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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2379-2387 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.025 Effects of a High-Fiber, Low-Fat Diet Intervention on Serum Concentrations of Reproductive Steroid Hormones in Women With a History of Breast CancerFrom the Departments of Family and Preventive Medicine and Reproductive Medicine, and the Cancer Prevention and Control Program, University of California, San Diego; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA; Arizona Cancer Center, University of Arizona, Tucson, AZ; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Kaiser Permanente Center for Health Research, Portland, OR; and the Women's Healthy Eating and Living Study Group Address reprint requests to Cheryl L. Rock, PhD, RD, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0901; e-mail: clrock{at}ucsd.edu
PURPOSE: Diet intervention trials are testing whether postdiagnosis dietary modification can influence breast cancer recurrence and survival. One possible mechanism is an effect on reproductive steroid hormones. PARTICIPANTS AND METHODS: Serum reproductive steroid hormones were measured at enrollment and 1 year in 291 women with a history of breast cancer who were enrolled onto a randomized, controlled diet intervention trial. Dietary goals for the intervention group were increased fiber, vegetable, and fruit intakes and reduced fat intake. Estradiol, bioavailable estradiol, estrone, estrone sulfate, androstenedione, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and sex hormone-binding globulin were measured. RESULTS: The intervention (but not the comparison) group reported a significantly lower intake of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at 1-year follow-up (P < .001). Significant weight loss did not occur in either group. A significant difference in the change in bioavailable estradiol concentration from baseline to 1 year in the intervention (–13 pmol/L) versus the comparison (+3 pmol/L) group was observed (P < .05). Change in fiber (but not fat) intake was significantly and independently related to change in serum bioavailable estradiol (P < .01) and total estradiol (P < .05) concentrations. CONCLUSION: Results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit weight loss. Increased fiber intake was independently related to the reduction in serum estradiol concentration.
Breast cancer accounts for 31% of cancers and 15% of cancer deaths among women in the United States.1 As a result of a reduction in mortality rate concurrent with continued high incidence rates,1,2 the number of women in the United States who are breast cancer survivors is increasing. Despite encouraging 5-year survival rates, women diagnosed with breast cancer who have completed initial treatments remain at risk for recurrent cancer, and they are at higher risk for new primary breast cancers and early death than are women not diagnosed with breast cancer.3 A possible relationship between diet and risk for primary breast cancer has been the focus of much scientific interest and research during the last several decades. Fewer data on the relationship between diet and risk for recurrence or survival after breast cancer diagnosis have been examined and reported.4 However, results from observational studies suggest that diet may influence prognosis, and diet intervention trials are testing whether postdiagnosis dietary modification can reduce risk for cancer recurrence and increase overall survival.5,6 There are several mechanisms by which diet composition might influence overall survival after the diagnosis of breast cancer, following initial treatments. One possible mechanism is through an effect on reproductive steroid hormones. An important characteristic of normal mammary-cell proliferation and differentiation is the responsiveness of these cells to estrogens,7 in addition to the cellular factors and mitogens that can affect growth regulation in all cell types. Thus, minimizing estrogen stimulation following the diagnosis of breast cancer is a standard management strategy. In fact, antiestrogen therapy has emerged as one of the most effective treatments for the management of endocrine-responsive breast cancers, which account for approximately two thirds of cases, as demonstrated in randomized clinical trials.7-9 Because it has been suggested that adopting a low-fat diet may reduce serum estrogen concentrations, the effect of reducing dietary fat on serum estrogens has been examined in several feeding studies and short-term diet interventions targeting healthy premenopausal and postmenopausal women, summarized in a meta-analysis by Wu et al.10 However, other factors confound the interpretation of these studies, including substantial weight loss and increased fiber intake. An energy deficit and weight reduction would be expected to promote reduced serum gonadal hormone concentrations, regardless of diet. Animal and human feeding studies have demonstrated that dietary fiber can independently reduce circulating estrogen concentra-tions,11-15 so the specificity of an effect of change in fat intake (as opposed to other dietary changes) cannot be assumed. High-fiber foods, such as whole grains and vegetables, are rich sources of other dietary constituents that may influence estrogen metabolism (eg, indoles, isoflavones).16,17 The short-term nature of these studies of diet modification on serum estrogens (most being < 5 months in length) in healthy women is another limiting feature. Homeostatic regulatory mechanisms could adjust to altered rates of biosynthesis and metabolism or fecal losses so that serum concentrations return to their original levels over time, which would limit long-term clinical significance. The effects of a low-fat diet intervention on serum estrogen concentrations have been previously examined in two small groups of postmenopausal women diagnosed with breast cancer. In 19 women participating in the Women's Intervention Nutrition Study (WINS) feasibility study, serum estradiol (but not total estrogen or estrone) concentration decreased at 6 months in association with a reduction in fat intake (from 34% to 22% of energy intake).18 However, body weight was reduced by an average of 3.5% during that time period, and no control group was followed concurrently. In a second subset of 93 WINS participants, significant changes in average serum estradiol or estrone concentration were not observed in either the intervention or control group at 18-month follow-up.19 The purpose of the present study was to examine the effects of a high-vegetable, high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer during their first year of participation in a randomized clinical trial testing the effect of diet modification on disease recurrence and survival. Another purpose of the study was to examine the relationships between changes in the intakes of fiber and fat and changes in serum bioavailable estradiol and total estradiol concentrations from baseline to 1 year in these study participants.
