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From the Clinical Research Centers |
Department of Food Science and Nutrition (A.M.D., B.E.M., X.X., M.S.K.) and Obstetrics and Gynecology, University of Minnesota, St. Paul, Minnesota 55108; Department of Obstetrics and Gynecology (T.C.N.), University of Minnesota, Minneapolis, Minnesota 55455; and the Department of Obstetrics and Gynecology (W.R.P.), University of Rochester, Rochester, New York 14642
Address all correspondence and requests for reprints to: Dr. Mindy S. Kurzer, Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, Minnesota 55108. E-mail: kurze001{at}tc.umn.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It has been proposed that isoflavones exert their cancer-preventive effects in part as a result of hormonal actions. Isoflavone intake has been associated with infertility in Australian sheep grazing on isoflavone-rich clover (7) as well as in the captive cheetah (8). Ovariectomized rats fed isoflavones have been shown to exhibit enhanced mammary gland proliferation, increased plasma PRL concentrations, significant estrogenic effects on vaginal cytology (9), and significantly increased uterine weight (10).
Few epidemiological studies have investigated the associations between isoflavone intake and endogenous reproductive hormones in humans, and the few available data are inconsistent. Urinary isoflavones have been correlated positively with plasma sex hormone-binding globulin (SHBG) and negatively with plasma free estradiol (E2) and free testosterone in premenopausal Finnish women (11, 12), and a negative association has been shown between soy intake and plasma E2 in premenopausal Japanese women (13).
Human intervention studies have shown modest and inconsistent hormonal effects of isoflavone consumption in premenopausal women. Reported effects include increased (14) or unchanged (15) follicular phase length; decreased (14) or unchanged (15) midcycle LH and FSH; increased (14, 16), decreased (17), or unchanged (15) E2; decreased dehydroepiandrosterone sulfate (DHEA-S) (17); and decreased (17) or unchanged (14, 16) luteal phase progesterone. Soy intervention studies have not confirmed the epidemiological associations between urinary isoflavones and plasma SHBG (14, 15, 16) and testosterone (14). A related study assessing the effects of consumption of flaxseed, a rich source of the phytoestrogen lignans, showed increased luteal phase length, luteal phase progesterone/E2 ratio, and midfollicular testosterone (18).
Isoflavones have also been shown to exert effects on thyroid hormones, cortisol, and insulin. Animals fed soybeans have been reported to develop goiters (19) and increased T4 concentrations (20), and in vitro studies have shown that isolated isoflavones inhibit thyroid peroxidase, an enzyme involved in thyroid hormone synthesis (21). Genistein has been reported to decrease cortisol production when added to human fetal adrenal cortical cells, possibly due to inhibition of the enzyme cytochrome p450c21 (22). Finally, monkeys consuming soy protein have shown significantly improved insulin sensitivity (23).
The purpose of the current study was to clarify the hormonal effects of soy isoflavones in premenopausal women. For this study, we used 2 different isoflavone concentrations and compared them to an isoflavone-free soy control in 14 free living women. Each diet period was more than 3 menstrual cycles in length, and isoflavones were consumed relative to body weight. Menstrual cycles were divided into 4 precisely defined phases to assess the effect of diet on plasma hormones.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Potential subjects were selected after a phone questionnaire,
interview, and health screening. Exclusionary criteria included
vegetarian, high fiber, high soy, or low fat diets; regular consumption
of vitamin and mineral supplementation greater than the recommended
dietary allowances; athleticism; cigarette smoking; antibiotic or
hormone use within 6 months; history of chronic disorders, including
endocrine or gynecological diseases; benign breast disease; regular use
of medication including aspirin; current pregnancy or lactation;
irregular menstrual cycles; less than 90% or more than 120% ideal
body weight; weight change of more than 10 lb within the previous year
or weight change of more than 5 lb within the previous 2 months;
consumption of more than 2 alcoholic beverages/day; and a history of
food allergies. Fourteen subjects completed the entire study (Table 1
).
