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Endocrine Care |
Departments of Preventive Medicine and Community Health (L.-J.W.L., K.E.A., J.J.G.) and Obstetrics and Gynecology (M.N.), The University of Texas Medical Branch, Galveston, Texas 77555
Address correspondence and requests for reprints to: Lee-Jane W. Lu, Ph.D., Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, 700 Harborside Drive, Galveston, Texas 77555-1109. E-mail: LLu{at}UTMB.EDU
Abstract
Soy intakes have been associated with reduced rates of breast cancer in some Asian populations. The isoflavones daidzein and genistein and other components of soybeans may modulate endocrine function and lead to beneficial health effects. This study determined the effects of a soy diet containing minimum amounts of isoflavones on circulating levels of ovarian hormones and gonadotropins. Nine healthy, regularly cycling women consumed a constant soya-containing diet on a metabolic unit starting on day 2 of a menstrual cycle until day 2 of the next cycle. The soy diet was calculated to maintain constant body weight and included a 36-oz portion of soymilk that provided 334 kilocalories and less than 5 mg/day of total isoflavones. The energy distribution of the soy diet was 35.9% fat, 14.0% protein, and 49.8% carbohydrate whereas the home diets averaged 39% fat, 16.6% protein, and 42.5% carbohydrate. For the group, the soya diet provided more carbohydrate (P = 0.002) and less protein (P = 0.005) than the home diets. Daily consumption of the soya diet reduced daily circulating levels of 17ß-estradiol over the entire menstrual cycle by 20% (P < 0.01, paired t test, two-tailed) and progesterone by 33% (P < 0.0001) compared with levels during the home diet period, but had no effect on LH, FSH, or sex hormone-binding globulin. The decreases in follicular phase 17ß-estradiol during the soy diet can be accounted for by changes in energy intakes, nutrient density, and fiber intake, whereas changes in luteal phase 17ß-estradiol were most strongly associated with differences in fiber intake. Changes in progesterone levels were most strongly associated with changes in protein intake and much less with other nutrients. Isoflavones were not detectable in plasma and urine during either the soy or home diet periods. These results suggest that at least under the conditions of this study, a soy diet with low levels of isoflavones and low energy intake from protein can reduce circulating ovarian steroids without altering gonadotropins. Our results are consistent with previous studies showing decreased ovarian hormone levels and decreased risk of breast cancer in populations consuming soya diets and an inverse relationship between animal protein intake and breast cancer risk and, therefore, may have implications for breast cancer prevention.
BREAST CANCER IS an important public health problem, especially in more affluent Western countries (1). Epidemiological studies have associated dietary consumption of soy products with a reduced risk for breast cancer (2, 3, 4, 5, 6, 7, 8). Case-control studies in premenopausal women in Singapore (3, 4), in Japanese women in Japan (5), and in pre- and postmenopausal Asian women in California and Hawaii (6) and a cohort study in Japanese women in Japan (2), for example, have shown that breast cancer risk was inversely related to soy intake. Two case-control studies found an inverse relationship between urinary phytoestrogen excretion and breast cancer risk (7, 9). These epidemiological observations are supported by results of animal studies in which soya feeding was protective against experimentally induced mammary tumors (10, 11, 12, 13, 14, 15). However, one casecontrol study of women in China (16) and one prospective study of women in Japan (17) failed to support such a relationship.
A large body of evidence suggests that ovarian hormone levels (18, 19, 20, 21, 22) and related reproductive factors (e.g. age of menarche, menopause, and parity) (23) influence breast cancer development. 17ß-Estradiol stimulates breast and endometrium cell proliferation (19). Progesterone antagonizes the proliferative effect of 17ß-estradiol on the endometrium. However, the fact that breast cell proliferation increases during the luteal phase of the menstrual cycle, when progesterone concentrations are the highest, suggests that progesterone may enhance breast cell proliferation (19, 24).
Soya contains many chemopreventive components including Bowman Birk protease inhibitors, inositol phosphates, phytosterols, saponins, and the isoflavones genistein and daidzein (25). Isoflavones are weak estrogens (26, 27), induce cell differentiation, and inhibit cell proliferation (28), angiogenesis (29), tyrosine kinase (30), and topoisomerase II (31). However, many of these effects were observed in vitro at concentrations of isoflavones above physiological levels and with biphasic dose responses (32, 33). Hsieh et al. (27) showed that genistein can enhance the growth of human breast cancer cells transplanted into nude mice. It is, therefore, important to assess the roles of isoflavones in humans.
