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. Author manuscript; available in PMC: 2006 Feb 16.
Published in final edited form as: Eur J Clin Nutr. 2005 Mar;59(3):369–375. doi: 10.1038/sj.ejcn.1602083

Urinary isoflavone excretion as a compliance measure in a soy intervention among young girls: a pilot study

G Maskarinec 1,*, C Oshiro 2, Y Morimoto 1, S Hebshi 1, R Novotny 2, AA Franke 1
PMCID: PMC1369574  NIHMSID: NIHMS8277  PMID: 15523482

Abstract

Objective

To investigate the compliance of young girls with a soy intervention.

Design

An 8-week dietary intervention and urine sample collection.

Setting

Free-living girls.

Subjects

A convenience sample of 8-to 14-y-old girls (20 started and 17 finished the study) recruited through flyers distributed to staff members and previous study participants.

Intervention

The girls consumed one daily serving of soymilk, soy nuts, or tofu, completed 3-day food records, kept daily soy intake logs, and collected weekly urine samples.

Main outcome measures

Compliance with the intervention was evaluated by daily soy intake logs, 3-day food records analyzed by the center’s Food Composition and Food Groups Servings Databases, and weekly urinary isoflavone excretion using high-pressure liquid chromatography. The statistical analysis included paired t-tests, analysis of variance, and Spearman’s rank-order correlation coefficients.

Results

Daily soy intake logs indicated a mean intake of 6.28 servings out of a maximum of 7.0 servings per week. The food records revealed a six-fold increase in isoflavone intake during the study period (P < 0.01) which was confirmed by an increase in urinary isoflavone excretion of similar magnitude (23.3–142.1 nmol/mg creatinine, P = 0.02).

Conclusions

This study demonstrated the ability of young girls to consume one daily soy serving and the usefulness of urinary isoflavones as a primary compliance measure. The high urinary isoflavone excretion levels detected in girls as compared to adult women suggest less intestinal degradation and/or greater absorption of isoflavones in nonadult populations. This finding requires further investigations into the pharmacokinetics of isoflavones.

Keywords: nutrition, intervention, soy foods, girls, phytoestrogens, compliance

Introduction

A diet high in soy has been associated with protection against breast cancer as evident in countries and ethnic groups that experience low breast cancer risk. According to experimental (Lamartiniere et al, 1995; Murrill et al, 1996; Hilakivi-Clarke et al, 1999) and epidemiological studies (Shu et al, 2001; Wu et al, 2002), the timing of soy exposure during developmental years may be crucial for the protective effects from soy. In animals, prepubertal exposure to soy appears to be more effective than adult exposure in reducing mammary tumor formation (Lamartiniere et al, 2002). Furthermore, two case-control studies revealed that women with high soy intake during adolescence had half the risk of breast cancer as compared to those who consumed fewer soy foods (Shu et al, 2001; Wu et al, 2002). Thus, regular soy consumption during childhood and adolescence may lower the risk for breast cancer later in life. A plausible mechanism for the protective effects of soy points to the effect of isoflavones, a group of phytoestrogens, because of their estrogen-like structure (Setchell, 1985). Isoflavones may promote or accelerate the differentiation of breast tissue structures resulting in less epithelial proliferation and lower concentration of estrogen and progesterone receptors (Russo & Russo, 1995). To date, neither this hypothetical mechanism nor the feasibility of conducting a soy intervention among young girls has been investigated. Moreover, although the association between soy consumption and urinary isoflavone excretion in adults has been well documented (Maskarinec et al, 1998; Seow et al, 1998; Chen et al, 1999; Lampe et al, 1999; Setchell et al, 2003), no data on children are available. In the present pilot study, we explored the feasibility of teaching young girls to consume one daily serving of soy food for 8 weeks. This paper describes the subjects’ overall compliance with the study regimen determined by 3 measures (3-day food records, daily soy intake logs, and urinary isoflavone excretion) and the observed changes in overall diet composition and quality.

