The influence of cigarette smoking on the plasma , leukocyte, and cervicovaginal cell ascorbic acid levels in 46 healthy smokers and healthy nonsmokers was investigated. Coded peripheral venous blood and cervicovaginal lavage specimens obtained after informed consent were analyzed simultaneously for their ascorbic acid content. The findings suggest that smoking affects the levels and distribution of ascorbic acid. In smokers (n = 16), the number of exfoliated cervicovaginal epithelial cells and leukocyte ascorbic acid levels was significantly higher (p less than 0.01, p less than 0.05, respectively) compared with nonsmokers (n = 30). In addition, cervicovaginal cell ascorbic acid, plasma reduced and total ascorbic acid levels were significantly lower (p less than 0.001, p less than 0.01, p less than 0.01, respectively). The exfoliated epithelial cell ascorbic acid levels in nonsmokers was fourfold greater than that of leukocytes. The implications of these findings within the context of free radical-induced cellular perturbations in smokers are discussed.

Placebo-controlled trial of indole-3-carbinol in the treatment of CIN.

Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrera EA, Mathis JM. Department of Obstetrics and Gynecology, Louisiana State University Medical Center-Shreveport, 1501 Kings Highway, Shreveport, Louisiana, 71130-3932, USA.

Gynecol Oncol 2000 Aug;78(2):123-9

OBJECTIVE: Most precancerous lesions of the cervix are treated with surgery or ablative therapy. Chemoprevention, using natural and synthetic compounds, may intervene in the early precancerous stages of carcinogenesis and prevent the development of invasive disease. Our trial used indole-3-carbinol (I-3-C) administered orally to treat women with CIN as a therapeutic for cervical CIN. METHODS: Thirty patients with biopsy proven CIN II-III were randomized to receive placebo or 200, or 400 mg/day I-3-C administered orally for 12 weeks. If persistent CIN was diagnosed by cervical biopsy at the end of the trial, loop electrocautery excision procedure of the transformation zone was performed. HPV status was assessed in all patients. RESULTS: None (0 of 10) of the patients in the placebo group had complete regression of CIN. In contrast 4 of 8 patients in the 200 mg/day arm and 4 of 9 patients in the 400 mg/day arm had complete regression based on their 12-week biopsy. This protective effect of I-3-C is shown by a relative risk (RR) of 0.50 ((95% CI, 0. 25 to 0.99) P = 0.023) for the 200 mg/day group and a RR of 0.55 ((95% CI, 0.31 to 0.99) P = 0.032) for the 400 mg/day group. HPV was detected in 7 of 10 placebo patients, in 7 of 8 in the 200 mg/day group, and in 8 of 9 in the 400 mg/day group. CONCLUSIONS: There was a statistically significant regression of CIN in patients treated with I-3-C orally compared with placebo. The 2/16 alpha-hydroxyestrone ratio changed in a dose-dependent fashion. Copyright 2000 Academic Press.

Oral contraceptive use and risk of invasive cervical cancer.

Brinton LA; Reeves WC; Brenes MM; Herrero R; de Britton RC; Gaitan E; Tenorio F; Garcia M; Rawls WE Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892.

Int J Epidemiol (England) Mar 1990, 19 (1) p4-11

A case-control study of 759 invasive cervical cancer patients and 1430 controls in Panama, Costa Rica, Colombia and Mexico enabled an evaluation of risk in relation to oral contraceptive use . Overall use was associated with a 21% nonsignificant elevation in risk, with some further increases in risk for more extensive durations of use. Although risks were similar for recent and non-recent users (RRs = 1.3 versus 1.2), recent long-term users were at highest risk (RR for 5+ years use = 1.7, 95% Cl 1.1-2.6). Relationships were similar for women with and without a recent Pap smear, arguing against detection bias. There was little evidence that other risk factors, including smoking and detection of human papillomaviruses (HPV), altered the effects of oral contraceptives. The risk associated with oral contraceptives was significantly increased for adenocarcinomas (RR = 2.2), whereas for squamous cell tumours the effect was minimal (RR = 1.1). These results provide some support for an adverse effect of oral contraceptives on cervical cancer risk, although possibly limited only to a subpopulation of cases.

Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives.

Butterworth CE Jr; Hatch KD; Gore H; Mueller H; Krumdieck CL

Am J Clin Nutr (United States) Jan 1982, 35 (1) p73-82

Forty-seven young women with mild or moderate dysplasia of the uterine cervix (cervical intraepithelial neoplasia) diagnosed by cervical smears, received oral supplements of folic acid, 10 mg, or a placebo (ascorbic acid, 10 mg) daily for 3 months under double-blind conditions. All had used a combination-type oral contraceptive agent for at least 6 months and continued it while returning monthly for follow-up examinations. All smears and a biopsy obtained at the end of the trial period were classified by a single observer without knowledge of treatment status using an arbitrary scoring system (1 normal, 2 mild, 3 moderate, 4 severe, 5 carcinoma in situe). Mean biopsy scores from folate supplemented subjects were significantly better than in folate-unsupplemented subjects (2.28 versus 2.92, respectively; p less than 0.05). Final versus initial cytology scores were also significantly better in supplemented subjects (1.95 versus 2.32, respectively; p less than 0.05), unchanged in patients receiving the placebo (2.27 versus 2.30, respectively). Before treatment the mean red cell folate concentration was lower among oral contraceptive agent users than nonusers (189 versus 269 ng/ml, respectively; p less than 0.01) and even lower among users with dysplasia (161 versus 269 ng/ml, respectively; p less than 0.001). Morphological features of megaloblastosis were associated with dysplasia and also improved in folate supplemented subjects. These studies indicate that either a reversible, localized derangement in folate metabolism may sometimes be misdiagnosed as cervical dysplasia, or else such a derangement is an integral component of the dysplastic process that may be arrested or in some cases reversed by oral folic acid supplementation.

Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial

Butterworth Jr. C.E.; Hatch K.D.; Soong S.-J.; Cole P.; Tamura T.; Sauberlich H.E.; Borst M.; Macaluso M.; Baker V. Department of Nutrition, Sciences, University of Alabama,Birmingham, AL 35294-3360 United States

American Journal of Obstetrics and Gynecology 1992, 166/3 (803-809)

Objective: We attempted to evaluate the effect of oral folic acid supplementation on the course of cervical dysplasia .

Study design: A total of 235 subjects with grade 1 or 2 cervical intraepithelial neoplasia were randomly assigned to receive either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection, and blood folate levels were monitored at 2-month intervals. Outcome data were subjected to chisup 2 analysis.

Results: The prevalence of human papillomavirus type 16 infection initially was 16% among subjects in the upper tertile of red blood cell folate versus 37% in the lower tertile (trend p = 0.035). After 6 months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection.

Conclusion: Folate deficiency may be involved as a cocarcinogen during the initiation of cervical dysplasia , but folic acid supplements do not alter the course of established disease.

Folate deficiency and cervical dysplasia

Butterworth Jr. C.E.; Hatch K.D.; Macaluso M.; Cole P.; Sauberlich H.E.; Soong S.-J.; Borst M.; Baker V.V. Nutrition Sciences Department, University of Alabama, UAB Station,Birmingham, AL 35294-3360 United States

Journal of the American Medical Association 1992, 267/4 (528-533)

Objective. - To test the hypothesis that nutritional deficiency affects the incidence of cervical dysplasia in young women.

Design and Setting. - Case-control study. Participants were derived from community family-planning clinics and referrals to a colposcopy center.

Participants. - A total of 726 subjects were screened, yielding 294 cases of dysplasia and 170 controls defined by coexistent cytologic and colposcopic evidence.

Main Outcome Measures. - Planned prior to data collection. Odds ratios were computed using logistic regression models to evaluate association between cervical dysplasia and sociodemographic, sexual, and reproductive factors; smoking; oral contraceptive use; human papillomavirus (HPV) infection; and 12 nutritional indices determined by blind analysis of nonfasting blood specimens.

Results. - The number of sexual partners, parity, oral contraceptive use, and HPV-16 infection were significantly associated with cervical dysplasia . Plasma nutrient levels were generally not associated with risk. However, red blood cell folate levels at or below 660 nmol/L interacted with HPV-16 infection. The adjusted odds ratio for HPV-16 was 1.1 among women with folate levels above 660 nmol/L but 5.1 (95% confidence interval, 2.3 to 11) among women with lower levels. Interactions of red blood cell folate levels with cigarette smoking and parity were also present but were not statistically significant.

Conclusion. - Low red blood cell folate levels enhance the effect of other risk factors for cervical dysplasia and, in particular, that of HPV-16 infection.

Folate status, women's health, pregnancy outcome, and cancer

Butterworth Jr. C.E. Dept. of Nutrition Sciences, University of Alabama,Birmingham, AL 35294 United States

Journal of the American College of Nutrition (United States) 1993, 12/4 (438-441)

Key observations by Dr. Lucy Wills 65 years ago have led to the identification of folate as a nutrient essential for the prevention of megaloblastic anemia of pregnancy. The more recently discovered relationships of folate status to cervical dysplasia , neural tube defects, and atherosclerosis are reviewed here.

Genetic damage in exfoliated cells of the uterine cervix. Association and interaction between cigarette smoking and progression to malignant transformation?

Cerqueira E.M.M.; Santoro C.L.; Donozo N.F.; Freitas B.A.; Pereira C.A.D.B.; Bevilacqua R.G.; Machado-Santelli G.M. Dr. E.M.M. Cerqueira, Av. Princesa Isabel, No. 114, Porto da Barra, Salvador Bahia Brazil

Acta Cytologica (United States) 1998, 42/3 (639-649)

OBJECTIVE: To determine, through the micronucleus (MN) test, the cytogenetic effects of cigarette smoking on exfoliated cells from the uterine cervix in women with normal smears and women with inflammatory atypia, squamous intraepithelial lesion (SIL) (cervical intraepithelial neoplasia [CIN] 1-3) and cervical cancer.

STUDY DESIGN: The study group consisted of 200 women divided into three subgroups: group 1 (n = 116), women periodically undergoing cervical cytology and residents of Salvador-Bahia; group II (n = 57), women residing in Sao Paulo and previously selected because of a possible cytopathologic test positive for such conditions as human papillomavirus infections or malignant or premalignant cervical lesions (CIN 1-3); group III (n=27), inmates of the Tatuape Penal Institution, Sao Paulo. All the women underwent cytologic and colposcopic examination, and biopsies were performed on 68 of them.

RESULTS: Considering the sample as a whole and using the chisup 2 test for rare events, the number of MNs in smokers was significantly greater than in nonsmokers. It was also greater in women with larger exposure to smoking . The occurrence of MN was significantly lower in women with normal smears (smokers or nonsmokers) than in those showing any kind of pathologic alterations. In nonsmokers the occurrence of MN was similar between those with inflammatory atypia (IA) or low grade (L) SIL (CIN 1) and significantly higher in women with more severe lesions or high grade (H) SIL (CIN 2 or 3). Smokers with LSIL (CIN 1) showed a higher number of MNs than nonsmokers with a comparable diagnosis and smokers with IA. No differences were observed when compared with smokers with HSIL (CIN 2 and 3). MN occurrence was not associated with other risk factors for SIL or cancer development, such as age at first coitus, number of sexual partners, multiparity and use of hormonal contraceptives.

CONCLUSION: These results suggest that the mutagenic effect of cigarette smoking occurs in cervical cells and that the progression of SIL is associated with increased frequency of chromosomaI damage. Moreover, the data suggest that cigarette smoking introduces an additional risk to the progression of low grade LSIL (CIN 1). MN testing would be helpful in monitoring smokers with this kind of lesion.

The American Medical Association Encyclopedia of Medicine 1989.

Clayman, C.B., Ed.

New York: Random House.

The role of sexual factors in the aetiology of cervical dysplasia

de Vet HC; Knipschild PG; Sturmans F Department of Epidemiology, University of Limburg, Maastricht, The Netherlands.

Int J Epidemiol (England) Oct 1993, 22 (5) p798-803

The effect of sexual behavior on the risk for cervical dysplasia was evaluated in a case-control study. Cases (n = 257) had a histologically confirmed diagnosis of cervical dysplasia . Controls (n = 705) were sampled from the general population. A postal questionnaire was used to obtain information about, among other things, age at first sexual intercourse, number of sexual partners, current frequency of intercourse and contraceptive use. Information was also collected about other risk factors for cervical dysplasia , in order to adjust for possible confounding. We observed higher risks for cervical dysplasia (mild, moderate and severe) with increasing number of sexual partners. This effect appeared to be dependent on smoking behaviour. For women who reported more than six sexual partners, the adjusted odds ratio (aOR) was 9.1 (95% CI: 3.5-23.7) for non-smokers, and 26.4 (95% CI: 11.8-58.8) for women who smoked < or = 20 cigarettes per day. The effects of age at first sexual intercourse and current frequency of intercourse disappeared after adjustment for other risk factors. Use of oral contraceptives for < 10 years increased the risk (aOR = 2.3; 95% CI: 1.2-4.6). Thus, the number of sexual partners, especially in combination with smoking behaviour, appeared to be the most important risk factor for cervical dysplasia .

Risk factors for cervical dysplasia: implications for prevention.

de Vet HC; Sturmans F Department of Epidemiology, University of Limburg, Maastricht, The Netherlands.

Public Health (England) Jul 1994, 108 (4) p241-9

This study assessed the aetiologic and public health importance of various risk factors for cervical dysplasia. A case-control design was used in which all cases had a histologically confirmed mild, moderate or severe cervical dysplasia. Controls were sampled from the general population. A total of 257 cases and 705 controls returned a postal questionnaire about marital status, sexual behaviour and contraceptive use, smoking behaviour and dietary intake of some nutrients . An increased risk was observed for women who were smokers and women who reported more than one sexual partner. For women who reported more than six sexual partners, the adjusted odds ratio was 11.5 (95% CI: 6.6-20.2); for women who smoked more than 20 cigarettes per day, an adjusted odds ratio of 2.5 (95% CI: 1.6-3.9) was found. Use of oral contraceptives for more than 10 years increased the risk: the adjusted odds ratio was 2.3 (95% CI: 1.2-4.5). The population attributable risk percentage (PAR%) of these three risk factors together was 72%, while number of sexual partners, number of cigarettes smoked and oral contraceptive use alone amounted to a PAR% of 57%, 29% and 8% respectively. Considering the preventive potential against the background of causality of the relationships and the social acceptability of the proposed changes, it is concluded that cervical cancer and its precursors might for the greater part be prevented by behavioural changes, such as reducing smoking and using contraceptive barrier methods.

Use of oral contraceptives and risk of invasive cervical cancer in previously screened women.

Ebeling K; Nischan P; Schindler C

Int J Cancer (United States) Apr 15 1987, 39 (4) p427-30

Within the context of a larger hospital-based case-control study carried out to assess the efficacy of cervical cancer screening, the possible association between oral contraceptives and risk of invasive cervical cancer has been studied as well. Because in the GDR cytological screening is an integral part of the gynaecological basic care, only a few women reported oral contraceptive use but had no Pap-smears in that study. Thus, the analysis was confined to those 129 cases and 275 controls who had at least one screening Pap-smear in their history and were below the age 55. The significantly increased relative risks for users decreased after adjustment for factors of sexual behaviour and interval since last Pap-smear but remained statistically significant or at borderline significance for some categories of usage. This concerns, in particular, long-term use (7+ years) and early onset of use (less than or equal to 24 years) with relative risks of 1.8 and 3.0, respectively.

The Mosby Medical Encyclopedia 1996.

Glanze, W.D., Ed.

St. Louis, MO: C.V. Mosby.

Stress and hopelessness in the promotion of cervical intraepithelial neoplasia to invasive squamous cell carcinoma of the cervix

Goodkin K; Antoni MH; Blaney PH

J Psychosom Res (England) 1986, 30 (1) p67-76

Stress and hopelessness have been associated with the development of invasive cervical cancer by previous research. Subjects in this study were recruited from a colposcopy clinic awaiting work-up of an abnormal pap smear and from those admitted to an in-patient gynecology ward for cone biopsy of the cervix or hysterectomy to treat a symptomatic pelvic mass thought to be uterine leiomyomas. After data collection, pathology reports and colposcopic findings were used to determine group assignment independent of subjects' knowledge of their diagnosis. A modest stress - promotion correlation was derived, which was greatly enhanced by significant interactions with low levels of cooperative coping style and for high levels of premorbid pessimism, future despair, somatic anxiety, and life threat reactivity. These stress -moderator interactions are discussed in terms of immune system deficit with concomitant enhancement of promotion of CIN to invasive squamous cell cervical cancer.

