Use of Oral Contraceptives and Serum Beta-Carotene

Use of oral contraceptives and serum beta-carotene

G Berg1, L Kohlmeier2 and H Brenner1

1Department of Epidemiology, University of Ulm, Albert-Einstein-Allee 43, 89069 Ulm, Germany and 2Department of Nutrition, University of North Carolina, Chapel Hill, NC 27514, USA

Objective: Antioxidants, in particular carotenoids, may in¯uence the risk for cardiovascular disease. This study investigates the in¯uence of oral contraceptives (OC) on the serum concentration of beta-carotene, which may in turn affect the risk of cardiovascular diseases due to its antioxidative impact. Design: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a 7 day food record, and blood samples. Setting: National health and nutrition survey among healthy people living in private homes in West Germany in 1987±1988. Subjects: Nonpregnant and nonlactating women aged 18±44 (n 610). Results: Overall, the use of OC was negatively associated with serum beta-carotene concentration in bi- and multivariable analyses after adjustment for age, smoking, alcohol consumption, dietary intake of beta-carotene, use of vitamin supplements, body mass index, pregnancies, and serum concentrations of total triglyceride and cholesterol. A strong interaction between OC use and age on beta-carotene concentration was observed. While no relationship between OC use and serum beta-carotene was seen in the youngest age-group (18±24 y), there was a modest but signi®cant negative association between OC use and beta-carotene levels among 25±34 y old women. The use of OC was associated with a strong decrease in beta-carotene levels among 35±44 y old women. The interaction between OC use and age could partly be explained by age dependent use of OC with higher estrogen content. Conclusions: OC use seems to be strongly related to serum beta-carotene levels, particularly among women above the age of 35. Further studies are needed to clarify the underlying mechanisms of this association and its implications for health risks of OC use. Sponsorship: The national health and nutrition survey was founded by the German Ministry of Research and Technology. Descriptors: oral contraceptive; beta-carotene; cardiovascular disease