Materials and methods

Subjects and study procedures

A convenience sample of 20 subjects, ages 8–14 y, was recruited through flyers distributed to staff at our center and to premenopausal women who had participated in a soy trial (Maskarinec et al, 2003). At a screening visit, a research dietitian provided a detailed explanation of the study. Subsequently, the subjects and their parents gave informed consent and provided information about ethnicity and medication usage. To evaluate usual soy intake, a modified version of a previously validated soy food-frequency questionnaire was administered (Williams et al, 2003). The University of Hawaii Committee on Human Studies approved the study protocol. During the 8-week intervention period, subjects were asked to consume one daily serving of sweetened plain soymilk (8.5 oz) or honey-roasted soy nuts (1 oz) as part of their usual diets. We provided individually packaged soymilk (Eden Soy Extra, Original, Eden Foods, Inc., Clinton, Ml, USA) and soy nuts (DrSoy Honey Roasted, DrSoy Nutrition, Irvine, CA, USA) for easy handling by young participants (Table 1). The serving sizes that provided at least 30mg isoflavones/day were designed to be at the lower end of that reported for adults in Asians countries (Adlercreutz et al, 1991; Wakai et al, 1999). Each serving of soymilk is fortified with 200 mg calcium and 40IU Vitamin D, During a soy food taste test, each subject determined her soy food choice for the duration of the study. Subjects already accustomed to tofu or to a certain brand of soymilk continued to use these alternatives to the foods provided. The recommended portion size for tofu was 3/4 cup (6.7 oz) to provide a comparable amount of isoflavones. After an initial dietary assessment, individualized nutritional counseling provided ideas on how to incorpotate soy foods into the diet daily without excessive weight gain. In addition, basic nutrition education, such as the US Department of Agriculture (USDA)’s Food Guide Pyramid (Center for Nutrition Policy and Promotion, 1996), healthful eating habits, and facts about fruits and vegetables, was provided. Twice during the study, memos of encouragement and nutrition games were mailed to the subjects. The details of the educational strategy have been described elsewhere (Oshiro et al, 2004).

Table 1.

Nutrient contents of soy foods for the intervention

Soy food Serving size (g) Energy (kcal) Protein (g) Isoflavones(mg)a
Tofu 189 118 11.2 37.6
Soymilk 250 135 6.5 37.8
Roasted soy nuts 28 134 10.0 31.2
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a

Analyzed by the analytical laboratory at CRCH

Compliance measures

The subjects’ compliance with daily soy consumption was evaluated through three measures: self-reported soy intake logs, 3-day food records, and urinary isoflavone excretion. Laminated, calendar style sticker sheets were used to keep a daily log of soy intake and weekly urine collections. After the completion of the study, the number of stickers was counted and averaged for each intervention week to evaluate the participants’ compliance with the study strategy. The girls’ recorded all foods at baseline and at the end of the study over 3 consecutive days including 1 weekend day. These records were reviewed with subjects to account for missing information and were analyzed for specific nutrients and for pyramid serving sizes using the Food Composition Database and Food Groups Servings Database at our center (Murphy, 2002), respectively. The Food Composition Database currently contains information for more than 2200 food items and is based on USDA values (US Department of Agriculture, 2003), laboratory analysis at the CRCH, and commercial publications. The Food Groups Servings Database is based on Food Guide Pyramid servings developed by the USDA (Center for Nutrition Policy and Promotion, 1996). Its purpose is to help the population in choosing healthy foods. Estimating food group intakes (as servings per day) makes it possible to compare regular dietary intake from food records to each of the food group recommendations in the Food Guide Pyramid (Sharma et al, 2003b), The database first disaggregates mixed dishes into their ingredients and then allocates them to each of 30 food groups (Sharma et al, 2003a). For example, milk is placed in the dairy group as well as in the discretionary fat group unless it is skim milk.

Because isoflavones are predominantly specific to soy foods and are excreted in urine within 24–36 h of consumption (Franke et al, 1995, 1998b; Setchell et al, 2003), urinary assessment of isoflavones is considered a biomarker for soy intake (Maskarinec et al, 1998). At baseline and for the subsequent 8 weeks, the girls collected their first morning urine on the most convenient weekend day in a 15ml cryovial. The weekly urine samples were stored in an airtight plastic container in the home freezer until the time of the final visit. A mixture of boric and ascorbic acid had been added to the containers to prevent the growth of bacteria that may break down the isoflavones. The stability of isoflavones in urine has been demonstrated by our lab; during 2 weeks at room temperature, we observed no significant degradation of isoflavones (unpublished data). The specimens were then analyzed for isoflavonoid content (genistein, daidzein, glycitein, equol, O-desmethylangolensin, dihydrogenistein, and dihydrodaidzein) using high-pressure liquid chromatography with photodiode array and coulometric detection (Franke & Custer, 1994; Franke et al, 1998b). We measured urinary creatinine in 0.01ml of urine using a test kit from Sigma Company (kit555, Sigma, St Louis, MO, USA), adjusted urine concentrations of isoflavones for creatinine levels, and reported final values in nmol/mg creatinine as done previously (Zheng et al, 1999; Dai et al, 2002).