Participants Data were obtained from a subgroup of 400 women enrolled onto the Women's Healthy Eating and Living (WHEL) study who completed dietary assessments and blood collections at baseline and 12 months. The WHEL study protocol, including selection criteria, data collection, and intervention methodology, is provided elsewhere.6 At study enrollment, data on general medical history and usage of medications were collected. Participants identified for this substudy were a systematic quota sample of the first 400 women randomly assigned to the WHEL study. Within each study group (intervention and comparison), we selected the first 100 participants with dietary data and who were younger 50 years at enrollment and the first 100 women older than 50 years. On average, the women were 2 years beyond cancer diagnosis at the time of enrollment. Each participant enrolled onto this substudy either took tamoxifen daily throughout the study period or did not take any tamoxifen during the study period, so tamoxifen use did not vary over time within any given individual. This medication may influence circulating reproductive steroid hormone concentrations and thus could interfere with the analysis. Six women were subsequently dropped from this analysis because of insufficient data. Blood collections in the WHEL study are not timed by menstrual-cycle phase, and interpreting relationships between hormonal data and diet in women with cyclic fluctuations would be subject to considerable error. Notably, most WHEL study participants who were premenopausal at their diagnosis of breast cancer experienced ovulatory failure in association with initial treatments. Thus, we applied two specific criteria to identify the participants in whom serum estrogen concentrations may be appropriately examined for change over time and in response to diet modifications for inclusion in this analysis: each participant must have reported no menstrual period in the 12 months before or after the enrollment date and had a serum concentration of follicle-stimulating hormone (FSH) > 10 mIU/mL, at both baseline and 12-month clinic visits (n = 291). The purpose of this FSH cut point was not to select women who were unambiguously postmenopausal, which would require a cut point FSH > 30 to 35 mU/mL. The targeted participants in this substudy consisted of women who were unlikely to exhibit cyclic estrogen secretion and thus were essentially perimenopausal or postmenopausal.
Procedures Relevant to this substudy, the protocol involved clinic visits at enrollment and 1 year, during which a fasting blood sample was collected, height and weight were measured using standard procedures, and body mass index (BMI, weight[kg]/height/[m2]) was computed. The institutional review boards of all the participating institutions approved procedures for this study, and written informed consent was obtained from all study participants before their enrollment.
