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Articles

Intake of Dietary Phytoestrogens Is Low in Postmenopausal Women in the United States: The Framingham Study^1–4

Miriam J. J. de Kleijn, Yvonne T. van der Schouw⁵, Peter W. F. Wilson^*, Herman Adlercreutz, Witold Mazur, Diederick E. Grobbee and Paul F. Jacques^**

Julius Center for Patient Oriented Research, University Medical Center Utrecht, Utrecht, The Netherlands; ^* The Framingham Heart Study, Boston University School of Medicine, Boston, MA; Department of Clinical Chemistry, University of Helsinki and Folkhälsan Research Center, Helsinki, Finland; and ^** Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA

⁵To whom correspondence should be addressed. E-mail: y.t.vanderschouw{at}jc.azu.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Many plants that are consumed contain phytoestrogens. Only a few published studies have examined the dietary intake of phytoestrogens in the general Western population. The potentially positive health effects of phytoestrogens might be of relevance to postmenopausal women. The aim of the present study was to estimate the intake of dietary isoflavones, coumestans and lignans by healthy Western postmenopausal women. For this purpose, we studied 964 postmenopausal, Caucasian women who participated in the Framingham Offspring Study and completed the Willett food-frequency questionnaire (FFQ). By searching the medical and agricultural literature and contacting experts, we identified food sources of phytoestrogens. The concentrations of the different isoflavones, coumestrol and lignans in each food in the FFQ were scored in seven categories and multiplied by the serving size of the food and the frequency of its consumption. The estimated daily median intake of the isoflavone daidzein was 39 µg (24–57 µg); of genistein, 70 µg (28–120 µg); of formononetin, 31 µg (13–44 µg); and of biochanin A, 6 µg (2–11 µg). Median total intake of isoflavones was 154 µg (99–235 µg). The main sources of isoflavones were beans and peas. The estimated daily intake of coumestans was 0.6 µg (0.2–1.7 µg), with broccoli as the main source. The estimated daily median intake of matairesinol was 19 µg (12–28 µg) and of secoisolariciresinol 560 µg (399–778 µg). The median total intake of lignans was 578 µg (416–796 µg). The main source of the lignans was fruits. The daily dietary intake of phytoestrogens in healthy postmenopausal Caucasian women in the United States is <1 mg.

KEY WORDS: • phytoestrogens • isoflavones • coumestans • lignans • postmenopausal women

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Postmenopausal estrogen use is associated with a lower cardiovascular disease risk, but also with an increased risk of endometrial cancer, breast cancer and venous thrombosis. Furthermore, postmenopausal women who use estrogen combined with progestagen (to prevent endometrial cancer) experience side effects such as vaginal bleeding. Consumption of plant foods has been associated with a lower risk of cardiovascular disease but also with a lower risk of several types of cancer, which might be ascribed in part to plant estrogenic compounds, the so-called phytoestrogens.

Phytoestrogens are plant substances that are structurally and functionally comparable to 17-ß-estradiol and that are capable of producing estrogenic effects (Fig. 1 ). Phytoestrogens bind to the estrogen receptor (ER) at low levels compared with endogenous estrogen (1) . By binding to the receptor, phytoestrogens may exert both estrogenic and antiestrogenic effects. It has been shown that in women consuming a phytoestrogen-rich diet, sex hormone binding globulin concentrations were increased (2 ,3) , hot flushes and vaginal dryness were reduced and bone mineral density was increased (4) . Animal studies and trials in humans showed that consuming soy, a food containing large amounts of phytoestrogens, improves the plasma lipoprotein profile by decreasing total cholesterol, LDL cholesterol and triglycerides (5 ,6) . Ecological and migrant studies have suggested that phytoestrogens, which are commonly consumed by Asian populations, play a role in preventing cardiovascular disease and certain types of hormonally responsive cancers (7 8 9) . There are indications from observational studies that phytoestrogens protect against breast cancer (10 11 12) and endometrial cancer (13) . Phytoestrogens can be classified in three groups, i.e., isoflavones, coumestans and lignans. The major isoflavones are genistein, daidzein, formononetin and biochanin A. Coumestrol is the most important coumestan. The major lignans are enterolactone and enterodiol, which are produced by colonic bacteria from their dietary precursors matairesinol and secoisolariciresinol. The highest concentration of isoflavones is found in soybeans, of coumestans in alfalfa and of lignans in linseeds (8) . Asian populations consume 20–50 g of soy daily, which is their major source of phytoestrogens, comparable to a daily intake of 20–80 mg phytoestrogens (7) . Consumption of foods high in phytoestrogens is uncommon in most Western countries. However, small concentrations of phytoestrogens have been measured in several fruits and vegetables (14 15 16 17) , and also in coffee (18) , tea (18) , beer (19) and wine (17) , which are frequently consumed by Western populations.