Statistical methods

The statistical analysis was performed using Microsoft® Excel 2000/XLSTAT©-Pro (Version 7.2, 2003, Addinsoft, Inc., Brooklyn, NY, USA); the significance level was set at P<0.05. To determine whether changes in nutrient intake and pyramid serving size occurred during the intervention period, we compared the difference of the measures at baseline and at the end of the study with paired t-tests. ANOVA was conducted to examine the changes in urinary isoflavone excretion during the 8-week intervention period. Furthermore, we used Spearman’s rank-order correlation coefficient to evaluate the relation between self-reported soy intake and urinary isoflavone excretion.

Results

Out of 20 girls, 17 aged 10.7 ± 2.0y, completed the 8-week protocol. Of the 17 girls, six subjects were exclusively Asian (Japanese, Chinese, Filipino, and Korean); another eight had at least one parent who was of Asian descent; and three girls reported Caucasian ancestry only (Table 2), The three Caucasian girls who did not complete the study cited difficulties in consuming soy foods and disinterest in collecting urine samples as reasons for dropping out. Out of the 17 subjects, 11 had consumed soymilk and other soy food products before entering into the study. The body mass index of all girls was below the 50th percentile for their age. No significant changes in mean weight or height were noted at the end of the study. None of the girls reported allergic reactions or health complications related to soy consumption.

Table 2.

Descriptive characteristics of 17 girls

Baseline
 Final
Mean ± s.d.a Mean ±s.d.
Age(y) 10.7 ± 2 —
Ethnicity (n)
Asian 6 —
Mixed 8 —
Caucasian 3 —
Height (cm) 144.6 ± 0.13 145.5 ± 0.12
Weight (kg) 35.9 ± 10.6 36.9 ± 11.0
BMIb (kg/m2) 16.8 ± 2.6 17.0 ± 2.7
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a

s.d. = standard deviation.

b

BMI = body mass index.

At baseline, usual soy food consumption ranged from 0 to 3 servings per week. During the intervention period, self-reported soy intake indicated good compliance with the intervention {Figure 1): a mean weekly intake of 6.28 servings, out of a maximum of 7 servings, was observed. Four girls occasionally consumed tofu, and one girl consumed a different brand of soymilk that her mother was drinking. The high self-reported intake was consistent with the food records {Table 3), which showed a statistically significant increase in isoflavone intake during the intervention period (from 5.4 to 32.6mg/day, P<0.01). Intake of thiamin and fiber, for which soymilk and soy nuts are good sources, was also significantly higher during the intervention period than at baseline (1.4 vs 1.2 mg/day, P = 0.01, and 13.1 vs 10.2g/day, P<0.01, respectively). We observed no other significant changes in nutrient intake, during the study period. Except for cow’s milk and soy food groups, the number of pyramid servings remained unchanged during the intervention (Table 4), The consumption of cow’s milk decreased by 1/2 serving (P− 0.03), while the consumption of soy food group (that included soymilk) increased by nearly one serving (P < 0.01).

Figure 1.

Figure 1

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Self-reported soy intake and urinary isoflavone excretion among 17 girls.

Table 3.