Human papillomavirus infection in incarcerated women.

Goodman, A.

HEPP News 2002 Jan; 5(1).

The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii.

Goodman MT; Kiviat N; McDuffie K; Hankin JH; Hernandez B; Wilkens LR; Franke A; Kuypers J; Kolonel LN; Nakamura J; Ing G; Branch B; Bertram CC; Kamemoto L; Sharma S; Killeen J Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA.

Cancer Epidemiol Biomarkers Prev (United States) Jun 1998, 7 (6) p537-44

Limited data from hematological studies suggest that certain nutrients, including carotenoids, tocopherols, and vitamin C , may protect against malignant change in cervical tissue. Recognizing that human papillomavirus (HPV) infection induces most neoplastic transformation of cervical tissue, the authors conducted a case-control study to examine the association of plasma micronutrient concentrations with the risk of cervical dysplasia after careful adjustment for HPV infection, using a sensitive and reliable HPV detection method. The sample included 147 multiethnic women, between 18 and 65 years of age, with biopsy-confirmed squamous intraepithelial lesions (SILs) of the cervix and 191 clinic controls identified between 1992 and 1996. Cases were identified through cytology and pathology logs in three clinics on Oahu, Hawaii. Controls were selected randomly from admission logs of the participating clinics. In-person interviews were conducted in the subjects' homes, and a fasting blood sample was drawn to measure plasma levels of lutein, lycopene, cryptoxanthin, total carotene, retinol, tocopherol, ascorbic acid, and cholesterol. The presence and type of HPV was determined in exfoliated cell samples using PCR dot blot hybridization. Mean plasma lycopene, total cryptoxanthin, and alpha-cryptoxanthin levels were lower among cases than controls. We found an inverse dose-response of alpha-cryptoxanthin, total tocopherol, and alpha-tocopherol to the odds ratios for cervical SIL after adjustment for HPV and other confounders. The odds ratio among women in the highest compared with the lowest quartile was 0.3 (95% confidence interval, 0.1-0.7) for alpha-cryptoxanthin and 0.3 (95% confidence interval, 0.1-0.8) for alpha-tocopherol. Negative trends in the odds ratios were suggested for other carotenoids and vitamin C , but these were weak, and confidence intervals were wide. Our results support existing evidence that high plasma levels of antioxidants may reduce the risk of cervical SILs independent of HPV infection. These findings are significant because diet is potentially modifiable, and nutrition education and dietary intervention might be targeted at specific high-risk groups.

Phase II trial of beta- all- trans- retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap

Graham V.; Surwit E.S.; Weiner S.; Meyskens Jr. F.L. Departments of Medicine, Obstetrics and Gynecology, University of Arizona Health Sciences Center, Tucson, AZ 85724 United States Western Journal of Medicine (United States) 1986, 145/2 (192-195)

Retinoids are effective suppressors of the phenotypic development of cancer in many animal systems, whether the process is initiated by chemical, physical or viral carcinogens. Cases of cervical intraepithelial neoplasia are excellent for studying the effectiveness of retinoids as chemopreventive agents because the process can be closely followed by serial colposcopic and pathologic (cytology or biopsy) means and changes in the condition safely monitored. We have previously conducted a phase I study of trans-retinoic acid (Tretinoin) given topically by a collagen sponge and cervical cap. A dose of 0.372% was selected for phase II trial . We have treated 20 patients with topical retinoic acid, and a complete response with total regression of disease was obtained in 50%. Systemic and cervical side effects were mild and vaginal side effects moderate but tolerable. These results provide a clinical basis for a randomized, double-blind phase III study to definitely answer the question of whether retinoic acid is an effective chemopreventive agent for cervical cancer.

Cancer statistics, 2001.

Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, USA.

CA Cancer J. Clin. 2001 Jan-Feb; 51(1): 15-36.

Each year the American Cancer Society compiles estimates of the number of new cancer cases and deaths expected in the US in the current year and the most recent data on cancer incidence, mortality, and survival. An estimated 1,268,000 new cases of cancer will be diagnosed in the year 2001 and an estimated 553,400 Americans will die from cancer. Overall cancer incidence and death rates have continued to decrease in men and women since the early 1990s, and the decline in overall cancer mortality has been greater in recent years. Despite reductions in age-adjusted rates of cancer death, the total number of recorded cancer deaths in the US continues to increase, due to an aging and expanding population. Large disparities in cancer incidence and mortality across racial/ethnic groups continue. Black men and women experience higher incidence of cancer and poorer survival than white men and women. The disparity in survival reflects both diagnosis of cancer at later disease stages, and poorer survival within each stage of diagnosis.

Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol.

Grubbs CJ, Steele VE, Casebolt T, Juliana MM, Eto I, Whitaker LM, Dragnev KH, Kelloff GJ, Lubet RL. Department of Nutrition Sciences, University of Alabama at Birmingham 35924, USA.

Anticancer Res 1995 May-Jun;15(3):709-16

Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women.

A case-control study of nutrient status and invasive cervical cancer. I. Dietary indicators

Herrero R.; Potischman N.; Brinton L.A.; Reeves W.C.; Brenes M.M.; Tenorio F.; De Britton R.C.; Gaitan E. Environmental Epidemiol Branch, National Cancer Institute, Executive Plaza North,Bethesda, MD 20892 United States

American Journal of Epidemiology (United States) 1991, 134/11 (1335-1346)

A study of 748 cases and 1,411 hospital and community controls in four Latin American countries evaluated the association between certain elements of diet and invasive cervical cancer. Subjects were interviewed about their adult consumption of 58 food items, including the major sources of putative protective agents (vitamin A, carotenoids, vitamin C, and folacin) as well as other behavioral and medical characteristics related to cervical cancer. Participation rates were above 95% for both cases and controls. After adjustment for age, study site, sexual and reproductive behavior, socioeconomic status, screening practices, and detection of human papillomavirus 16/18 by filter in situ hybridization, a slightly lower risk was observed for the highest quartiles of consumption of fruit and fruit juices, while no reductions in risk were associated with vegetables, foods of animal origin, complex carbohydrates, legumes, or folacin-rich foods. When nutrient indices were derived, significant trends of decreasing risk were observed for vitamin C (adjusted odds ratio (OR) = 0.69 for the highest vs. the lowest quartile; p for trend = 0.003), beta-carotene (OR = 0.68; p = 0.02), and other carotenoids (OR = 0.61; p = 0.003). Inclusion of vitamin C and beta-carotene in the same model attenuated the association with beta-carotene, while the association with vitamin C remained unchanged. The results are consistent with those of other investigations and provide support for a protective effect of vitamin C, carotenoids, and other substances found in the same fruits and vegetables against the development of invasive cervical cancer. However, the fact that the associations were driven by relation in two of the study sites and among women of higher socioeconomic status leaves open the possibility of selection bias or effects of unidentified aspects of dietary patterns.

Herpes simplex virus type 2: a possible interaction with human papillomavirus types 16/18 in the development of invasive cervical cancer.

Hildesheim A; Mann V; Brinton LA; Szklo M; Reeves WC; Rawls WE Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Int J Cancer (United States) Sep 30 1991, 49 (3) p335-40

A case-control study of 766 histologically confirmed incident cases of invasive cervical cancer and 1,532 hospital and community controls was conducted in Latin America to evaluate the etiologic role of herpes simplex virus type 2 (HSV-2) and to examine whether HSV-2 interacts with other risk factors. In addition to a personal interview, all subjects were asked to donate blood samples and cervical swabs for assessment of exposure to HSV-2 and human papillomaviruses (HPVs) respectively. Ninety-eight percent of cases and 91% of controls agreed to the interview and blood collection. Women testing positive for HSV-2 antibodies were found to have a 60% increased risk of cervical cancer compared with seronegative women (95% CI = 1.3, 1.9). Control for education, sexual and reproductive behavior, prior Pap-smear screening, smoking, oral contraceptive use , HPV-6/11 DNA, or HPV-16/18 DNA detection did not materially affect this estimate. No effect modification of HSV-2 by age, HPV-6/11 DNA, pregnancies, oral contraceptive use or cigarette smoking was observed. However, a significant interaction was detected between HSV-2 and HPV-16/18. Compared with women testing negative to both virus types, those positive for HSV-2 alone had a RR of 1.2 (95% CI = 0.9, 1.6), those positive for HPV-16/18 DNA alone had a RR of 4.3 (95% CI = 3.0, 6.0), and those positive for both viruses had a RR of 8.8 (95% CI = 5.9, 13.0). These findings corroborate recent laboratory evidence of a possible biological interaction between HSV-2 and HPV-16/18 in the development of cervical cancer. Further confirmatory studies are needed, given concerns with potential misclassification of exposure by the laboratory assays utilized.

Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia.

Ho GY; Palan PR; Basu J; Romney SL; Kadish AS; Mikhail M; Wassertheil-Smoller S; Runowicz C; Burk RD Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA ho@aecom.yu.edu

Int J Cancer (United States) Nov 23 1998, 78 (5) p594-9

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case-control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo-pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma alpha-tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of < or = 0.803 mg/dl (OR = 0.46). CIN was not associated with plasma retinol and beta - carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies.

Cervical intraepithelial neoplasia, cervical cancer, and HPV

Holly E.A.

Epidemiol./Biostatistics Department, School of Medicine, University of California,San Francisco, CA 94143 United States Annual Review of Public Health (United States) 1996, 17/- (69-84)

Major progress has been made to control cervical cancer in the United States and Europe using screening programs, although it remains a major cause of morbidity and mortality in the developing world. The association between cervical cancer and a sexually transmissible etiologic agent was hypothesized long before identification of human papillomaviruses (HPV) as agents that infected the genital tract. HPVs are among the most common sexually transmitted agents and have been shown to induce several squamous anogenital cancers, including squamous cell cancer of the cervix. After an etiologic role for HPV was identified in cervical cancer and CIN, efforts to understand the molecular biology of HPV were greatly expanded, enhanced by the advent of deoxyribonucleic acid (DNA) probes to identify HPV infection. Recent research has focused on specific types of HPV in relation to other recognized risk factors in the pathogenesis of CIN and invasive cervical cancer.

Chemopreventive action of selenium on methylcholanthrene-inducedcarcinogenesis in the uterine cervix of mouse.

Hussain SP; Rao AR Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Oncology 1992, 49 (3) p237-40

The placement of cotton thread impregnated with beeswax containingmethylcholanthrene (MCA, approximately 600 micrograms) inside the canal of the uterine cervix of virgin, adult mice results in the emergence of precancerous and cancerous lesions in the cervical epithelium. Employing this experimental carcinogenesis model system, the present study evaluates the chemopreventive action of selenium on the incidences of precancerous and cancerous lesions in the cervical epithelium. When selenium was administered through drinking water at the dose level of 1 ppm for 1 week before and 12 weeks following carcinogen thread insertion, the cervical carcinoma incidence, as compared to that in control mice (72%), was 37%. This decline in the incidence of carcinoma was significant (p less than 0.05). The incidences of hyperplasia and dysplasia show a decreasing trend with selenium treatment in MCA-thread-inserted animals.

Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice.

Jin L, Qi M, Chen DZ, Anderson A, Yang GY, Arbeit JM, Auborn KJ. Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.

Cancer Res 1999 Aug 15;59(16):3991-7

Mice that express transgenes for human papillomavirus type 16 under a keratin 14 promoter (K14-HPV16 mice) develop cervical cancer when they are given 17beta-estradiol chronically. We asked whether the antiestrogenic phytochemica indole-3-carbinol (I3C), found in cruciferous vegetables, administered at physiological doses, would prevent the cervical-vaginal cancer that is promoted in these mice by high doses of estrogen. We compared mice that were fed a control diet with those that were fed a diet supplemented with 2000 ppm I3C. In the group fed the control diet, at a dose of estradiol of 0.125 mg per 60-day release, 19 of 25 transgenic mice developed cervical-vaginal cancer within 6 months, and the remainder had dysplasia. Only 2 mice of 24 in the group fed the I3C supplemented diet developed cancer, and the remainder had dysplasia or hyperplasia. I3C reduced dysplasia in the nontransgenic mice. Similar results were obtained at a higher dose of estradiol (0.250 mg per 60-day release), and I3C helped to prevent morbidity associated with retention of fluid in the bladder that frequently occurred with the higher estradiol dose. Additionally, I3C appeared to reduce skin cancer in transgenic mice. These data indicate that I3C is a useful preventive for cervical-vaginal cancer and, possibly, other cancers with a papillomavirus component.

Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-Hispanic, black women.

Kantesky PA; Gammon MD; Mandelblatt J; Zhang ZF; Ramsey E; Dnistrian A; Norkus EP; Wright TC Jr Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA pkanetsk@cceb.med.upenn.edu

Nutr Cancer (United States) 1998, 31 (1) p31-40

We examined whether elevated levels of retinoids, carotenoids, folate , and vitamin E protected against cervical dysplasia among non-Hispanic, black women. We enrolled 32 women with incident cervical dysplasia , including cervical intraepithelial neoplasia (CIN) I, CIN II, and CIN III/carcinoma in situ, and 113 control women with normal cervical cytology in case-control study. Micronutrient levels were estimated from a food-frequency questionnaire (FFQ) and measured from blood samples. Information on risk factors for cervical neoplasia was elicited by interview. Hybrid capture was used to determine infection with human papillomavirus. After adjustment for potential confounders, analysis of micronutrient levels estimated from the FFQ suggested that women in the upper tertile of lycopene and vitamin A intake were one-third (odds ratio = 0.32, 95% confidence interval = 0.8-1.3) and one-fourth (odds ratio = 0.24, 95% confidence interval = 0.05-1.2) as likely, respectively, to have dysplasia as women in the lower tertile. Borderline protective trends (< or = 0.10) were apparent. Elevated levels of serum lycopene also suggested some protection against dysplasia. Results were not significant at alpha = 0.05 because of the small number of case women enrolled. Overall, correlations between estimates from the FFQ and serum levels were poor. This study indicates that, among black women, lycopene and perhaps vitamin A may play a protective role in the early stages of cervical carcinogenesis.

Risk factors for cervical neoplasia in Denmark.

Kjaer SK Danish Cancer Society, Institute of Caner Epidemiology, Copenhagen, Denmark.

