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Nutritional Methodology
Research Communication

A Single Measurement Is Inadequate to Estimate Enterolactone Levels in Danish Postmenopausal Women Due to Large Intraindividual Variation¹

The Department of Human Nutrition, Centre for Advanced Food Studies, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark

²To whom correspondence should be addressed. E-mail: hlh{at}kvl.dk.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Single measurements of enterolactone (ENL) used in epidemiologic studies are influenced by intraindividual variation. The objective of this controlled study was to investigate short-term intraindividual variations in serum and urine ENL. Based on these variations, the number of samples required to describe the basal ENL level was estimated. Healthy Danish postmenopausal women (n = 6) aged 54–67 y completed 3 study periods of 24 h within 2 mo. Blood samples were collected at 0, 4, 6, 8, 12, and 24 h and 24-h urine samples were collected. A low-lignan, standardized diet of 3 meals was served. ENL was measured by time-resolved fluoroimmunoassay. Intraindividual and interindividual variations were estimated using a mixed model with repeated measurements. Significant and systematic intraindividual within-day variations (CV) of 31% were observed in serum. Intraindividual day-to-day variations were 56% and overall intraindividual variation of samples collected at random times and on different days was estimated to be 64%. Describing this overall variation required 7 blood samples when estimated with a precision of 50% and 95% confidence. Day-to-day variations in 24-h urine samples were 49%. Large within-day and day-to-day variations suggest that a single measurement of ENL is inadequate to estimate the basal ENL level.

KEY WORDS: • phytoestrogens • lignans • single measurements

Lignans are diphenolic plant compounds comprising a group of phytoestrogens. They occur as glycosides in the fiber layer of plants (1) and are converted to the mammalian lignans, enterodiol and enterolactone (ENL),⁴ by the activity of the intestinal microflora in the proximal colon (2). Plant lignans are present in a variety of foods. Flaxseed is by far the richest source, but whole grains, nuts, vegetables, and beverages such as coffee, tea, and wine also contain considerable amounts (3) and are more widely consumed than flaxseed in the European diet (4,5). An increasing number of epidemiologic studies have found that ENL may reduce the risk of hormone-dependent cancers (6–8) and cardiovascular diseases (9). The ENL level is often evaluated by single measurements; however, concentrations of ENL may be highly variable when measured in biological samples, which makes it essential to investigate intraindividual variations in ENL.

The level of ENL in blood or urine reflects recent and habitual dietary intake of plant lignans (10–12) and the capacity and function of the intestinal microflora (13). These variables cause inter- and intraindividual variations in ENL levels that increase the inherent error and lessen the strength of any associations between exposure and outcome.

Large interindividual variations in levels of ENL (12,14,15) and considerable within-week and within-month intraindividual variations were observed among Finnish men and women consuming their normal diet (15). Knowledge of the within-day variations in ENL concentrations is based on high-lignan, single-meal studies (14,16,17). In those studies, ENL was found to peak 8–9 h after ingestion (14,16), and low diurnal variation in plasma levels was reported in pigs fed a rye-based diet (17); however, the size of the within-day variations was not reported.

The aim of this study was to investigate short-term intraindividual variations in serum and urine ENL in Danish, postmenopausal women. Furthermore, the number of samples required to determine the basal ENL level was estimated.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subjects and experimental design. Healthy Danish postmenopausal women (n = 6; defined as no menstruation for at least 2 y) completed the study. All women were nonsmokers, reported no use of dietary supplements, hormone replacement therapy, or other regular medications (including antibiotic use within the preceding 3 mo). Their mean age (±SD) was 62.0 ± 4.7 y and mean BMI was 24.4 ± 2.3 kg/m².

The present study was part of an intervention study examining the bioavailability of isoflavones from different test foods, designed as a multiple crossover study with 3 periods (ISOHEART). Additional samples were taken for ENL analysis over 3 separate 24-h periods, in which a standardized diet low in plant lignans was served. The study design and protocol were approved by the Municipal Ethical Committee of Copenhagen and Frederiksberg (KF 01–130/02).