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The study protocol was approved by the University of Minnesota institutional review board human subjects committee. The study consisted of three diet periods, each lasting three menstrual cycles plus 9 days. During each diet period, subjects were free living and consumed their habitual diets supplemented with one of three soy protein powders in a randomized cross-over design. Subjects started each diet period on day 2 of their menstrual cycles and were on an individualized study schedule for the duration of each diet period. The diet periods were separated by a washout period of approximately 3 weeks, from day 10 of the fourth menstrual cycle until day 1 of the next menstrual cycle.
Experimental diet
Subjects were permitted to consume their usual diets with detailed dietary instructions to minimize phytoestrogen consumption by avoiding soy, flaxseed, whole wheat products, seeds, sprouts, beans, and legumes in their ad libitum diets. In addition, subjects were required to avoid alcoholic beverages and vitamin/mineral supplements. Their diets were supplemented with three soy protein powders, each containing a similar macronutrient composition but a different concentration of isoflavones (Supro Brand Isolated Soy Protein, Protein Technologies International, St. Louis, MO). The three soy powders provided 0.15 ± 0.01 (control), 1.01 ± 0.04 (low-iso), and 2.01 ± 0.03 (high-iso) mg total isoflavones/kg BW·day (10 ± 1.1, 64 ± 9.2, and 128 ± 16 mg isoflavones/day, respectively), expressed as unconjugated phytoestrogen units. The proportions of genistein, daidzein, and glycitein averaged 55%, 37%, and 8%, respectively, with 97% of the daidzein and genistein and 91% of the glycitein present as their glucoside conjugates.
The soy powder was provided in daily packets and was kept frozen until the day it was to be consumed. The daily nutrient contribution of the soy powder averaged 290 KCal, 53 g protein, 15 g carbohydrate, and 1.9 g fat.
Study procedures
Each diet period lasted three menstrual cycles plus 9 days. To determine the day of ovulation, subjects performed home urinary LH testing (OvuQUICK Self-Test, Quidel, San Diego, CA) beginning on day 9 of each menstrual cycle until detection of the LH surge. Each subject also measured her daily basal body temperature (BBT) during diet period I to validate the LH surge results. Subjects whose OvuQUICK test results were ambiguous performed BBT measurements in diet periods II and III as well.
Fasting body weight was obtained in a hospital gown approximately every 7–10 days. Multiple skinfold thicknesses were obtained once at the start of the study and once at the end of each diet period. Skinfold thickness measurements were taken at triceps, biceps, suprailiac, and subscapular sites on the subject’s nondominant side. All measurements were performed by the same individual and were taken to the nearest 0.1 mm with a skinfold caliper (Cambridge Scientific Instruments, Ltd., Cambridge, MD). Body density was calculated from the sum of the four skinfold thicknesses, and a predictive equation was used to determine the percent body fat (24).
Complete 24-h urine collections were performed daily during menstrual cycle 3 of each diet period. Urine was collected in plastic bottles containing 1 g ascorbic acid/L and was separated into aliquots after the addition of sodium azide to a final concentration of 0.1%. Aliquots were frozen at -20 C until analysis.
Fasting blood was obtained every other day beginning 7 days after the LH surge in menstrual cycle 2 and continuing until the end of the diet period. Blood was drawn in heparinized tubes, plasma was separated, sodium azide and ascorbic acid were added to a final concentration of 0.1% each, and aliquots were frozen at -20 C until analysis.
Food records were obtained for 3 consecutive days during the follicular phase (days 7–9) and luteal phase (7–9 days after the LH surge) of every menstrual cycle.
Endometrial biopsies were performed once during menstrual cycle 3 of each diet period, between 9–11 days after a positive LH surge result. As this portion of the study was optional, 7 subjects underwent biopsies in all 3 diet periods, and 5 subjects underwent biopsies in 2 of the three diet periods, for a total of 31 biopsies.