Introduction cardial infarction was found to be lower with second generation OC compared to the risk associated with ®rst Taking oral contraceptives (OC) appears to be an important generation OC. Nevertheless, women using second genera- risk factor causing higher vascular morbidity and mortality tion OC are still exposed to a higher risk of myocardial in women, particularly venous thromboembolism (Realini infarction than non-users of OC. This particularly applies to and Goldzieher, 1985; Kalin and Zumoff, 1990; Grimes, women above 35 y of age and smokers (Grimes, 1992). In 1992; La Veccia, 1992), although results of epidemiologic the third generation new progestin-formulas like desoges- studies on the risk of cardiovascular disease are not homo- trel and gestoden were introduced (Speroff and DeCherney, geneous. This heterogeneity may partly be due to manifold 1993). Even though the latter preparations have less nega- methodologic problems of pertinent epidemiologic studies. tive in¯uence on lipoproteins, new studies showed that the Furthermore, changes in the formula of OC, the increasing incidence of venous thromboembolism is even higher in use of OC by young women free of cardiovascular risk women taking these new OC than in women using second factors, and ®nally the augmented overall use of OC have generation OC (WHO, 1995; Jick et al, 1995; Spitzer et al, complicated the assessment of the risk for users (Petitti, 1996). Therefore, other mechanisms for the impact of OC 1986). on cardiovascular disease require further investigation. The disturbance of the lipoprotein metabolism is dis- Several epidemiologic studies have addressed the pos- cussed as one potential pathogenetic mechanism linking sible protective role of beta-carotene, a provitamin with OC use with vascular disease (Godsland and Crook, 1994). antioxidant capacity, in the development of cardiovascular This applies particularly to the ®rst generation of OC. At disease. The consumption of fresh fruit and vegetables the beginning of the seventies, the second generation OC containing beta-carotene has been shown to be inversely with lower estrogen and progestin doses was developed related to mortality due to coronary artery disease and to (Thorogood and Vessey, 1990). The excess risk of myo- the risk of acute myocardial infarction (Palgi, 1981; Gra- menzi et al, 1990). The importance of beta-carotene serum levels in relation to these diseases has only recently been Correspondence: G Berg. Received 21 August 1996; revised 18 November 1996; accepted investigated. Riemersma and colleagues (1991) found a 22 November 1996 signi®cant inverse association between beta-carotene and Use of oral contraception and serum beta-carotene G Berg et al 182 angina pectoris in a population-based case-control study target population with respect to sex and age distribution yielding an odds ration (OR) of 2.6 comparing lowest and (Schneider et al, 1992). The present analysis on the highest quintile of beta-carotene intake. This association in¯uence of OC use on serum beta-carotene levels is was strongly reduced, however, after adjustment for smok- restricted to nonpregnant and nonlactating women aged ing (OR 1.4). In the EURAMIC study, Kardenaal et al, 18±44 y, who did not take other sex hormones (n 610). (1993) found a similar association analyzing fat tissue concentration of beta-carotene and myocardial infarction. Data collection In this study, the negative association persisted after adjust- Participants were recruited during all seasons and in all ment for smoking habits. In a longitudinal study carried out regions of West Germany and Berlin. They completed a in Switzerland, a signi®cantly increased risk for ischemic detailed questionnaire on medical history and various heart disease and stroke was found for subjects with sociodemographic and lifestyle factors including diet, initially low plasma levels of beta-carotene (Gey et al, smoking habits and OC use. Nutrient intake of beta- 1993). In a recent review of epidemiologic studies on the carotene and alcohol consumption were calculated from a role of carotenoids in cardiovascular disease prevention 7 day food record using the data base of the computerized Kohlmeier et al, (1995) conclude that beta-carotene intake German food-code (BLS: BundeslebensmittelschuÈssel; is a good marker of the risk for cardiovascular diseases. Kroke, 1992). The participants were instructed in the Even though beta-carotene is discussed mostly in context of recording of all food over a seven consecutive day period atherosclerotic processes, it might also be of interest to by trained staff. Records were assessed for completeness study its impact on the preservation of endothelial function, before coding. Use of vitamin supplements was de®ned as reduction of platelet aggregability, the alteration of ®brin intake of at least one supplement per month. This rather formationÐfactors which could also lead to a higher risk crude categorization re¯ects the fact that vitamin supple- for thrombosis (Bendich, 1993; Gaziano and Hennekens, ment intake is not common in Germany. Age was classi®ed 1993). in three categories (18±24/25±34/35±44 y) to allow com- Ever since the introduction of these drugs many studies parison to other analyses of the VERA-study and other have dealt with the in¯uence of OC use on changes