    Diets and lignan intake. The standardized, experimental diet was served at the department. Breakfast was served 5 min after collection of the baseline blood sample and consisted of sandwich bread, raspberry marmalade, and coffee with full cream milk. Orange juice, biscuits, and a chocolate bar were served as a supplement on all 3 occasions and 1 of these items was fortified with 50 mg of isoflavones. Lunch was served 6 h after baseline and included sandwich bread, cheese, butter, a salad, yoghurt, and coffee with full cream milk. Vegetarian pizza, a salad, banana, and coffee with full cream milk were served for dinner 10 h after baseline. Daily energy intake during the 24-h period was 8195 kJ consisting of 59% energy (E%) from carbohydrates, 12 E% from protein, and 29 E% from fat. All diet ingredients except water were weighed, prepared, and provided at the department. Water was consumed ad libitum; to control for confounding by ingestion of lignans, no other beverages were allowed.

Plant lignan intake was estimated using 24-h dietary recalls performed at baseline in the first study period. Lignan intake was estimated using published material (3,18). Nutrient values were calculated using the Dankost 2000 dietary assessment software (National Food Agency).

    Biochemical analysis. Blood samples were collected at 0, 4, 6, 8, 12, and 24 h, with samples (drawn after a 12-h fast) collected at 0 and 24 h. In addition, a 24-h urine collection was performed. Serum and urine samples were stored at –80°C until analysis. ENL concentrations were analyzed by time-resolved fluoroimmunoassay as described earlier (19–21). Duplicate analyses were carried out for serum and urine samples. Urine samples were diluted with assay buffer in concentrations of 1:101. Samples from each subject were analyzed in 1 batch to avoid intra-assay variations. ENL measurements were performed with DELFIA Fluorometer (Wallac Oy) and AutoDELFIA Automatic Immunoassay System (Wallac Oy) using kits from Wallac Oy (DELFIA research kit CR66–101).

Results are presented as a mean of the double determinations corrected by a factor of 0.8 to account for the 80% recovery. A deviation of 15% between duplicate measurements was accepted.

    Statistical methods. The variations were analyzed in a repeated model with time as a systematic factor and subjects and person-week as random factors. The person x week interaction was included because the individual baseline values varied among the periods. To compensate for larger variations in ENL concentrations in subjects with high levels of ENL, calculations were performed on a logarithmic scale. Homogeneity of variance and normal distribution among random effects were investigated by plots and histograms.

A test of a treatment effect was performed to examine a possible interaction between lignans and isoflavones in the fortified food compounds. No significant differences were found among the study periods (P = 0.84–0.94); the 3 periods were therefore regarded as identical, excluding the possibility of an interaction.

Serum samples collected from 0 to 12 h during each of the days were used to calculate within-day variation and were included in a test for a systematic effect of time within-day. In a test of a systematic day-to-day difference, the serum samples collected from fasting subjects at 0 h in the 3 study periods were used. A post-hoc test was performed when a significant difference was observed, and the models were used in calculating least-square means (LS means) of serum concentrations at each sampling time.

Estimates of intraindividual and interindividual variances (CV) were calculated by variance components obtained by the SAS PROC VARCOMP command. The intraindividual variance within-day was calculated using the following formula:

Day-to-day intraindividual variations in serum and urine were calculated analogously, whereas interindividual variation was estimated by the person-variance component only. Finally, overall intraindividual variation represents the variation in samples collected at a random time on a random day and was calculated by the addition of the within-day and day-to-day variances. The analytical variance was estimated by the mean intra-assay CV of the internal quality-control samples.

The number of samples required to estimate the basal ENL level within a certain precision (D) of the true mean was calculated using the following formula (22):

with Z = 1.96 corresponding to a 95% CI. The coefficient of variation (CV_A+I) includes analytical and intraindividual variation and was calculated as the sum of the estimated intraindividual and analytical variances.