The results of several studies of the effects of isoflavones on ovarian hormones in humans (34, 35, 36, 37, 38, 39, 40, 41, 42) have varied, probably due to differences in study design (43). In a previous study, we found that circulating ovarian hormone levels decreased during 1 month of consumption of soy containing significant quantities of isoflavones, when measured on three different menstrual cycle days in six premenopausal women (36). This is consistent with the results of a cross-sectional study of women in Japan (44). To gain a better understanding of the roles of nonisoflavone components of soy, in the present study, we determined the effects of a calculated diet containing soymilk from which more than 99% of the isoflavones had been removed on ovarian hormones and gonadotropins in premenopausal women.
Study Design and Methods
Study design
This was a longitudinal study that compared circulating hormone concentrations in premenopausal women during a baseline observation period while the subjects consumed their usual home diets to those during 1 month of a controlled diet that included soymilk. The study was approved by the Institutional Review Board of the University of Texas Medical Branch. Written informed consent was obtained from each subject.
Subject selection
Subjects were premenopausal women who were healthy as determined by history, physical examination, standard blood cell counts, clinical chemistry determinations, and serum ferritin levels. Vegetarians, smokers, and those who consumed more than two alcohol-containing drinks per month, had taken antibiotics within the preceding 3 months, had irregular menstrual cycles, or had taken contraceptive medications during the preceding 6 months were excluded. Contraceptive medications were not allowed during the study. Small doses of acetaminophen or aspirin were permitted. One subject was taking replacement levothyroxine (0.1–0.25 mg/day) for hypothyroidism and was determined to be euthyroid. Another took sertraline (25 mg/day) for mild depression before and during the study.
Baseline study period
Day 1 of each cycle (the first day of menstrual bleeding) was recorded throughout the study. Subjects underwent baseline studies as outpatients of the General Clinical Research Center (GCRC) for at least 3 months but no longer than 7 months while consuming their usual home diets, and were then placed on a soya diet for 1 month. Soy products were not part of the usual diet of any subject, and all were instructed to avoid soy products during the baseline observation period. The major purposes of the baseline observations were to assure that the subjects had regular cycles and to record cycle length. During the first month of the baseline period, blood was obtained on cycle days 5 (during the follicular phase), 12 (midcycle), and 22 (luteal phase) for measurement of 17ß-estradiol and progesterone. Subjects were retained in the study if luteal phase progesterone levels exceeded 4 ng/mL. During the second month of the baseline period, blood samples were collected on cycle days 5 and 7 and then daily from day 9 through the second day of the subsequent cycle. After a rest period of at least one menstrual cycle, subjects were studied as inpatients on the GCRC beginning on cycle day 2 and discharged on cycle day 2 of the next cycle. Intakes of energy, protein, carbohydrate, fat, and fiber during consumption of usual home diets were estimated using "Block’s Health Habit History Questionnaire" (45), and the values were used for comparison with intakes during the soya diet period.
Soya diet period
Subjects consumed a soya-containing diet for one menstrual cycle
on the GCRC. Meals and soymilk were consumed under direct supervision.
For each subject, the soya diet (including both soymilk and nonsoya
foods) was calculated to match that needed to maintain constant body
weight, based on the Harris-Bennedict equation, with adjustment for
physical activity (46, 47). The soya diet consisted of
three rotating daily menus and included a 36-oz portion of soymilk
daily that provided 334 kilocalories, 37.9 g soy protein, and
20.3 g soy oil. Soymilk was prepared from a soy powder from which
greater than 99% of the isoflavones had been removed by alcohol
extraction. According to the manufacturer (Protein Technologies Inc.,
St. Louis, MO), the isoflavone content of this product was 
4.5 mg
for the 36-oz (37.9 g soy protein) daily portion. Soymilk was ingested
between 1700 and 2000 h without other foods and in place of the
evening meal. The energy distribution of the soya diet was 35.9% fat,
14.0% protein, and 49.8% from carbohydrate daily (Table 1
), which is similar in macronutrient
distribution to that consumed by many residents of Western countries
(48).