in national health surveys such as NHANES (NCHS, 1984). carbohydrate, lipid, different enzymes, mineral and vitamin Current smoking status was de®ned dichotomously. A metabolism (Corson, 1986), but few have investigated the women was de®ned as a smoker when she reported smok- association between OC use and serum beta-carotene. ing one or more cigarettes per day or as nonsmoker Although the ®rst study from Briggs et al, (1972) did not otherwise. None of the women in these age groups reported ®nd any association between serum beta-carotene and OC smoking other products. The body mass index (BMI) was use, four studies found decreased levels of serum beta- used as a measure of relative body weight. A distinction carotene among OC users in bivariate analyses (Prasad et was made between women who had never been pregnant al, 1975; Horwitt et al, 1975; Yeung, 1976; Arab et al, and women who had one pregnancy or more. 1982). In a more recent bivariate analysis, Palan and OC use was categorized into current, past and never use. colleagues (1989) observed additive effects of OC use Information on OC use was almost complete; only two and smoking on the reduction of serum beta-carotene people refused to answer the questions about their contra- levels. None of the previous studies paid attention to the ception methods. The estrogen contents in currently used role of other potential confounders or effect modi®ers of OC was dichotomized in less than 50 mg ethylestradiol and the relation between OC use and beta-carotene. The role of equal to 50 mg ethylestradiol. None of the preparations covariates is of concern, however, since OC use is likely to listed by the participants had a higher content of ethyles- be associated with other potential determinants of serum tradiol. Progestin compounds were classi®ed according to beta-carotene, such as sociodemographic and nutritional their chemical structure into preparations with desogestrel, factors. Furthermore, none of the previous studies consid- levonorgestrel, lynestrenol/norethisteron or antiandrogen ered the different types of OC. The aim of the present study effective OC. The exact composition of OC was only is to analyze the association between OC use and serum partly given, otherwise it was classi®ed as `unknown'. beta-carotene concentration with particular attention to the Serum concentrations of beta-carotene, total triglycer- role of potentially important covariates including age, body ides and total cholesterol were obtained using blood sam- mass index, smoking habit, alcohol consumption, nutrient ples collected under fasting conditions in heparinized tubes intake, serum lipid concentrations, and ®nally the OC between 7 and 10 am. Blood samples were analyzed within preparations. The age dependency of the impact of OC two months of collection in a central laboratory. Beta- use on cardiovascular risks led us to pay particular attention carotene concentration in serum was analyzed by high- to potential interaction between OC use and age. performance liquid chromatography after extraction with ethanol and hexanol and was measured photometrically. Cholesterol and triglyceride were determined with enzy- Method matic chlorimetric assay. A detailed description of the Study population survey methodology has been published elsewhere (Spei- This analysis is based on a national health and nutrition tling et al, 1992). survey among healthy people in Germany conducted in 1987±1988 (VERA-studyÐVerbundstudie ErnaÈhrungser- Statistical analysis hebung und Risikofaktoren Analytik, a substudy within In a ®rst step, current, past and never users of OC were the German Nutrition Survey; Moch, 1994). A strati®ed compared with respect to beta-carotene levels and the random sample was drawn from the non-institutionalized covariates. To avoid possible confounding by age, the population aged 18±89 y in West Germany and Berlin. percentages and medians of covariates were age-adjusted With a participation rate of about 70%, 2006 men and to the entire study population by the direct method (Roth- women were recruited for this study. There were only man, 1986). Use of different OC preparations was assessed minor differences between the study population and the according to age-categories. In addition, for each of the Use of oral contraception and serum beta-carotene G Berg et al 183 three categories odds ratios with 95% con®dence limits Table 1 Age distribution of the women by OC use. VERA, 1987/1988 (CL) were calculated for the association of current use of OC with serum beta-carotene levels below 21.5 Use of OC mg/dl. The cutpoint of 21.5 mg/dl re¯ects recently proposed n Current Past Never classi®cation of desirable beta-carotene serum levels (StaÈ- Age [%] helin et al, 1988; Gey, 1994). The impact of OC use and 18±24 y 143 54.5 27.3 18.2 covariates (age, smoking, alcohol consumption, dietary 25±34 y 261 35.2 55.6 9.2 intake of beta-carotene, use of vitamin supplements, BMI, 35±44 y 204 12.3 67.6 20.1 history of pregnancy, serum concentration of cholesterol Total 608 32.1 53.0 14.9 and triglycerides) on the natural logarithm of serum beta- carotene concentration was assessed using simple and multiple linear regression. The aforementioned covariates which were found or suspected to be related to serum beta- Table 2 Characteristics of the women by OC