Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study.

OBJECTIVE: Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+). METHODS: A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type. RESULTS: 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively). CONCLUSIONS: Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.

Epithelial oestrogen receptor α is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα- and ERα+ CxCa. These results indicate that epithelial ERα is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERα rather than epithelial ERα mediates oncogenic E2 signalling in CxCa. Our results support stromal ERα signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The risk of cervical atypia in oral contraceptive users.

BACKGROUND: The interactions of oral contraceptive (OC) use, risk of human papillomavirus (HPV) infection and associated cellular atypia are complex. We investigated the association between history of OC-use, and cytological or histopathological abnormalities in a cohort of non-HPV vaccinated originally 16-17-year-old women participating the PATRICIA trial for 4 years. METHODS: The total number of hepatitis A-virus (control) vaccine recipients participating in the clinical PATRICIA trial in Finland was 2399. Nine-hundred and ninety-nine women returned questionnaires on living conditions-life habits and sexual health after completing the study. Mean age at answering the questionnaire at the end of the clinical trial was 22 years. Age at sexual debut varied between 12 and 16 years for majority of the women. Cervical cytological samples were obtained every 6 months throughout the PATRICIA trial. The relative risk of cervical atypia associated with time since start of oral contraceptives use was calculated as odds ratio (OR) with 95% confidence interval (CI) using logistic regression. RESULTS: Compared to never-users, the smoking and age-at-sexual-debut adjusted relative risk of cervical intraepithelial neoplasia grade 1 (CIN1) in women who had started the use of oral contraceptives for more than 1 year was low (OR 0.2, 95% CI: 0.1-0.7). Risk of cytological atypia was also reduced (OR 0.6) albeit not significantly (95% CI: 0.3-1.3). CONCLUSIONS: Use of oral contraceptives does not increase the risk of cervical atypia but when established might instead be protective.

Altered microRNA expression patterns during the initiation and promotion stages of neonatal diethylstilbestrol-induced dysplasia/neoplasia in the hamster (Mesocricetus auratus) uterus.

Treatment of Syrian hamsters on the day of birth with the prototypical endocrine disruptor and synthetic estrogen, diethylstilbestrol (DES), leads to 100% occurrence of uterine hyperplasia/dysplasia in adulthood, a large proportion of which progress to neoplasia (endometrial adenocarcinoma). Consistent with our prior gene expression analyses at the mRNA and protein levels, we now report (based on microarray, real-time polymerase chain reaction, and in situ hybridization analyses) that progression of the neonatal DES-induced dysplasia/neoplasia phenomenon in the hamster uterus also includes a spectrum of microRNA expression alterations (at both the whole-organ and cell-specific level) that differ during the initiation (upregulated miR-21, 200a, 200b, 200c, 29a, 29b, 429, 141; downregulated miR-181a) and promotion (downregulated miR-133a) stages of the phenomenon. The biological processes targeted by those differentially expressed miRNAs include pathways in cancer and adherens junction, plus regulation of the cell cycle, apoptosis, and miRNA functions, all of which are consistent with our model system phenotype. These findings underscore the need for continued efforts to identify and assess both the classical genetic and the more recently recognized epigenetic mechanisms that truly drive this and other endocrine disruption phenomena.

Biologic Disease-Modifying Antirheumatic Drugs and Risk of High-Grade Cervical Dysplasia and Cervical Cancer in Rheumatoid Arthritis: A Cohort Study.

OBJECTIVE: Recent research showed an increased risk of high-grade cervical dysplasia and cervical cancer associated with rheumatoid arthritis (RA). The purpose of this study was to examine whether this risk was associated with the use of biologic versus nonbiologic disease-modifying antirheumatic drugs (DMARDs). METHODS: We identified RA patients in the US Medicaid and commercial insurance databases (for the years 2000-2012) who were starting treatment with either a biologic or a nonbiologic DMARD. High-grade cervical dysplasia or cervical cancer was identified with a validated claims-based algorithm, and we assessed utilization of gynecologic procedures. To control for potential confounders, those starting therapy with a biologic DMARD were matched 1:1 to those starting therapy with a nonbiologic DMARD according to the propensity score (PS). Hazard ratios (HRs) and rate ratios (RRs) in the PS-matched Medicaid and commercial insurance cohorts were pooled by an inverse variance-weighted fixed-effects model. RESULTS: We included 14,729 pairs of patients initiating biologic and nonbiologic DMARDs from the Medicaid cohort and 7,538 pairs from the commercial insurance cohort. During 73,389 person-years of active treatment with either biologic or nonbiologic DMARDs, 95 cases of high-grade cervical dysplasia or cervical cancer occurred in the 2 cohorts. The HR for high-grade cervical dysplasia or cervical cancer associated with biologic DMARD use was 1.25 (95% confidence interval [95% CI] 0.78-2.01) in the Medicaid cohort and 1.63 (95% CI 0.62-4.27) in the commercial insurance cohort, with a pooled HR of 1.32 (95% CI 0.86-2.01). The rate of gynecologic procedures involving the uterine cervix was not different between the 2 groups (pooled RR 0.96 [95% CI 0.90-1.02]). CONCLUSION: Among women with RA, initiation of therapy with a biologic DMARD was associated with a numerically significant, but not statistically significant, increase in the risk of high-grade cervical dysplasia or cervical cancer as compared to initiation of a nonbiologic DMARD.

Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract.

BACKGROUND: Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia. OBJECTIVE: We explored whether neoplasia risk remains elevated among DES-exposed women as they age. STUDY DESIGN: In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort. RESULTS: The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age <45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age ≥45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs for DES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for ≥8 weeks' gestation), and lowest when exposure began >15th week (HR, 1.14; 95% CI, 0.59-2.20). CONCLUSION: CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits.

Embarazo cornual y metotrexato en multidosis / Cornual pregnancy and multidose methotrexate

El embarazo cornual es una patología poco frecuente pero con una elevada mortalidad si no se diagnostica precozmente. La ecografía vaginal permite un diagnóstico precoz y la realización de un tratamiento conservador con metotrexato, reduciendo la morbimortalidad materna. Presentamos un caso de una gestante diagnosticada de embarazo cornual derecho no accidentado que fue tratada con metotrexato multidosis con éxito

Cornual pregnancy is a rare condition but has high mortality unless diagnosed early. Early diagnosis with transvaginal ultrasound allows conservative treatment with methotrexate, thus reducing maternal morbidity and mortality. We report a case of an unruptured right cornual pregnancy successfully treated with multidose systemic methotrexate

Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis.

BACKGROUND: Immunosuppression is a mainstay of therapy for both induction and maintenance of remission for inflammatory bowel disease (IBD). Women who are chronically immunosuppressed have been shown to be at higher risk of developing cervical high-grade dysplasia and/or carcinoma. There is contradictory data whether immunosuppressed patients with IBD have the same risk profile for cervical cancer as patients with solid organ transplant or HIV infection. OBJECTIVE: To determine whether the risk of cervical high-grade dysplasia and/or cancer is higher in patients with IBD on immunosuppressive therapy compared with the rates in the general population. METHODS: The studies were restricted to full-text retrospective cohort studies and case controls that had a high (6-9) Newcastle-Ottawa Score. RESULTS: All pooled analyses were based on a random-effects model. Five cohort studies and 3 case-control studies of patients with IBD on any immunosuppression with cervical high-grade dysplasia/cancer (n = 995) were included in the meta-analysis. The total IBD population in these studies was 77,116. Patients with IBD had an increased risk of cervical high-grade dysplasia/cancer compared with healthy controls (odds ratio = 1.34, 95% confidence interval: 1.23-1.46). Heterogeneity was detected (I = 34.23, Q = 10.64, df = 7; P = 0.15). The source was found to be the type of study, as well as the odds ratio presented (crude versus adjusted). CONCLUSIONS: There is sufficient evidence to suggest an increased risk of cervical high-grade dysplasia/cancer in patients with IBD on immunosuppressive medications compared with the general population. Given this increased risk, increased screening intervals are indicated.

Adverse health outcomes in women exposed in utero to diethylstilbestrol.

BACKGROUND: Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS: We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS: In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

Dietary exposure to brominated flame retardants and abnormal Pap test results.