Dietary and Physical Activity Data
At baseline and 12 months, the frequency, duration, and intensity of physical activity were assessed by questionnaire and converted into metabolic equivalents (METs). Total energy expenditure was obtained by weighting time spent per week by METs: mild physical activity was weighted 3 METs, moderate activity was weighted 5 METs, and vigorous activity was weighted 8 METs. Walking METs were assigned by walking speed. Unknown-speed or 2 mph walking was weighted 2 METs; 3 mph walking was weighted 3 METs, 4 mph walking was weighted 4 METs, and
Biochemical Measurements The method for the measurement of estradiol, estrone, androstenedione, and testosterone is a modification of the method described by Anderson et al,22 using radioimmunoassay (RIA) for quantification. The measurement of bioavailable estradiol is based on the method described by Tremblay and Dube.23 Commercially available RIA kits (Diagnostic Systems Laboratories, Webster, TX) were used to measure estrone sulfate and DHEA sulfate. The laboratory interassay coefficient of variation (CV) is 9.9% for estradiol, 5.12% for bioavailable estradiol, 11.8% for estrone, 3.88% for estrone sulfate, 7.92% for androstenedione, 9.2% for testosterone, and 5.07% for DHEA sulfate. The concentrations of the steroids are determined against a standard that is commercially available (ICN Pharmaceuticals, Costa Mesa, CA). The cross-reactivities of antibodies used in the RIAs have been checked against all closely related substances, and any cross-reacting substances are separated in the column chromatography step before the RIA is conducted. Commercially available kits were used for quantification of SHBG and FSH. SHBG is useful in the interpretation of serum estrogen concentrations, and FSH was used to screen subjects for inclusion in this substudy. The method for SHBG is a time-resolved fluoroimmunoassay (Delphia SHBG, E G & G, Diagnostic Systems Laboratories), and the laboratory interassay CV is 5.94%. The method for FSH is an RIA (FSH Immunoradiometric Assay, Diagnostic Products Corp, Los Angeles, CA), and the laboratory interassay CV is 3.59%.
Statistical Analysis
Table 1 summarizes demographic and other characteristics of the study participants. There were no significant differences at baseline in age, BMI, level of physical activity, and tamoxifen usage between the two study groups examined in this analysis. Although ethnic/racial distribution is comparable in the two study groups in the clinical trial population,6 this subsample of postmenopausal women did have significantly more minority-group representation in the intervention compared with the comparison group (16% v 8%, respectively; P < .05). Of this substudy sample of 291 nonmenstruating women with FSH > 10 mU/mL at enrollment and 1 year, 110 had an FSH concentration > 10 and less than 30 mU/mL.
Table 2 summarizes body weight and intakes of energy, fiber, and percent energy intake from carbohydrate, fat, and protein at baseline and 12 months in the two study groups. At 12 months, mean BMI was 27.6 kg/m2 (standard deviation [SD], 5.6 kg/m2) in the comparison group and 27.7 kg/m2 (SD, 6.4 kg/m2) in the intervention group, which did not differ from baseline. Similar to the characteristics of a previously described subsample of WHEL study subjects,24 weight loss was not observed in the majority of these women: 218 women (75%) were within 5% of their baseline weight at 12 months, weight loss of  5% baseline weight occurred in 35 women (12%), and 38 women (13%) gained > 5% of their baseline weight at 12 months. Level of physical activity did not change significantly from baseline to 12 months in either study group (data not shown).
As shown in Table 2, there were no significant differences in the intakes of the study groups at baseline. At 1-year follow-up, the intervention group had a significantly lower intake of energy from fat and a significantly higher intake of fiber and carbohydrate than the comparison group (P < .001). As expected, an inverse correlation between energy intake from fat and fiber intake was observed (Pearson r = –0.39; P < .05), likely due to the nutritional guidance provided and the distributions of these dietary constituents in foods. Serum concentrations of reproductive steroid hormones and SHBG did not differ significantly between the two study groups at baseline (Table 3). A significant difference in the baseline to 1-year change in serum bioavailable estradiol concentration in the intervention versus comparison group was observed (P < .05). The change in serum total estradiol in the intervention versus comparison group differed in the expected direction, but this difference did not reach statistical significance (P < .10). Within the intervention group, bioavailable estradiol concentration decreased significantly (P < .05). Changes in total estradiol and SHBG concentrations observed in the women in the intervention group were not statistically significant (P < .10). No significant changes in serum hormone and SHBG concentrations were noted in the comparison group participants.
Weight loss was associated with an increase in SHBG concentration in both study groups. Women who lost 5% of initial body weight from baseline to one year (n = 35) exhibited a significant increase in serum SHBG concentration (from an average of 72.0 to 84.8 nmol/L; P < .05). Women on tamoxifen (n = 172), who constituted 59% of the study subjects, exhibited a greater decline in estradiol and bioavailable estradiol concentrations than did women not on tamoxifen (n = 119; Table 4). However, an important difference between these two subgroups is that the women on tamoxifen versus those not on tamoxifen had a significantly lower BMI at baseline (averaging 26.8 v 28.8 kg/m2, respectively; P < .01). Also, analysis across subgroups categorized by study arm and tamoxifen usage is constrained by significantly different baseline bioavailable estradiol concentrations (P < .001), and the subgroup cell sizes and variances in these subgroup data are shown in Table 4.