Analytical methods
All plasma samples were analyzed for E2, estrone (E1), estrone sulfate (E1-S), progesterone, LH, and FSH. Plasma samples from days 2–5 of menstrual cycles 3 and 4 were also analyzed for testosterone, androstenedione, DHEA, DHEA-S, cortisol, total T4, free T4, total T3, free T3, thyroid-binding globulin (TBG), TSH, insulin, PRL, and SHBG. To reduce the effects of interassay variability, all samples from each subject were analyzed in duplicate in the same batch along with a plasma pool control. E2, E1, E1-S, testosterone, androstenedione, DHEA, DHEA-S, cortisol, insulin, and SHBG were determined by double antibody RIA, using 125I-labeled hormone (Diagnostics Systems Laboratories, Inc., Webster, TX). Progesterone was determined by single antibody-coated tube RIA using 125I-labeled hormone (Diagnostics Systems Laboratories, Inc.). LH and FSH were determined by immunoradiometric assay using 125I-labeled antibody (Diagnostics Systems Laboratories, Inc.). PRL, total T3, and TSH were determined by double antibody RIA using 125I-labeled hormone (Diagnostic Products Corp., Los Angeles, CA). Total T4, free T4, and free T3 were determined by single antibody-coated tube RIA using 125I-labeled hormone (Diagnostic Products Corp.). TBG was determined by double antibody RIA using 125I-labeled T4 (Incstar Corp., Stillwater, MN). Intraassay variabilities were 2.3%, 1.6%, 1.6%, 2.7%, 3.8%, 3.0%, 0.8%, 1.3%, 1.6%, 1.1%, 2.5%, 1.6%, 1.9%, 1.3%, 1.6%, 1.3%, 1.4%, 1.7%, 1.8%, and 0.9%, and interassay variabilities were 7.7%, 14.8%, 22.4%, 9.8%, 6.3%, 10.3%, 4.3%, 3.6%, 3.3%, 2.5%, 1.3%, 3.5%, 4.9%, 4.3%, 7.7%, 2.0%, 6.5%, 10.0%, 3.8%, and 1.6% for E2, E1, E1-S, progesterone, LH, FSH, testosterone, androstenedione, DHEA, DHEA-S, cortisol, total T4, free T4, total T3, free T3, TBG, TSH, insulin, PRL, and SHBG, respectively.
Urine samples collected on the days surrounding the plasma LH surge in menstrual cycle 3 were analyzed for urinary LH by a double antibody RIA using 125I-labeled hormone (Diagnostic Products Corp.). To reduce the effects of interassay variability, all samples from each subject were analyzed in the same batch. The intraassay variability was 1.4%, and the interassay variability was 7.4%.
Food records were analyzed using Nutritionist IV, version 4.0 (The Hearst Corp., San Bruno, CA). For each 3-day food record, averages were calculated for energy, protein, carbohydrate, dietary fiber, fat, cholesterol, saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, and all known essential micronutrients.
All endometrial biopsy specimens were evaluated by the same pathologist according to well established criteria for normal histological changes that occur after ovulation, reflecting increased exposure of the endometrium to progesterone (25). For each biopsy specimen, such histological dating was compared to the actual number of days following ovulation, and the difference between the two was determined. Conventionally, a luteal phase defect or lag is diagnosed when the histological dating lags behind the expected findings (based on when ovulation occurred) by more than 2 days.
Data analysis
To allow adaptation to the diet, only menstrual cycles 2 and 3 were used to determine total cycle length as well as follicular phase and luteal phase lengths. Follicular phase was defined as day 1 of the menstrual cycle through the day of ovulation. Luteal phase was defined as the remainder of the cycle through the day before the next menses. In most cases, the day of ovulation was assumed to be the day after the LH surge, as determined by a positive OvuQUICK result. If the OvuQUICK results were ambiguous, plasma hormones, urinary LH, and BBT charts were used as adjuncts, allowing for precise identification of the day of ovulation by a reproductive endocrinologist (W.R.P.). Phase lengths were excluded from the statistical analyses for three subjects who had ambiguous OvuQUICK and BBT results in menstrual cycle 2, because there were no plasma hormone values to help establish the day of ovulation. Phase and cycle lengths were also excluded for the subject who had unusually long anovulatory cycles in menstrual cycle 3 of the low-iso and high-iso diets.