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Serum levels of ferritin were monitored biweekly throughout the study. If the serum ferritin fell below 10 ng/mL during the study, an oral iron supplement was provided.
Hormone analysis
Serum concentration of 17ß-estradiol was measured by a specific RIA after extraction with hexane and ethyl acetate (vol/vol, 3:2), as described previously (49). Progesterone levels were measured by direct RIA using commercial kits (Diagnostic Systems Laboratories Inc., Webster, TX) (36). Blank and control sera were run with each assay. Assays were performed in duplicate. Levels of LH and FSH were measured by immunoradiometric assay using commercial kits (Diagnostic Systems Laboratories Inc.). Levels of sex hormone-binding globulin (SHBG) were measured by time-resolved fluoroimmunoassay using a commercial kit (Wallac, Inc., Geithersburg, MD). The intra-assay coefficients of variation (CV) were 4–8% and interassay variation was 5–9%. Steroids in the baseline and treatment samples of each subject were analyzed together in a single batch.
Analysis of soya isoflavones genistein and daidzein in soymilk, urine, and serum
Isoflavone content in soymilk and urine after the addition of an internal standard, 4',7-dihydroxyflavone, was measured by gas chromatography with flame ionization detection, as described previously (50). Amounts of isoflavones were calculated from the peak areas of each isoflavone relative to that of the internal standard. Gas chromatography peak areas were linear for isoflavone concentrations of 0.1–2.0 µg/µL. Amounts of conjugated isoflavones were expressed as amounts of the aglycone forms.
Serum levels of daidzein and genistein were analyzed by competitive
enzyme-linked immunoassays, using monoclonal antibodies generated
against daidzein and genistein, and horseradish peroxidase conjugates
of daidzein and genistein as tracers, as described previously
(51, 52). The detection limit of the assay was 0.1 ng/well
(0.1 ng/250 µL assay medium or 0.05–0.1 ng/µL plasma). Sera were
obtained daily 15 h after soymilk ingestion. Daidzein and genistein
were measured in 1/3 cycle of the blood samples (once every third day).
Results were expressed as amounts of free forms of the isoflavones.
Mean values for samples analyzed for each diet period were
calculated.
Data analysis
The main outcome measures were serum concentrations of 17ß- estradiol, progesterone, LH, and FSH, and menstrual cycle length. Due to cyclic changes in hormone levels, summary measures of the data were used in the data analysis (53). The hormone data were expressed as areas under the concentration time curves (AUCs), mean daily levels, and peak levels, as appropriate for assessing changes in hormones over two entire cycles under the two different dietary conditions.
Serum levels of hormones obtained once every other day initially and daily after day 9 until day 2 of the next cycle were used to calculate area under the serum concentration vs. time curves (AUC, concentration x time) using WinNonlin software (Scientific Consulting Inc., Cary, NC). AUC represents the integrated or cumulative exposure to these cyclic hormones during each dietary period. The AUC was divided by the number of days to obtain the mean daily level. Peak levels represent the maximum levels recorded during the cycle and during the follicular and luteal phases. AUCs and mean daily levels were calculated for the entire cycle and for the follicular and luteal phases using the day of the serum LH surge as a reference point. The LH surge represents the end of the follicular phase and the beginning of the luteal phase. For graphical analysis of the time courses of hormone levels, mean values were plotted using the day of serum LH surge as a reference point.
Each outcome summary measure (i.e. cycle lengths, AUCs, mean
daily levels, and peak levels) was analyzed across the entire cycle,
and then also within the follicular and the luteal phases. Most
comparisons were for within-subject changes and used a mixed model
approach (54). To determine the contribution of covariate
nutrient intakes on hormone changes, adjustment for intakes of total
energy and individual macronutrient (protein, fat, carbohydrate, and
fiber) were performed using analysis of covariance with the SAS
procedure MIXED (SAS Institute, Inc., Cary, NC).
The adjustment was made by adding the covariate to the model one at a
time due to small sample size. Each model was tested for effect
modification of body mass index (BMI) by including interactions of
baseline BMI (below median vs. 
median) with treatment.