Nutrient analysis of 3-day food records among 17 girls

Baseline
 Intervention
Nutrient Mean + s.db Mean±s.d. Change, % P-valuea
Energy (kcal/day) 1632+479 1585±408 −2.9 0.60
Protein (g/day) 61 +23 65±18 + 6.6 0.46
Fat (g/day) 58 + 16 54±17 −6.9 0.35
Saturated fat (g/day) 20.1 +5.6 19.2 ± 7.4 −4.5 0.67
Cholesterol (m g/day) 186±90 163 ± 81 −12.4 0.37
Calcium (mg/day) 804 ±424 724 ± 376 −9.9 0.40
Magnesium (mg/day) 199±74 222 ± 62 + 11.6 0.18
Iron (mg/day) 10.4 ± 5.0 10.6 ± 3.8 + 1.9 0.83
Thiamin (mg/day} 1.18±0.47 1.41 ±0.49 + 19.5 0.01
Riboflavin (mg/day) 1.55 ±0.63 1.49 ± 0.57 −5.2 0.65
Niacin (mg/day) 13.7 ± 5.8 14.5 ± 5.2 + 5.8 0.54
Folate (μg/day) 244 ±92 271 ±141 + 11.1 0.32
Vitamin D (IU/day) 184 ± 145 127 ± 86 −31.0 0.09
Fiber (g/day) 10.2±4.0 13.1 ± 4.7 + 28.4 0.01
Isoflavones (mg/day) 5.4 ± 10.2 32.6 ± 18.7 + 504 0.01
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a

Results from paired t-tests.

b

s,d, = standard deviation.

Table 4.

Pyramid servings calculated from 3-day food records among 17 girls

Baseline
 Intervention
Food group (servings/day) Mean±s.d.b Mean + s.d. Change, mean P-valuea
Total grain 6.2 ± 2.5 6.0 ± 2.3 −0.2 0.70
 Whole grain 0.7 ± 0.5 0.9 ± 0.8 + 0.2 0.23
Total vegetables 1.4 ± 0.6 1.5 ± 1.1 0.1 0.64
Total fruit 1.2 ± 0.8 1.3 ± 1.0 + 0.1 0.46
Total dairy 1.8 ± 1.1 1.4 ± 0.9 −0.4 0.08
 Milk 1.4 ± 0.9 0.9 ± 0.6 −0.5 0.03
 Yogurt 0.1 ± 0.1 0 ± 0.1 −0.1 0.45
 Cheese 0.4 ± 0.3 0.5 ± 0.4 + 0.1 0.36
Meat, poultry, fish 2.8 ± 1.5 2.8 ± 1.6 0 0.93
 Meat (red) 0.9 ± 0.9 1.3 ± 1.4 + 0.4 0.23
 Poultry 0.8 ± 0.7 0.7 ± 0.9 −0.1 0.95
 Fish 0.6 ± 1.1 0.5 ± 0.6 −0.1 0.62
Eggs 0.2 ± 0.2 0.2 ± 0.2 0 0.52
Soybean productsc 0.2 ± 0.3 1.0 ± 0.5 + 0.8 < 0.001
Nuts and seeds 0.1 ± 0.2 0.2 ± 0.3 + 0.1 0.23
Legumes 0.1 ± 0.1 0.1 ± 0.1 0 0.39
Discretionary fat (g) 42.7 ± 10.7 39.3 ± 14.0 −3.4 0.31
Added sugars (tsp) 17.1 ± 6.4 15.6 ± 8.7 −1.5 0.17
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a

Results from paired t-tests.

b

s.d. = standard deviation.

c

Edamame (boiled, green soybeans) is not included due to its low isoflavone content.

Out of the 17 subjects, 16 collected all nine urine samples; one subject collected only four samples at baseline, midway and the final week. The majority of samples were collected on Saturday as instructed. The mean urinary isoflavone excretion during the study period was significantly higher than at baseline (P = 0.02; Figure 1); on average, it increased more than six-fold from 23.3 to 142.1 nmol/mg creatinine. However, given the limited variation in soy intake, the correlation coefficient suggested only a modest relation between urinary isoflavone excretion and self-reported soy intake (r = 0.16, P = 0.05).

Discussion

In this pilot study among school-aged girls, three measures of compliance indicated a high adherence to the study regimen of consuming one serving of soy per day. Self-reported soy intake showed greater than 90% compliance (6.3 out of 7.0 servings/week) during weeks 2–8; 3-day food records demonstrated a significantly higher intake of isoflavones and other nutrients that are abundant in soy foods. The most objective measure, urinary isoflavone excretion, increased more than six-fold from baseline.