View larger version (24K): [in this window] [in a new window]   Figure 1. Chemical structures of naturally occurring phytoestrogens and endogenous estradiol.

Our goal was to estimate the mean intake of dietary isoflavones, coumestans and lignans in healthy Western postmenopausal women. For this purpose, we assessed dietary phytoestrogen intake with the Willett food-frequency questionnaire (FFQ) (21) in 964 postmenopausal Caucasian women who participated in the Framingham Offspring Study. All available literature on phytoestrogen concentrations of food was used to extract data on phytoestrogen contents of the food items present in the FFQ.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects.

The Framingham Heart Study, an epidemiologic study of heart disease, was established in Framingham, MA between 1948 and 1950 with a cohort of 5209 men and women aged 30–59 y (22) . By 1971, the original cohort included 1644 husband-wife pairs and 378 individuals who had developed cardiovascular disease. The offspring of these subjects and their spouses were invited to participate, and 5135 of the 6838 eligible individuals participated in the first Framingham Offspring Study examination (23) . This study was approved by the Human Investigations Review Committee at New England Medical Center and by the Institutional Review Board for Human Research at Boston University Medical Center. The offspring cohort has undergone repeat examinations at 3- to 4-y cycles. Between January 1991 and December 1994, 3799 members of the offspring cohort, of whom 1061 (27.9%) were postmenopausal women (at least 1 y after last menses), participated in the fifth examination cycle. For this analysis, we excluded women who did not fill in a FFQ, who left 12 or more items blank on this questionnaire and those with an implausibly high (16.7 kJ) or low (<2.5 kJ) total energy intake (n = 97). After these exclusions, 964 postmenopausal women remained for analysis.

Identifying food sources of phytoestrogens.

To locate published laboratory analysis data for the phytoestrogen content of food items, we conducted a search of the medical (Medline) and agricultural (Agricola) scientific literature and contacted several experts in the field of phytoestrogens. We searched for data on measurements of the phytoestrogens daidzein, genistein, formononetin, biochanin A, coumestrol, matairesinol and secoisolariciresinol in foods. We also searched the literature with the terms phytoestrogens, plant estrogens, isoflavones, coumestans, isoflavones, lignans, enterolactone and enterodiol. We expanded our database with unpublished measured data (W. Mazur and H. Adlercreutz, Department of Clinical Chemistry and Folkhälsan Research Center, University of Helsinki, Finland) on lignan contents of some food items using an isotope dilution gas chromatography/mass spectrometry method (24) .

Food-frequency questionnaire.

The self-administered FFQ on dietary intake developed by Willett and colleagues (21) was used to assess usual food consumption. This questionnaire lists 130 individual food items with specified portion sizes; study participants were asked how often, on average, they had consumed these food items during the previous year. Nine responses were possible, ranging from "never or less than once per month" to "more then six times per day." The questionnaire also requested information about the use of specified vitamin and mineral supplements, the brand of breakfast cereal and included open-ended sections for information on foods and supplements not specified on the questionnaire.

