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Validation of a Phytoestrogen Food Frequency Questionnaire with Urinary Concentrations of Isoflavones and Lignan Metabolites in Premenopausal Women

Osteoporosis Research Program (M.R.F., G.A.H.)
Division of Rheumatology (G.A.H.)
Women's College Hospital, Department of Nutritional Sciences (L.U.T.)
Department of Health Policy, Management and Evaluation (G.A.H.)
Faculty of Medicine, University of Toronto, Institute for Clinical Evaluative Sciences, Toronto, Ontario, CANADA (G.A.H.)

Address correspondence to: Gillian A. Hawker, MD, MSc, FRCP(C), Osteoporosis Research Program, Women's College Hospital, 76 Grenville Street, Toronto, Ontario M5S 1B2, CANADA. E-mail: g.hawker{at}utoronto.ca

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: The purpose of this study was to examine the association between dietary intake of phytoestrogens estimated by a food frequency questionnaire (FFQ) with urinary metabolites.

Methods: Participants were 26 premenopausal, Caucasian women aged 25 to 42 years. Dietary intake of isoflavones (genistein and daidzein) and lignans (secoisolariciresinol and matairesinol) were estimated by a 53-item interviewer-administered FFQ on two occasions, reflecting ‘habitual’ (previous 2 months) and ‘recent’ (previous 2 days) dietary intake. Isoflavone (genistein, daidzein) and lignan (enterolactone, enterodiol and secoisolariciresinol) concentrations were measured in 24-hour urine samples by gas chromatography-mass spectrometry. Correlations between FFQ (habitual and recent, separately) and urinary metabolite values were assessed using Spearman correlation coefficients.

Results: Mean habitual isoflavone and lignan intakes were 13.7 mg/day and 13.8 mg/day, respectively. Mean urinary concentrations of isoflavones and lignans were 17.4 umol/day and 20.6 umol/day, respectively. Recent and habitual isoflavone intakes were correlated with urinary excretion of metabolites (r = 0.64, p < 0.001 and r = 0.54, p = 0.004, respectively). Urinary excretion of lignans was also modestly correlated with recent and habitual lignan intakes (r = 0.46, p = 0.02 and r = 0.40, p = 0.05, respectively).

Conclusions: Our results support the use of this FFQ as a measure of dietary isoflavone and lignan intake in epidemiological studies.

Key words: food frequency questionnaire, phytoestrogens, urinary metabolites, isoflavones, lignans

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
There has been considerable interest directed towards the consumption of soy products and other sources of dietary phytoestrogens, likely in response to their perceived potential benefits on menopausal symptoms, postmenopausal bone health and cancer risk [1–4]. Increased recognition of the potential health benefits of phytoestrogens has heightened the need for an instrument that can estimate exposure to phytoestrogens in epidemiological studies.

Dietary phytoestrogens include two major classes, lignans and isoflavones. Lignans, primarily secoisolariciresinol diglycoside (SDG) and matairesinol, are found widely in fruits, vegetables, legumes, cereals and flaxseed [1,5]. Isoflavones are structurally and functionally similar to endogenous estrogen [6]. Genistein and daidzein, and their glycosides, genistin and daidzin, are the main compounds within the isoflavone class and are found in the highest concentration in soybeans [1]. Within the body, the colonic microflora metabolize plant lignans to the mammalian lignans, enterolactone and enterodiol [7], and hydrolyse genistin and daidzin to their aglycones, genistein and daidzein [8,9]. Daidzein is further metabolized to equol in some individuals [10]. They are then absorbed, undergo enterohepatic circulation and are excreted in the urine [11,12]. Dietary intake of phytoestrogens has been associated with urinary excretion of related metabolites in controlled trials [13–15] and observational studies [9,16,17].