All statistical analyses were performed using SAS (SAS Institute, Inc.). All results were expressed as mean ±
SEM. Unless stated otherwise (e.g.
paired t test), all P values are two-tailed, from
the mixed model regression analysis, and are considered significant if
P less than or equal to 0.05.
Results
Subject enrollment and dietary intakes
Characteristics of the nine women who completed the study are
shown in Table 1
. Six were Caucasians, three were African-Americans,
and all but one was nulliparous. The baseline mean BMI was 25.8 ±
3.5 (SD) kg/m2. All women had regular
cycles (CV in cycle length during the 3-month baseline of 5.7–11%).
Cycle lengths, body weight, and BMI did not differ between the home and
soy diet periods. For the group, average intakes of total energy and
fat between home diets and the soya diet did not differ significantly.
The soya diet on average provided more carbohydrate (49.8%
vs. 42.5% of calories, P = 0.002), less
protein (14% vs. 16.6%, P = 0.005), and
less fiber (6.4 g vs. 13.8 g/day, P = 0.02,
Table 1) than did the home diets. There were individual variations in
these dietary intakes. Because of individual variations in cycle
length, the number of soy feeding days also differed somewhat among
subjects.
Dietary intakes and urinary and serum levels of isoflavones
We determined the isoflavone content of the soy powder to be 5.6 mg per 37.9 g soy protein per day of soy intake, which is similar to the 4.5 mg determined by the manufacturer. Isoflavones were measured in all urine samples collected during the entire soy cycle from two of the nine study subjects, and, as expected, isoflavones were not detected. These data suggest that the soya diet was, indeed, very low in isoflavones and is referred to as isoflavone free. Serum levels of isoflavones were determined in daily samples from every third cycle day during both diet periods. Serum daidzein levels of 0.15 ± 0.02 µg/mL (mean ± SEM) for the home diet period were significantly higher than those of 0.08 ± 0.05 µg/mL during the isoflavone-free soy diet (P = 0.02, paired t test). Serum levels of genistein were 0.16 ± 0.02 µg/mL during the home diet period and 0.17 ± 0.04 µg/mL during the isoflavone-free soy diet period (P = 0.65). However, these levels are at the sensitivity limits of the immunoassays.
Effects on 17ß-estradiol levels
Due to the cyclic nature of ovarian hormones, 17ß-estradiol (and
progesterone, LH, and FSH, see below) levels were studied daily during
both the follicular and luteal phases. Because interindividual
variation in cycle length is largely attributable to variation in
follicular phase length (55, 56), the day of the LH surge
was used as a reference point for separation of the follicular and the
luteal phases. The levels of 17ß-estradiol averaged for each cycle
day decreased over the full cycle during soymilk ingestion (Fig. 1A), as did AUC (Fig. 1B), mean daily
level for each cycle ( = AUC/cycle length), and peak levels (Fig. 1C)
of 17ß-estradiol in most subjects. These decreases in circulating
17ß-estradiol levels were evident when analyzed over the entire
cycle, over the follicular phase, and over the luteal phase. For the
total cycle, follicular phase and luteal phase AUCs (pg/mL x
day), the 17ß-estradiol decreased by 20% during soya diet feeding
(P values from 0.005 to 0.03, Fig. 1B). Average daily levels
(pg/mL) of 17ß-estradiol decreased by 16–19% during the follicular
and the luteal phases of the cycle (P values from 0.03 to
0.07, Fig. 1C). Peak levels of 17ß-estradiol during the follicular
phase were suppressed by 24% during the soya diet
(P = 0.004, Fig. 1C).
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The group mean level of progesterone for each luteal phase day
decreased during the low isoflavone soya diet (Fig. 2A). The luteal phase AUCs (Fig. 2B, P = 0.0002) and luteal phase mean daily levels (Fig. 2C, P 
0.002) of progesterone were lower during the
soya diet than during the home diets in all nine subjects, with mean
decreases of 30%. The peak levels were lower in eight subjects
(Fig. 2C, P = 0.01). Progesterone levels during the
follicular phase were generally very low, as expected, and the
difference during the two dietary periods was not statistically
significant (P > 0.2).
