent vulvovaginal candida, compared with control subjects. More patients than control subjects reported a history of condyloma, bacterial vaginosis, and herpes genitalis. No differences were seen between patients and control subjects regarding sexual hormone binding globulin, dihydroepiandrosterone, testosterone or Hemoglobin A1c. CONCLUSION: Morning rise salivary cortisol level is blunted in women with recurrent vulvovaginal candida, which indicates signs of chronic stress. The higher incidence of vulvovaginal infections in these women compared with control subjects may reflect impaired immunity, which may be due to chronic stress.

Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome.

Vulvar vestibulitis syndrome (VVS) is a long lasting disorder of superficial dyspareunia in young women. Quantitative sensory testing, including mechanical and temperature pain thresholds and warm/cold difference limen (WCL), was performed in the vestibular mucosa in 22 women (mean age 25.0 years) with vestibulitis and 20 control subjects (mean age 25.6 years). The tests were carried out on days 7-11 of the menstrual cycle. Patients had allodynia to mechanical testing with von Frey filaments, 14.3+/-3.1mN in the symptomatic posterior area as compared with 158+/-33.5mN in healthy subjects, P<0.0001. The pain threshold to heat was 38.6+/-0.6 degrees C in patients and 43.8+/-0.8 degrees C in controls, P<0.0001. In addition, pain threshold to cold was 21.6+/-1.2 degrees C in patients whereas cooling down to 6 degrees C was usually not painful in controls. WCL was 4.9+/-0.5 degrees C in patients and 9.6+/-1.5 degrees C in healthy subjects, P<0.01. The results are compatible with the hypothesis that patients with VVS have an increased innervation and/or sensitization of thermoreceptors and nociceptors in their vestibular mucosa.

Types of human papillomavirus revealed in cervical adenocarcinomas after DNA sequencing.

In a collection of 173 cervical adenocarcinomas, the prevalence of HPV in relation to the age of women and the distribution of the various oncogenic types of HPV were evaluated. The tumour material was analysed by PCR of the HPV L1 gene followed by direct DNA sequencing and/or the polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) technique for the identification and typing of HPV. In 68% (117/173) of the adenocarcinomas, HPV was present. A significant correlation was observed between the prevalence of HPV and age: in women younger than 40 years, HPV was present in 88%, whereas in women 60 years and older, it was found in only 39% (p<0.001). Among the HPV-positive tumours, type 18 predominated (52%) followed by type 16 (35%) and type 45 (7.7%) while other oncogenic types of HPV (31 and 59) were rarely found. HPV 16 was relatively more frequent in older women but this observation was not significant (p=0.06). HPV-typing by PCR and direct DNA sequence analysis is more specific than analysis by PCR-SSCP, especially among the less frequently occurring types of HPV. Our results further show that the prevalence of HPV in women with cervical adenocarcinomas is age-related and that the most frequently occurring types of HPV are 18, followed by 16 and 45. We have concluded that the oncogenic role of HPV in cervical squamous carcinomas and adenocarcinomas is, in some respects, discrepant.

Using imiquimod for genital warts in female patients.

Genital warts (GW) are the manifestation of infection with specific types of human papillomavirus (HPV), one of the most common sexually transmitted viral infections in the world. Genital warts can be either raised (exophytic) or flat. Exophytic genital warts are most commonly secondary to inoculation of the basal epithelium with nononcogenic HPV types 6 and 11, whereas flat warts are usually secondary to potentially oncogenic HPV types 16 and 31. Genital warts can occasionally cause irritation and discomfort, particularly during intercourse, although most cases are asymptomatic. It is the psychosocial effects of infection, such as a sense of shame, depression, and anxiety, that represent the more significant toll for most patients with GW. Current therapies for GW are mainly ablative and do not directly enhance the immune response to HPV. Therefore, recurrence is a problem for many patients. Imiquimod 5% cream is a patient-applied therapy that directly enhances the immune response to HPV and is safe and effective for the treatment of GW. A reduction in viral load is observed following treatment. Low recurrence rates compared to other treatment modalities may be due to the stimulation of the cell-mediated immune response by imiquimod.

Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis?

OBJECTIVE: To analyze possible differences in somatosensory perception in the vestibular mucosa in healthy women associated with the use of oral contraceptives. STUDY DESIGN: Quantitative sensory tests were performed on the vestibular mucosa in 39 healthy women. Twenty women were using oral contraceptives containing 30-40 microg ethinyl estradiol combined with various progestins; 19 women with regular menstrual periods not using oral contraceptives served as controls. The testing included mechanical and heat pain thresholds and detection thresholds of warmth and cold in the anterior and posterior part of the vestibule. RESULTS: Significant lower mechanical pain thresholds were observed in both areas tested in women using oral contraceptives. The most sensitive area was the posterior vestibule in the group using oral contraceptives with a mechanical pain threshold of 72 +/- 10 ( +/-SEM) mN as compared to 161 +/- 3 mN (p < 0.01), in the controls. The result of the thermotest showed no significant differences between the groups. CONCLUSION: Oral contraceptives may induce increased sensitivity in the vestibular mucosa in healthy women and might be one contributingfactor in the development of vulvar vestibulitis.

Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis.