APMIS Suppl (Denmark) 1998, 80 p1-41

With the overall goal of elucidating the risk factor pattern for cervical neoplasia, two case-control studies and a prospective cohort study were conducted. The first case-control study focused on female lifestyle risk factors. It was designed to include all women (aged 20-49 years) in Greater Copenhagen, diagnosed with invasive cervical cancer or carcinoma in situ (CIS) from January 1985 to December 1986. They were identified from the Danish Cancer Registry. An age-stratified control group was randomly selected from the study area by means of The Danish Central Population Register. Information on risk factors was collected using a self-administered questionnaire. The study, which included 586 women with CIS, 59 women with cervical cancer, and 614 control subjects, confirmed that CIS and invasive cervical cancer share similar risk factors. Both disease entities were strongly associated with sexual and venereal factors. This applied especially to lifetime number of sexual partners and age at first episode with genital warts (proxy measure for human papillomavirus (HPV)), supporting that HPV infection in the adolescent cervix is associated with a higher risk of cervical neoplasia compared with such an infection later in life. Our results also suggested that parity, oral contraceptive use, and smoking may be important risk factors. In the second case-control study, we identified all women with one lifetime sexual partner based on the questionnaire information obtained in the first case-control study. To investigate the role of the "male factor", the women were invited to participate in the study together with their husband. In all, 41 case couples and 90 control couples were enrolled. Data collection included a personal interview, blood samples, and penile swabs from the males. The most significant risk determinants of cervical neoplasia were a history of genital warts in the male and non-use of condoms, emphasizing the venereal nature and pointing to HPV as an important agent. Genital warts are usually associated with the low-risk HPVs (types 6 and 11) rather than with the high-risk HPV types. However, an explanation for the observed relationship between risk of cervical neoplasia and genital warts in the woman herself and in her male partner could be, that they are more likely also to harbour the high-risk HPV types. Only 2 case husbands and no control husbands had HPV DNA detected in the penile swabs (ViraPapR, ViraTypeTM). As the number of cells in the swab always exceeded 3 x 10(4), the result may reflect shortcomings in the test kit used. From our population-based prospective cohort study of 11,088 women, we selected the prevalent cases (199 women with LSIL/HSIL(low-grade/high-grade squamous intraepithelial neoplasia), 131 women with ASCUS (atypical squamous cells of undetermined significance)), and 1000 random controls (women and normal cervical cytology). At enrollment, the women were personally interviewed and had a gynecological examination including cervical swabs for HPV testing and a Pap smear. HPV DNA detection was done using polymerase-chain-reaction methods. Cervical HPV infection (especially with the high-risk types) was the out-standing risk factor for all grades of neoplasia, the association being strongest for HSIL. Women with high-risk HPV infection had a nearly 33-fold increased risk of HSIL compared to HPV-negative women. Possible risk factors for cervical neoplasia in HPV-positive women included smoking, non-use of barrier contraceptives and parity. If analysis was restricted to histologically confirmed high-grade lesions, the proportion of cases that could be attributed to HPV infections was 80%. The importance and urgent need for studies which include HPV as an adjunct to cervical cytology is emphasized. Greater effort should be made to determine the usefulness of this modality (HPV diagnostics) in cervical cancer screening or in the management of cervical neoplasia, especially ASCUS and LSIL.

Folic acid deficiency megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives

Kornberg A; Segal R; Theitler J; Yona R; Kaufman S Dep Hematol., Assaf Harofeh Med. Cent., 70300 Zerifin.

Isr J Med Sci 25 (3). 1989. 142-145. Israel Journal of Medical Sciences

A 34-year-old women developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives for 4 years. Low levels of folic acid and vitamin B12 were found. Both the complete recovery after therapy with the vitamins, and the absence of other causes of vitamin B12 and folate deficiency , suggest that the vitamin deficiencies were caused by the oral contraceptives and resulted in the rare combination of megaloblastic anemia and polyneuropathy. The poor response to vitamin B12 alone, and the development of anemia and polyneuropathy 4 months after cessation of vitmain B12 therapy suggest that folate deficiency was the primary problem.

A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression.

Liu T; Soong SJ; Alvarez RD; Butterworth CE Jr Biostatistics Unit, University of Alabama at Birmingham 35294-3300, USA.

Cancer Epidemiol Biomarkers Prev Jun 1995, 4 (4) p373-80

To evaluate the effect of potential risk factors, especially human papillomavirus type 16 (HPV-16) infection and nutritional status on the course of cervical dysplasia , we analyzed data from an intervention trial conducted from 1985 to 1990, in Birmingham, Alabama. With the use of data of four repeated evaluations of dysplasia at an interval of 2 months, specific relationships between HPV-16 infection, plasma retinol and zinc levels, and dysplasia progression were evaluated through longitudinal data analysis of generalized estimating equations. Repeated assessments of nutritional status from blood samples, HPV-16 infection, and dysplasia diagnosis were available from 206 women. Dysplasia diagnosis was confirmed by both Papanicolaou smear and colposcopy examinations and was classified as normal, low, or high grade squamous intraepithelial lesions according to the Bethesda system and assigned a score of 0, 1, or 2, respectively. Generalized estimating equation analyses were performed with assumptions of variance of Poisson and link of logarithm. Separate analyses were also conducted for HPV-16-positive and HPV-16-negative women. By multivariate modeling with adjustment for age, race, smoking, oral contraceptive use, and plasma levels of nutrients, HPV-16 infection was found to be related to the progression of cervical dysplasia , with a relative risk of 1.19 and a 95% confidence interval of 1.03-1.38. High plasma levels of retinol were related to the regression of cervical dysplasia , especially in HPV-16-positive women. A protective effect was also observed for high levels of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)

[Relation between selenium and cancer of uterine cervix]

Lou H; Wu R; Fu Y Zhejiang Cancer Hospital, Hangzhou.

Chung Hua Chung Liu Tsa Chih (China) Mar 1995, 17 (2) p112-4,

Selenium (Se) concentration in serum, hair, normal cervix tissue ortissue of cervix cancer of 20 cases with cancer of uterine cervix (surveygroup), 21 with myoma of the uterus and 1 with cervical polys (control group), but also in rice, water and soil in the high and low incidence areas of cervical cancer was determined. The results showed that Se concentration in serum and cancer tissue of uterine cervix in patients with cancer of uterine cervix was significantly lower than that in the control group (< 0.05), but no significant difference of Se concentration in hair was observed (< 0.05), However Se concentration in rice, water and soil in the high incidence areas of cervical cancer was significantly lower than that in the low incidence areas (< 0.05). Se deficiency may play a role in the carcinogenesis of uterine cervix.

Smoking and carcinoma in situ of the uterine cervix.

Lyon JL; Gardner JW; West DW; Stanish WM; Hebertson RM

Am J Public Health (United States) May 1983, 73 (5) p558-62

We carried out a case-control study of 217 cases of in situ carcinoma of the uterine cervix and 243 controls chosen from the general population of Utah. We found a relative risk of 3.0 for cigarette smoking after controlling for sexual and socioeconomic risk factors. The smoking association was strongest in the youngest age group (ages 20-29), reaching seventeenfold, and was weaker in the older age groups. These data suggest that cigarette smoking may be an independent risk factor for cancer of the uterine cervix, after considering sexual behavior and other well-established risk factors.

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial

Meyskens Jr. F.L.; Surwit E.; Moon T.E.; Childers J.M.; Davis J.R.; Dorr R.T.; Johnson C.S.; Alberts D.S. Irvine Clinical Cancer Center, University of California, 101 The City Dr.,Orange, CA 92668 United States

Journal of the National Cancer Institute (United States) 1994, 86/7 (539-543)

Background: Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%.

Purpose: This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.

Methods: Analyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test.

Results: RA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible.

Conclusions: A short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects. Implications: A derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible.

Human papillomavirus, smoking, and cancer.

Moore TO, Moore AY, Carrasco D, Vander Straten M, Arany I, Au W, Tyring SK. Department of Surgery, Baylor University Hospital, Dallas, TX, USA.

J. Cutan. Med Surg. 2001 Jul-Aug; 5(4): 323-8.

BACKGROUND: The effect of smoking on human papillomavirus (HPV) activity and subsequent dysplasia and neoplasia remains controversial. OBJECTIVE: To determine any reported effects of smoking on either HPV activity or HPV-related dysplasia/cancer using retrospective analysis of the literature from 1966 through 1998 via Toxline and PubMed to search for "smoking," "papillomavirus," and "cancer." CONCLUSION: Several recent large studies demonstrated that smoking was associated with a greater incidence of cervical, vulvar, penile, anal, oral, and head and neck cancer in a dose-dependent fashion, while other studies did not show any correlation between smoking and cervical dysplasia after multivariate adjustment. Recent studies have also indicated that smoking may be more closely related to high-grade lesions of the cervix and vulva. These data provide evidence of an association between HPV, smoking, and cancer. Progression of dysplasia likewise seems to be associated with smoking. Several groups have attempted to discern whether the connection between smoking and cervical cancer is from local immunosuppression and/or from direct carcinogenic effects.

Serum retinol level and risk of subsequent cervical cancer in cases with cervical dysplasia.

Nagata C, Shimizu H, Higashiiwai H, Sugahara N, Morita N, Komatsu S, Hisamichi S. Department of Public Health, Gifu University, School of Medicine, Japan.

Cancer Invest 1999;17(4):253-8

We followed up on 134 women who had been diagnosed with cervical dysplasia to examine the relationship of dietary and serum vitamin A to subsequent cervical cancer. The subjects were women attending the Papanicolaou test screening for residents in Miyagi, Japan and histologically diagnosed as having cervical dysplasia between October 1987 and September 1988. Personal interviews were carried out, and blood samples were taken on the date of diagnosis of cervical dysplasia. The subjects were followed-up with cervical smear and colposcopy at about 3-month intervals from the date of interview until the end of February 1995. During the follow-up, 8 women (5.9%) developed cancer in situ or invasive cervical cancer and 106 (79.1%) reverted to normal. The rate of progression of the cancer in situ or invasive cervical cancer was 4.5 times higher in women with lower serum retinol levels than those with higher serum retinol levels (p = 0.08). The results suggest an association of low serum retinol level with development of cervical cancer.

Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan.

Nagata C, Shimizu H, Yoshikawa H, Noda K, Nozawa S, Yajima A, Sekiya S, Sugimori H, Hirai Y, Kanazawa K, Sugase M, Kawana T. Department of Public Health, Gifu University School of Medicine, Japan.

Br J Cancer 1999 Dec;81(7):1234-7

The relationships between risk of cervical dysplasia and dietary and serum carotenoids and vitamins were investigated in a case-control study. Cases were 156 women who attended Papanicolaou test screening in nine institutes affiliated with Japan Study Group of Human Papillomavirus (HPV) and Cervical Cancer and had cervical dysplasia newly histologically confirmed. Age-matched controls were selected from women with normal cervical cytology attending the same clinic. Blood sample and cervical exfoliated cells were obtained for measuring serum retinol, alpha-carotene, beta-carotene, zeaxanthin/lutein, cryptoxanthin, lycopene and alpha-tocopherol and for HPV detection. Higher serum level of alpha-carotene was significantly associated with decreased risk of cervical dysplasia after controlling for HPV infection and smoking status (odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.04-0.62 for the highest as compared with the lowest tertile). Decreased risk for the highest tertile of serum lycopene (OR = 0.28) was marginally significant. Decreased risks observed for the highest tertiles of beta-carotene (OR = 0.65) and zeaxanthin/lutein (OR = 0.53), were not statistically significant.

Preventing cervical cancer. Progress in prevention, detection, and treatment.

NCI.

Plans & Priorities for Cancer Research 2001. Bethesda, MD: National Cancer Institute/National Institutes of Health.

Beta- carotene levels in exfoliated cervicovaginal epithelial cells in cervical intraepithelial neoplasia and cervical cancer.

Palan PR; Mikhail MS; Basu J; Romney SL Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY 10461.

Am J Obstet Gynecol (United States) Dec 1992, 167 (6) p1899-903

OBJECTIVE: The purpose of this study was to measure beta-carotene levels in exfoliated epithelial cervicovaginal cells collected by a lavage technique in normal women and patients with histopathologically diagnosed cervical intraepithelial neoplasia and cervical cancer.

STUDY DESIGN: In a cross-sectional sampling of women (n = 105), cervicovaginal cells and plasma beta-carotene levels were assayed with high-pressure liquid chromatography. In addition, beta-carotene levels were measured in exfoliated epithelial samples of cervicovaginal cells obtained from women (n = 24) enrolled in an ongoing oral beta-carotene supplementation clinical trial.

RESULTS: Cervicovaginal cells and plasma beta-carotene levels were found to be significantly decreased in women with cervical intraepithelial neoplasia and cervical cancer as compared with controls (< 0.0001, analysis of variance). Retinol levels in cervicovaginal cells were undetectable. The beta-carotene levels in cervicovaginal cells were markedly increased in the majority of patients (79%) after oral supplementation as compared with baseline levels in women enrolled in the beta-carotene clinical trial.

CONCLUSION: The study demonstrates that changes of in situ cellular beta-carotene concentrations are measurable in samples of exfoliated epithelial cells obtained by a noninvasive saline lavage harvesting technique. The current findings further support our previous hypothesis that beta-carotene deficiency may have an etiologic role in the pathogenesis of cervical intraepithelial neoplasia and/or cervical cancer.

Risk factors for cervical intraepithelial neoplasia.

Parazzini F; La Vecchia C; Negri E; Fedele L; Franceschi S; Gallotta L Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Cancer (United States) May 1 1992, 69 (9) p2276-82

To evaluate risk factors for cervical intraepithelial neoplasia (CIN), data were collected in a case-control study based on 366 patients (58 with CIN class 1, 70 with CIN class 2, and 238 with CIN class 3) and 323 control subjects with normal cervical smears interviewed on selected days at the same screening clinics where cases had been identified. No relationship emerged between indicators of socioeconomic status (education and social class) and risk of mild/moderate (considered together) and severe dysplasia. A total of 55 (43%) patients with CIN class 1 or 2, 107 (45%) patients with CIN class 3, and 94 (29%) controls were current smokers. The corresponding relative risk (RR) estimates for current versus never smokers were 1.9 (95% confidence interval [CI] 1.2 to 3.0) for patients with CIN class 1 or 2 and 2.5 (95% CI 1.7 to 3.6) for patients with CIN class 3, and the risk increased with the number of cigarettes smoked per day. No relationship was observed between oral contraceptive use , parity, spontaneous or induced abortions and the risk of CIN, but patients tended to report earlier age at first birth than control subjects. Compared with women reporting their first birth before the age of 20 years, the risk estimates were 0.5 and 0.4, respectively, for patients with CIN 1 or 2 and patients with CIN 3 in women reporting first birth at 20 to 24 years of age. The risk estimates were 0.5 and 0.6 for those reporting their first birth at age 25 or later, but the trends in risk were not statistically significant. The number of sexual partners was directly associated with the risk for both histopathologic subgroups. Compared with women reporting no intercourse or their first intercourse after 22 years of age, women with first intercourse before the age 18 had a RR estimate of CIN class 1 or 2 of 2.3 and of CIN class 3 of 2.4, with the trends in risk being statistically significant. This study confirms considerable similarities in the epidemiology of mild/moderate and severe cervical dysplasia. In addition, it suggests consistency between the epidemiology of intraepithelial and invasive cervical neoplasia for risk factors that are likely to act on one of the first stages of the process of carcinogenesis (i.e., indications of sexual habits) but differences for hormone-mediated factors (i.e., reproductive variables or oral contraceptives).

The Drug-Induced Nutrient Depletion Handbook, Second Edition 2001.

Pelton, R., LaValle, J., Hawkins, E.

Hudson, OH: Lexi-Comp.

A case-control study of nutrient status and invasive cervical cancer. II. Serologic indicators

Potischman N.; Herrero R.; Brinton L.A.; Reeves W.C.; Stacewicz-Sapuntzakis M.; Jones C.J.; Brenes M.M.; Tenorio F.; De Britton R.C.; Gaitan E. Environ. Epidemiology Branch, National Cancer Institute,Bethesda, MD United States

American Journal of Epidemiology (United States) 1991, 134/11 (1347-1355)

A study of 387 cases and 670 controls from four Latin American countries evaluated the hypothesis that lower serum levels of eight micronutrients were associated with a higher risk of invasive cervical cancer. The serologic analyses were restricted to a sample of subjects with stage I and II disease to minimize effects of the disease on the serologic markers. Ninety-four percent of eligible subjects donated blood samples, which were analyzed for carotenoids, retinol, and tocopherols by high-pressure liquid chromatography. Cases did not differ significantly from controls in mean serum levels of retinol, cryptoxanthin, lycopene, alpha-carotene, lutein, or alpha-tocopherol. The mean level of beta-carotene was lower and the mean level of gamma-tocopherol was higher among cases as compared with controls. After adjustment for age, study site, sexual and reproductive behavior, socioeconomic status, screening practices, detection of human papillomavirus types 16/18, cholesterol, and triglycerides, a trend of decreasing risk was associated with higher levels of beta-carotene (p for trend = 0.05), with the adjusted odds ratio decreasing to 0.72 for the highest versus the lowest quartile. beta-Carotene results were similar by stage of disease, which argues against an effect of disease progression on nutrient values. Unexpectedly, increasing risks were observed as the level of gamma-tocopherol increased (odds ratio = 2.09; p for trend = 0.03); however, levels were higher among stage II cases as compared with stage I cases, suggesting a metabolic alteration resulting from the disease process. The concordance in the strength and direction of the blood and dietary results, presented in the accompanying report (Herrero R, Potischman N, Brinton LA, et al., American Journal of Epidemiology 1991;134:1335-46), supports a role for beta-carotene or foods rich in beta-carotene in the etiology of cervical cancer. This study also indicates that simultaneous analysis using serologic and dietary nutrient indicators allows better discrimination of the association.