OBJECTIVE: This study examined a possible association of dietary exposure to polybrominated biphenyls (PBBs), a brominated flame retardant, and self-reported abnormal Pap test results and cervical dysplasia as a precursor to cervical cancer. METHODS: Women in Michigan who ingested contaminated poultry, beef, and dairy products in the early 1970s were enrolled in a population-based cohort study in Michigan. Serum PBB and serum polychlorinated biphenyl (PCB) concentrations were measured. Reproductive history and health information, including Pap test results, were self-reported by participants. RESULTS: Of the women, 23% (223 of 956) reported an abnormal Pap test. In unadjusted analyses, self-reporting an abnormal Pap test was associated with younger age, current smoking (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.19-2.17), and longer duration of lifetime use of oral contraceptives (≥10 years; HR 1.92, 95% CI 1.21-3.06). When adjusting for PCB exposure, age at the interview, and smoking history, there was a slightly elevated risk of self-reporting an abnormal Pap test among the highly exposed women compared to women with nondetectable PBB concentrations (PBB≥13 µg/L, HR 1.23, 95% CI 0.74-2.06); however, the CI was imprecise. When breastfeeding duration after the initial PBB measurement was taken into account, there was a reduced risk of self-reporting an abnormal Pap test among the highly exposed women who breastfed for ≥12 months (HR 0.41, 95% CI 0.06-3.03; referent group: women with nondetectable PBB concentrations who did not breastfeed). CONCLUSIONS: It remains important to evaluate the potential reproductive health consequences of this class of chemicals as well as other potential predictors of abnormal Pap tests.

Regression of cervical intraepithelial neoplasia by zerumbone in female Balb/c mice prenatally exposed to diethylstilboestrol: involvement of mitochondria-regulated apoptosis.

BACKGROUND: Cervical cancer is the second most common cause of cancer death in women. We have demonstrated previously that zerumbone (ZER) has an anti-cancer effect towards human cervical cancer cells (HeLa). METHODS: Anti-cancer properties of ZER were investigated using female Balb/c mice exposed prenatally to diethylstilboestrol. Female offspring have been treated with ZER (4, 8 and 16 mg/kg), normal saline and cisplatin (10mg/kg; positive control). The anti-cancer properties of ZER were evaluated using histopathology, TdT-mediated dUTP nick end labeling (TUNEL) Assay and immunohistochemical staining of Bcl-2-associated X protein (Bax), a key protein in mitochondrial pathway of apoptosis. In addition, laser capture microdissection microscopy isolated RNA was amplified using reverse transcriptase polymerase chain reaction (RT-PCR) based on the specific primer of B-cell lymphoma 2 (Bcl-2). RESULTS: Treatment with ZER resulted (P<0.05, chi(2) statistics) in the regression of cervical intraepithelial neoplasia (CIN) resembling cisplatin effect (10mg/kg). TUNEL micrographs showed the absence of apoptosis in cancerous tissues treated with normal saline compared to ZER and cisplatin where abundant apoptotic cells were noticed. A post hoc analysis showed a significant (P<0.01) difference in mean percentage of apoptosis between normal saline treatment (0%), ZER (15.7%) and cisplatin (21.7%). Immunohistochemical staining of Bax protein revealed that ZER modulates the expression of this apoptosis marker. Administration of ZER has also modulated the expression of Bcl-2 gene. CONCLUSION: These findings showed that ZER induces apoptosis efficiently in cervical tissues from female Balb/c mice treated prenatally with diethylstilboestrol. This suggested that ZER, a plant-derived compound, could be introduced as a new chemo-preventive agent for CIN in future.

The precancerous effect of emitted cooking oil fumes on precursor lesions of cervical cancer.

Although cooking emission from high-temperature frying has been deemed a Group 2A carcinogen by the International Agency for Research on Cancer, little is known about its impact on cervical tumorigenesis. To investigate the precancerous consequence of cooking oil fumes on cervical intraepithelial neoplasm (CIN), a community-based case-control study, which takes all known risk factors into consideration, was conducted in Taiwan. From 2003 to 2008, in a Pap smear screening and biopsy examination network, 206 pathology-verified women with inflammations/atypical squamous cells of undetermined significance or CIN grade-1 (CIN1) and 73 with CIN2-3 (defined as low-grade squamous intraepithelial lesions (LGSIL) and high-grade squamous intraepithelial lesions (HGSIL), respectively); and 1,200 area-and-age-matched controls with negative cytology were recruited. Multinomial logistic regression was applied in the multivariate analysis to determine the likelihood of contracting LGSIL or HGSIL. The risks of the two lesions increased with the increase of carcinogenic high-risk human papillomavirus DNA load, with a clear dose-response relationship. Chefs were observed to experience a 7.9-fold elevated HGSIL risk. Kitchens with poor fume ventilation during the main cooking life-stage correlated to a 3.7-fold risk of HGSIL, but not for LGSIL. More than 1 hr of daily cooking in kitchens with poor fume conditions appeared to confer an 8.4-fold HGSIL risk, with an 8.3-fold heterogeneously higher odds ratio than that (aOR = 1.0) for LGSIL. Similar risk pattern has been reproduced among never-smoking women. Our findings demonstrate the association between indoor exposure to cooking fumes from heated oil and the late development of cervical precancerous lesions. This final conclusion needs to be verified by future research.