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Circulating levels of LH and FSH were measured during both dietary
periods to determine the role of these two gonadotropins on
soya-induced changes in 17ß-estradiol and progesterone levels (
Figs. 1–2). As shown in Fig. 3, consumption of
the soya diet for 1 month did not influence the total cycle, cycle mean
daily, or peak levels of LH and FSH. The cycle profiles of ovarian
steroids and gonadotropins of our study subjects (
Figs. 1–3) were
typical for premenopausal women (56, 57, 58).
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SHBG levels were measured in selected samples. Based on LH surge day, sera from the early follicular phase, midfollicular phase, LH surge day, midluteal phase, and last day of a cycle were analyzed for SHBG. The mean cycle level was calculated for each diet cycle for each subject and used for statistical analysis. Group mean cycle SHBG levels for home diets and the isoflavone-free soy diet were 50.7 ± 21.3 nmol/L (range, 24.6–83.3) and 48.7 ± 24.4 nmol/L (range, 28.5–86.7), respectively. SHBG levels did not differ between the two diet periods (P = 0.59).
Effects of macronutrients on hormone levels
Because the soy diet contained significantly less protein and more
carbohydrate than did the home diets (Table 1), adjustment for
differences in these and other nutrient intakes were made one at a time
during statistical analysis (Table 2).
For total cycle and luteal phase levels of 17ß-estradiol (AUCs and
mean daily levels) and peak 17ß-estradiol levels, the results from
the statistical test between the two dietary periods remained
significant after adjustment for differences in intake of energy,
protein, carbohydrate, and fat (in most cases P <
0.05) but did not for fiber (P > 0.10). However, for
follicular phase levels of 17ß-estradiol, adjustment for all
macronutrients changed the test results from significant to
nonsignificant (Table 2).
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During the soy diet, increases in soy protein intake (6.5% of total
energy intake) were accompanied by decreases in nonsoy protein intakes
such that protein intake was maintained at 14% of total energy.
Relationships between progesterone levels and nonsoy protein intakes
during the two different dietary periods were analyzed by regression
analysis as shown in Fig. 4. During home
diets, which did not contain soy protein, individual progesterone
levels correlated highly with individual total protein intakes
(expressed as percentage of energy from protein in Fig. 4, r2 = 0.77, slope = 2.6, P =
0.002). During the soy diet, progesterone levels also correlated well
with percentage of energy from nonsoy protein ( = %-total protein –
%-soy protein, R2 = 0.25, slope = 11.5,
P = 0.18). However, the slopes of these two lines
differed.
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Discussion
To determine the effects of the nonisoflavone components of
soybeans on ovarian hormone levels in premenopausal women, hormone
levels were compared during a soycontaining diet with minimal
amounts of isoflavones and home diets that did not include soy or
isoflavones. Feeding a soy diet containing 14% of energy as protein
that included 6.5% soy protein effectively reduced circulating
levels of 17ß-estradiol and progesterone (Figs. 1 and 2), in the
absence of isoflavones (<5 mg isoflavones per day). This effect
occurred throughout the menstrual cycle. The changes observed were
similar to previous observations with isoflavone-containing soy diets
(36) and suggest that the synthesis and/or metabolism of
these two ovarian steroids may be affected at least in part by soy
components other than isoflavones. As with isoflavone-containing soy
(36), the isoflavone-free soy diet did not alter
circulating levels of gonadotropins (Fig. 3), suggesting again that the
effects of soy diets on ovarian hormones are not mediated by
gonadotropins. Because the isoflavone-free soy diet did not affect SHBG
levels, the effects on hormone levels are not due to altered SHBG
levels.
None of our study subjects gained weight during the month of soya
feeding because they consumed similar amounts of energy during both
dietary periods (Table 1). BMI and fat intakes, each of which may
influence hormone levels and cancer risk (59, 60) were not
predictors of the observed soya-induced changes in ovarian steroid
hormone levels. Effects on hormone levels were not associated with
basal BMI of the study subjects. The study subjects consumed more
carbohydrate during the soya diet than during the home diet period
(Table 1), but adjustment for individual differences in carbohydrate
intakes did not alter the effect of soy feeding on ovarian hormone
levels.
In contrast, adjustment for differences in protein intake accounted for
the observed differences in follicular phase 17ß-estradiol and luteal
phase progesterone levels between the two diet periods (Table 2).