Plasma vitamin C and uterine cervical dysplasia.

Romney SL; Duttagupta C; Basu J; Palan PR; Karp S; Slagle NS; Dwyer A; Wassertheil-Smoller S; Wylie-Rosett J

Am J Obstet Gynecol (United States) Apr 1 1985, 151 (7) p976-80

Plasma concentrations of vitamin C were determined in a case-control study of women (n = 80) who had sought a Papanicolaou test in the Bronx Municipal Hospital Center. Controls (n = 34) were women having negative cytologic tests, negative colposcopic findings, and no known gynecologic dysfunction. Cases (n = 46) were defined as women who had either one positive or two consecutive suspicious Papanicolaou smears in a 12-month period. The mean concentration of vitamin C in the plasma was significantly lower in the cases than in the controls (0.36 versus 0.75 mg/dl, p less than 0.0001). Cases were further stratified according to the histopathologic diagnosis. The data direct attention to a possible etiologic association of vitamin C in human cervical epithelial abnormalities. A clinical trial with vitamin C intervention is suggested.

Chemoprevention of cancer of uterine cervix: a study on chemoprevention of retinamide II from cervical precancerous lesions.

Ruidi C, Aihua D, Peiyu B, Zhongru G, Huazao L, Shifeng S, Rui H, Shiping X. Cancer Institute, Chinese Academy of Medical Sciences, Pan Jia Yuan, Beijing, China.

J. Cell. Biochem. Suppl 1997; (28-29): 140-3.

Dysplasia of the uterine cervix is a recognized precancerous condition. Because of the observed ability of retinoids to suppress various cell lines in vitro, a number of clinical studies have examined the effect these agents have on cervical dysplasia, with the object of developing a means of chemoprevention of cervical malignancies in women at risk. Three cervical cancer chemoprevention trials with Retinamide II (RII) have been conducted at the Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China. A pilot study used RII to intervene in cases of precancerous cervical dysplasia. Twenty-seven women with mild, moderate, or severe cervical dysplasia, pathologically confirmed, were treated by RII suppositories, 10 mg QD, given intravaginally for 6 months (each course lasting 3 months). The results indicated that after the second course, the overall response rate was 96.29% and the complete response rate was 88.89%. In general, side effects were mild. A little cervical and vaginal irritation was well tolerated. In the second double-blind study, patients with precancerous cervical lesions were randomized into two groups, one treated with RII suppository intravaginally and the other with a placebo, once daily for 50 days in two courses. Precancerous lesions in 68.76% of patients in the treatment arm disappeared, with an overall effective rate of 74.29% after two courses of treatment with RII. Its curative effect was approximately that of laser beam radiation and electrocautery (< 0.05), and differed significantly (< 0.01) from that of traditional antiinflammatories. RII can be a major measure in prevention and treatment of cervical cancer in high-incidence areas in China. In the third trial, we are conducting a randomized double-blind study placebo controlled, in a high-incidence area of cervical cancer (Xiang-Yuan county, Shang Xi Province, China). At present, the patients are being followed up and the study will be completed after 2 years.

The effect of oral contraceptives on the apparent vitamin B6 status insome Sudanese women.

Salih EY; Zein AA; Bayoumi RA Faculty of Medicine, University of Khartoum, Sudan.

Br J Nutr (England) Sep 1986, 56 (2) p363-7

1. In vitro activation of erythrocyte aspartate aminotransferase (EC2.6.1.1) activity by pyridoxal phosphate was used to assess vitamin B6 nutritional status in forty Sudanese women taking combined, low-dose oralcontraceptives (oestrogen-progestogen; OC) and in thirty healthy, non-pregnant women not taking OC.

2. Fourteen (35%) out of forty OC users showed apparent vitamin B6 deficiency.

3. Side-effects associated with OC were more common among the apparently vitamin-B6-deficient OC users than among OC users and non-OC users not deficient in vitamin B6.

Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia

Schiffman MH; Bauer HM; Hoover RN; Glass AG; Cadell DM; Rush BB; Scott DR ; Sherman ME; Kurman RJ; Wacholder S; et al Epidemiology and Biostatistics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

J Natl Cancer Inst (United States) Jun 16 1993, 85 (12) p958-64

BACKGROUND: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long-sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent.

PURPOSE: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection.

METHODS: We studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV.

RESULTS: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex partners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women.

CONCLUSION: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV.

IMPLICATIONS: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance.

Estrogen metabolite ratios and risk assessment of hormone-related cancers. Assay validation and prediction of cervical cancer risk.

Sepkovic DW, Bradlow HL, Ho G, Hankinson SE, Gong L, Osborne MP, Fishman J. Strang-Cornell Cancer Research Laboratories, New York, New York 10021, USA.

Ann N Y Acad Sci 1995 Sep 30;768:312-6

No abstract available.

Pyridoxine, the pill and depression.

P.W.Alexander Simpson Lab. Metab. Res., St Mary's Hosp. Med. Sch., London W2

United Kingdom Journal of Pharmacotherapy (United Kingdom) 1980, 3/1 (20-29)

Depression is associated with altered metabolism of brain amines which are derived from tryptophan and tyrosine, the metabolism of which is also deranged by oral contraceptives (OC). The effects of OC on tryptophan metabolism are mediated by induction of the rate-limiting enzyme of its major catabolic pathway, and impaired pyridoxal phosphate (derived from vitamin B6)-dependent co-enzyme function. The majority of women on OC have functional B6 deficiency, but a small proportion have vitamin B6 deficiency with evidence of lowered tissue levels of this vitamin. As the dose of pyridoxine recommended for the treatment of depression of women on OC is excessive and may have metabolic side-effects, the minimum dose of pyridoxine has to be established that will correct the symptoms and metabolic abnormalities in women with OC-induced deficiency of vitamin B6.

Dietary vitamins A, C, and E and selenium as risk factors for cervical cancer.

Slattery ML; Abbott TM; Overall JC Jr; Robison LM; French TK; Jolles C; Gardner JW; West DW Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City 84132.

Epidemiology Jan 1990, 1 (1) p8-15

The relation between cervical cancer and dietary intake of vitamins A, C,and E, beta-carotene, and selenium was examined in a population-based case-control study in Utah. Cervical cancer cases (n = 266) and population-based controls (n = 408) were interviewed between 1984 and 1987. Protective effects were observed for vitamins A, C, and E and beta-carotene but were attenuated by age, level of education, and lifetime cigarette use. Associated risk (comparing highest with lowest quartiles of intake) went from 0.53 (crude) to 0.71 (adjusted) for vitamin A; from 0.55 (crude) to 0.82 (adjusted) for beta-carotene; from 0.45 (crude) to 0.55 (adjusted) for vitamin C; from 0.58 (crude) to 0.60 (adjusted) for vitamin E; and from 0.95 (crude) to 0.70 (adjusted) for selenium. Adjustment for number of sex partners and church attendance, factors significantly related to cervical cancer risk, only slightly attenuated these adjusted risk estimates.

Protective effect of dietary brussels sprouts against mammary carcinogenesis in Sprague-Dawley rats.

Stoewsand GS, Anderson JL, Munson L. Department of Food Science and Technology, Cornell University, Geneva, NY 14456.

Cancer Lett 1988 Mar;39(2):199-207

The effect of dietary brussels sprouts (Brassica oleracea, L.) on mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in Sprague-Dawley female rats. Rats fed a 20% brussels sprouts diet only during the initiation period of carcinogenesis had a palpable mammary tumor incidence of 13%, while those fed a casein-cornstarch semi-purified diet during this initiation period had a tumor incidence of 77% after 15 weeks post DMBA dose. When the rats were switched from the semi-purified diet to the 20% Brussels sprouts diet at this time, there appeared to be a regression of small mammary tumors after 6 weeks on this dietary treatment. This regression was transitory since during the final 10 weeks of this 1 year study, 100% of this group of rats developed tumors. The rats fed the 20% brussels sprouts diet during tumor initiation exhibited a 67% incidence of fibroadenomas. The rats fed the semi-purified diet during initiation, but switched later to the brussels sprouts diet, showed over a 90% incidence of adenocarcinomas.

Folate deficiency and oral contraceptives

Streiff RR Veterans Administration Hospital and the College of Medicine, University of Florida, Gainesville, Florida reprints: AMA Department of Foods and Nutrition, 535 N. Dearborn Street, Chicago, Illinois 60610

J. Am. Med. Assoc.; Vol 214 Iss Oct 5 1970, P105-108, (Ref 38)

ASHP The report concerns 7 cases of folate deficiency and anemia apparently due to orally administered contraceptives and studies on the effect of this type of medication on folate absorption.

Low serum selenium concentration in patients with cervical or endometrial cancer.

Sundstrom H; Yrjanheikki E; Kauppila A

Int J Gynaecol Obstet (Ireland) Feb 1984, 22 (1) p35-40

Serum concentrations of selenium were determined in 37 patients with cervical and 64 patients with endometrial cancer. The patients had lower (P less than 0.001) serum concentrations of selenium than the age-, weight-and place of residence-matched paired control women. There was no difference in the selenium concentration between various age groups or different clinical stages of cervical or endometrial cancer. A low serum concentration of selenium might be a contributing factor in uterine carcinogenesis.

Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells.

Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. Breast Cancer Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

J Natl Cancer Inst 1992 Apr 15;84(8):634-8

BACKGROUND: Estrogens are potent mammary tumor promoters influencing post-initiation events via epigenetic mechanisms. The upregulation (i.e., induction) of the C16 alpha-hydroxylation pathway during 17 beta-estradiol (E2) biotransformation has been associated with mammary cell transformation. The action of E2 metabolites on tumorigenic transformation, however, is poorly understood. PURPOSE: The newly established mammary epithelial cell line C57/MG, derived from the C57BL mouse strain, was used to examine whether E2 or its metabolites, 16-hydroxyestrone (16 alpha-OHE1) and estriol (E3), function as initiators of mammary cell transformation. METHODS: DNA repair (hydroxyurea-insensitive thymidine uptake), estrogen metabolism (3H exchange to form 3H2O), hyperproliferation (increased cell number), and acquisition of anchorage-independent growth (soft-agar colonies) were used as quantitative end points to measure the relative extent of transformation. RESULTS: Treatment of cells with 200 ng/mL 16 alpha-OHE1 resulted in a 55.2% increase in DNA repair synthesis, a 23.09% increase in proliferative activity, and a 18-fold increase in the number of soft-agar colonies, relative to the solvent controls (P less than .0001). The extent of upregulation of the three end points was similar to that induced by the genotoxic mammary carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA, positive control). DMBA treatment also upregulated the ratio of 16 alpha/C2 hydroxylation of E2 leading to increased formation of 16 alpha-OHE1. E2 and E3 were not effective in upregulating these markers for transformation. CONCLUSION: These results demonstrate that in nontransformed C57/MG cells, 16 alpha-OHE1 may function as an initiator, perturbing the intermediate biomarkers for preneoplastic transformation.

Cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix.

Trevathan E; Layde P; Webster LA; Adams JB; Benigno BB; Ory H

JAMA (United States) Jul 22-29 1983, 250 (4) p499-502

We conducted a case-control study of cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix. Cases were black women 17 to 55 years of age who were attending a dysplasia clinic and had biopsy-confirmed cervical pathologic conditions. Controls were women who were attending the family planning clinic at the same hospital and who had at least two normal Papanicolaou smears. Results were adjusted for age, number of sexual partners, age at first intercourse, socioeconomic status, and oral contraceptive use. Cigarette smoking was significantly associated with carcinoma in situ , severe dysplasia, and mild-moderate dysplasia (relative risks, 3.6, 3.3, and 2.4, respectively). Cumulative exposure to cigarette smoking (as measured by pack-years smoked) was strongly related to the risk of these conditions; women with 12 or more pack-years of exposure had relative risks of 12.7, 10.2, and 4.3, respectively, for the three conditions. There was some evidence that the risk was greatest in women who began smoking in their early teenage years. A reduction in the risk of cervical cancer appears to be another inducement for young women not to smoke.

Oral contraceptive use and adenocarcinoma of cervix

Ursin G; Peters RK; Henderson BE; d'Ablaing G 3rd; Monroe KR; Pike MC Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90033-9987.

Lancet (England) Nov 19 1994, 344 (8934) p1390-4

The incidence of adenocarcinoma of the cervix in the USA more than doubled between the early 1970s and the mid 1980s among women under 35 years of age. It was suggested that this increase was due to the introduction of oral contraceptives in the early 1960s. Adenocarcinoma of the cervix diagnosed in women born after 1935 was identified between 1977 and 1991 from the Los Angeles County Cancer Surveillance Program. Data from personal interviews of 195 cases and 386 controls (matched on age, race, and neighbourhood) were analysed. Information on medical, sexual, contraceptive, and reproductive history, previous cervical smears, and sexually transmitted diseases was collected. Compared with never use, ever use of oral contraceptives was associated with twice as great a risk of adenocarcinoma of the cervix (adjusted odds ratio 2.1, 95% CI 1.1-3.8). The highest risk was observed for oral contraceptive use for more than 12 years (4.4, 1.8-10.8). No additional increased risk was found for early age at start of oral contraceptive use, use before age 20 or before first pregnancy, time since first use, time since last use, or particular formulations, once total duration of use had been accounted for.

Change of vitamin a status and its influence on cervical dysplasia

Volz J.; Van Rissenbeck A.; Blanke M.; Melchert F.; Schneider A.; Biesalski H.K. OA Universitats-Frauenklinik, Theodor-Kutzer-Ufer 10,68135 Mannheim Germany

Zentralblatt fur Gynakologie (Germany) 1995, 117/9 (472-475)

In 34 patients with HVP-infection of the cervix and in 40 patients with CIN III standardised biopsies were taken from the involved area and normal cervical epithelium for determination of the local concentration of retinylester. In all cases diagnosis was confirmed colposcopically, cytologically and by histology. HPV infection was confirmed by in situ hybridisation. Determination of retinylester was performed by HPLC. No significant difference of local retinyl-palmitate concentration was detectable in HPV infected versus normal tissue. Retinyl-palmitate concentration was extremely lower in CIN III compared with normal cervical epithelium and HPV-infected tissue. The determination of plasma level of retinol showed no significant difference between the two groups. So it can be presumed that the reduction of retinyl-palmitate in CIN III is a local process and a local supplementation of Vitamin A might contribute to the prevention of cervical neoplasia.

Dietary vitamin C and uterine cervical dysplasia

Wassertheil-Smoller S.; Romney S.L.; Wylie-Rosett J.; et al. Dept. Commun. Hlth, Albert Einstein Coll. Med., Bronx, NY 10461 United States

American Journal of Epidemiology (United States) 1981, 114/5 (714-724)

A case-control study of women with cervical abnormalities identified through Pap smears, was conducted in the Bronx, New York, to explore the relationship between nutritional intake and cervical dysplasia. Nutrient intake was estimated from computer analysis of three-day food records and 24-hour recall for 169 study participants (87 cases, 82 controls), including a subset of 49 pairs matched for age, race and parity. Mean vitamin C intake per day from three-day food record for controls was 107 mg, compared to 80 mg for cases (< 0.01). Analysis of matched pairs showed similar results; 29% of cases compared to 3% of controls in matched subset had vitamin C intake less than 50% of the recommended daily allowance, yielding a ten-fold increase in risk of cervical dysplasia as estimated by odds ratio (< 0.05). Younger age, greater frequency of sexual intercourse and younger age at first intercourse were associated with higher risk of cervical dysplasia. Multiple logistic analyses indicated that low vitamin C intake is an independent contributor to risk of severe cervical dysplasia when age and sexual activity variables are controlled. Approximately 35% of US women in their reproductive years have daily vitamin C intake below 30 mg, and 68% have vitamin C intake below 88 mg. If other studies confirm these findings, it may be important to explore a possible protective role of supplementary vitamin C for women at high risk of cervical cancer.