use, age-standardized. carotene concentration on the basis of previous studies VERA, 1987/88 were a priori de®ned and included in the modelling. All Use of OC variables were retained in the multivariable modelling Total Current Past Never regardless of their statistical signi®cance. The log transfor- (n 608) (n 195) (n 322) (n 91) mation was necessary because of the highly skewed distribution of serum beta-carotene concentrations. Intake of Current smoker [%] 52.6 53.3 55.5 49.5 beta-carotene and other serum concentrations were likewise Alcohol drinkers [%] 88.0 92.8 86.1 91.3 One or more pregnancies [%] 63.1 59.6 66.8 56.5 log-transformed. We used untransformed values for age, Vitamin supplement use [%] 11.6 7.0 11.8 14.6 BMI and alcohol intake in all analyses. Because of the Nutrient intake (median) missing values in one or more variables, 29 of 610 women Beta-carotene [mg/day] 1.5 1.4 1.4 1.6 were excluded from the multivariable analysis. One value Cholesterol [mg/day] 407.3 405.4 404.9 411.3 of beta-carotene concentration, which exceeded the mean Energy [kcal/day] 2143 2053 2160 2182 Body mass index (BMI) [%] by more than ®ve standard deviations even after log < 19 kg/m2 8.9 8.0 9.8 7.1 transformation, was regarded as an extreme and potentially 19 and < 24 kg/m2 61.5 63.2 60.9 61.3 in¯uential outlier and was excluded from the model. After 24 kg/m2 29.6 28.8 29.4 31.6 exclusion of this outlier, the log-transformed values of Serum concentration (median) Beta-carotene [mg/dl] 29.7 25.1 32.5 31.2 serum beta-carotene concentration were close to normally Cholesterol [mg/dl] 189.0 191.5 191.4 179.6 distributed. Collinearity diagnostics in the multivariable Triglyceride [mg/dl] 75.5 91.2 66.9 69.5 models were performed using the Belsley-Kuh-Welch- criteria. Collinearity was not found to be of concern in these analyses. Finally we analysed the in¯uence of estrogen contents and progestin compounds of OC preparations 19 kg/m2. Serum concentrations of beta-carotene strongly on serum beta-carotene in bi- and multivariate linear differed by OC use: The median serum level of beta- regression with the same covariates. carotene was lower in the group of current OC users (median: 25.1 mg/dl) than in past and never users (median: 32.5 mg/dl and 31.2 mg/dl, respectively). The Results median serum triglyceride concentration also varied Table 1 describes the age distribution of OC users and non- strongly by OC use. It ranged from 66.9 mg/dl users: 195 women (32% of the study population) were and 69.5 mg/dl in past and never users, respectively, to current users of OC, 322 women (53%) had used OC in the 91.2 mg/dl in current users. Serum concentration of total past, and 91 women (15%) had never used OC. Current OC cholesterol seemed to be less affected by current OC use. users on the average were younger than past and never The estrogen contents and progestin compounds of the users. 54.5% of women at the age of 18±24 currently used OC used in this study population are shown by age- OC, compared to 35.2% in the age group of 25±34 y and categories in Table 3. None of the 152 women who 12.3% in the oldest age group (35±44 y). Two thirds of provided information on their OC preparations reported to current OC users were under 30 y of age. take the `minipill' which only contains progestin. The OC The age-adjusted distribution of covariates by OC use is used were in general newer preparations with lower estro- summarized in Table 2. Smoking and alcohol consumption gen and progestin doses. With regard to the estrogen- were very common and unrelated to OC use in this study content, preparations containing less than 50 mg ethylestra- population with an overall prevalence of about 50% and diol were more frequently used (70% of the known pre- 90%, respectively. A history of pregnancies was more parations), especially by women aged 18±24 y (79%). In frequent in past OC users (66.8%) than in current and contrast, women aged 35±44 y more frequently used pre- never users (59.6% and 56.5%, respectively). Only 7.0% of parations containing 50 mg ethylestradiol. The examination the current OC users took vitamin supplements, as com- of progestin-compounds showed that desogestrel was the pared to 12.4% of women not taking OC. Examination of most commonly used progestin, particularly in the youngest nutrient intake revealed no relevant differences between age group. Lynestrenol/norethisteron containing OC were current, past and never users of OC. Current OC users had a less frequently used by the youngest OC users (18±24 y) marginally smaller intake of beta-carotene than past and than by OC users in the other age-categories. never users, but there was a wide range of intake within all As shown in Table 4, 25% of the total study population groups. The percentage of overweight women with known OC use (148 of 582 women) had beta-carotene (BMI 24 kg/m2) was slightly higher in never users of levels below the desirable value of 21.5 mg/dl. This per- OC (31.6%) than in past (29.4%) and current (28.8%) centage was considerably higher in current OC users (34%) users. Only a minority of women (8.9%) had a BMI below than in other women (21%) yielding an overall odds ratio of Use of oral contraception and serum beta-carotene G Berg et al 184 Table 3 Distribution of OC preparations with respect to age categories. VERA, 1987/88