The purpose of this study was to evaluate the validity of a semi-quantitative food frequency questionnaire (FFQ) to estimate phytoestrogen intake. The FFQ was developed and used in the Toronto Osteoporosis Prevention Study, a prospective cohort study investigating risk factors for premenopausal bone loss, but may potentially be used in other epidemiological studies where phytoestrogens are of interest. Estimates of dietary intake of isoflavones and lignans based on the FFQ were compared with biochemical indices of phytoestrogen intake, urinary metabolites.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Subjects
Subjects were 26 healthy, Caucasian, premenopausal women, aged 25 to 42 years, recruited from a cohort of women participating in a larger prospective study. Exclusion criteria for the longitudinal study included prior diagnosis of osteoporosis or specific comorbid conditions (such as Crohn's disease, symptomatic hyperthyroidism, rheumatoid arthritis, bilateral oophorectomy, anorexia nervosa), use of any medications known to be associated with bone loss (treatment for infertility or endometriosis, use of systemic corticosteroid therapy for more than 3 months duration at any time in the past, use of Dilantin for at least 3 months ever, and daily use of inhaled corticosteroids), recent pregnancy or breastfeeding, current use of oral contraceptives or oligomenorrhea. Participants were selected for the current study based on self-reported dietary intake of phytoestrogens at the baseline study visit for the larger cohort study. Women in the highest and lowest quartiles of estimated isoflavone and/or lignan intake were contacted by phone by the study coordinator and invited to participate. Ethics approval was obtained from the local ethics review committee and all women provided written informed consent prior to participation.

Dietary Assessment
Intake of phytoestrogens was assessed by a semi-quantitative FFQ containing 53 items during an interviewer-assisted interview. The object of this FFQ was not to precisely calculate individual dietary intake of phytoestrogens, but to establish a reliable method by which to characterize individuals as high, moderate or low phytoestrogen consumers. The FFQ was developed to be as inclusive as possible, containing all major sources of phytoestrogens and their metabolites. Available phytoestrogen databases [6,18–22] were used to identify foods that were sources of phytoestrogens. Foods that contained high levels of phytoestrogens or other food items that, although poorer sources of phytoestrogens, had the potential to contribute significantly to phytoestrogen intake due to the higher consumption of these foods, were considered for inclusion. Major foods included in the questionnaire were soy milk, soy products such as tofu and soybased meat and cheese alternatives, soybeans, breads and cereals, brown rice, legumes, vegetables, fruit, flaxseed, coffee and tea (Table 1). Consumption frequency categories (i.e. daily, weekly, monthly) and serving size categories were added to the food list to complete the FFQ.

Participants reported their dietary intake on two occasions. At the first visit, subjects were asked to report their "habitual" intake (i.e. number of servings) of each food during the previous two-month period. Foods consumed less than once per month were not included. At the second visit, conducted on the day that the urine sample was completed and delivered to the study office, participants reported their dietary intake during the previous 48 hours (i.e. "recent" intake). Three-dimensional food models (Nasco, Fort Atkinson, WI) were used as visual aids to improve recall.

Urine Collection
At the first study visit, participants were provided supplies and instructed in the collection of a 24-hour urine sample. To control for variation in the phase of menstrual cycle, 24-hour urine samples were collected voluntarily on any day between the 11th and 15th day of the menstrual cycle. Urine samples were collected in portable containers with 3 g of ascorbic acid to prevent oxidative degradation and microbial contamination. Samples were stored at 4–6°C until processed. Samples were delivered to the study office on the day that collection was completed. After measuring total volume, samples were dispensed into 10 ml aliquots, preserved with 1 mg sodium azide/1 ml urine and stored in centrifuge vials at –20°C. The samples were analysed for total concentration of isoflavone (genistein, daidzein and equol) and lignan (enterodiol, enterolactone and secoisolariciresinol) contents using a previously described gas chromatography-mass spectrometry method routinely used in our laboratory [23–25], which was a modification of other methods [26,27].

