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Objective: Both smoking and the release of nitric oxide (NO) in the uterine cervix are determinants for high-risk human papillomavirus (hrHPV) infection. We compared the cervical NO release between smoking and non-smoking women with and without hrHPV infection., Design: Open clinical cohort study., Setting: University Hospital in Finland., Population: One hundred and twenty-five smoking and 301 non-smoking women, with (n = 244) and without (n = 182) hrHPV infection. In total, 264 women showed cytological and/or histological cervical epithelial changes., Methods: The presence of hrHPV was tested by an HPV DNA test and the release of NO was assessed from NO metabolites in the cervical fluid by the Griess reaction., Main Outcome Measures: The difference in cervical NO release between smoking and non-smoking women with and without hrHPV., Results: Infection with hrHPV in smokers (70%) was more frequent (p = 0.001) than in non-smokers (52%). As a whole, smoking was accompanied by a 35% decrease (p = 0.04) in NO release in hrHPV-infected women (35.9 μmol/L, 95% confidence interval 27.0-44.2) compared with non-smoking hrHPV- infected women (48.3 μmol/L, 95% confidence interval 38.0-56.2). No difference in NO release between smokers and non-smokers was seen in women with healthy cervical epithelium, but smoking was accompanied by a suppressed (26%) NO release (p = 0.03) in women with either cytological or histological changes., Conclusions: Smoking may suppress NO release in the uterine cervix in women with hrHPV infection., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

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., (© 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.)

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., (Copyright © 2010 UICC.)

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.

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.

Background: Nitric oxide (NO) is a factor in cervical ripening, perhaps under the control of progesterone. We studied the effects of the antiprogesterone mifepristone on the release of NO and on the expression of inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) in the uterine cervix of women in early pregnancy., Methods: Thirteen women were treated with oral mifepristone (200 mg), and 15 women were studied as controls. Cervical fluid samples were collected before treatment then hourly up to 3 h, and the samples were assayed for the concentration of nitric oxide metabolites (NOx). In addition, cervical biopsy samples from six women treated with mifepristone and from six controls were assessed for iNOS and eNOS by immunohistochemistry and Western blotting., Results: In 1-3 h, mifepristone induced 7.4- to 17.2-fold elevations in cervical fluid NOx concentrations; no change was seen in the controls. The expression of both iNOS and eNOS was detected in the cervical cells. The expression of cervical iNOS was strong in five of the six women treated with mifepristone but was not strong in any of the six control women., Conclusion: This is the first study to show that mifepristone stimulates the release of NO and the expression of iNOS in cervical cells of women in early pregnancy. This may be one mechanism by which mifepristone initiates cervical ripening.

Objective: The cells of the human uterine cervix synthesize nitric oxide, which may be a factor in cervical ripening. We studied the effect of misoprostol on cervical nitric oxide release in nonpregnant and pregnant women., Study Design: Seventy-two nonpregnant (n=15) and pregnant (n=57; 26 in early pregnancy, 31 in late pregnancy) women were treated with either vaginal misoprostol (n=54) or vaginal placebo (n=18). The dose of misoprostol was 400 mug in nonpregnant and early pregnancy group, and 25 mug in late pregnancy group. Serial cervical fluid samples, collected before and up to 3 hours after misoprostol/placebo, were assessed for the concentration of nitric oxide metabolites by means of the Griess reaction., Results: Placebo had no effect on cervical fluid nitric oxide metabolite level. In 1 to 3 hours, misoprostol induced 4.3- to 5.2-fold elevations in cervical fluid Nox concentrations in early pregnancy (P < .01), and 4.4- to 18.2-fold elevations in late pregnancy (P < .01), but these responses did not differ significantly from each other. Misoprostol had no effect on cervical fluid nitric oxide metabolites in nonpregnant women. There was a trend towards a relationship between cervical nitric oxide stimulation after misoprostol and cervical ripening., Conclusion: Vaginal misoprostol stimulates cervical nitric oxide release in pregnancy. This suggests a joint action of nitric oxide and prostaglandins in cervical ripening.

Nitric oxide (NO) affects cervical ripening. We studied cervical NO release in women with nonviable pregnancy before signs of abortion. Women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7) were selected by means of vaginal ultrasonographic examination from a population seeking early pregnancy termination; 140 women with amenorrhea-matched normal gestation were studied as controls. Cervical fluid samples were assessed for NO metabolites (Nox) by means of Griess reaction. Cervical fluid Nox was more often detectable in women with missed abortion (90%) and blighted ovum (87%) than in the control women (55%; P = 0.01), and Nox levels in women with missed abortion [median, 59.4 mumol/liter; 95% confidence interval (CI), 30.3-81.8] and blighted ovum (25.6 mumol/liter; 95% CI, 14.1-53.0) were 14 and 6 times higher (P < 0.001 and P = 0.002, respectively) than in the control group (4.3 mumol/liter; 95% CI, <3.8 to 6.4). Nox levels in women with tubal pregnancy were normal. In women with nonviable pregnancy, the lower the level of progesterone, expressed as a percentage of that in the control women, the higher (r = -0.69; P < 0.001) the level of cervical fluid Nox, and those with low pretreatment Nox levels failed to abort completely after mifepristone-misoprostol or expectant management more often (P = 0.04) than women with high Nox levels (28% vs. 4%); no such relationship was seen in the control group. Increased preabortal cervical NO release may contribute to cervical ripening and the onset of clinical abortion.