During both dietary periods, progesterone levels correlated well with
individual protein intakes from nonsoy sources, but the slopes of the
two regression lines differed (Fig. 4). These data suggest that the
relationship of progesterone and nonsoy protein intake is modified
according to which diet the subjects were on (Fig. 4) and soy protein
may be one of the effect modifiers of this relationship. For luteal
phase 17ß-estradiol levels, only adjustment for fiber intake affected
the unadjusted P values, suggesting that luteal
17ß-estradiol is affected by fiber intake. During the soy-feeding
period, subjects consumed less fiber than during the home diet period
(Table 1). Perhaps, because soy fiber modifies cecal content of organic
acids (61) and may influence intestinal flora and
intestinal function (62), the kinetics of enterohepatic
circulation and the excretion of 17ß-estradiol may be altered by the
soy diet.
Results from previous studies (34, 35, 36, 37, 40, 41, 42, 43) on the
effects of soy feeding on ovarian hormone levels have varied, most
likely due to differences in study design. Most of these studies
intended to test the hypothesis that the breast cancer preventive
effects of soy diets were mediated by isoflavones, and to obtain high
intakes of isoflavones, the intake of soy protein was often also
increased significantly. Of those studies in which energy and nutrient
intakes were reported (34, 40, 41, 43), we estimate that
protein intake during the soy feeding periods was about 20% of daily
energy. Results from the present study suggest that an increase in
protein intake per se may increase ovarian hormone levels,
which, in turn, may offset any inhibitory effects of isoflavones or
other chemopreventive components of soy on ovarian hormone levels. In a
study to determine the effects of soy feeding on ovarian hormone levels
in free-living women in Japan (42), soymilk feeding
reduced 17ß-estradiol levels by 25% in the intervention group when
compared with preintervention baseline levels of this group. However,
the mean decreases in the intervention and the control, nonintervention
arms were not significantly different and this may be due to
differences in protein intakes between the treatment group, which
consumed on average 16% energy from protein, and the control group,
which consumed, on average, 14% energy from protein (42).
Our study subjects consumed an average of 16.6% of energy from protein
during home diets and 14% during soy feeding (Table 1). Thus, to study
the effects of phytoestrogens on ovarian hormone levels, it may be
important to control for protein and other nutrient intakes.
Relationships between breast cancer and protein intake have been studied less than the relationships to fat intake (reviewed in Ref. 63). Ecological data (64) and limited case-control studies in women in Italy (65, 66), Hawaii (67), and Singapore (3), but not Japan (68), suggest an inverse relationship between animal protein intake and breast cancer risk. In rats, a low casein diet was found to be effective in lowering PRL and ovarian hormones (69, 70), a result consistent with our observations in humans. Anderson et al. (71, 72) found that decreasing the protein to carbohydrate ratio of the diet can alter testosterone and corticosteroid levels and estradiol 2-hydroxylation in men, but intervention studies in women of the relationships between protein and ovarian hormones are limited. A better understanding of these relationships has implications for dietary intervention to reduce breast cancer risk.
Limited data on soy intakes of Asian populations show that soy food and soy protein intakes can be as high as 400 and 40 g/day, respectively, with a median protein intake estimated at 2–8.7 g/day (3, 16, 73). In this study, subjects ingested 37.9 g soy protein per day, which is in the upper portion of this range of soy protein intake. Thus, ovarian hormone levels can be reduced with physiologically relevant levels of soy intake. Our results may have implications for breast cancer prevention by soy dietary intervention.
Acknowledgments
We thank Ann Livengood of the GCRC, The University of Texas Medical Branch, for designing the research diets; the excellent technical assistance of Amy Nimmo, Emily Thomas, Amber Zwernemann, and Xin Ma; and the nursing and dietary research assistance provided by the staff of the GCRC, The University of Texas Medical Branch. Protein Technology Inc. (St. Louis, MO) generously provided the isoflavone free soy powder for this research.
Footnotes
1 Supported by U.S. Public Health Service Grants: NIH Grants CA65628,
CA56273, and CA45181; National Center for Research Resources
General Clinical Research Center Grant MO1-RR-00073; and Grant
AICR95B119. 
Received September 19, 2000.
Revised March 8, 2001.
Accepted March 22, 2001.
References
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