All statistical analyses and calculations were performed using SAS version 6.12 (SAS Institute). Differences with P < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
ENL concentrations in serum ranged from 22.8 to 137 nmol/L with a median of 60.3 nmol/L and a mean of 80.9 nmol/L. A mean urine excretion of 18.4 µmol/d (range 7.43–36.1 µmol/d) and a median excretion of 22.6 µmol/d were observed.

A trend curve of mean serum ENL concentrations in Danish postmenopausal women is presented in Figure 1. The ENL concentration declined from baseline to 4 h, after which a peak was observed at 6 h. After 6 h, mean concentrations declined to 12 h and were maintained at the same level until 24 h. Curves of serum ENL concentrations for 2 different individuals during each study period are presented in Figure 2. Similar patterns in serum ENL concentrations were observed in all subjects despite large interindividual differences in ENL concentrations.

View larger version (14K): [in this window] [in a new window]   FIGURE 1 Trend curves of serum ENL concentration in postmenopausal women who consumed a standardized low-lignan diet. Values are means of 3 study periods ± SEM, n = 6. Means were higher at baseline (***P < 0.001) and 6 h (**P < 0.01) than at other times.

View larger version (25K): [in this window] [in a new window]   FIGURE 2 Changes in serum ENL concentrations in 2 of 6 postmenopausal women who consumed a standardized low-lignan diet during each of 3 study periods.

Intraindividual within-day and day-to-day variations were estimated to be 31 and 56%, respectively, for serum (Table 2), and day-to-day variation in 24-h urine samples was 49%. The overall intraindividual variation of samples collected at random times and on different days was estimated to be 64% (Table 2). Interindividual variations in serum and urinary levels of ENL exceeded the intraindividual variation and were estimated to be 72 and 58%, respectively. The analytical variation assessed by the mean intra-assay CV of the internal quality-control samples was 11.4%.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In the present study, large intraindividual variations in ENL were observed in Danish postmenopausal women. Within-day serum levels of ENL varied by 31%, whereas day-to-day variations were 56%. The overall intraindividual variation of samples collected at random times and on different days was estimated to be 64%. Estimating mean ENL concentration within 50% of the true mean when overall intraindividual variations were considered required 7 blood samples. These results suggest that a single blood sample is inadequate to estimate the basal level and that the variation is reduced by using blood samples from fasting subjects, i.e., day-to-day variation vs. overall variation. Daily variations in urinary ENL excretion were less than those in serum concentrations, and fewer samples were required to determine the mean ENL concentration. The major methodological concerns with urine collection include poorer compliance and a less specific immunoassay for ENL determination (21).

Given the fact that plant lignans are steadily fermented, converted, and liberated from the food matrix, only small fluctuations in serum ENL were expected with the low-lignan, low-fiber diet provided to the subjects in the 24-h period. Furthermore, plasma ENL concentrations were reported to peak 9 h after consumption of flaxseed (14,16). In this study, a peak in plasma ENL was observed 6 h after breakfast. The lignans provided during breakfast were ingested primarily in liquid orange juice. This peak may reflect both a faster transit time due to the fasting condition and the presence of an easily digested food compound with high bioavailability, suggesting that concentrations of ENL vary in response to meals when lignan intake is limited.

The finding of a systematic within-day variation is in conflict with the study by Bach Knudsen et al. (17), who reported low diurnal variation in plasma ENL concentrations in pigs after a rye-based high-lignan diet was fed. The lack of agreement between that and the present study is most likely due to larger variability in quantitative lignan intake and bioavailability of plant lignans in the human diet compared with pigs. The low lignan intake in the present study and systematic variations in mean ENL concentrations suggest an imbalance or an unsaturated ENL body pool, which would also appear to exist in subjects whose habitual diet includes periodic intake of lignans. Nesbitt et al. (16) showed no variations in plasma ENL concentrations over a 24-h period after supplementation with flaxseed, suggesting that variations in response to meals are reduced by the enterohepatic circulation after a period with constantly high lignan intake.

