Cervical nitric oxide release in Chlamydia trachomatis and high-risk human papillomavirus infection.

OBJECTIVE: To compare cervical fluid nitric oxide release in women with and without Chlamydia trachomatis and high-risk human papillomavirus infection (hrHPV). DESIGN: An open clinical study. SETTING: University Hospital of Helsinki. POPULATION: Thirty-nine women with (n=21) and without C. trachomatis (n=18). METHODS: Chlamydia trachomatis and/or hrHPV were studied by using specific RNA- and DNA-based tests. Levels of cervical fluid nitric oxide metabolite (NOx) were assessed by the Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical fluid NOx between women with and without C. trachomatis and hrHPV. RESULTS: Fourteen (67%) C. trachomatis-infected women and three (17%) noninfected women had concomitant hrHPV. The level of cervical fluid NOx in women with C. trachomatis (median 37.5 µmol/l, 95% confidence interval 26.1-50.9) was higher (p=0.02) than that in C. trachomatis-noninfected women (median 19.7 µmol/L, 95% confidence interval 5.6-30.0). The presence of hrHPV did not associate with any difference in NOx levels between C. trachomatis-infected or -noninfected women. CONCLUSIONS: Chlamydia trachomatis was associated with increased release of nitric oxide metabolites in the uterine cervix. This stimulus was stronger than that of hrHPV, because no additional rise in NOx was seen in women with concomitant C. trachomatis and hrHPV infection.

Cervical nitric oxide release and persistence of high-risk human papillomavirus in women.

Nitric oxide may serve as one cofactor for human papillomavirus (HPV)-induced development of cervical cancer. Therefore, we first assessed the levels of cervical fluid nitric oxide metabolite (NOx) in 283 women with and without high-risk (hr) HPV. The NOx level in women with hr HPV (48.4 µmol/L [95% CI: 39.4-56.6], n = 199) was higher (p < 0.001) than that in women without hr HPV (24.6 µmol/L [95% CI: 19.1-38.7], n = 84). Second, we evaluated if cervical fluid NOx levels could predict the persistence of hr HPV. Therefore, we followed up 113 women with detectable hr HPV without any treatment for 12 mo and repeated hr HPV test. High-risk HPV persisted in 72 women (64%) and disappeared in 41 women (36%). The median basal levels of NOx were higher (p = 0.02) in women with persistent hr HPV (56.9 µmol/L [95% CI: 48.7-81.0]) compared to those with eradicated hr HPV (37.7 µmol/L [95% CI: 27.0-58.0]). The NOx level higher than the 75th percentile (>87.0 µmol/L) predicted hr HPV persistence (OR = 4.1 [95% CI: 1.3-13.1]). This cutoff level of NOx showed 33% sensitivity and 90% specificity in predicting the persistence of hr HPV, but it failed to predict cytological progression or regression in 12 mo. In conclusion, high cervical fluid NOx appears to be connected to the persistence of hr HPV, but the low predictive capacity of NOx prevents its clinical use at this phase.

Association between high risk papillomavirus DNA and nitric oxide release in the human uterine cervix.

OBJECTIVE: Local cervical factors may determine the outcome of human papillomavirus (HPV) infection. Nitric oxide (NO) may be one such factor, since it is produced by uterine cervical cells and it takes part in both immunological and carcinogenic reactions. We studied the association between the presence of cervical high risk (hr) HPV DNA and NO in the cervical canal in women. METHODS: High risk HPV DNA status was assessed from 328 women by using a specific DNA test and the release of cervical NO was assessed as nitrate/nitrite in cervical fluid. Cervical NO was then compared between women showing different status of hr HPV DNA and different cytological and histological findings. RESULTS: High risk HPV DNA was present in 175/328 (53%) women. The cervical NO release in women with hr HPV DNA was 90% higher compared to hr HPV DNA negative women (p<0.001) (median 45.2 micromol/L; 95% CI 35.2-53.1 vs. 23.8 micromol/L; 95% CI 21.0-26.1). This elevation was not affected by parity, use of oral contraception, intrauterine devices, or signs of bacterial vaginosis or candida infection. Cytologically healthy epithelium and epithelium with mild cytological or histological changes showed elevated NO release if hr HPV DNA was present. CONCLUSIONS: The presence of hr HPV DNA is associated with an increased release of NO in the human uterine cervix. The clinical significance of this phenomenon remains open.

Abnormal cervical cytology is associated with increased nitric oxide release in the uterine cervix.

OBJECTIVE: The human uterine cervix is capable of producing nitric oxide (NO). We studied the impact of cytological changes on the release of cervical NO. DESIGN: Population-based case-control study. SETTING: City of Helsinki, Finland. POPULATION: Cervical cytology tests and cervical fluid samples were collected in 297 women. METHODS: Cervical cytology tests, classified according to Bethesda criteria, were specifically analyzed for changes typically seen in human papillomavirus (HPV) infection, and the level of NO metabolites (NOx) in cervical fluid was assessed by Griess reaction. MAIN OUTCOME MEASURES: The difference in cervical fluid NOx between normal and abnormal cytology. RESULTS: Cervical cytology was normal in 219 women and abnormal in 78 women. Among women with abnormal cytology there was both a higher detection rate (89% vs. 71%) and a higher concentration of NOx (median 22.5 micromol/l, 95% CI 14.6-31.9 vs. 11.0 micromol/l, 95% CI 8.0-16.7) compared to women with normal cytology. Age, parity, use of oral contraceptives, phase of the menstrual cycle, or history of miscarriage or termination of early pregnancy were not linked to an increased cervical NOx level. CONCLUSIONS: Cervical cell changes (suggestive of HPV infection) are accompanied by an increased release of NO in the human cervix. The significance of this finding remains uncertain, but in theory, increased release of NO could modify the outcome of cervical infection.