Both at baseline and during the intervention period, the girls reported a lower than recommended intake of pyramid servings except for the meat group (Basiotis et al, 2002). Low intake compared to the recommendations was especially notable in the intake of fruits and vegetables: the daily intakes of fruits at baseline and during the intervention period were 1.2 and 1.3 servings, respectively, as compared to the recommended 2.7–3.0 servings; the daily intakes of vegetables were 1.4 and 1.5 servings, respectively, as compared to the recommended 2.0–3.0 servings. Furthermore, the intakes of grains at baseline and during the intervention period were 6.2 and 6.0 servings, respectively, as compared to the recommended 7.8–9.0 servings; the intakes of dairy foods were 1.8 and 1.4 servings, respectively, as compared to the recommended 2–3 servings. The intake of cow’s milk was also lower by 1/2 serving during the intervention period; this could have been the result of an increase in soymilk consumption. Moreover, we noted a nonsignificant drop in calcium (−10%) and vitamin D (−31%) intake. This decreased intake might have been due to the lower calcium and vitamin D content of soymilk (200mg and 40IU per 8.45oz) than cow’s milk (~300mg and ~100IU per 8.0oz) despite fortification. Such decrease in calcium and vitamin D intake is of concern for a longer intervention in light of the recommended intake (1300 mg/day for calcium and 200 IU for vitamin D) for this age group and would warrant further supplementation, fortification, or other method to increase calcium and vitamin D intake. For example, additional calcium-rich soy foods, such as tofu coagulated with calcium sulfate, may be encouraged in a future study. In addition, as dairy may have other health benefits, an effort to maintain some dairy intake should be made (Ntambi et al, 2002). Otherwise, the analysis of the food records indicated that the nutritional quality of the customary diets remained fairly constant and improved slightly in terms of thiamin and fiber.

Based on the reported low-energy intake, under-reporting of food intake may have occurred in both sets of the food records. Under-reporting is a common issue in adult populations (Willett, 1998) and might also occur among young subjects. However, the fact that the body mass index was below the 50th percentile for all girls partially explains the relatively low caloric intake. As in many nutritional studies, uncertainty about the accuracy of dietary intake data was a limitation of this study. Previous children’s intervention studies (Beech et al, 2003; Rochon et al, 2003) collected dietary data by unannounced, multiple 24-h recalls on nonconsecutive days via telephone interviews or personal interviews during returned visits; such a method, if adopted, may reduce the burden on subjects (especially of this young age group) and enhance the quality of collected data.

A slight decline in urinary isoflavone excretion in the second half of the study contrasted with self-reported soy intake data, which remained high throughout the study and suggested a continuing high level of soy consumption. Furthermore, the findings from the final 3-day food records indicated a daily consumption of one serving of soy food. These conflicting results raise questions about the accuracy of the self-reported data and support the importance of having multiple compliance measures. Given the association between dietary soy intake and urinary isoflavone excretion observed in previous soy intervention studies in adults (Karr et al, 1997; Maskarinec et al, 2003), urinary isoflavone excretion likely provides a more objective measure than self-reported dietary data in children. On the other hand, the decline in urinary isoflavone excretion levels could also result from a longer time period between urine collection and soy food consumption. For example, if soy foods were initially consumed in the evening and during later weeks in the morning, the overnight urine samples would contain fewer isoflavones due to the short half-life of these compounds (Franke et al, 1998a; Setchell et al, 2003; Zubik & Meydani, 2003). Furthermore, the declining trend of urinary isoflavone excretion levels might also reflect a decreasing bioavailability during continuous exposure (Lu et al, 1996).