Within-month variations of 68% for both serum and 24-h urine were estimated in a Finnish population (15) and were slightly larger than the variations found in the present study. In the Finnish study, 3 blood samples were required to estimate individual mean level of ENL concentration with an 80% CI within 50% of the true mean. Blood samples were collected in the afternoon after a 4-h fast and the estimated variations may be enlarged in response to meals. The variations were of the same magnitude as the corresponding overall intraindividual variation estimated in the present study and the same number of blood samples was required to estimate mean ENL concentration when the overall variation and similar CI and precision are used (data not shown). The study population in the Finnish study of Stumpf and Adlercreutz (15) consisted of 20 young men and women with a presumed larger lignan intake, which may augment variations in serum ENL. However, the higher lignan intake may be compensated for by a faster transit time (23), resulting in reduced lignan uptake and therefore variations in serum ENL similar to those found in the present study.

The lignan intakes estimated in the 24-h recalls correspond to previously estimated intakes in a Finnish population (5); in addition, previously estimated day-to-day variations (15) correspond to those observed in the present study. For that reason, the observed within-day variations are expected to be comparable to those existing in a general population, which is characterized by a low and variable lignan intake. However, the median serum concentration of ENL was high among the women in the present study compared with previously reported concentrations in postmenopausal women (7,11,24). In addition, the largest peaks at 6 h tended to be observed among women with high levels of serum ENL. This indicates that women with the highest levels of serum ENL respond more to lignan intake, which could have resulted in larger variations in ENL than would be observed in the general population. In addition, baseline measurements reflected lignan intake of a nonstandardized meal the evening before blood sampling, which may have led to higher ENL concentrations during the first hours of the study period, thereby resulting in larger within-day variations.

In epidemiologic studies in which single measurements of ENL from nonfasting subjects are often used, high intraindividual variation can be accounted for by an increased sample size. If the intraindividual variation found in the present study was applied, such an increase would require an 80% enlargement of the study population using the formulas of Nierenberg and Stuckel (25) and Canner (26). Instead of increasing sample size, Rossner and Willet (27) suggested the use of a correlation coefficient corrected for intraindividual variations. The coefficient expresses the effect of intraindividual variation on the strength of any association between exposure and outcome. If such a correlation factor were calculated using the intraindividual variation in the present study, any true association would be enlarged by 19%.

In conclusion, a single measure of serum or urine is inadequate to estimate the basal ENL level due to large intraindividual variation. Intraindividual day-to-day variations in urinary ENL excretion were smaller; thus a single urine collection is a better measure of basal ENL level than a single blood sample. Repeated measurements and a standardized procedure for blood sampling, including a period of preceding fast, will be necessary in future studies to minimize daily intraindividual variations.

	ACKNOWLEDGMENTS

 
We thank Leif Jakobsen for excellent technical assistance and Professor Ib Skovgaard for statistical advice.

	FOOTNOTES

 
¹ Supported in part by the Danish Food Technology Research Programme FØTEK 3 (Fr 5011–11-0034) and by the Commission of the European Communities, specific RTD programme "Quality of Life and Management of Living Resources" (QLK-2001–00221). It does not necessarily reflect its views and in no way anticipates the Commission’s future policy in this area.

³ Present address: Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

⁴ Abbreviations used: ENL, enterolactone; LS means, least-square means; MAT, matairesinol; SECO, secoisolariciresinol.

Manuscript received 19 December 2003. Initial review completed 4 February 2004. Revision accepted 17 February 2004.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Hausner, H. Articles by Tetens, I. Search for Related Content PubMed PubMed Citation Articles by Hausner, H. Articles by Tetens, I.