Before reproductive hormone data analysis, the menstrual cycle was divided into four phases, each reflecting a distinct hormone milieu: early follicular (EF; days 2 and 4), midfollicular (MF; days 7 and 9), periovulatory (PO; ovulation -3, ovulation -1, and ovulation +1), and midluteal (ML; ovulation +5, ovulation +7, and ovulation +9). For subjects whose blood was not drawn on the days used in the phase definitions, interpolation using values obtained on the surrounding days was used for the data analyses. Data from the PO and ML phases were excluded for one subject who had anovulatory cycles in menstrual cycle 3 of the low-iso and high-iso diets.
The area under the curve (AUC) for plasma progesterone was calculated from the day of ovulation in menstrual cycle 3 through the first day of menstrual cycle 4. The AUC for urinary LH was calculated from days ovulation -3 through ovulation +3 in menstrual cycle 3. Peak urinary LH values were also identified. Three cycles were eliminated from urinary LH analyses due to incomplete urine collections and ambiguous laboratory results.
Statistical analysis
Statistical analyses were performed using the Statistical Analysis System (SAS Institute, Inc., Cary, NC) (26). Repeated measures ANOVA was performed on all end points, controlling for subject, diet, menstrual cycle, and menstrual cycle phase. Due to unequal variance between menstrual cycle phases, the effects of diet on plasma reproductive hormones were examined within each phase separately, controlling for subject, diet, and menstrual cycle. All results are expressed as the mean ± SD or the mean ± SE. In the event of missing data, least squares means (lsmeans) are presented to account for the imbalance. Significance was considered at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Body weight, body
mass index, and percent body fat did not change significantly during
the study.
The dietary data are presented in Table 2. There were no significant differences
among the three diets in content of energy, fiber, or any macro- or
micronutrients. Prestudy diet records, however, showed significantly
lower consumption of energy (P = 0.03), protein
(P = 0.0001), riboflavin (P = 0.01),
vitamin B12 (P = 0.0001), vitamin D
(P = 0.01), calcium (P = 0.0001), iron
(P = 0.0001), magnesium (P = 0.002),
phosphorus (P = 0.0001), and manganese
(P = 0.0001) and significantly higher consumption of
dietary fiber (P = 0.0001).
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Plasma reproductive hormone data are presented in Table 3. In the MF phase, E1 was
significantly decreased by the high-iso diet compared to the low-iso
diet (P = 0.02). In the PO phase, LH (P
= 0.009) and FSH (P = 0.04) were significantly
decreased by the low-iso diet compared to the control diet. Urinary LH
concentrations during the PO phase (AUC and peak LH) were consistent
with the plasma data, showing a nonsignificant trend toward decreased
excretion with increased isoflavone consumption (data not shown).
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Table 4 summarizes data for the other
plasma hormones analyzed. Of the 14 hormones analyzed during days 2–5
of menstrual cycles 3 and 4, the only significant effects of diet
occurred with free T3 and DHEA-S. Free
T3 was decreased by the high-iso diet compared to the
low-iso and control diets (P = 0.02), and
DHEA-S was decreased by the high-iso diet compared to the
low-iso diet (P = 0.02).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The isoflavone doses used in this study were selected to fall near the range of intakes reported for typical Asian diets. Previous reports have suggested typical intakes of 25–100 mg isoflavones/day (27). Thus, our low-iso dose (64 mg isoflavones/day) fell within this range, and our high-iso dose (128 mg isoflavones/day) was somewhat higher.