Scoring phytoestrogen intake.

Using the information from our review of the literature, we calculated and assigned for each food item in the FFQ values for the isoflavones daidzein, genistein, formononetin, biochanin A, coumestrol, and for the lignans matairesinol and secoisolariciresinol, according to the following protocol. All values found in the literature were converted to mg per 100 g food. Values expressed on a dry weight basis were converted to a wet weight basis either by using moisture content provided by the author, by assuming commonly expected moisture content for that particular food (25) , or by using adjustments for the method of preparation (26) (Table 1 ). When the specific phytoestrogen content was reported as "a trace" or "traceable," the value of 0.00001 mg/100 g was assigned, which was based on the sensitivity of the method used (24) . When more values were reported from the same or different original sources in the literature we used the highest value to score the phytoestrogen content of a food. If wet and dry weights were reported from different original sources in the literature, we used the reported wet weight value. If the questionnaire listed similar food items on the same line, we used the phytoestrogen data for the food most commonly eaten. If values for the most common food were unavailable, any value found on one of the other food items in the line was used. When there was no information available on the lignan precursors matairesinol and secoisolaraisinol we estimated these values by using data on the biologically active products enterolactone and enterodiol (16) . If we did not have any information about the phytoestrogen content of a food item, we assigned a value using data of a similar food item if available. If no data were available, we assumed the value to be zero. We estimated the amount of the phytoestrogens in breakfast cereals by using the fiber content of the cereal as a proxy for the phytoestrogen content, using the Nutrition Data system of the University of Minnesota [University of Minnesota, Nutrition Data System (1998); http://www.ncc.umn.edu (March 2001; data not freely accessible)]. The average phytoestrogen content of wheat bran and rye bran was used to estimate the amount of phytoestrogen per gram fiber. Each phytoestrogen content of a food item was then scored in seven categories (Table 2 ).Finally, we multiplied the score of each food item in milligrams by the serving size of the food. This final phytoestrogen amount of each food item was multiplied by the frequency of the consumption of that food and then summed across foods to obtain the total individual intake of each phytoestrogen.

Mean intake with standard deviation and median intake with interquartile range are presented for each phytoestrogen. The percentage of intake of isoflavones, coumestans and lignans from different food sources are presented.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Table 2 lists the phytoestrogen level per 100 g of the food item in the Willett FFQ. The richest sources of daidzein (mg/100 g dry weight) are tofu, peas, alfalfa, nuts, tea and coffee. Genistein, another isoflavone, is found in tofu, nuts, beans, dark bread and coffee. The isoflavone formononetin is present mainly in alfalfa sprouts, nuts and beer. The isoflavone biochanin A is also found in alfalfa sprouts and nuts, although in a lower concentration compared with formononetin. Coumestrol, the dietary coumestan, is found mainly in alfalfa sprouts and broccoli. Lignans concentrate in berries and some vegetables; matairesinol is found mainly in broccoli, strawberries, blackberries, dark bread and tea, and the richest sources of secoisolaraisinol are grapefruits, cranberries, blueberries, zucchini, coffee and tea.