A phase I trial of topically applied trans-retinoic acid in cervical dysplasia-clinical efficacy.

Weiner SA; Surwit EA; Graham VE; Meyskens FL Jr

Invest New Drugs 1986, 4 (3) p241-4

Forty-two patients were entered into a phase I trial to evaluate the vitamin A derivative, trans-retinoic acid, in cervical intraepithelial neoplasia. Treatment consisted of four consecutive 24-h applications of retinoids via an inert collagen sponge in a cervical cap. Patients were followed for response at 3-month intervals using cytology, colposcopy, and selected biopsies. Thirty-six patients were evaluable (mild dysplasia, 13; moderate dysplasia, 17; severe dysplasia, 6) with follow-up from 5 to 18 months. Complete regression was seen in 2/14 (14%) patients treated with concentrations of 0.05%----0.1167% and in 10/22 (45%) patients treated with concentrations of 0.1583%----0.484% (p less than 0.05). One patient with negative biopsies at 12 months has subsequently recurred at 18 months.

Megaloblastic changes in the cervical epithelium: association with oral contraceptive therapy and reversal with folic acid

Whitehead N; Reyner F; Lindenbaum J Harlem Hospital, Lenox Avenue and 135th Street, New York, New York 10037

J. Am. Med. Assoc.; Vol 226 Iss Dec 17 1973, P1421-1424, (Ref 20)

ASHP Megaloblastic abnormalities of cervicovaginal cells similar to those seen in severe folate and vitamin B12 deficiency were found in 22 (19%) of 115 women taking oral contraceptive agents (combined estrogen-progestogen or progestogens only). Similar changes were not observed in any of 51 controls not taking these medications. The cytologic abnormalities could not be related to hematologic findings or serum folate and vitamin B12 concentrations. The changes reverted to normal or improved markedly in all 8 patients treated with pharmacologic doses of folic acid for 3 weeks. It is hypothesized that oral contraceptive agents induce a localized interference with folate metabolism at the end organ level.

World Health Report 1997.

WHO.

Geneva: World Health Organization.

Influence of vitamin A on cervical dysplasia and carcinoma in situ

Wylie-Rosett J.A.; Romney S.L.; Slagle N.S.; et al. Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY 10461 United States

Nutrition and Cancer (United States) 1984, 6/1 (49-57)

A case-control study was undertaken to determine the dietary intake of vitamin A in women having abnormal uterocervical cytology. The study groups (87 cases and 82 controls) were drawn from a population of women who received a screening Pap test in the ambulatory health care section of a large municipal hospital center. A subset of cases (with abnormal cytology) were matched to controls for age, ethnicity, socioeconomic status, and parity. Nutrient intake and retinol binding protein concentrations were determinde; epidemiological data were also obtained. It was found that the subset of cases with severe dysplasia or carcinoma in situ (CIS) were more likely to have a total dietary vitamin A intake below the pooled median (3,450 IU) and/or a beta-carotene intake below the pooled median (2,072 IU) than were normal controls (< 0.05 and < 0.025, respectively). Odds ratios revealed approximately a 3-fold greater risk for severe dysplasia or CIS in women with lowered vitamin A or beta-carotene intake. In addition, retinol binding protein was either absent or undetectable in 78.8% of the dysplastic tissue samples, versus 23.5% of the normal tissue samples (< 0.005).

Folic acid and cervical dysplasia

Zarcone R.; Bellini P.; Carfora E.; Vicinaza G.; Raucci F. Via Cappuccini, 16,Montesarchio (BN) Italy

Minerva Ginecologica (Italy) 1996, 48/10 (397-400)

The localized folate deficiency, which is sometimes misdiagnosed as cervical dysplasia, because of morphologic similarities between the cytologic features of megaloblastosis seen with folate deficiency and the changes associated with dysplasia, could be a component of the dysplastic process. In this study we attempted the effect of oral folic in women with cervical dysplasia . A total of 154 subjects with grade 1 or 2 CIN were randomly assigned either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection and blood folate levels were monitored at 2 month intervals. After 6-months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection. Folate deficiency may be involved as a cocarginogen during the initiation of cervical dysplasia , but folic acid supplements do not alter the course of estabilished disease.

Diet and estrogen status: the cruciferous connection.

Zeligs, M.,

J. Med. Food 1998; 1(2): 67-81.

No abstract available.

Epidemiologic studies of vitamins and cancer of the lung, esophagus, and cervix.

Ziegler RG

Adv Exp Med Biol (United States) 1986, 206 p11-26

Epidemiologic studies of the relationships between vitamins and 3 types of cancer are reviewed. First, the widely reported association between vitamin A and beta -carotene and risk of lung cancer is considered. In a large population-based case-control study of lung cancer among white males in New Jersey, increased intake of vegetables, dark green vegetables, dark yellow-orange vegetables, and carotenoids were each associated with reduced risk, but intake of retinol or total vitamin A was not related. The protective effect of vegetables was limited to current and recent cigarette smokers, which suggests that vegetable intake prevents a late-stage event in carcinogenesis. Consumption of dark yellow-orange vegetables was consistently more predictive of reduced risk than either the total carotenoid index or consumption of any other food group, possible because of the high content of beta -carotene in this food group. The results and limitations of other epidemiologic studies of diet and lung cancer are reviewed. Second, the evolving relationship between multiple micronutrient deficiencies and esophageal cancer is discussed. In a death certificate-based case-control study of esophageal cancer in black males in Washington, D.C., several indicators of general nutritional status, including consumption of fresh or frozen meat and fish, dairy products and eggs, and fruit and vegetables, and the number of meals eaten per day, were inversely and independently correlated with the risk of esophageal cancer. Estimates of intake of micronutrients, such as carotenoids, vitamin C , thiamin, and riboflavin, were less strongly associated with reduced risk than were the broad food groups that provide most of each micronutrient. Thus no single micronutrient deficiency was identified. Other studies suggest that generally poor nutrition may partially explain the susceptibility of urban black men to esophageal cancer. Finally, the postulated association between low folacin levels and risk of cervical cancer is examined. Among women who use oral contraceptives, serum and red blood cell folacin levels were reported to be lower among those with cervical dysplasia . In a clinical trial involving oral contraceptive users, cervical dysplasia gradually decreased in the group supplemented with oral folate but remained unchanged in the group given the placebo. Other epidemiologic studies of diet and cervical cancer are discussed.

CERVICAL DYSPLASIA
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	Dietary and serum carotenoids and cervical intraepithelial neoplasia.
	Plasma vitamin C and uterine cervical dysplasia.
	Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-Hispanic, black women.
	Serum micronutrients and the subsequent risk of cervical cancer in apopulation-based nested case-control study.
	Change of vitamin a status and its influence on cervical dysplasia
	Folates: supplemental forms and therapeutic applications.
	Folic acid and cervical dysplasia
	Folate status, women's health, pregnancy outcome, and cancer
	Epidemiologic studies of vitamins and cancer of the lung, esophagus, and cervix.
	Folate deficiency and cervical dysplasia
	Antineoblastic activity of antioxidant vitamins: the role of folic acid in the prevention of cervical dysplasia.
	[Folic acid and cervix dysplasia]
	Folate deficiency, cancer and congenital abnormalities. Is there a connection?
	Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial
	Hypomethylation in cervical tissue: is there a correlation with folate status?
	Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives.
	Megaloblastic changes in the cervical epithelium: association with oral contraceptive therapy and reversal with folic acid
	Folic acid deficiency megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives
	Megaloblastic anemia in a vegetarian taking oral contraceptives.
	Folate deficiency and oral contraceptives
	Influence of vitamin A on cervical dysplasia and carcinoma in situ
	Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial
	Phase II trial of beta- all- trans- retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap
	A phase I trial of topically applied trans-retinoic acid in cervical dysplasia-clinical efficacy.
	Retinoids and the prevention of cervical dysplasias.
	Use of vitamins A and D in chemoprevention and therapy of cancer: control of nuclear receptor expression and function. Vitamins, cancer and receptors.
	Specificity of retinoid receptor gene expression in mouse cervical epithelia.
	Studies of retinoids in the prevention and treatment of cancer.
	Antioxidant nutrients: associations with persistent human papillomavirus infection.
	Content of beta - carotene in blood serum of human papillomavirus infected women with cervical dysplasias.
	Premalignant lesions: role of antioxidant vitamins and beta-carotene in risk reduction and prevention of malignant transformation.

Dietary and serum carotenoids and cervical intraepithelial neoplasia.

VanEenwyk J; Davis FG; Bowen PE
Department of Epidemiology and Biostatistics, School of Public Health, University of Illinois, Chicago.
Int J Cancer (United States) Apr 22 1991, 48 (1) p34-8

A case-control study examined the association between cervical intra-epithelial neoplasia (CIN) and serum and dietary alpha-carotene, beta-carotene, cryptoxanthin, lutein, and lycopene. Cases (n = 102) had biopsy confirmed CIN I, II or III. Controls matched for age, ethnic origin and clinic (n = 102) had normal Pap smears. Participants completed health history and food frequency questionnaires. Fasting venous blood samples were assayed for serum carotenoids. Multivariable conditional logistic regression analyses yielded odds ratios and 95% confidence intervals (CIs) for those in quartiles 3, 2, and 1 (lowest) compared to quartile 4 (highest) of serum lycopene of 3.5 (1.1-11.5), 4.7 (1.2-17.7) and 3.8 (1.1-12.4), respectively. Similar analyses yielded adjusted odds ratios (ORaS) and 95% CIs of 4.6 (1.1-19.7), 5.8 (1.6-21.3) and 5.4 (1.3-23.3) for dietary intake of lycopene. The findings for lycopene-rich foods (tomatoes) were consistent with this result. CIN was not associated with the lutein. Findings for alpha-carotene, beta-carotene and cryptoxanthin were ambiguous. Quartile of vitamin C intake was also inversely associated with CIN with ORaS and 95% CIs of 3.7 (0.9-14.6), 4.1 (1.0-17.2), and 6.4 (1.4-30.0) for those in quartiles 3, 2, and 1 compared to quartile 4.

Plasma vitamin C and uterine cervical dysplasia.

Romney SL; Duttagupta C; Basu J; Palan PR; Karp S; Slagle NS; Dwyer A; Wassertheil-Smoller S; Wylie-Rosett J
Am J Obstet Gynecol (United States) Apr 1 1985, 151 (7) p976-80

Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-Hispanic, black women.

Kantesky PA; Gammon MD; Mandelblatt J; Zhang ZF; Ramsey E; Dnistrian A; Norkus EP; Wright TC Jr
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA
pkanetsk@cceb.med.upenn.edu
Nutr Cancer (United States) 1998, 31 (1) p31-40

We examined whether elevated levels of retinoids, carotenoids, folate , and vitamin E protected against cervical dysplasia among non-Hispanic, black women. We enrolled 32 women with incident cervical dysplasia , including cervical intraepithelial neoplasia (CIN) I, CIN II, and CIN III/carcinoma in situ, and 113 control women with normal cervical cytology in case-control study. Micronutrient levels were estimated from a food-frequency questionnaire (FFQ) and measured from blood samples. Information on risk factors for cervical neoplasia was elicited by interview. Hybrid capture was used to determine infection with human papillomavirus. After adjustment for potential confounders, analysis of micronutrient levels estimated from the FFQ suggested that women in the upper tertile of lycopene and vitamin A intake were one-third (odds ratio = 0.32, 95% confidence interval = 0.8-1.3) and one-fourth (odds ratio = 0.24, 95% confidence interval = 0.05-1.2) as likely, respectively, to have dysplasia as women in the lower tertile. Borderline protective trends (p < or = 0.10) were apparent. Elevated levels of serum lycopene also suggested some protection against dysplasia. Results were not significant at alpha = 0.05 because of the small number of case women enrolled. Overall, correlations between estimates from the FFQ and serum levels were poor. This study indicates that, among black women, lycopene and perhaps vitamin A may play a protective role in the early stages of cervical carcinogenesis.

Serum micronutrients and the subsequent risk of cervical cancer in apopulation-based nested case-control study.

Batieha AM; Armenian HK; Norkus EP; Morris JS; Spate VE; Comstock GW
Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
Cancer Epidemiol Biomarkers Prev (United States) Jul-Aug 1993, 2 (4) p335-9

A nested case-control study was conducted in Washington County, MD, to determine whether low serum micronutrients are related to the subsequent risk of cervical cancer. Among the 15,161 women who donated blood for future cancer research during a serum collection campaign in 1974, 18 developed invasive cervical cancer and 32 developed carcinoma in situ during the period January 1975 through May 1990. For each of these 50 cases, two matched controls were selected from the same cohort. The frozen sera of the cases and their matched controls were analyzed for a number of nutrients. The mean serum levels of total carotenoids, alpha-carotene, beta-carotene, cryptoxanthin, and lycopene were lower among cases than they were among controls. When examined by tertiles, the risk of cervical cancer was significantly higher among women in the lower tertiles of total carotenoids (odds ratio 2.7; 95% confidence limit, 1.1-6.4), alpha-carotene (odds ratio, 3.1; 95% confidence limit, 1.3-7.6), and beta-carotene (odds ratio, 3.1; 95% confidence limit, 1.2-8.1) as compared to women in the upper tertiles and the trends were statistically significant. Cryptoxanthin was significantly associated with a lower risk of cervical cancer when examined as a continuous variable. Retinol, lutein, alpha- and gamma-tocopherol, and selenium were not related to cervical cancer risk. Smoking was also strongly associated with cervical cancer. These findings are suggestive of a protective role for total carotenoids, alpha-carotene and beta-carotene in cervical carcinogenesis and possibly for cryptoxanthin and lycopene as well.

Change of vitamin a status and its influence on cervical dysplasia

Volz J.; Van Rissenbeck A.; Blanke M.; Melchert F.; Schneider A.; Biesalski H.K.
OA Universitats-Frauenklinik, Theodor-Kutzer-Ufer 10,68135 Mannheim Germany
Zentralblatt fur Gynakologie (Germany) 1995, 117/9 (472-475)

Folates: supplemental forms and therapeutic applications.

Kelly GS
gregnd@worldnet.att.net
Altern Med Rev (United States) Jun 1998, 3 (3) p208-20

Folates function as a single carbon donor in the synthesis of serine from glycine, in the synthesis of nucleotides form purine precursors, indirectly in the synthesis of transfer RNA, and as a methyl donor to create methylcobalamin, which is used in the re-methylation of homocysteine to methionine. Oral folates are generally available in two supplemental forms, folic and folinic acid. Administration of folinic acid bypasses the deconjugation and reduction steps required for folic acid . Folinic acid also appears to be a more metabolically active form of folate , capable of boosting levels of the coenzyme forms of the vitamin in circumstances where folic acid has little to no effect. Therapeutically, folic acid can reduce homocysteine levels and the occurrence of neural tube defects, might play a role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis, appears to be a rational aspect of a nutritional protocol to treat vitiligo, and can increase the resistance of the gingiva to local irritants, leading to a reduction in inflammation. Reports also indicate that neuropsychiatric diseases secondary to folate deficiency might include dementia, schizophrenia-like syndromes, insomnia, irritability, forgetfulness, endogenous depression, organic psychosis, peripheral neuropathy, myelopathy, and restless legs syndrome. (103 Refs.)

Folic acid and cervical dysplasia

Zarcone R.; Bellini P.; Carfora E.; Vicinaza G.; Raucci F.
Via Cappuccini, 16,Montesarchio (BN) Italy
Minerva Ginecologica (Italy) 1996, 48/10 (397-400)

Folate status, women's health, pregnancy outcome, and cancer

Butterworth Jr. C.E.
Dept. of Nutrition Sciences, University of Alabama,Birmingham, AL 35294 United States
Journal of the American College of Nutrition (United States) 1993, 12/4 (438-441)

Epidemiologic studies of vitamins and cancer of the lung, esophagus, and cervix.

Ziegler RG
Adv Exp Med Biol (United States) 1986, 206 p11-26

Folate deficiency and cervical dysplasia

Butterworth Jr. C.E.; Hatch K.D.; Macaluso M.; Cole P.; Sauberlich H.E.; Soong S.-J.; Borst M.; Baker V.V.
Nutrition Sciences Department, University of Alabama, UAB Station,Birmingham, AL 35294-3360 United States
Journal of the American Medical Association 1992, 267/4 (528-533)

Objective. - To test the hypothesis that nutritional deficiency affects the incidence of cervical dysplasia in young women.