The six-fold increase in urinary isoflavone excretion from baseline that we observed among the young girls during the intervention period closely resembled the magnitude of increase described among premenopausal women in a previous soy intervention study (Maskarinec et al, 2003), However, we noted that these girls excreted 3 times higher levels of isoflavones both at baseline and during the intervention period than the premenopausal women who consumed 50% more soy than the girls. The respective isoflavone levels at baseline and during the intervention were 23.3 and 142.1 nmol/mg creatinine for girls and 7.5 and 44nmol/mg creatinine for premenopausal women. Two epidemiologic studies among women in Singapore (Seow et al, 1998) and Shanghai (Zheng et al, 1999) reported mean urinary isoflavone excretion levels in the same range as in our adult women: 4.7 and 5.7nmol/mg creatinine, respectively. The mean daily intake was reported as 4.7mg isoflavones (less than half a serving of food) in Singapore and approximately one daily serving in Shanghai, Differences between the study populations, such as body weight, intestinal maturity, variations in gut microflora, and timing of urine sample collections, might partially account for the higher excretion levels among young girls. However, it appears likely that the bioavariability is greater in girls due to a higher absorption efficiency for isoflavones or a lower degree of degradation by the gut flora. The metabolic state of a growing organism with higher energy needs at a younger age may be also a factor. Finally the higher daily creatinine excretion in adult women than in girls may affect the standardization of urinary isoflavone excretion; this requires investigations that compare urinary isoflavone excretion in 24-h urine samples. Until the pharmacokinetics of isoflavones in children has been studied in detail, we can only speculate on the potential health implications of the high urinary isoflavone excretion rates among children.

Although it has been proposed (Irvine, 1995) that soy-based infant formulas may impair the physical, physiological and behavioral development, a long-term follow-up study in men and women who had been fed soy formula during infancy (Strom et al, 2001) detected no adverse effects on more than 30 outcomes. In our study, the girls reported no health complications related to soy consumption. However, several subjects and parents had a problem with the limited food choices, which may have contributed to the declining compliance towards the end of the study. In addition to offering more variety in soy foods, nutritionists should introduce age-appropriate recipes (Neumark-Sztainer et al, 1999; Beech et al, 2003). With the growing offer of soy foods in Western countries (Soy Foods Association of North America, 2003; Soyatech Inc., 2003), such as soy ice cream, soy muffins and cookies, soy burgers, and new flavors of soymilk, it will be possible to identify acceptable food choices with concentrations of soy protein and isoflavones that are equivalent to those in traditional foods. In an intervention study (Beech et al, 2003) targeted at obesity prevention, cooking demonstrations and additional group activities encouraged subjects to meet other children and share their experience with each other; our participants also expressed at the end of the study that they would have enjoyed having additional group activities. Moreover, previous children’s studies supported parental involvement in nutrition education and dietary recalls, which might be crucial for the successful outcome of dietary intervention studies involving young participants (Van Horn et al, 1993; Beech et al, 2003; Rochon et a!, 2003).

The present study was the first to investigate the feasibility of prescribing one daily soy serving to young girls. Due to the short duration, small sample size, and our geographic location that has a large influence of Asian food culture, the generalizability of the study’s results to a larger population is limited. In particular in populations who consume small to moderate amounts of soy only occasionally, different methods of compliance assessment may be necessary because urinary isoflavones reflect primarily the intake within the past 48-h. Multiple urine collections could correct this drawback (Franke & Custer, 1994). Our intervention shows that, urinary isoflavone excretion appears to be an effective compliance measure for soy intake among this population. Some questions about the self-reported intake according to the daily soy logs remain. This method may be less effective than urinary isoflavone excretion and requires improvement. Additional efforts toward enhancing the overall diet quality and maintaining high compliance rates may be also needed. This study demonstrated that young girls are able to follow nutritional instructions and incorporating one daily serving of soy into their diet. For larger studies that want to examine the effects of regular soy intake among child populations on breast cancer risk, frequent assessment of urinary isoflavone excretion can provide a good measure of dietary compliance. The high urinary isoflavone excretion levels detected in girls as compared to adult women requires further investigations into the pharmacokinetics of isoflavones.

Acknowledgments

We are grateful to the girls who participated in this study. This investigation was supported by a Research Centers in Minority Institutions Award, P20 RR11091, from the National Center for Research Resources, National Institutes of Health. Thank you to DrSoy Nutrition, Aloha Tofu Factory and Foodland Supermarkets for supplying us with soy foods. We would also like to acknowledge our dedicated staff members for their efforts, including Andrew Williams, MA, Debra Petitpain, MS, RD, and Laurie Custer, BS.

Footnotes

Guarantor. G Maskarinec

Contributors: GM conceived the idea for the study and directed the project, the analysis, and the manuscript preparation; CO developed the nutritional education strategy; CO and YM prepared the first draft; YM performed the statistical analysis; SH coordinated the project and wrote part of the methods; RN provided nutritional consultation; AAF participated in the planning and was responsible for the analytical work; all authors reviewed the final manuscript.

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