The estimated daily median intake (25th–75th percentiles) of the isoflavone daidzein was 39 µg (24–57 µg); of genistein, 70 µg (28–120 µg); of formononetin, 31 µg (13–44 µg); and of biochanin A, 6 µg (2–11 µg) (Table 3 ). Median total intake of isoflavones was 154 µg (99–235 µg). The main sources of dietary isoflavones in this population were beans and peas, tea and coffee, and nuts (Table 4 ). The estimated daily intake of coumestans was 0.6 µg (0.2–1.7 µg). The main source of coumestan was broccoli. The estimated daily median intake of matairesinol was 19 µg (12–28 µg) and of secoisolariciresinol, 560 µg (399–778 µg). The median total intake of lignans was 578 µg (416–796 µg). The main source of lignan in this population was "other fruits" (plums, bananas, cantaloupe, watermelon, and apples or pears), breads, cereals, rice and grain, and berries.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Before interpreting these data, some issues must be addressed. By using a FFQ, we were able to quantify the average intake of dietary phytoestrogens in the previous year. This is particularly important for a study of dietary phytoestrogen intake because foods containing high amounts of phytoestrogens are most likely to be consumed weekly or monthly, not on a daily basis. Biochemical indicators are found in urine and blood specimens (27 ,28) and can be used as a measure of dietary phytoestrogen intake; however, these measurements often represent only a short period of intake, i.e., several to 24 h before sampling (29 30 31) . Biochemical indicators might provide an index of intake and subsequent metabolism by the gut flora, and therefore serve as a measure of bioavailability. Unfortunately the usefulness of these biochemical indicators of dietary intake is restricted; isoflavone excretion in the urine is substantial only in Asian populations (7 ,31) and until now, only lignans can be measured reliably in blood (32) .

Dietary assessment methods such as 24-h dietary recall and food record methods also represent a relatively short period of intake. The underlying principle of the FFQ approach is that average long-term diet is the conceptually important exposure rather than intake of a few days (33) .

Instead of using the exact measurements of phytoestrogen concentration reported in the literature, we decided to score the highest literature values into seven categories (Table 1) . By doing so, we avoid the suggestion of a degree of precision for which the reported data in the literature are too limited and too preliminary. By using this method, we decreased considerably the degree of misclassification of our determinant of interest, phytoestrogen intake. Differences in the phytoestrogen concentration of food items between types, brands or different countries are not taken into account in this data set because the number of measurements reported in the literature is limited. Most measurements have been performed in one country (Finland), using only a few types or brands. By using categories instead of exact amounts of phytoestrogen content, these differences also do not bias our results as long as they are within a 10-fold range of the data we used for our classification. Our main concern is error in measurement of phytoestrogen intake produced by missing data on some of the food items consumed in the Western diet. We did have data on almost all vegetable and fruit items in the FFQ, which are the food groups most likely to contain phytoestrogens. The industrial use of soy flour could result in the presence of phytoestrogens in food items such as donuts and white bread; however, the processing of soy flour likely reduces the amounts of phytoestrogens in these products.

The results indicate that the intake of lignans with the Western diet is much higher then the intake of isoflavones. Recent findings in the laboratory of one of the authors (H.A.) indicated that the presence of several enterolactone precursors is much more abundant than of the two (secoisolariciresinol and matairesinol) measured until now. When methods for the measurements of these precursors become available, the true lignan values will increase at least 10-fold in foods such as cereals. This means that the lignans are the most abundant phytoestrogen in the Western diet.

To our knowledge, this study is the first to determine daily food intake of phytoestrogens in postmenopausal Western women. Until now, only one research group also quantified the dietary intake of phytoestrogens to address the association between dietary intake of phytoestrogens and prostate cancer in a case-control study (34 ,35) . This group used an adapted Block FFQ to measure the intake of several phytoestrogens (36) . The Block FFQ was modified to include frequently consumed ethnic foods and foods that were previously reported to be important sources of phytoestrogens. Furthermore, adjustments were made for cooking and preparation, and the original values as reported in the literature were used to determine the intake. These values in general correspond to the values reported in our study (Table 3) because this research group was using the same published sources. The median dietary intakes of genistein, daidzein, secoisolariciresinol and matairesinol reported in the prostate cancer study were comparable to the intakes in our study among postmenopausal women. In our study, we used the 130-item Willett FFQ. No relevant differences in ability to detect associations between nutrient intake and disease have been reported for the Willett and Block FFQ (37) . Biochanin A and coumestrol intakes were higher and formononetin intake was lower in the earlier study among men compared with our study. This higher intake of some of phytoestrogens could be explained in part by the addition of several specific food items (i.e., soy sauce, soy cheese, green tea) containing high amounts of phytoestrogens to the Block FFQ used in the study among men. Furthermore, a difference in the dietary pattern between men and women is a possible explanation for the differences found. In this study, mean (and sometimes median) values of phytoestrogen contents were used instead of a scoring of the highest reported value in categories. This could also explain in part the differences between the intake of phytoestrogens in our study and the intake measured in the prostate cancer study.