Statistics
Descriptive statistics were used to describe subject characteristics and dietary phytoestrogen intakes. Spearman rank correlations were used to assess the relationship between recent and habitual intake of isoflavones and lignans. Spearman rank correlations were also used to assess the relationship between dietary intake of phytoestrogens and urinary phytoestrogen excretion. The level of agreement between the estimated dietary intakes and urinary excretion was also assessed by calculating the percentage of subjects categorized into the same and opposite tertiles of intake and urinary excretion (i.e. high, medium and low intake/excretion based on the distribution within the subjects). The Kappa statistic was also calculated. Statistical analyses were performed using SPSS (Version 11.0.1, SPSS Inc, 2001). Statistical significance was assumed at the two-tailed level of 0.05.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Mean age of the 26 participants was 34.7 ± 5.6 years (range: 25–42 years). Eleven percent of participants self-identified as vegetarians. Mean body mass index was 25 kg/m² (range: 16–39 kg/m²).

Dietary Intake
There was wide variation in intake of isoflavones and lignans; the distributions of intake were significantly right-skewed. Table 2 shows the mean and median intakes for isoflavones, lignans and total phytoestrogens estimated by the ‘habitual’ (previous 2 month) and ‘recent’ (previous 48 hour) FFQs. The top contributors to isoflavone and lignan intake are reported in Table 3. Elapsed time between the first and second dietary assessments was dependent on the collection of the 24-hour urine sample during the middle of the menstrual cycle and averaged 32 days. There was a significant correlation between estimated intake of isoflavones and lignans reported on the habitual (previous 2 months) and recent (previous 48 hour) FFQs (Spearman r = 0.69 and 0.69, p < 0.001, respectively).

Dietary Intake vs Urinary Metabolites
Urine volumes ranged from 0.8–4.0 L (mean volume 2.2 ± 0.8 L). There was variation in urinary excretion of phytoestrogens. Urinary concentrations of lignan and isoflavone metabolites are reported in Table 4. Table 5 presents Spearman correlation coefficients between dietary estimates of phytoestrogen intake and urinary metabolite concentrations. We observed significant, modest correlations between concentrations of urinary isoflavone and lignan metabolites and dietary intake estimated on both occasions. Estimates of recent dietary phytoestrogen intake were more strongly correlated with urinary excretion than were estimates of habitual phytoestrogen consumption (Table 5). The percentage of subjects classified into the same tertile for dietary intake and urinary excretion was 46% for lignan and 54% for isoflavones. Fifteen and eight percent of subjects were misclassified into opposite tertiles for lignans and isoflavones, respectively. Values of Kappa ranged from 0.191 (p = 0.17) for lignans to 0.310 (p < 0.05) for isoflavones.

	DISCUSSION

The degree of correlation observed between urinary isoflavone concentrations and our estimates of dietary intake were in the magnitude of 0.5–0.6. This is in keeping with past research where correlations of 0.2 to 0.5 have been observed between estimates of dietary intakes and biochemical indices [28]. As expected, estimates of dietary isoflavone intake during the urine collection period were more highly correlated with urinary excretion than were estimates of habitual intake. This is a reflection of both the recent consumption and the relatively rapid metabolism of these compounds (It has been reported that urinary isoflavone excretion peaks 8–12 hours after ingestion [29]). Our results are at least as good, if not better, than prior studies that have examined the correlation between dietary and urinary isoflavone estimates where correlations of 0.3–0.5 have been reported [16,30–32].

Few observational studies have examined the relationship between estimates of dietary intake and urinary excretion of lignans. Excretion of lignans has been significantly associated with intake of fruits, total dietary fibre and fibre from grains estimated by food records [11,12,16]. Others have found no association between lignan excretion and dietary intake of lignans [33] or intake of dietary fibre or vegetables and fruit [16] measured by FFQ. Our study is the first to demonstrate a significant correlation between dietary lignan consumption estimated by FFQ methods and urinary metabolites. It should be noted that, in the current study, the correlation observed between dietary intake and urinary excretion was weaker for lignans than isoflavones. This is likely due to the wide variety of foods containing lignans, making precise estimation of lignan intake more challenging. We did not assess the use of oral antimicrobials which may have decreased phytoestrogen metabolite levels through their effect on intestinal microflora [34]. Inter-individual differences in the absorption rates and intestinal microbial modification of phytoestrogens [10,29,35] may also explain the lack of a stronger correlation between dietary phytoestrogen intake and urinary metabolites.