Age-categories OC total 18±24 years 25±34 years 35±44 years n 608 n 143 n 261 n 204

Use of OC [n] No use [n] 413 65 169 179 Use [n] Total 195 78 92 25 Preparation known 152 65 72 15 Estrogen content [%]a < 50mg Ethylestradiol 70.4 78.5 61.1 20.0 50mg Ethylestradiol 29.6 21.5 38.9 80.0 Progestin compound [%]a Desogestrel 40.8 49.2 33.3 40.0 Lynestrenol/Norethisteron 19.1 9.3 27.8 20.0 Levonorgestrel 29.6 27.7 31.9 26.7 Antiandrogen 10.5 13.8 7.0 13.3

aKnown preparation is 100%.

Table 4 Bivariate analysis of the association between OC and beta-carotene serum levels below 21.5 mg/dl by age categories. VERA, 1987/88

Age

Total 18±24 years 25±34 years 35±44 years Use of OC Use of OC Use of OC Use of OC

Beta-carotene n yes nob yes nob yes nob yes nob

< 21.5 mg/dl 148 84 84 23 13 29 35 12 36 21.5 mg/dl 434 125 309 55 47 57 128 13 134

ORa 1.9 1.5 1.9 3.4 [95% CL] [1.3±2.8] [0.7±3.6] [1.0±3.5] 1/3±8.9]

aOdds Ratio for the association of current OC use with beta-carotene concentration below 21.5 mg/dl. bReference group for OR.

1.9 (95% CL: 1.3±2.8) for the association of OC use with Tables 6 and 7 show the association of the estrogen beta-carotene concentration below 21.5 mg/dl. Strati®cation contents or progestin compounds of OC with serum beta- by age showed that the association of OC use with serum carotene levels in bivariate and multivariable regression beta-carotene concentration below the desirable level was analyses. The analysis was restricted to women above 24 y much stronger among 35±44 y old women (OR: 3.4) than whose serum beta-carotene levels are affected by OC use. among age groups 18±24 y (OR: 1.5) and 25±34 y (OR: The limited sample size of our study did not allow to 1.9). address potential interaction between use of speci®c OC The strong interaction between OC use and age was preparations and age with adequate power. All preparations con®rmed in the multiple linear regression analysis. The were related with a decrease of serum beta-carotene, but the addition of the interaction terms between OC use and age decrease was much larger for OC with higher contents of contributed signi®cantly to the prediction (P 0.008 for ethylestradiol (50 mg) than for other OC (see Table 7). partial F-test). Therefore these terms were retained in the Different progestin compounds in OC seemed to be equally model, and the association between OC use and log-serum related to a decrease of serum beta-carotene concentration. beta-carotene levels is shown separately by age groups for An exception were levonorgestrel containing OC which both bivariate and multiple linear regression in Table 5. were only related to a marginal non-signi®cant decrease of While only a small and not signi®cant relationship between serum beta-carotene. Our data did not allow to distinguish OC use and serum-beta-carotene was observed in the the impact of estrogen content and progestin compounds on youngest age-group (18±24 y), there was a modest, sig- serum beta-carotene levels since both factors are highly ni®cant negative association between OC use and beta- correlated. carotene levels in the middle age group (25±34 y). In women aged 35±44 y, OC use was associated with a strong decrease in beta-carotene levels. We also observed Discussion a signi®cant negative relationship with serum beta-carotene This study found an inverse relation of OC use with serum of smoking, alcohol intake, BMI and triglycerides. There beta-carotene along with a strong interaction between OC was a positive relationship between beta-carotene intake, use and age. While no relationship between OC use and cholesterol serum concentration and beta-carotene serum serum beta-carotene was observed in the youngest age- levels. The multivariable analysis revealed no signi®cant group (18±24 y), OC use was associated with a moderate association of the history of pregnancies and vitamin and strong decrease in beta-carotene levels in women aged supplement intake with beta-carotene serum concentration. 25±34 and 35±44 y, respectively. In the oldest age group, Overall, 27% of the variance of the natural logarithm of the negative association between OC use of beta-carotene serum beta-carotene was explained by the predictors was much stronger than the well known negative associa- included in the multivariable model. tion between smoking and serum beta-carotene. In this age Use of oral contraception and serum beta-carotene G Berg et al 185 Table 5 Predictors of serum beta-carotene concentration (mg/dl)b in bivariate and multiple linear regression. VERA, 1987/ 88