Results of the linear regression analysis, in which changes in bioavailable estradiol and total estradiol concentrations were modeled as a function of changes in dietary intakes of fiber and percent energy from fat, are shown in Table 5. Change in fiber intake, but not change in fat intake, was significantly independently related to change in bioavailable estradiol and total estradiol concentration (P < .05), when controlled for baseline serum hormone concentration, tamoxifen usage, and change in BMI.
Results from this study indicate that a high-vegetable, high-fiber, low-fat diet intervention is associated with a significant reduction in serum bioavailable estradiol concentration in women diagnosed with breast cancer, the majority of whom did not exhibit concurrent weight loss during the time period under study. Analysis of these data also suggests that the degree of change in fiber intake, but not the change in fat intake, is independently related to the degree of change in serum estradiol concentration. Estrogenic stimulation is believed to play a causal role in the pathogenesis of breast cancer,7 and in laboratory animal experiments, estrogens have been observed to promote breast tumorigenesis.25 In human studies, evidence to suggest a relationship between serum concentrations of estrogens and risk for breast cancer is fairly consistent.7,26 A recent analysis of nine prospective studies found a highly significant relationship between serum bioavailable estradiol concentration and risk for breast cancer in postmenopausal women.27 Few data relating serum estrogens to risk for recurrence in women after diagnosis of breast cancer have been collected or reported. However, given the favorable effect of antiestrogen therapy on prognosis in endocrine-responsive breast cancers,7-9 dietary strategies that reduce estrogen stimulation of peripheral tissue may help to reduce risk of recurrence and improve the likelihood of survival in women with a history of breast cancer. The relationships between diet and serum estrogens and other reproductive steroid hormones have been examined in a few observational studies in various cohorts of healthy women. Holmes et al28 observed significant inverse (rather than direct) relationships between reported fat intake and total estradiol and bioavailable estradiol concentrations, adjusted for age, BMI, physical activity, adult weight change, and intakes of energy, protein and alcohol, in a sample of 380 healthy postmenopausal women enrolled in the Nurses' Health Study. A significant association between fiber intake and hormone concentrations was not observed in that study; however, the greatest inverse association between fat intake and estradiol was observed in women reporting the lowest fiber intake.27 Three other cross-sectional studies that examined the relationships between diet and serum estrogen concentrations in postmenopausal women found no significant associations.29-31 In the cross-sectional studies examining associations between diet and reproductive steroid hormones in premenopausal women, the results are inconsistent. Energy intake was inversely associated with plasma androstenedione and DHEA sulfate concentrations, averaged across the three menstrual cycle phases, and the ratio of polyunsaturated to saturated fat (but not total fat intake) was significantly inversely associated with plasma estradiol and estrone concentrations during the luteal phase of the menstrual cycle, in one study of 90 premenopausal women.32 In a cohort of 50 premenopausal Japanese women, total serum estradiol concentration was directly associated with fat intake and inversely associated with fiber intake, adjusted for cycle length, age, and energy intake (but not BMI).33 Significant associations between diet and serum SHBG concentration have generally not been observed in cross-sectional studies.30 In a large sample of pre- and postmenopausal rural Chinese women aged 35 to 64 years (n = 3,250), intakes of various foods were found to be variably associated with SHBG concentration, unadjusted for energy intake or BMI; however, these associations were not significant when adjusted for insulin concentration and other factors.34 In contrast, BMI has been consistently inversely associated with serum SHBG concentration,35 and weight loss facilitated by diet modification, increased exercise, or gastric bypass surgery results in significantly increased SHBG concentration.36,37 Insulin inhibits SHBG synthesis and also stimulates the synthesis of sex steroids in concert with other growth factors.38 As previously reported, serum insulin has not been observed to change in response to the high-fiber, low-fat WHEL study diet intervention,39 and the majority of women in the present study did not exhibit weight loss. Regardless of study group assignment, SHBG concentration was significantly reduced in the women in the present study who lost weight. Thirteen feeding studies and short-term diet interventions targeting healthy premenopausal and postmenopausal women formed the basis of a meta-analysis of the relationship between low-fat diet modification and serum estrogens.10 On average, a 13% reduction in serum estradiol concentration was observed in all subjects combined, with postmenopausal women exhibiting an average reduction of 23% in studies ranging from 3 to 20 weeks in length. However, weight loss occurred in the subjects in a majority of these studies, and weight loss has well-established effects on serum estrogen concentrations regardless of diet composition. Also, dietary fiber was substantially increased concurrent with reduced fat intake in the majority of those studies, so the results cannot be interpreted as indicating a specific effect of fat intake.