Combination of zerumbone and cisplatin to treat cervical intraepithelial neoplasia in female BALB/c mice.

Recent in vitro and in vivo studies have demonstrated that zerumbone (ZER) possesses anticancer properties. The main objective of this study was to examine the effectiveness of the combination of ZER and cisplatin (CIS) to treat cervical intraepithelial neoplasia (CIN) in vivo. Microculture tetrazolium assay and immunohistochemistry of proliferating cellular nuclear antigen were used to study the antitumor effect of ZER. Prenatally exposed female BALB/c mice were used as a model. The progenies with CIN were injected peritoneally with isotonic sodium chloride solution (positive control), CIS, ZER, and a combination of both compounds. All treated and untreated mice were humanely killed, and serum and cervix were obtained for interleukin 6 analysis and histopathologic studies using hematoxylin and eosin staining, respectively. Zerumbone has revealed an antitumor effect on human cervical cancer cells and downregulates immunoexpression of proliferating cellular nuclear antigen (P < 0.05). In vivo study indicates that ZER at 16 mg/kg and CIS at 10 mg/kg have a regressing effect on CIN. The combination of ZER and CIS also showed similar effectiveness in regressing CIN. Our results indicate that the combination of ZER and CIS has modulated the serum level of interleukin 6 when compared with that in mice treated with isotonic sodium chloride solution (P < 0.05). The effectiveness of combining ZER and CIS could be further explored as a new therapeutic intervention of early precancerous stages of carcinogenesis before the invasive stage begins.

Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix.

OBJECTIVE: The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the United States is associated with changes in DNA methyltransferase-1 (Dnmt-1) expression in cells involved in cervical carcinogenesis. METHODS: Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-1992) and after (2000-2002) mandatory folic acid fortification were used to examine the expression of Dnmt-1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the prefortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt-1, its assessment, and data entry were blinded with regard to the fortification status. RESULTS: Age- and race-adjusted mean percentage of cells positive for Dnmt-1 or the Dnmt-1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN, or carcinoma in situ) detected in the postfortification period compared with the prefortification period (P < 0.05, all comparisons). The degree of Dnmt-1 was significantly higher (P < 0.0001) in CIN > or = 2 lesions compared with CIN < or = 1 lesions, regardless of the fortification group. CONCLUSION: These results suggest that mandatory fortification with folic acid in the United States seems to have resulted in a change in the degree of expression of Dnmt-1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt-1, validating these results in other study populations and/or with other techniques of assessing Dnmt-1 will increase the scientific credibility of these findings.

[State of the hypothalamo-hypophyseal-ovarian system in young nullipara women with ectopia of the cervix of uterus during taking the hormonal contraceptives].

Background diseases of the cervix of the uterus play one of the leading roles in the structure of gynecological pathology and present the risk of the development precancerous changes. Ectopia is observed in the structure of precancerous processes of the cervix of the uterus in 38, 8% of women and in 42, 2% cases of gynecological diseases. Our aim is to investigate the content of gonadotropic and steroid hormones in the blood plasma of young nullipara women with different types of ectopia during taking hormonal contraceptives. Cohort study has been carried out by using simple blind method. The quantitative data analyses were performed using the Statistical Package for the Social Sciences (SPSS) in order to reveal the correlation between taking of oral hormonal contraceptives and the hormone content in the blood plasma among young nullipara women with different types of ectopia. Descriptive statistics were calculated for all the study variables. The results displayed correlation between taking the oral hormonal contraceptives and changes of hormonal background in young women with ectopia of the cervix of the uterus during taking hormonal contraceptives. The study show that the secretions of gonadotropic hormone and ovary hormone peculiarities depend on the type of ectopia of the cervix of the uterus. The effect of hormonal contraception on cervix of the uterus of young nullipara women with ectopia was investigated. The oral contraceptive, Exluton is recommended in young nullipara women with ectopia.

Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies.