Design and Setting. - Case-control study. Participants were derived from community family-planning clinics and referrals to a colposcopy center.

Participants. - A total of 726 subjects were screened, yielding 294 cases of dysplasia and 170 controls defined by coexistent cytologic and colposcopic evidence.

Conclusion. - Low red blood cell folate levels enhance the effect of other risk factors for cervical dysplasia and, in particular, that of HPV-16 infection.

Antineoblastic activity of antioxidant vitamins: the role of folic acid in the prevention of cervical dysplasia.

Grio R; Piacentino R; Marchino GL; Navone R
Department of Gynecology and Obstetrics, University of Turin, Italy.
Panminerva Med (Italy) Dec 1993, 35 (4) p193-6

The authors made a study on 90 patients affected by various degrees of uterine cervix dysplasia searching for folic acid plasmatic concentrations. The team members affected by CIN have been compared with a test team consisting of women with normal pap-test and vaginoscopy. The study proved that the average levels of folic acids have significantly decreased in cases of dysplasia compared with the test team. These results allow stating that low folic acid plasmatic concentrations may be associated with cervix neoplasms development.

[Folic acid and cervix dysplasia]

Zarcone R; Bellini P; Carfora E; Vicinanza G; Raucci F
Istituto di Ginecologia ed Ostetricia, II Universita degli Studi, Napoli.
Minerva Ginecol (Italy) Oct 1996, 48 (10) p397-400

The localized folate deficiency, which is sometimes misdiagnosed as cervical dysplasia , because of morphological similarities between the cytologic features of megaloblastosis seen with folate deficiency and the changes associated with dysplasia, could be a component of the dysplastic process. In this study we attempted the effect of oral folic in women with cervical dysplasia . A total of 154 subjects with grade 1 or 2 CIN were randomly assigned either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection and blood folate levels were monitored at 2 month intervals. After 6-months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection. Folate deficiency the initiation of cervical dysplasia , but folic acid supplements do not alter the course of established disease.

Folate deficiency, cancer and congenital abnormalities. Is there a connection?

Christensen B Seksjon for farmakologi Institutt for klinisk biologi Universitetet i Bergen.
Tidsskr Nor Laegeforen (Norway) Jan 20 1996, 116 (2) p250-4

The biochemical role of folate is in the interconversion of one-carbon units in intermediary metabolism; a process in which a methyl group is formed de novo. The methyl group is subsequently transferred to adenosylmethionine, which is an important methyl donor in the methylation of DNA. A negative correlation exists between the intake of folate in pregnancy and the occurrence of neural tube defects and certain malignant brain tumours in children. Numerous clinical studies have pointed to an association between folate status in adults and both the occurrence of cancer and the premalignant changes, cervical dysplasia , bronchial metaplasia, and colorectal adenomas. Folate deficiency may cause chromosomal damage, due to impaired DNA synthesis or repair. Moreover, decreased production of adenosylmethionine may influence the expression of developmental genes and of oncogenes and/or tumour suppressor genes through disturbed methylation of DNA. (45 Refs.)

Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial

Butterworth Jr. C.E.; Hatch K.D.; Soong S.-J.; Cole P.; Tamura T.; Sauberlich H.E.; Borst M.; Macaluso M.; Baker V.
Department of Nutrition, Sciences, University of Alabama,Birmingham, AL 35294-3360 United States
American Journal of Obstetrics and Gynecology 1992, 166/3 (803-809)

Objective: We attempted to evaluate the effect of oral folic acid supplementation on the course of cervical dysplasia .

Conclusion: Folate deficiency may be involved as a cocarcinogen during the initiation of cervical dysplasia , but folic acid supplements do not alter the course of established disease.

Hypomethylation in cervical tissue: is there a correlation with folate status?

Fowler BM; Giuliano AR; Piyathilake C; Nour M; Hatch K
Arizona Cancer Center, University Medical Center, University of Arizona, Tucson 85716, USA.
Cancer Epidemiol Biomarkers Prev Oct 1998, 7 (10) p901-6

We have shown previously that DNA hypomethylation is significantly associated with grade of cervical intraepithelial neoplasia (CIN; Y.I. Kim et al., Cancer, 74: 893-899, 1994). The objective of this study was to further describe this relationship and to investigate the role of folate in the observed association of DNA hypomethylation and CIN. Eighty-three patients with abnormal PAP smear results were referred to the Cervical Dysplasia Clinic at the University of Arizona for colposcopic examination and biopsy. Patients completed a short questionnaire and provided a nonfasting serum sample. DNA hypomethylation was assessed by incubating DNA extracted from biopsy samples with [3H]methyl-S-adenosylmethionine and Sss 1 methylase. Cervical tissue and serum folate concentrations were assessed using a microbiological assay. All folate levels were log transformed prior to statistical analysis. The histological distribution of the samples was: 7 adjacent normal, 30 CIN I, 18 CIN II, 13 CIN III, and 11 carcinoma in situ (CIS). The mean age of participants was 29.8 +/- 9.6 years. DNA hypomethylation was significantly different between select histological levels. Both cervical tissue folate and serum folate levels were significantly correlated to methylation level (P = 0.0211 and P = 0.0569, respectively). Smoking, hormonal contraceptive use, parity, and human papillomavirus infection were not associated with DNA hypomethylation or folate status. The current use of vitamins was significantly associated with serum folate level but not with methylation or cervical folate levels. These data extend our earlier findings that DNA hypomethylation is an early event in cervical carcinogenesis. To conclude that the folate level is significantly related to DNA hypomethylation, further investigation of DNA hypomethylation of specific genes is required.

Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives.

Butterworth CE Jr; Hatch KD; Gore H; Mueller H; Krumdieck CL
Am J Clin Nutr (United States) Jan 1982, 35 (1) p73-82

Megaloblastic changes in the cervical epithelium: association with oral contraceptive therapy and reversal with folic acid

Whitehead N; Reyner F; Lindenbaum J
Harlem Hospital, Lenox Avenue and 135th Street, New York, New York 10037
J. Am. Med. Assoc.; Vol 226 Iss Dec 17 1973, P1421-1424, (Ref 20)

Folic acid deficiency megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives

Kornberg A; Segal R; Theitler J; Yona R; Kaufman S
Dep Hematol., Assaf Harofeh Med. Cent., 70300 Zerifin.
Isr J Med Sci 25 (3). 1989. 142-145. Israel Journal of Medical Sciences

Megaloblastic anemia in a vegetarian taking oral contraceptives.

Green JD
South Med J; Vol 68, Iss 2, 1975, P249-50

A case is reported of megaloblastic anemia resulting from folate deficiency in a vegetarian who had been taking oral contraceptives for eight years. A brief report of the pertinent literature is included.

Folate deficiency and oral contraceptives

Streiff RR
Veterans Administration Hospital and the College of Medicine, University of Florida, Gainesville, Florida
reprints: AMA Department of Foods and Nutrition, 535 N. Dearborn Street, Chicago, Illinois 60610
J. Am. Med. Assoc.; Vol 214 Iss Oct 5 1970, P105-108, (Ref 38)

ASHP The report concerns 7 cases of folate deficiency and anemia apparently due to orally administered contraceptives and studies on the effect of this type of medication on folate absorption.

Influence of vitamin A on cervical dysplasia and carcinoma in situ

Wylie-Rosett J.A.; Romney S.L.; Slagle N.S.; et al.
Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY 10461 United States
Nutrition and Cancer (United States) 1984, 6/1 (49-57)

A case-control study was undertaken to determine the dietary intake of vitamin A in women having abnormal uterocervical cytology. The study groups (87 cases and 82 controls) were drawn from a population of women who received a screening Pap test in the ambulatory health care section of a large municipal hospital center. A subset of cases (with abnormal cytology) were matched to controls for age, ethnicity, socioeconomic status, and parity. Nutrient intake and retinol binding protein concentrations were determinde; epidemiological data were also obtained. It was found that the subset of cases with severe dysplasia or carcinoma in situ (CIS) were more likely to have a total dietary vitamin A intake below the pooled median (3,450 IU) and/or a beta-carotene intake below the pooled median (2,072 IU) than were normal controls (p<0.05 and p<0.025, respectively). Odds ratios revealed approximately a 3-fold greater risk for severe dysplasia or CIS in women with lowered vitamin A or beta-carotene intake. In addition, retinol binding protein was either absent or undetectable in 78.8% of the dysplastic tissue samples, versus 23.5% of the normal tissue samples (p<0.005).

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial

Meyskens Jr. F.L.; Surwit E.; Moon T.E.; Childers J.M.; Davis J.R.; Dorr R.T.; Johnson C.S.; Alberts D.S.
Irvine Clinical Cancer Center, University of California, 101 The City Dr.,Orange, CA 92668 United States
Journal of the National Cancer Institute (United States) 1994, 86/7 (539-543)

Purpose: This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.

Phase II trial of beta- all- trans- retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap

Graham V.; Surwit E.S.; Weiner S.; Meyskens Jr. F.L.
Departments of Medicine, Obstetrics and Gynecology, University of Arizona Health Sciences Center, Tucson, AZ 85724 United States
Western Journal of Medicine (United States) 1986, 145/2 (192-195)

A phase I trial of topically applied trans-retinoic acid in cervical dysplasia-clinical efficacy.

Weiner SA; Surwit EA; Graham VE; Meyskens FL Jr
Invest New Drugs 1986, 4 (3) p241-4

Retinoids and the prevention of cervical dysplasias.

Romney SL; Palan PR; Duttagupta C; Wassertheil-Smoller S; Wylie J; Miller G; Slagle NS; Lucido D
Am J Obstet Gynecol (United States) Dec 15 1981, 141 (8) p890-4

Women with abnormal cytology were matched with normal control subjects for age, parity, ethnicity, and socioeconomic class and participated in a blind case-control study focused on the role of nutrition in cervical dysplasia . Sucrose gradient ultracentrifugation studies for determination of the presence and concentration of the binding proteins for retinol and retinoic acid were performed on colposcopic biopsy tissue specimens. The nutritional survey revealed statistically significant differences for vitamins A and C and beta carotene . Retinol binding protein was absent or minimally detectable and inversely related to the severity of the dysplasia. It is proposed that a double-blind clinical trial be conducted to evaluate whether retinoids may pharmacologically inhibit, arrest, or reverse cervical dysplasia .

Use of vitamins A and D in chemoprevention and therapy of cancer: control of nuclear receptor expression and function. Vitamins, cancer and receptors.

Niles RM
Department of Biochemistry and Molecular Biology, Marshall University School of Medicine, Huntington, WV 25755, USA.
Adv Exp Med Biol 1995, 375 p1-15

Vitamin A is metabolized to several biologically active compounds, the best known of which is retinoic acid. This compound has been shown to inhibit the growth of a variety of tumor cells and to induce a more differentiated phenotype in several tumor types. Vitamin D is metabolized to the active compound 1,25-dihydroxyvitamin D3. This vitamin is well-known for its role in maintaining calcium homeostasis in the body. Recently it has been shown that vitamin D3 can also inhibit tumor cell replication and stimulate differentiation of selected tumor types. Retinoic acid is being used clinically to treat promyelocytic leukemia, head and neck tumors as well as cervical dysplasia . Use of vitamin D3 clinically has been restricted by its affect on calcium metabolism. Recently, however, new analogs of vitamin D3 have been developed which have much less calcium mobilizing activity, yet still retain their tumor inhibitory properties. The action of both of these vitamins is mediated by nuclear receptors which have the same structure as steroid receptors. There are three nuclear retinoic acid receptors (RAR alpha, beta, and gamma), but only one vitamin D3 nuclear receptor. These receptors are expressed in very small amounts. Since the ligand should be in vast excess of receptor (ie not limiting), we explored the possibility that response to vitamin A might be mediated by control of RAR expression. Using B16 mouse melanoma cells as a model system, we found that RAR alpha and gamma mRNAs were constitutively expressed. RAR beta mRNA was induced by treatment of the cells with RA. Induction of RAR beta mRNA occurred within 1h and was not inhibited by cycloheximide. The mRNA for all three RARs was dramatically decreased with 8-bromo-cyclic AMP treatment and could not be rescued by addition of RA. Analysis of RAR gamma revealed that this decrease occurred within 1h of exposure to 8-bromo-cyclic AMP and was not blocked by simultaneous treatment with cycloheximide. Nuclear extracts from cyclic AMP-treated cells showed a large decrease in protein binding to a retinoic acid response element (RARE) oligonucleotide compared to control cells. This correlated with a marked reduction of RA-stimulated RARE-reporter gene activity in transfected cells which were treated with cyclic AMP. Pre-treatment of B16 cells with cyclic AMP prior to RA addition dramatically reduced induction of PKC alpha, an early marker of RA-induced cell differentiation. Thus, cyclic AMP can antagonize the physiological actions of RA via its ability to inhibit RAR expression.

Specificity of retinoid receptor gene expression in mouse cervical epithelia.

Darwiche N; Celli G; De Luca LM
Differentiation Control Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Endocrinology May 1994, 134 (5) p2018-25

Retinoids are powerful regulators of epithelial differentiation and are essential for its maintenance. Because retinoids are necessary for cervical epithelial differentiation, they have been used as chemopreventive agents of cervical dysplasia and neoplasia. We were interested in determining whether different cervical epithelial phenotypes express specific retinoid receptors. The cervical epithelium contains the two phenotypes, stratified squamous and simple columnar, which join at the squamocolumnar junction. In addition, the simple columnar epithelium undergoes squamous metaplasia in response to vitamin A deficiency. Therefore, the cervical epithelium is suitable to study the expression pattern of the retinoid receptors in the three phenotypes, simple columnar, stratified squamous, and squamous metaplastic, simultaneously. The distribution pattern of the major retinoic acid receptor (RAR) isoforms (alpha 1, alpha 2, beta 2, beta 3, gamma 1, and gamma 2) and retinoid-X receptors (RXR alpha, -beta, and -gamma) was studied by in situ hybridization. At the tissue level, RAR alpha (1 and 2) and RXR (alpha and beta) transcripts and, to a lesser extent, RAR gamma (1 and 2) transcripts were associated with the cervical stratified squamous subjunctional epithelium. The simple columnar epithelium, which is highly responsive to vitamin A status, expressed high levels of RAR alpha (1 and 2), RAR beta (2 and 3), and RXR (alpha and beta) transcripts. Only RAR beta (2 and 3) and RXR (alpha and beta) transcripts were down-modulated by the condition of vitamin A deficiency and expressed less in squamous metaplastic foci than the simple columnar epithelium. RXR gamma was undetectable in all three cervical epithelia. At the cellular level, basal and suprabasal expression was found for RARs, and preferential localization of RXRs was seen in basal cells. RXRs are auxiliary proteins for a variety of other nuclear receptors with which they form heterodimers, including RARs. The fact that RXRs are mainly localized in basal and columnar cells of the cervix suggests the need for the regulation and diversity generated by potential heterodimeric interactions in these rapidly proliferating cells in vivo. The unique pattern of expression and localization of the RARs and RXRs in different cervical epithelial tissues and cell types supports the hypothesis that they perform specific functions in cervical epithelial differentiation. This is in contrast to the major isoforms of each RAR, which have similar patterns of expression in the different cervical epithelial phenotypes and cell types, suggesting a redundancy in function.

Studies of retinoids in the prevention and treatment of cancer.

Meyskens FL
J Am Acad Dermatol Apr 1982, 6 (4 Pt 2 Suppl) p824-7

Investigation of retinoids for anticancer activity in humans, either in the chemopreventive or treatment mode, has been little studied. We summarize here our ongoing investigations in four different areas: (1) secondary prevention of cervical dysplasia with topical application of all-trans-retinoic acid; (2) adjuvant treatment of resected high-risk stage I and II malignant melanoma with bacille Calmette Guerin (BCG) plus or minus oral vitamin A ; (3) topical vitamin A acid therapy for cutaneous metastatic melanoma; an (4) oral isotretinoin as an anticancer agent.