Median isoflavone intake in this study was similar [36] or slightly greater [37–41] than intakes reported in studies among American and European women but substantially lower than intakes reported among Asian populations [31,40,42]. Urinary isoflavone concentrations were also lower than levels observed in Asian studies, where daidzein and genistein excretion levels have been in the magnitude of 10–17 umol/day and 10–14 umol/day, respectively [31,42]. It is likely that isoflavone intake is underestimated in Western diets. Despite the documented correlation between dietary isoflavone intake and urinary isoflavone metabolites, we observed isoflavone metabolites in the urine of the majority of participants who reported no habitual dietary isoflavone intake. Lampe et al also detected urinary isoflavones among low soy consumers [16]. These observations may be due to consumption of processed foods containing additives of soy protein or soy flour that are not easily quantifiable. Other unidentified, non-soy based foods may contribute to isoflavone intake.

Lignan intake and excretion values were greater than reported among other populations, where mean dietary intake has been less than 1 mg/day [39,43,44] and urinary excretions have ranged from 2–5 umol/day [16,17,45]. Variation in dietary sources of lignans between populations may explain the differences in dietary lignan intake estimated in the current study compared with previous research. Other studies have reported that vegetables, cereals, fruit, berries, coffee, tea and orange juice were the top contributors to lignan intake [20,43,46], whereas the main foods contributing to dietary lignan intake in the current study included flaxseed, tea, breads and lentils. As noted in Table 3, the contribution of flaxseed to dietary intake was quite high and was primarily due to the consumption of whole or ground flaxseed. This high consumption of flaxseed could explain the greater lignan intake and metabolite levels of our group compared to previous studies. These differences in dietary sources of lignans strengthen the need for dietary instruments that have been validated for the population under study.

Several factors should be taken into consideration when interpreting our data. Our subjects were a sub-sample of healthy volunteers participating in a prospective study investigating risk factors for osteoporosis, selected based on self-reported dietary intake and therefore may not be representative of all premenopausal, Caucasian women. However, this is unlikely to bias our study as our objective was to evaluate the performance of our FFQ rather than estimate levels phytoestrogen exposure among our population. Lengthy food frequencies have the potential to overestimate dietary intake. Unfortunately, we did not estimate caloric intake and were unable to adjust estimates of phytoestrogen intake from the 53 items included in our FFQ accordingly. However, it is more likely that we have underestimated dietary intake evidenced by the detection of isoflavone metabolites in the urine of several subjects reporting no intake of isoflavone containing foods. Estimation of dietary phytoestrogen intake was limited by the incompleteness of currently available databases of the phytoestrogen content of foods. As these databases expand, it is possible that the correlations between dietary and urinary estimates of phytoestrogens will improve.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Urinary excretion of phytoestrogen metabolites was significantly and positively associated with lignan and isoflavone intakes estimated by FFQ. The correlation coefficients between habitual dietary intake and urine concentrations observed in this study are sufficiently high, demonstrating the adequacy of our instrument for estimating isoflavone and lignan intake in epidemiological studies.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Funding of this research project was provided by the Canadian Institutes of Health Research Grant #MT15645. Dr. Hawker received support through a Canadian Institutes of Health Research Scientist Award and currently as the F.M. Hill Chair in Academic Women's Medicine at the University of Toronto.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Dr. Hawker received support through a Canadian Institutes of Health Research Scientist Award and currently as the F.M. Hill Chair in Academic Women's Medicine at the University of Toronto. Funding of this research project was provided by the Canadian Institutes of Health Research Grant #MT15645.

Received October 11, 2005. Accepted May 19, 2006.

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TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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This Article Abstract Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by French, M. R. Articles by Hawker, G. A. Search for Related Content PubMed PubMed Citation Articles by French, M. R. Articles by Hawker, G. A.