Two previous reports from the WINS, a clinical trial testing the effect of a low-fat diet on recurrence and survival in postmenopausal women with a history of breast cancer, have examined associations between low-fat diet modification and serum estrogen concentrations in small cohorts. In the WINS feasibility study, 19 of 27 postmenopausal breast cancer survivors completed the counseling sessions, and serum estradiol (but not estrone) was reduced by 37% at 4-month follow-up in those women.18 Average weight loss in the subjects during that period of time was approximately 2.3 kg. In a subset of 93 women enrolled in WINS, randomized into control or low-fat diet intervention groups, overall significant changes in serum estrogens in the intervention group were not observed, although analysis of subgroups based on baseline concentration revealed differential responses.19 Intervention group subjects with baseline serum estradiol A specific mechanism by which dietary fat could influence reproductive steroid hormone status has not been demonstrated. One suggestion is that increased serum free fatty acids could displace estradiol from serum albumin, thus increasing free estradiol concentration.40,41 However, the biologic and clinical significance of this proposed effect is unknown, because serum concentration of SHBG is a more important determinant of the proportion of estradiol that is available to enter the breast epithelial cells. In contrast, fiber is a dietary constituent for which there is some supportive biologic evidence of a possible mechanism, involving interference with the enterohepatic circulation of estrogens.14,15 Fiber supplementation in animals results in an increase in fecal estrogens,11 and in vitro binding studies demonstrate that lignin, oats, barley and wheat bran are excellent binders of estradiol.14 The short-term effects of wheat bran supplements on serum estrogens has been examined in two small cohorts of women, with variable results. Rose et al13 found wheat bran fiber supplementation at a level of 10 g/d or 20 g/d for 2 months to result in significant reductions in serum estrone and estradiol concentrations in a target group of 58 premenopausal women. In 17 postmenopausal women, 35 g/d wheat bran administration for 5 to 6 weeks did not affect serum estradiol, androstenedione, or SHBG concentrations.42 The present study did not use an experimental design that could directly compare the effects of fat and fiber on serum reproductive hormones, but results from the regression analysis suggest that change in fiber intake, and not change in fat intake, was specifically associated with change in serum estradiol concentration. It is possible that differential accuracy in estimating these intakes might confound the associations that were observed, particularly if the intake of fat was not captured as accurately as that of fiber. However, the reported change in carbohydrate and fat intake in the intervention group participants has been validated by changes in the plasma lipid profile over the same time frame of the present study.39 Also, two diet assessment approaches (dietary recalls and a food frequency questionnaire) identified a similar magnitude of change in fat and fiber intakes for the intervention-group participants.20 We also found that the effect of diet modification on serum estradiol was greater in women on tamoxifen compared to nonusers of tamoxifen. Tamoxifen has previously been shown to significantly increase serum concentrations of SHBG, DHEA, estrone and estradiol in postmenopausal breast cancer patients.43-45 An important characteristic of the participants in the present study is that the tamoxifen users were well beyond the initial treatment phase, and tamoxifen use (or nonuse) was consistent when the diet intervention efforts occurred. Notably, the women in this study who were using tamoxifen had lower relative body weight than the nonusers, and adiposity is independently associated with increased serum estrogen concentrations.46 Small sample sizes of the subgroups when categorized by tamoxifen use and study group assignment and large variances further constrain the interpretation of these results. In the present study, we did not observe an effect of diet modification on serum androgen concentrations, which have been directly associated with increased risk for breast cancer in previous observational studies.27 Few previous observational or intervention studies have examined the relationships between dietary factors and serum androgens, and the majority of these studies did not find significant associations.28,32,47 A limitation of this study is that a single blood sample was assayed at each time period (baseline and 1-year follow-up), which is characteristic of most of the previous relevant studies. Assaying multiple samples might allow better characterization of the reproductive steroid hormone status of these women.48 However, multiple measurements of serum estradiol concentration have been shown to be highly correlated in the majority of the studies that addressed this issue in postmenopausal (v premenopausal) women,48 presumably due to reduced influence of cyclic fluctuations and problems with achieving precision in the timing of blood collection. Although larger than previous studies that have assessed the effect of changing diet composition on serum concentrations of reproductive steroid hormones, the sample size in the present study was still limited in view of the considerable variance for these hormone concentrations. Sample size limitations combined with large variability likely explains why the change in bioavailable estradiol (but not total estradiol) was observed in the intervention versus comparison group. Other limitations are that the study involved free-living participants, self-reported dietary data, and variability in food content. Thus, proposing mechanisms or an effect of specific dietary factors would be subject to error. A strength of this study is its duration (12 months). Under these circumstances, the findings suggest that the effect of diet modification on serum bioavailable estradiol concentration may be sustained and thus may exert clinically significant effects on risk for recurrence and overall survival. In summary, results from this study indicate that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women diagnosed with breast cancer. The majority of the study participants did not exhibit concurrent weight loss in association with the diet intervention, which suggests that diet composition per se may exert an influence on serum estrogens. Increased fiber intake was independently related to the reduction in serum estradiol concentration.