Antioxidant nutrients: associations with persistent human papillomavirus infection.

Giuliano AR; Papenfuss M; Nour M; Canfield LM; Schneider A; Hatch K
Arizona Cancer Center, University of Arizona, Tucson 85724, USA
minority@azcc.arizona.edu
Cancer Epidemiol Biomarkers Prev Nov 1997, 6 (11) p917-23

Research from the past several years has definitively shown intermediate and high risk-type human papillomavirus (HPV) infection to play a significant role in cervical carcinogenesis. Persistent compared with intermittent infection appears to confer an elevated risk, and cofactors may be necessary to allow the virus to progress to cervical cancer. We explored the association between circulating concentrations of the antioxidant nutrients (alpha- and beta-carotene, lutein, lycopene, beta-cryptoxanthin, alpha-tocopherol, gamma-tocopherol, and ascorbate) and persistent HPV infection among 123 low-income Hispanic women who were all nonsmokers and were not currently using vitamin and mineral supplements. In addition, the association between these nutrients and grade of cervical pathology, independent of HPV status, was assessed. Intermediate and high risk-type HPV infection was assessed by the Digene Hybrid Capture System at two time points, 3 months apart. At the second interview, cytology, colposcopy, and a fasting blood draw were conducted. Mean concentrations of serum and plasma antioxidant nutrients were calculated within categories of HPV status (two times HPV negative, one time HPV positive, and two times HPV positive) and colposcopy. Adjusted mean concentrations of serum beta-carotene, beta-cryptoxanthin, lutein, and alpha- and gamma-tocopherol were on average 24% (P < 0.05) lower among women two times HPV positive compared with either two times HPV negative or one time HPV positive. Independent of HPV status, alpha-tocopherol was significantly inversely associated with grade of cervical dysplasia (normal, 21.57 microM; cervical intraepithelial neoplasia III, 17.27 microM). The results obtained in this study need to be confirmed in larger cohort studies with a longer follow-up period.

Content of beta - carotene in blood serum of human papillomavirus infected women with cervical dysplasias.

Kwasniewska A; Tukendorf A; Semczuk M
Department of Obstetrics and Gynecology, Medical Academy, Lublin, Poland.
Arch Immunol Ther Exp (Warsz) (Poland) 1996, 44 (5-6) p309-13

Studies were carried out in 528 women hospitalized in the Department of Obstetrics and Gynecology Medical Academy in Lublin. Besides the control group, patients were classified according to the observed histopathological changes in the cervix (CIN) and found infections with human papillomavirus (HPV). In all cases beta -carotene content in blood serum was examined. HPV infection was probably a cause of decrease of beta -carotene content. It was found that with increased advancement of cervical dysplasia the level of beta carotene in serum decreased.

Premalignant lesions: role of antioxidant vitamins and beta-carotene in risk reduction and prevention of malignant transformation.

Singh VN; Gaby SK
Department of Clinical Nutrition, Hoffmann-La Roche, Inc., Nutley, NJ 07110-1199.
Am J Clin Nutr Jan 1991, 53 (1 Suppl) p386S-390S

Epidemiological studies have shown that diets rich in one or more antioxidant nutrients may reduce the risk of cancers of the lung, uterine cervix, mouth, and gastrointestinal tract. Study of premalignant lesions offers a comparatively expedient approach to identifying and evaluating the efficacy of the cancer chemopreventive components of foods. Some recent findings suggest roles for beta-carotene and/or vitamin C in reversing or reducing the risk of cervical dysplasia and oral leukoplakia. There are some indications that vitamin C and beta-carotene may reduce the risk of atrophic gastritis and gastric cancer. Additional epidemiological and molecular biology studies and clinical intervention trials using premalignant lesions as the marker of specific cancer risks should become an important component of future research in the area of cancer chemoprevention. (57 Refs.)

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CERVICAL DYSPLASIA
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	Growth retardation in human cervical dysplasia-derived cell lines by beta - carotene through down-regulation of epidermal growth factor receptor.
	Growth suppression and induction of heat-shock protein-70 by 9-cis beta - carotene in cervical dysplasia-derived cells.
	Oral contraceptive use and adenocarcinoma of cervix
	Comparison of oral contraceptive use in women with adenocarcinoma and squamous cell carcinoma of the uterine cervix.
	Oral contraceptive use and invasive cervical cancer.
	Oral contraceptive use and risk of invasive cervical cancer.
	Use of oral contraceptives and risk of invasive cervical cancer in previously screened women.
	Long-term use of oral contraceptives and cervical neoplasia: an association confounded by other risk factors?
	Oral contraceptives and cervical neoplasia
	Case-control study of risk factors for cervical squamous- cell neoplasia in Denmark. III. Role of oral contraceptive use.
	Oral contraceptive use and cervical intraepithelial neoplasia.
	Oral contraceptive use and the incidence of cervical intraepithelial neoplasia
	A case-control study of oral contraceptive use in women with adenocarcinoma of the uterine cervix.
	A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression.
	Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation
	Stress and hopelessness in the promotion of cervical intraepithelial neoplasia to invasive squamous cell carcinoma of the cervix
	[Relation between selenium and cancer of uterine cervix]
	Serum selenium and the risk of cancer, by specific sites: case-controlanalysis of prospective data.
	Chemopreventive action of selenium on methylcholanthrene-inducedcarcinogenesis in the uterine cervix of mouse.
	Dietary vitamins A, C, and E and selenium as risk factors for cervicalcancer.
	[Concentration of selenium and vitamin E in the serum of women withmalignant genital neoplasms and their family members]
	Relationship between the cervical uterine cancer evolution and selenium concentration in urine determined by NAA
	Activation analysis of selenium in cancer research
	Low serum selenium concentration in patients with cervical or endometrialcancer.
	Pyridoxine, the pill and depression Adams P.W.Alexander Simpson
	Physiological and psychological effects of vitamins E and B-6 on women taking oral contraceptives
	Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophanon carbohydrate metabolism.
	Does use of oral contraceptives enhance the toxicity of carbon disulfidethrough interactions with pyridoxine and tryptophan metabolism?
	Drug--vitamin B6 interaction.
	The effect of oral contraceptives on the apparent vitamin B6 status insome Sudanese women.

Growth retardation in human cervical dysplasia-derived cell lines by beta - carotene through down-regulation of epidermal growth factor receptor.

Muto Y; Fujii J; Shidoji Y; Moriwaki H; Kawaguchi T; Noda T
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Am J Clin Nutr Dec 1995, 62 (6 Suppl) p1535S-1540S

We used newly established cervical dysplasia -derived cell lines to elucidate a molecular mechanism of the preventive action of beta - carotene in cervical multi-step carcinogenesis. Liposomal beta - carotene was added to the culture medium for human cervical dysplasia cell lines, CICCN-2 from cervical intraepithelial neoplasia grade I (CIN I), CICCN-3 from CIN II, and CICCN-4 from CIN III, and human cervical carcinoma-derived cell lines such as CICCN-6, CICCN-18, and HeLa cells. beta - Carotene (10 mumol/L) induced significant growth retardation in three cervical dysplasia cell lines but not in three cervical carcinoma-derived cell lines. Binding activities of epidermal growth factor (EGF) and cellular amounts of either messenger RNA for EGF receptor gene or EGF receptor protein were all highest in CICCN-4 cells. Cell surface binding, as well as internalization, of 125I-labeled EGF was rapidly reduced after beta - carotene treatment in dysplasia cell lines and 170-kD protein bands of EGF receptor disappeared from protein immunoblots at day 3 of the treatment. Cellular amounts of EGF receptor messenger RNA remained constant until day 3 of the treatment and were substantially reduced after day 7. Chromatin condensations, morphologic evidence for apoptotic cell death, were observed at day 1 by staining. From these results, we contend that prevention of cervical carcinogenesis by beta - carotene is due to induction of apoptosis in cervical dysplastic cells, which are premalignant cells in cervical multi-step carcinogenesis, via down-regulation of EGF receptor protein.

Growth suppression and induction of heat-shock protein-70 by 9-cis beta - carotene in cervical dysplasia-derived cells.

Toba T; Shidoji Y; Fujii J; Moriwaki H; Muto Y; Suzuki T; Ohishi N; Yagi K
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Life Sci (England) 1997, 61 (8) p839-45

The aim of the present study was to determine to what extent 9-cis beta- carotene , one of the most abundant naturally-occurring cis-isomers of beta -carotene , can inhibit the growth of cervical dysplasia -derived cells in comparison with all-trans beta -carotene . We found that 9-cis beta -carotene was dose-dependently more effective than all-trans beta - carotene . Both carotenes induced the intracellular accumulation of heat-shock protein-70 (HSP70), and the treated cells showed morphological changes indicative of apoptosis. The results of the present study strongly suggest that the induction of HSP70 by beta -carotene might be involved in beta - carotene -mediated suppression of the cell growth through apoptosis.

Oral contraceptive use and adenocarcinoma of cervix

Ursin G; Peters RK; Henderson BE; d'Ablaing G 3rd; Monroe KR; Pike MC
Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90033-9987.
Lancet (England) Nov 19 1994, 344 (8934) p1390-4

Comparison of oral contraceptive use in women with adenocarcinoma and squamous cell carcinoma of the uterine cervix.

Honore LH; Koch M; Brown LB
Department of Pathology, University of Alberta, Edmonton, Canada.
Gynecol Obstet Invest (Switzerland) 1991, 32 (2) p98-101

The possible link between oral contraceptives (OCs) and cervical adenocarcinoma was tested by a case-case study of prior and current OC use in women with adenocarcinoma and squamous cell carcinoma. Cases were matched by age, year of diagnosis, and stage of the lesion, and personal, reproductive, and contraceptive data were obtained by mailed questionnaires. Except for smoking, which was significantly more prevalent in women with squamous cell carcinoma, the two groups were identical, with similar OC exposure. This study does not support the idea that OCs modulate the expression of cervical neoplasia in favor of adenocarcinoma.

Oral contraceptive use and invasive cervical cancer.

Parazzini F; la Vecchia C; Negri E; Maggi R
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Int J Epidemiol (England) Jun 1990, 19 (2) p259-63

The relationship between oral contraceptive use and the risk of invasive cervical cancer was investigated using data from a hospital-based case-control study conducted in the greater Milan area, Northern Italy. A total of 367 women under 60 years of age with a histologically confirmed diagnosis of invasive cervical cancer was compared with a group of 323 controls admitted for a spectrum of acute conditions, non-gynaecological, hormonal or neoplastic and apparently unrelated to oral contraceptive use . Cases had used oral contraceptives more frequently than controls, the age-adjusted relative risk (RR) being 1.53 (95% confidence interval 0.99-2.36). The risk increased with duration of use: compared with never users the age-adjusted RR was 1.48 for up to two years and 1.83 for more than two years (chi 2(1) = 5.28, p = 0.02). Allowing for major identified potential confounding factors, including sexual and reproductive habits, by means of multiple logistic regression, did not explain the association (multivariate RR 1.85 for ever use, 1.05 for up to two years and 2.47 for more than two years). When the interaction between oral contraceptive use and parity or sexual habits was analysed, the effects of various factors appeared independent: the point estimate for multiparous oral contraceptive users versus nulliparous never users was 8.01. There was no consistent influence on risk of invasive cervical cancer of age at first use, whereas the RRs were slightly greater for women who had first used oral contraceptives less than ten years before or had last used them less than five years before diagnosis: these findings, however, were far from significant.

Oral contraceptive use and risk of invasive cervical cancer.

Brinton LA; Reeves WC; Brenes MM; Herrero R; de Britton RC; Gaitan E; Tenorio F; Garcia M; Rawls WE
Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892.
Int J Epidemiol (England) Mar 1990, 19 (1) p4-11

Use of oral contraceptives and risk of invasive cervical cancer in previously screened women.

Ebeling K; Nischan P; Schindler C
Int J Cancer (United States) Apr 15 1987, 39 (4) p427-30

Long-term use of oral contraceptives and cervical neoplasia: an association confounded by other risk factors?

Hellberg D; Valentin J; Nilsson S
Contraception Oct 1985, 32 (4) p337-46

One-hundred-and-forty women with cervical intraepithelial neoplasia (CIN) found during pregnancy were compared to 280 pregnant age-matched controls. Information was obtained on obstetrical and gynecological history, sexual behaviour, contraceptive use and smoking of the female and of the male partner. Oral contraceptive use for 60 months or more was significantly associated with CIN. This significance vanished when the effect of confounding factors was controlled for in a log-linear analysis. According to these results, long-term oral contraceptive use does not seem to be a causal factor of CIN, but these women constitute a high risk group due to sexual history and smoking habits and should thus be referred for a regular cytological screening.

Oral contraceptives and cervical neoplasia

Brinton L.A.
Environmental Epidemiology Branch, National Cancer Institute, Executive Plaza North, Bethesda, MD 20892 United States
Contraception 1991, 43/6 (581-595)

Although initial studies examining the relationship of oral contraceptives to risk of cervical neoplasia were reassuring, more recent studies provide some evidence of a positive relationship, particularly for long-term usage. Results, however, are difficult to interpret, because of a variety of methodologic complexities, including potential sources of confounding and bias. Sexual behavior and Pap smear screening have been identified as important confounders, but in several well-controlled studies residual excess risks of nearly 2-fold persist for users of 5 or more years. A possible promotional effect of oral contraceptives is suggested by higher risks associated with recent usage. There also is some suggestion of a stronger effect for adenocarcinomas than for squamous cell tumors. A relationship is biologically possible, given findings of hormone receptors in cervical tissue and the fact that oral contraceptives have been found to induce cervical hyperplasia. In addition, oral contraceptives may induce proliferation of the human papillomaviruses, the leading suspect agent for cervical cancer. Although a number of lines of evidence support a relationship of oral contraceptives to cervical cancer risk, firm conclusions await the results of additional studies that specifically address some of the methodologic shortcomings of previous investigations. In particular, additional follow-up studies are needed to define the effect of oral contraceptives on the natural history of cervical lesions.

Case-control study of risk factors for cervical squamous- cell neoplasia in Denmark. III. Role of oral contraceptive use.

Kjaer SK; Engholm G; Dahl C; Bock JE; Lynge E; Jensen OM
Danish Cancer Society, Copenhagen.
Cancer Causes Control (England) Nov 1993, 4 (6) p513-9

The role of oral contraceptive (OC) use in relation to the risk of cervical neoplasia (squamous cell) was investigated in a population-based case-control study in Denmark of 586 women with histologically verified cervical carcinoma in situ (CIS), 59 women with invasive cervical cancer from Copenhagen, and 614 controls drawn at random from the female population in the study area. Ever use of OCs was associated with an increased crude risk for carcinoma in situ (relative risk [RR] = 1.8, 95 percent confidence interval [CI] = 1.3-2.5). The crude risk in relation to invasive carcinoma was 1.6 (CI = 0.7-3.5). After adjustment for potential confounders (excluding human papillomavirus), the risks were marginally increased, but not statistically significant (CIS: RR = 1.4, CI = 0.9-21: invasive: RR = 1.3, CI = 0.5-3.3). The risk increased with duration of use; compared with never users, the adjusted RR for carcinoma in situ was 1.9 (CI = 1.1-3.1) for women who had used OCs for six to nine years, and 1.7 (CI = 1.0-2.7) for women who used OCs for 10 years or more. This was independent of years since last use since both recent and non-recent long-term users were at an increased risk. This trend in risk with duration did not apply to the same extent to invasive lesions. The observation that the risks related to OC use were found both in women who had ever had a Pap smear and in women who had never been screened previously may speak against detection bias as an important factor.

Oral contraceptive use and cervical intraepithelial neoplasia.

Coker AL; McCann MF; Hulka BS; Walton LA
Department of Epidemiology and Biostatistics, University of South Carolina, Columbia 29208.
J Clin Epidemiol (England) Oct 1992, 45 (10) p1111-8

To explore the somewhat controversial relationship between oral contraceptives and pre-invasive cervical cancer, 103 cases of biopsy-confirmed cervical intraepithelial neoplasia (CIN) II or CIN III were compared with 258 controls who had normal cervical cytology. Cases were slightly less likely than controls to have ever used oral contraceptives; the odds ratio, controlling for age, socioeconomic status, barrier method use, smoking history, age at first sexual intercourse, number of sex partners, current marital status, and number of Pap smears, was 0.7 (95% CI 0.3-1.6). Recency, latency, duration, and age at first oral contraceptive use were evaluated and in no instance was oral contraceptive use positively associated with CIN. This study adds to the body of knowledge that oral contraceptives are not associated with pre-invasive cervical cancer. Further, if oral contraceptive users continue to be regularly screened, their risk of developing the more invasive lesions should be very low.