Estrogens act by binding to the ER, an intranuclear binding protein; two types have now been identified, ER and ERß. These receptors, like all steroid hormone receptors, are transcription factors that modify gene expression when they are activated (38) . Phytoestrogens bind to ER with low affinity compared with endogenous estrogens and, depending on the tissue, may exert either estrogenic or antiestrogenic effects. These effects are comparable to the effects of Selective Estrogen Receptor Modulators such as Tamoxifen and Raloxifen. With both estrogenic and antiestrogenic effects, it is possible to reduce the risk of cardiovascular diseases as well as the risk of breast cancer. The use of traditional hormone replacement therapy is related to a lower cardiovascular risk but also with an increased risk of breast cancer.

Antiestrogens are thought to exert their effect by decreasing the concentration of cytoplasmic ER and by complexing with the receptor, thus preventing biosynthetic processes associated with tissue development (39) . In postmenopausal women, endogenous estrogen levels are very low and phytoestrogens are more likely to bind to ER, leading to biological effects (20) . Postmenopausal women are at high risk of cardiovascular disease and breast cancer, and effective preventive treatments could have a major effect on morbidity and mortality.

The effects of phytoestrogens on different hormone-related diseases have been studied primarily in Asian populations, who consume 20–50 g soy/d, or in trials with soy supplements given to people consuming a Western diet. For the former group, the high level of phytoestrogens contained in soy is comparable to an intake of 20–80 mg phytoestrogens (7) . The effects of daily intakes of low dietary phytoestrogens have not yet been studied. To be able to study dietary phytoestrogen intake more precisely in relation to disease risk and incidence, a comprehensive and complete database of isoflavonoid, coumestan and lignan contents of the most common foods in the Western diet should be developed, including data on milk products and "fast food"(possibly containing soymilk or soy flour), to increase the comprehensiveness and accuracy of the nutrient database. The data that have been collected for this study together with the existing database on isoflavones can be used as a basis for an expanded database. Availability of such data will enable longitudinal studies of the health effects of dietary phytoestrogen intake in populations consuming a Western diet.

This study shows that dietary intake of isoflavones, coumestans and lignans in healthy postmenopausal Caucasian women in the United States is low. In spite of the low intakes, recommendations for changes in the diet of postmenopausal women to increase dietary phytoestrogens may be premature before the health benefits of phytoestrogens are clearly demonstrated.

	ACKNOWLEDGMENTS

 
We are grateful to the Framingham participants for their essential contribution to this study. We thank Julia Peterson and Sheila Bingham for their useful advice, and Sharon Rich for her important help with the data analyses.

	FOOTNOTES

 
¹ Published in abstract form [de Kleijn, M.J.J., van der Schouw, Y. T., Wilson, P.W.F., Grobbee, D. E. & Jacques, P. F. (2000) Intake of dietary phytoestrogens in postmenopausal women: the Framingham Heart Study. J. Nutr. 130: 705S (abs.)].

² Supported by the Foundation "De Drie Lichten," "De Gelderfonds" of the Dutch Heart Foundation and the Foundation "Girard de Mielet van Coehoorn" of the University Medical Center, Utrecht, in the Netherlands. Financial support for this project was also provided by the U.S. Department of Agriculture, under agreement No. 58–1950-9–001.

³ Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.

⁴ The authors have no financial relationship with the supporting foundations. P.F.J. has a financial relationship with the U.S. Department of Agriculture. The supporting foundations and the U.S. Department of Agriculture did not control or influence the decision to submit the final manuscript for publication.

Manuscript received October 24, 2000. Initial review completed December 15, 2000. Revision accepted March 8, 2001.

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