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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 .

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.

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)

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.

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]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.)

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.