Oral contraceptive use and the incidence of cervical intraepithelial neoplasia

Gram IT; Macaluso M; Stalsberg H
Institute of Community Medicine, University of Tromso, Norway.
Am J Obstet Gynecol Jul 1992, 167 (1) p40-4

OBJECTIVE: Our objective was to examine the relationship between oral contraceptive use and the incidence of cervical intraepithelial neoplasia.

STUDY DESIGN: In a prospective follow-up study of 6622 women participating in the Second Tromso Study conducted in 1979 and 1980 in Tromso, Norway, women aged 20 to 49 years answered a questionnaire regarding their smoking history, dietary habits, alcohol consumption, and oral contraceptive use . They were then followed for 10 years with data from the Pathology Registry of the University Hospital.

RESULTS: The age-adjusted incidence rate of cervical intraepithelial neoplasia was 897 per 100,000 person years among noncurrent and 1295 per 100,000 person years among current oral contraceptive users as of 1979. After adjusting for age, marital status, smoking, and frequency of alcohol intoxication the relative rate for current users was 1.5 (95% confidence interval 1.1 to 2.1), and the relative rate for past users was 1.4 (95% confidence interval 1.0 to 1.8), as compared with those who had never used oral contraceptives before 1979.

CONCLUSION: These findings support the hypothesis that the occurrence of cervical intraepithelial neoplasia is increased by oral contraceptive use .

A case-control study of oral contraceptive use in women with adenocarcinoma of the uterine cervix.

Persson E; Einhorn N; Pettersson F
Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden.
Eur J Obstet Gynecol Reprod Biol (Netherlands) Sep 1987, 26 (1) p85-90

To evaluate oral contraceptive (OC) use as a possible cause of the changed ratio between adenocarcinoma and squamous cell carcinoma of the uterine cervix a case-control study was performed. The OC use among 23 women with adenocarcinoma of the uterine cervix was compared with that of a matched group of 46 women with squamous cell carcinoma. No differences in percentage of OC use, duration of such use or period of OC use in relation to diagnosis could be demonstrated between the two groups compared.

A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression.

Liu T; Soong SJ; Alvarez RD; Butterworth CE Jr
Biostatistics Unit, University of Alabama at Birmingham 35294-3300, USA.
Cancer Epidemiol Biomarkers Prev Jun 1995, 4 (4) p373-80

Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation

Butterworth Jr. C.E.; Hatch K.; Cole P.; Sauberlich H.E.; Tamura T.; Cornwell P.E.; Soong S.-J.
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 United States
American Journal of Clinical Nutrition 1988, 47/3 (484-486)

It has been suggested that oral supplements of folic acid interfere with the intestinal absorption of zinc and may have toxic side effects. The concentrations of Zn and folate in blood were monitored in a group of women with cervical dysplasia randomly assigned to receive 10 mg/d of either folic acid (pteroylglutamic acid) or ascorbate. Fifty subjects were evaluated after 2 mo; 21 of the same subjects were evaluated again after 4 mo. No untoward clinical effects were observed. Significant elevation of erythrocyte folate above the baseline value was observed in the supplemented group but not in the placebo group (p < 0.001). The concentration of Zn in plasma and erythrocytes did not change significantly in either the folate -treated or placebo groups after 2 and 4 mo. It is concluded that carefully controlled clinical intervention trials of this type do not impose a risk of depleting the concentration of Zn in erythrocytes and plasma.

Stress and hopelessness in the promotion of cervical intraepithelial neoplasia to invasive squamous cell carcinoma of the cervix

Goodkin K; Antoni MH; Blaney PH
J Psychosom Res (England) 1986, 30 (1) p67-76
[published erratum appears in J Psychosom Res 1987;31(5):659]

[Relation between selenium and cancer of uterine cervix]

Lou H; Wu R; Fu Y
Zhejiang Cancer Hospital, Hangzhou.
Chung Hua Chung Liu Tsa Chih (China) Mar 1995, 17 (2) p112-4,

Selenium (Se) concentration in serum, hair, normal cervix tissue ortissue of cervix cancer of 20 cases with cancer of uterine cervix (surveygroup), 21 with myoma of the uterus and 1 with cervical polys (control group), but also in rice, water and soil in the high and low incidence areas of cervical cancer was determined. The results showed that Se concentration in serum and cancer tissue of uterine cervix in patients with cancer of uterine cervix was significantly lower than that in the control group (P < 0.05), but no significant difference of Se concentration in hair was observed (P > 0.05), However Se concentration in rice, water and soil in the high incidence areas of cervical cancer was significantly lower than that in the low incidence areas (P < 0.05). Se deficiency may play a role in the carcinogenesis of uterine cervix.

Serum selenium and the risk of cancer, by specific sites: case-controlanalysis of prospective data.

Nomura A; Heilbrun LK; Morris JS; Stemmermann GN
J Natl Cancer Inst Jul 1987, 79 (1) p103-8

From 1971 to 1975, serum specimens were obtained from 6,860 men ofJapanese ancestry in Hawaii. Since then, the following numbers of newly diagnosed cases with epithelial cancer have been identified: 82 colon, 71 lung, 66 stomach, 32 rectum, and 29 urinary bladder. The stored sera of the 280 cases and of 293 randomly selected controls were tested to determine their levels of selenium. There was no association of serum selenium with lung, stomach, or rectal cancer. An increase in relative risk (RR) was noted only for subjects in the lowest quintile of selenium values, as compared to the RR for subjects in the highest quintile, for colon (RR = 1.8) and urinary bladder cancer (RR = 3.1), but neither of these RR estimates was statistically significant (P = .09 and P = .07, respectively). Further work is needed to determine whether the antioxidant properties of selenium protect against specific types of cancer.

Chemopreventive action of selenium on methylcholanthrene-inducedcarcinogenesis in the uterine cervix of mouse.

Hussain SP; Rao AR
Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Oncology 1992, 49 (3) p237-40

Dietary vitamins A, C, and E and selenium as risk factors for cervicalcancer.

Slattery ML; Abbott TM; Overall JC Jr; Robison LM; French TK; Jolles C; Gardner JW; West DW
Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City 84132.
Epidemiology Jan 1990, 1 (1) p8-15

[Concentration of selenium and vitamin E in the serum of women withmalignant genital neoplasms and their family members]

Drozdz M; Tomala J; Jendryczko A; Banas K
Ginekol Pol (Poland) Jun 1989,60 (6) p301-5

Lower concentrations of selenium and vitamin E were found in the serum of 50 women with malignant neoplasms of the genitals as compared with the concentrations in 55 healthy women family members of the patients living with them in common households. The degree of concentration decrease of these substances in the serum depended on the location of the tumour, and in cases of cervical neoplasms was 28% for selenium and 12% for vitamin E of the values in controls while in cases of ovarian neoplasms it was 34% and 37% respectively and in endometrial tumours it was 40% and 23% respectively. The third studied group comprised 36 healthy subjects not belonging to the families of the patients. The highest concentrations of selenium and vitamin E were found in the serum in the third group of women. The results suggest that various family factors not analysed in this study affect the concentrations of selenium and vitamin E in the serum of women with malignant neoplasms of genitals and in their family members.

Relationship between the cervical uterine cancer evolution and selenium concentration in urine determined by NAA

Navarrete M.; Cabrera L.; Martinez T.; Revel G.; Meyer J.P.; Guarner J. M. Navarrete,
National University of Mexico, Faculty of Chemistry, Bldg. D., C.U. 04510 Mexico City Mexico
Journal of Radioanalytical and Nuclear Chemistry (Hungary) 1997, 217/2 (167-169)

Neutron activation analysis of Se in urine roaches an optimum sensitivity few ppb) and precision (+/- 12%) when the traces are complexed without using a carder by ammonium pyrrolidindithiocarbamate (APDC) at pH 1.5-2 and adsorbed on activated carbon filters. In this way the selenium traces analysis have been carded out through sup 7sup 7sup mSe in 45 urine samples on a pre-separation basis by cyclic activation of the carbon filters. The selenium concentration in our blanks is virtually zero, because APDC proved to be selenium free and selenium mass in 50 mg of activated carbon used as a filter is 20 times below our qualitative detection limit and 144 times below our quantitative detection limit. The samples were first of day urine from healthy and ill women suffering cervical uterine cancer, at different evolution stages: incipient, intermediate and advanced, with no treatment, and surgery, radiotherapy, chemotherapy, or a combined treatment. The results show a consistent trend to increase the selenium trace concentration during the intermediate stage, whereas it is the same than normal for incipient cases, and it decreases to the lowest concentrations for advanced cases.

Activation analysis of selenium in cancer research

Navarrete M.; Cabrera L.; Martinez T.; Revel G.; Meyer J.P.; Stampfler A.
National University of Mexico, Faculty of Chemistry,04510 Mexico City Mexico
Journal of Radioanalytical and Nuclear Chemistry (Hungary) 1995, 195/1 (91-95)

The method described in a previous work to separate trace amounts of selenium in organic samples without using a carrier, based on the adsorption on active carbon filters of the complex formed with ammonium pyrrolidindithiocarbamate (APDC) at pH 1.5-2, has been applied to urine samples from 15 female patients suffering from cervical uterine cancer. With this type of sample the method reaches a maximum sensitivity (few ppb) with a good statistical variation (+/- 12%). Since the highest concentrations of selenium in human tissues is found in the kidney, and the elimination of this element is mainly by the urine, the method seems to be a powerful tool in the research about the human metabolism of selenium. This paper shows a possible relation of selenium concentration in human urine and the evolution time of cervical uterine cancer, in spite of limits imposed by the statistical error plus the inhomogeneity of the sample.

Low serum selenium concentration in patients with cervical or endometrialcancer.

Sundstrom H; Yrjanheikki E; Kauppila A
Int J Gynaecol Obstet (Ireland) Feb 1984, 22 (1) p35-40

Pyridoxine, the pill and depression Adams P.W.Alexander Simpson

Lab. Metab. Res., St Mary's Hosp. Med. Sch., London W2
United Kingdom Journal of Pharmacotherapy (United Kingdom) 1980, 3/1 (20-29)

Physiological and psychological effects of vitamins E and B-6 on women taking oral contraceptives

Applegate W V; Forsythe A; Bauernfeind J B
South. Calif. Perm. Med. Group, 8010 Parkway Dr., La Mesa, Calif. 92041, USA.
Int J Vitam Nutr Res 49 (1). 1979. 43-50.

A substantial number of women on oral contraceptives have low blood levels of vitamin E. When d,l .alpha.-tocopheryl 1200 IU is administered daily for 3-4 mo., there is improvement of hematocrit for those attaining a serum level greater than 11 mcg/ml and serum vitamin E level is significantly elevated. Platelet count is depressed into the low normal range so caution should be exercised in administering vitamin E in high doses to patients already on medication such as aspirin or thiazides that may further depress platelet function or count. No toxicity or side effects from using high doses of vitamin E could be discerned. Vitamin B6 almost completely nullified the effect of vitamin E on hematocrit, platelet count and serum vitamin E when administered concurrently. Vitamin B6 30 mg/day also significantly elevated mood in 56% of the women who received it. The diet of women on oral contraceptives should be supplemented with vitamin E and vitamin B6 (administered at separate times). The importance of supplementing vitamin B6 becomes even more urgent when one considers that urinary metabolites resulting from the abnormal breakdown of tryptophan in the presence of vitamin B6 deficiency are implicated in the production of cancer of the urinary bladder. The depressing of platelet count by high doses of of vitamin E in women taking oral contraceptives can be considered beneficial as these women are predisposed to deep vein thrombosis.

Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophanon carbohydrate metabolism.

Adams PW; Wynn V; Folkard J; Seed M
Lancet (England) Apr 10 1976, 1 (7963) p759-64

Carbohydrate metabolism and vitamin-B6 status were assessed before andafter pyridoxine administration in 46 women taking combinedoestrogen-progestagen oral contraceptives (O.C.). 18 women had evidence of tissue depletion of vitamin B6, although all the women had abnormal tryptophan metabolism, including increased urinary xanthurenic acid (X.A.) excretion. In the women with vitamin B6 deficiency, administration of this vitamin caused elevation of fasting blood-pyruvate levels, and reduction in plasma glucose, insulin, and blood-pyruvate responses after an oral glucose load. These changes in carbohydrate metabolism were not found in the 28 non-vitamin-B6-deficient women. These results indicate that carbohydrate intolerance in women on O.C. is unlikely to be mediated by the formation of a complex of X.A. with insulin, as has formerly been proposed. Since the synthesis of the tryptophan metabolite quinolinic acid, an inhibitor of the heptaic enzyme phosphoenolpyruvate carboxykinase, may be enhanced by the administration of pyridoxine, it is suggested that this metabolite might be the important factor in the improvement of glucose tolerance in the vitamin-B6-deficient women. This conclusion is supported by the improvement in glucose tolerance observed in 6 women on O.C. and in 4 patients with glucocorticoid excess who were not vitamin-B6 deficient, when they were given tryptophan to augment the synthesis of quinolinic acid.

Does use of oral contraceptives enhance the toxicity of carbon disulfidethrough interactions with pyridoxine and tryptophan metabolism?

Calabrese EJ
Med Hypotheses (England) Jan 1980, 6 (1) p21-33

It is proposed that oral contraceptive (OC) users are at increased risk to experiencing adverse psychological disorders (e.g. irritability, depression) from exposures to elevated levels of carbon disulfide (CS2). This theory is based on studies indicating that both OCs and CS2 induce either a vitamin B6 deficiency and/or enhance its requirement. Since disruptions of B6 metabolism are thought to explain, at least in part, the adverse psychological effects of OCs and CS2, it is speculated that joint exposure to these substances may result in an exaggerated disruption of B6 metabolism with the development of CS2 induced adverse psychological effects occurring at exposure levels below those normally associated with adverse effects.

Drug--vitamin B6 interaction.

Bhagavan HN; Brin M
Curr Concepts Nutr 1983, 12 p1-12

In conclusion, there are several drug types that can interfere withvitamin B6 metabolism. In most cases, the interaction involves a complex formation between the drug (or a derivative) and the reactive coenzyme PLP, resulting in a Schiff base. Such an interaction leads to an inactivation of PLP (and also of the drug). Other types of interaction involve (a) stimulation of vitamin B6-dependent pathways and (b) competition with PLP for the binding site on the enzyme. Examples of the above are the steroid hormones (oral contraceptives). In most instances, overt symptoms of vitamin B6 deficiency due to chronic ingestion of these drugs are observed, and neurological problems seem to be rather frequent. Because of the reactive nature of the coenzyme PLP and the ease with which it can interact with drugs, sub-clinical (marginal) vitamin B6 deficiency should be suspected in the absence of overt clinical signs. Once the vitamin B6 problem has been identified, the condition can usually be treated by judicious use of large doses of vitamin B6 without compromising the clinical efficacy of the drug. (22 Refs.)

The effect of oral contraceptives on the apparent vitamin B6 status insome Sudanese women.

Salih EY; Zein AA; Bayoumi RA
Faculty of Medicine, University of Khartoum, Sudan.
Br J Nutr (England) Sep 1986, 56 (2) p363-7

1. In vitro activation of erythrocyte aspartate aminotransferase (EC2.6.1.1) activity by pyridoxal phosphate was used to assess vitamin B6nutritional status in forty Sudanese women taking combined, low-dose oralcontraceptives (oestrogen-progestogen; OC) and in thirty healthy, non-pregnant women not taking OC.

2. Fourteen (35%) out of forty OC users showed apparent vitamin B6 deficiency.

3. Side-effects associated with OC were more common among the apparently vitamin-B6-deficient OC users than among OC users and non-OC users not deficient in vitamin B6.

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