Objective: Nitric oxide may be a factor in cervical ripening. We compared the nitric oxide metabolite levels in cervical fluid in women going beyond term and in women delivering spontaneously at term., Methods: We studied a total of 208 women with singleton pregnancies: 108 women who went beyond term (294 days or longer), and 100 women who went spontaneously into labor at term. Cervical fluid samples, collected well before the initiation of labor, were assessed for nitric oxide metabolites using an assay with a detection limit of 3.8 micromol/L., Results: Women going beyond term had detectable levels of nitric oxide metabolites in their cervical fluid (60%) less often (P =.001) than women delivering at term (87%). The nitric oxide metabolite concentration in cervical fluid in women going beyond term (median 23.5 micromol/L; 95% confidence interval less than 3.8, 31.8) was 4.5 times lower (P <.001) than that in women delivering at term (median 106.0 micromol/L; 95% confidence interval 81.8, 135.0). Such a difference (14.0 versus 106.0 micromol/L) also existed when only the 66 women going into spontaneous postterm labor were included in the comparison. Both nulliparous (median less than 3.8 micromol/L) and parous (median 31.3 micromol/L) women going beyond term had lower (P <.01) cervical fluid nitric oxide metabolite levels than nulliparous and parous women delivering at term (medians 76.1 and 101.3 micromol/L, respectively). In the postterm group, women with cervical fluid nitric oxide metabolite concentrations at or below the median failed more often (P <.001) to progress in labor and had longer (P =.02) duration of labor than those with cervical fluid nitric oxide metabolite concentrations above the median., Conclusion: Reduced cervical nitric oxide release may contribute to prolonged pregnancy., Level of Evidence: II-2

Background: Diseases with low-grade inflammation perturb endothelial function. We investigated whether preterm premature rupture of membranes (PPROM) is associated with endothelial dysfunction, as assessed by the levels of endothelium-derived nitric oxide metabolites (NOx) and E-selectin in maternal serum., Methods: The concentrations of NOx and E-selectin were measured in 32 pregnant women with PPROM and in 27 healthy gestational age-matched control women. The grade of inflammation was estimated by measuring serum C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations., Results: NOx and E-selectin concentrations were not different in PPROM patients as compared to controls. In 17 patients with PPROM, CRP rose above 12 mg/L. In this group, IL-6 concentration was significantly higher than among controls, but concentrations of NOx and E-selectin remained unaltered. There was a negative correlation between the levels of NOx, CRP and IL-6 and the interval from PPROM to delivery. The levels of NOx correlated positively with those of IL-6., Conclusions: PPROM, with or without CRP and IL-6 surges, does not affect endothelial function markedly, as judged from the unaltered concentrations of NOx and E-selectin in maternal serum.

Objective: Cervical tissue expresses all the isoenzymes of nitric oxide synthase. We studied the concentrations of nitric oxide metabolites in the cervical fluid in nonpregnant (n = 11) and pregnant women (n = 106)., Study Design: Cervical fluid was collected into a Dacron polyester swab, and nitric oxide metabolites were eluted into physiologic saline solution, which was assayed for nitric oxide metabolites with the Griess reaction. The detection limit of the method is 0.2 micromol/L., Results: Cervical fluid nitric oxide metabolite was detectable in 46% of nonpregnant women (median, <0.2 micromol/L; 95% CI, 0-49), in 63% of women in early pregnancy (median, 11 micromol/L; 95% CI, 0-23) and in 82% of women in late pregnancy (median, 128 micromol/L; 95% CI, 21-276). In late pregnancy, the cervical fluid nitric oxide metabolite level was higher in women with Bishop score of > or =6 (median, 163 micromol/L; 95% CI, 105-276) than in women with Bishop score of <6 (median, 86 micromol/L; 95% CI, 21-99). Cervical fluid nitric oxide metabolite concentration before the onset of labor in parous women (median, 97 micromol/L; 95% CI, 78-283) was higher (P =.008) than that in nulliparous women (median, 28 micromol/L; 95% CI, 0-95). Cervical fluid nitric oxide metabolites before the initiation of labor (median, 33 micromol/L; 95% CI, 0-95) rose to 3.5-fold (median, 115 micromol/L; 95% CI, 78-284) after the commencement of uterine contractions and showed a significant relationship to Bishop score (r = 0.39, P =.01). Cervical fluid nitric oxide metabolite concentrations were not relative to simultaneous plasma nitric oxide metabolite levels (n = 41 women, r = 0.14, P =.41). Rupture of fetal membranes tended to decrease cervical fluid nitric oxide metabolite levels, whereas gentle cervical manipulation elevated it 6.6-fold in 1 minute. The administration of glyceryl trinitrate (0.5 mg, nitric oxide donor) intracervically resulted in a significant rise in the cervical fluid nitric oxide metabolite level in 2 minutes., Conclusion: Cervical fluid nitric oxide metabolite level rises after cervical ripening, nitric oxide donor administration, or cervical manipulation, which supports a role for cervical nitric oxide in cervical ripening.