Bivariate regression Multiple regression

Betaa 95% CL Betaa 95% CL

Current OC-use [yes/no] Age 18±24 y 70.03c 70.25; 0.19c 0.01 70.19; 0.20 Age 25±34 y 70.17c 70.33; 70.02c 70.18 70.33; 70.03 Age 35±44 y 70.62c 70.90; 70.34c 70.47 70.17; 70.24 Current smoking [yes/no] 70.33 70.44; 70.23 70.20 70.30; 70.11 Alcohol intake [g/d] 70.01 70.01; 70.00 70.01 70.01; 70.00 Ever pregnant [yes/no] 70.01 70.11; 0.10 70.06 70.18; 0.05 Vitamin supplements [yes/no] 0.18 0.02; 0.34 0.15 70.00; 0.28 Beta-carotene intake [mg/d]b 0.31 0.25; 0.37 0.27 0.21; 0.33 BMI [kg/m2] 70.02 70.34; 70.01 70.02 70.03; 70.01 Triglycerides in serum [mg/dl]b 70.24 70.36; 70.13 70.18 70.06; 70.31 Cholesterol in serum [mg/dl]b 0.04 70.24; 0.32 0.34 0.07; 0.62 r2 0.27 F 15.98 P 0.0001

aBold letters: signi®cantly different from zero at alpha 0.05. bLog-transformed. cBivariate regression for current OC use is carried out separately in respective age categories.

Table 6 Estrogen content as predictor of serum beta-carotene concentration in women aged 25±44 y in bivariate and multiple linear regression. VERA, 1987/88 (reference group non-users of OC)

Bivariate regression Multiple regressionb

Betaa 95% CL Betaa 95% CL

Estrogen content < 50 mg Ethylestradiol 70.16 70.35; 0.01 70.13 70.30; 0.03 50 mg Ethylestradiol 70.44 70.67; 70.21 70.38 70.59; 70.17 Unknown 70.31 70.54; 70.06 70.34 70.56; 70.12 r2 0.29

aBold letters: signi®cantly different from zero at alpha 0.05. bAdjustment for age, current smoking, alcohol consumption, use of vitamin supplement, beta-carotene intake, BMI, serum concentrations of triglyceride and cholesterol. group, about half of the OC users had serum levels of beta- serum beta-carotene concentration (Table 6 and 7). By carotene below the desirable serum level of 21.5 mg/dl. contrast, OC containing the older progestin compounds This cutpoint of 21.5 mg/dl (4 mmol/l) was suggested in like lynestrenol/norethisteron lead to a similar decrease of the Basel study and con®rmed in various epidemiologic serum beta-carotene concentration than OC containing the studies (namely, MONICA Vitamin Substudy, Edinburgh newest one (desogestrel). Angina-Control, US-Health Professional Study, NHANES Further investigation is needed to establish a mechanism I) (Gey, 1994). The cutpoint was proposed with regard to of the in¯uence of OC use and different OC preparations on cancer and cardiovascular diseases. To evaluate the sensi- serum beta-carotene levels. In former studies (Prasad et al, tivity of the odds ratios to the cutpoint used, we considered 1975; Horwitt et al, 1975; Yeung, 1976), the substantial the median (29.9 mg/dl) as cutpoint in an additional analy- increase of retinol under OC use is put forward as an sis. The results were similar in relation to the age-depen- explanation. The increase might probably be due to an dent effect of OC on serum beta-carotene. activation of the production of the retinol binding protein Our ®ndings con®rm those of older studies except for (Mooij et al, 1991), thus possibly increasing the conversion one (Briggs et al, 1972) which assessed associations of OC of beta-carotene into retinol. The effect of OC on retinol is use with beta-carotene levels in bivariate analyses (Prasad mainly caused by estrogen and not by progestin (Anataya- et al, 1975; Horwitt et al, 1975; Yeung, 1976; Arab et al, kul et al, 1984), Palan and colleagues (1989) described 1982). Another more recent bivariate analysis (Palan et al, another possible mechanism: OC use in¯uences the low- 1989) also found a signi®cantly lower beta-carotene serum density lipoprotein fraction (LDL), the plasma carrier concentration in current OC users as well an additive effect protein for beta-carotene. The effect of estrogens and of OC use and smoking. However, none of the previous progestins on the lipid metabolism is controversial and studies strati®ed for age, nor considered additional covari- depends on their composition, therefore the increase in ates other than smoking. In particular, the potential role of LDL varies with different types of OC (Fortherby, 1985). speci®c OC preparations had not been addressed. The older generations of OC, however, which contain One possible mechanism which could explain the age higher amounts of ethylestradiol and larger contents of dependency of decreased beta-carotene concentration by the progestins norethisteron or levonorgestrel, were found OC use are the different types of OC used by older women. to increase LDL-cholesterol (Burkman, 1988; Fortherby, Women above 24 y of age more often used older prepara- 1985). Furthermore, increased oxidative stress due to OC tions containing higher amounts of ethylestradiol. Those use which in turn rises serum concentration of copper, are the preparations which lead to a higher decrease of could contribute to the decrease of beta-carotene levels. Use of oral contraception and serum beta-carotene G Berg et al 186 Table 7 Progestin compound as predictor of serum beta-carotene concentration in women aged 25±44 y in bivariate and multiple linear regression. VERA, 1987/88 (reference group non-users of OC)