BACKGROUND: Combined oral contraceptives are classified by the International Agency for Research on Cancer as a cause of cervical cancer. As the incidence of cervical cancer increases with age, the public-health implications of this association depend largely on the persistence of effects long after use of oral contraceptives has ceased. Information from 24 studies worldwide is pooled here to investigate the association between cervical carcinoma and pattern of oral contraceptive use. METHODS: Individual data for 16,573 women with cervical cancer and 35,509 without cervical cancer were reanalysed centrally. Relative risks of cervical cancer were estimated by conditional logistic regression, stratifying by study, age, number of sexual partners, age at first intercourse, parity, smoking, and screening. FINDINGS: Among current users of oral contraceptives the risk of invasive cervical cancer increased with increasing duration of use (relative risk for 5 or more years' use versus never use, 1.90 [95% CI 1.69-2.13]). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in-situ cancer, and in women who tested positive for high-risk human papillomavirus. Relative risk did not vary substantially between women with different characteristics. INTERPRETATION: The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases. 10 years' use of oral contraceptives from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1000 in less developed countries and from 3.8 to 4.5 per 1000 in more developed countries.

[Hormonal contraception and cervix of the uterus pathology].

The effect of hormonal contraception on cervix of the uterus of young nullipara women with ectopia was investigated. Cohort study was carried out by using simple blind method. By means of statistical data manipulation correlation between the application of hormonal contraceptives and changes of colposcopy pictures in the zone of pathology was displayed. Excluton showed low percent anomalous colpscopy picture in pathology zone. Excluton was declared as medicine of choice for nullipara women with ectopia. Still it is necessary to conduct a strong dynamic control of cervix of the uterus (colposcopy and pap-smear test) in order to avoid complications.

Oral contraceptives are not an independent risk factor for cervical intraepithelial neoplasia or high-risk human papillomavirus infections.

BACKGROUND: Oral contraception (OC) has been proclaimed by the IARC as a risk factor of cervical cancer (CC), on prolonged use by high-risk human papillomavirus (HPV) positive women. However, the available data are far from complete, and more evidence is necessary on the potential confounding effects of sexual behavior and HPV infection. The aim of the present was study to analyse the risk estimates for OC users in order to develop several intermediate end-point markers in cervical carcinogenesis. PATIENTS AND METHODS: A cohort of 3,187 women, enrolled in a multi-center screening trial in three New Independent States (NIS) of the former Soviet Union (the NIS Cohort Study), was stratified into three groups according to their contraception modes: i) non-users of contraception, ii) non-OC users and iii) OC users. These groups were analysed forpredictors of three outcome measures: a) exposure to HR-HPV; b) progression to high-grade cervical intraepithelial neoplasia (CIN2/3 and HSIL); and c) persistence/clearance of HR-HPV and cytological abnormalities during a prospective follow-up. RESULTS: All three groups had an identical prevalence of HR-HPV (HCII and PCR), Pap smear abnormalities and CIN histology, but differed significantly (p=0.0001) with regard to all key variables of sexual behaviour, known as risk factors for CC. Predictors of HR-HPV, CIN2/3 and HSIL were different in the three groups, reflecting these different sexual preferences. Use of OC was not a significant predictor of CIN2/3 or HSIL in HPV-positive or HPV-negative women. Outcomes of cervical disease and HR-HPV infection were unrelated to contraception. In a multivariate regression model mode of contraception was of no predictive value for either HR-HPV or high-grade CIN. CONCLUSION: Sexual behaviour is different among OC users, non-OC users and in nonusers of contraception; these risk factors predispose women to HR-HPV, high-grade CIN, and determine the outcome of their cervical disease/HR-HPV infection. The use of OC is not an independent risk factor for any of these intermediate end-point markers of cervical carcinogenesis. Failure to record these epidemiological data inevitably leads to erroneous conclusions about the role of OC as an independent risk factor of cervical cancer.

Mandatory fortification with folic acid in the United States is not associated with changes in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis.

The purpose of this study was to evaluate whether mandatory fortification of grain products with folic acid in the USA is associated with changes in global DNA methylation in cells involved in cervical carcinogenesis. Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-92) and after mandatory folic acid fortification (2000-02) were used to examine for global DNA methylation in specific lesions involved in cervical carcinogenesis by using a monoclonal antibody specific for 5 methyl cytosine (5-mc). The total number of lesions examined was 152 in the pre-fortification period and 172 in the post-fortification period. Immunohistochemical staining for 5-mc, the assessment of methylation status and data entry were blinded with regard to the fortification status. Age- and race-adjusted mean percentage of cells positive for 5-mc or the 5-mc score was not significantly different (P>0.05) between the pre- and post fortification periods in any of the individual lesions evaluated (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN or carcinoma in situ). The degree of global DNA methylation was significantly higher (P<0.0001) in >or= CIN 2 lesions compared to