The Women's Healthy Eating and Living Study Group: University of California, San Diego, Cancer Prevention and Control Program, San Diego, CA: John P. Pierce, PhD (principal investigator); Cheryl L. Rock, PhD, RD; Susan Faerber, BA; Vicky A. Newman, MS, RD; Shirley W. Flatt, MS; Sheila Kealey, MPH; Loki Natarajan, PhD; Jacqueline Major, MS; Linda Wasserman, MD, PhD; Center for Health Research, Portland, OR: Cheryl Ritenbaugh, PhD; Mark Rarick, MD; Kaiser Permanente Northern California, Oakland, CA: Bette J. Caan, DrPH; Lou Ferenbacher, MD; Stanford University/University of California, San Francisco, Palo Alto, CA: Marcia L. Stefanick, PhD; Robert Carlson, MD; University of Arizona, Tucson & Phoenix, AZ: James R. Marshall, PhD; Cynthia A. Thomson, PhD, RD; James Warnecke, MD; University of California, Davis, Davis, CA: Ellen B. Gold, PhD; Mary N. Haan, DrPH.; Sidney Scudder, MD; University of California, San Diego Cancer Center, San Diego, CA: Vicky E. Jones, MD; Kathryn A. Hollenbach, PhD; The University of Texas M.D. Anderson Cancer Center, Houston, TX: Lovell A. Jones, PhD; Richard Theriault, DO.
The authors indicated no potential conflicts of interest.
Supported by National Cancer Institute grant CA69375; California Cancer Research Fund grant 99-00548V-10147; National Institutes of Health grants M01-RR00827, M01-RR00079, and M01-RR00070; and the Walton Family Foundation. Presented in part at the 11th Annual Research Conference on Diet, Nutrition and Cancer, American Institute for Cancer Research, Washington, DC, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30% energy from fat). The intervention group was encouraged to consume five vegetable servings/day, three fruit servings/day, 16 fl oz vegetable juice/day, 30 g/d fiber, and 15% to 20% energy from fat. An intensive telephone-based diet counseling program, twelve group cooking classes, and printed materials were used to promote diet modification in the intervention group.
2 analysis or independent t-tests were used to compare the characteristics of the two study groups at enrollment. Independent t-tests were used to compare intakes of the two study groups at baseline and 1-year follow-up. Serum hormone concentrations exhibited distributions that were highly skewed, so these values were log transformed to improve normality before analysis. Baseline and 1-year serum hormone concentrations and differences in baseline to 1-year changes were compared in the intervention group versus the comparison group using independent t-tests. Independent t-tests also were used to examine serum estradiol and bioavailable estradiol concentrations and differences in baseline to 1-year changes as a function of tamoxifen use within study groups. Paired t-tests were used to examine changes from baseline to 1 year in the serum hormone concentrations within the intervention and comparison groups. Using linear regression analysis, changes in bioavailable estradiol and total estradiol concentrations were modeled as a function of change in intakes of fiber and percent energy from fat, controlled for baseline serum hormone concentration, tamoxifen usage, and change in BMI. All analyses were performed using the Statistical Analysis System (SAS) version 8.01 and SAS STAT User's Guide, Version 6 (SAS Institute Inc, Cary, NC). 