Bivariate regression Multiple regressionb

Betaa 95% CL Betaa 95% CL

Progestin component Desogestrel 70.30 70.54; 70.06 70.26 70.48; 70.04 Lynestrenol/norethisteron 70.40 70.68; 70.13 70.32 70.56; 70.09 Levonorgestrel 70.09 70.34; 0.16 70.06 70.29; 0.17 Antiandrogene 70.36 70.83; 0.12 70.36 70.77; 0.05 Unknown 70.31 70.56; 70.06 70.34 70.56; 70.12 r2 0.29

The increase of serum copper depends on the estrogen importance of the estrogen content in OC, and their content, although it was shown that levonorgestrel may implications for the health risks associated with OC use. reduce this effect (Song et al, 1989). From the public health point of view, it appears prudent to Besides the age- and preparation-dependent relationship recommend consumption of vegetables rich in beta-caro- of OC use with beta-carotene, we found a signi®cant tene to women using OC. At the same time increased relationship between serum beta-carotene and smoking, efforts are badly needed to reduce the high prevalence of alcohol intake, BMI, triglycerides, nutrient intake and smoking among women using OC as observed in our study. total cholesterol levels. These results are similar to ®ndings from other studies using multiple linear regression to AcknowledgementÐThe VERA-study was supported by Federal Ministry analyze the determinants of beta-carotene in the population of Research and Technology Grants No. 704752, 704754 and 704766. The (Willett et al, 1983; Stryker et al, 1988; Roidt et al, 1988; authors are responsible for the content of this publication. Ascherio et al, 1992; Herbert et al, 1994; Hesker and Schneider, 1994). These studies, which analyzed determinants of serum beta-carotene among samples including References both men and women, did not address the potential role Amatayakul K, Uttaravichai C, Singkamani R & Ruckphaopunt S (1984): of OC use. Most studies found a signi®cant association Vitamin metabolism and the effects of multivitamin supplementation in between gender and beta-carotene serum concentrations. oral contraceptive users. Contraception 30, 179±196. Three of these studies (Stryker et al, 1988; Ascherio et al, Arab L, Schellenberg B & Schlierf G (1982): Nutrition and HealthÐA 1992; Hesker and Schneider, 1994) analyzed the determi- survey of young men and women in Heidelberg. Ann. Nutr. Metab. 26, nants of serum beta carotene separate for both genders; in Suppl 1, 1±244. Ascherio A, Stampfer MJ, Colditz GA, Rimm EB, Litin L & Willett WC all cases, the proportion of the explained variance was less (1992): Correlations of vitamin A and E intakes with the plasma 2 2 for women (r 0.25±0.29) than for men (r 0.30±0.42). concentration of carotenoids and tocopherols among American men In our study the explained variance increased from 24±27% and women. J. Nutr. 122 (9), 1792±1801. when OC use was taken into account which implies that OC Bendich A (1993): Biological functions of dietary carotenoids. Ann. N. Y. Acad. 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