This randomized double-blind placebo controlled study assessed the vaginal colonization of lactic acid bacteria and clinical outcome. Vaginal capsules containing L gasseri LN40, Lactobacillus fermentum LN99, L. casei subsp. rhamnosus LN113 and P. acidilactici LN23, or placebos were administered for five days to 95 women after conventional treatment of bacterial vaginosis and/or vulvovaginal candidiasis. Vulvovaginal examinations and vaginal samplings were performed before and after administration, after the first and second menstruation, and after six months. Presence of LN strains was assessed using RAPD analysis. LN strains were present 2-3 days after administration in 89% of the women receiving LN strains (placebo: 0%, p < 0.0001). After one menstruation 53% were colonized by at least one LN strain. Nine percent were still colonized six months after administration. Ninety-three percent of the women receiving LN strains were cured 2-3 days after administration (placebo: 83%), and 78% after one menstruation (placebo: 71%) (ns). The intervention group experienced less malodorous discharge 2-3 days after administration (p = 0.03) and after the second menstruation (p = 0.04), compared with placebo. In summary, five days of vaginal administration of LN strains after conventional treatment of bacterial vaginosis and/or vulvovaginal candidiasis lead to vaginal colonization, somewhat fewer recurrences and less malodorous discharge.

Chronic stress in women with localised provoked vulvodynia.

BACKGROUND: Localised provoked vulvodynia (former vulvar vestibulitis syndrome) is the most common cause of superficial dyspareunia among young women. In a clinical setting, it is obvious that many women with localised provoked vulvodynia show signs of chronic stress. The objective of this study was to compare chronic stress in a group of women with localised provoked vulvodynia, referred to the vulvar unit at the Division of Obstetrics and Gynecology, Danderyd Hospital, Stockholm, Sweden with control women of the same age and educational level, using two independent methods. METHODS: Forty-three women with localised provoked vulvodynia and 35 healthy control women underwent a gynecological examination, filled in a health questionnaire, and self-collected saliva for analysis of cortisol at awakening and after 15, 30 and 45 min (morning awakening cortisol). Thirty-three patients and 28 controls completed a stress questionnaire. RESULTS: Morning awakening cortisol was blunted in women with localised provoked vulvodynia (p < 0.05), indicating chronic stress. The stress questionnaire showed more signs of burnout (p < 0.005), and emotional (p < 0.05) and bodily symptoms of stress (p < 0.005) in women with localised provoked vulvodynia compared with control subjects (students t-test). CONCLUSION: More women with localised provoked vulvodynia showed blunted morning awakening cortisol and reported more symptoms of stress compared with healthy control women of the same age.

Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening.

BACKGROUND: Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS: We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS: Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS: Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

A comparison of the human papillomavirus test and Papanicolaou smear as a second screening method for women with minor cytological abnormalities.

BACKGROUND: Of the estimated one million Papanicolaou (pap) smears performed annually in Sweden, about 4% show any degree of abnormality. Approximately, 1% of these cases contain moderate or severe atypia (high-grade squamous intraepithelial lesions) and the rest contain low-grade atypia. Recommendations for the management of minor abnormalities vary in various parts of Sweden. Generally, a second Pap smear is obtained 4-6 months after the first one showing low-grade atypia. The aim of this study is to compare the sensitivity of human papilloma virus (HPV)-DNA testing for the detection of cervical intraepithelial neoplasia (CIN) 2-3 with that of a second Pap smear in women, who had low-grade atypia in their first Pap smear. METHODS: Women with low-grade atypia in the Stockholm area, detected at a population-based cytology screening, were enrolled. A repeat Pap smear, HPV test, and colposcopically directed biopsies were obtained. For the detection of HPV, Hybrid Capture II (HC II) was used. RESULTS: The HPV-DNA test was positive in 66% of the 177 participating women. The sensitivity of the second Pap smear and HPV-DNA test to detect CIN 2-3 was 61 (95% CI = 45-74) and 82% (95% CI = 67-91), respectively. The positive and negative predictive values of HPV testing were 27 (95% CI = 18-35) and 89% (95% CI = 80-97), respectively. CONCLUSIONS: In Sweden, a second Pap smear is often obtained for the follow-up of women with low-grade atypia. The results of our study show that compared to the second Pap smear, HPV testing with HC II is a more sensitive method for detecting high-grade lesions.

Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence.

OBJECTIVE: Evaluation of colposcopic and histopathological findings in women screened for cervical human papillomavirus deoxyribonucleic acid persistence. STUDY DESIGN: A total of 12 527 women, aged 32 to 38 years old, attending the population-based cervical cancer screening program in Sweden were randomized 1:1 to mock testing or human papillomavirus deoxyribonucleic acid testing by general primer 5+/6+ polymerase chain reaction and subsequent typing. Human papillomavirus deoxyribonucleic acid-positive women with a normal Papanicolaou smear (n=341) and an equal number from the control group were human papillomavirus tested on average 19 months later. One hundred nineteen women with type-specific human papillomavirus persistence and 111 controls were referred to colposcopy, and 84.8% attended. RESULTS: Histopathology from colposcopically directed biopsies confirmed cervical intraepithelial neoplasia grade 2 or 3 in 28 of 100 of the women with human papillomavirus deoxyribonucleic acid persistence and in 2 of 95 among controls. CONCLUSION: Among women with normal Papanicolaou smear attending population-based screening, the positive predictive value of human papillomavirus deoxyribonucleic acid persistence for detection of biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 was 29%.

Chlamydia trachomatis infection and persistence of human papillomavirus.

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.