We did not observe significant effects of isoflavone consumption on lengths of the follicular phase, luteal phase, or total menstrual cycle. These results are consistent with reports showing no significant effects of soy consumption on menstrual cycle and luteal phase lengths (14, 17), although there has been one report of increased follicular phase length with soy consumption (14) and one report of increased luteal phase length with flaxseed consumption (18). Consistent with our hormone results was our observation of no effect of diet on histological dating of the luteal phase endometrial biopsy specimens, suggesting no clinically important effect of isoflavone consumption to make a luteal phase defect either more or less likely.
The low-iso diet, containing an average of 64 mg isoflavones/day, significantly decreased plasma LH and FSH in the PO phase compared to the control diet. Although we saw no statistically significant effect of diet on urinary LH, trends in both the AUC and the peak urinary LH were consistent with the plasma LH findings. These findings are similar to previous reports of significantly decreased midcycle concentrations of LH and FSH after soy isoflavone consumption (14). As the LH surge is thought to occur as a result of positive feedback by estrogen (28), attenuated midcycle elevations of gonadotropins may reflect antiestrogenic actions of isoflavones. Plasma gonadotropin concentrations were not further decreased by the high-iso diet, suggesting that the maximum effects of isoflavones on gonadotropin concentrations may occur at levels of consumption near our low-iso dose.
We did not observe significant effects of isoflavone consumption on plasma E2 during any phase of the menstrual cycle. These findings differ from those of Lu et al. (17), who observed decreased E2 on menstrual cycle days 12–14 and 20–22, Cassidy et al. (14) who observed increased E2 during the follicular phase, and Petrakis et al. (16), who observed increased E2 during a composite menstrual cycle.
Isoflavone consumption did not affect E1-S, although the high-iso diet significantly decreased E1 during the MF phase compared to the low-iso diet. Neither E1-S nor E1 concentrations have been reported in other human soy studies.
There were no significant effects of isoflavone consumption on ML progesterone concentrations or the progesterone/E2 ratio during any phase of the menstrual cycle, although there may have been a trend toward decreased progesterone/E2 ratio with increasing isoflavone consumption. The lack of a significant effect on progesterone is consistent with previous reports (14, 15, 16) from studies of women consuming 23–70 mg isoflavones/day. Although Lu et al. (17) reported decreased progesterone on day 22 of the menstrual cycle, the day of blood collection was not standardized relative to ovulation, and this effect was probably due to a delayed progesterone peak secondary to an altered cycle length (17).
Our observation of significantly decreased plasma DHEA-S with the high-iso diet is consistent with data from previous studies (17). However, the small magnitude of this change makes it unlikely to be of physiological importance, particularly as there was an opposite change with the low-iso diet and no effect on DHEA.
We found no significant effects of isoflavone consumption on concentrations of testosterone, SHBG, androstenedione, or DHEA. Our testosterone and SHBG results are consistent with those of other studies in premenopausal women (14, 15, 16). Our results are also consistent with a recent cross-sectional study that reported no significant association between soy intake and SHBG (13). There are no other reports of DHEA or androstenedione concentrations in humans after soy consumption.
Concentrations of free T3 were significantly lower during the high-iso diet. However, given the lack of effects on total and free T4 as well as TSH, we believe that this change is not of physiological importance despite in vitro studies showing that isoflavones inhibit thyroid peroxidase (21). Animal studies have actually shown an increase in T4 concentrations after soy protein feeding (20).
We did not observe significant effects of diet on cortisol, insulin, or PRL concentrations. Our cortisol finding is inconsistent with work in human fetal adrenal cortical cells showing decreased cortisol production after genistein treatment (22). Our insulin finding is in agreement with animal studies reporting no change in plasma insulin concentrations when monkeys were fed soy protein (23), and our PRL results are consistent with those from other phytoestrogen feeding studies performed in premenopausal women (16).
There are a number of differences in study design that could contribute to the differences between our results and those previously reported from studies of premenopausal women. First, our diet periods were considerably longer (over three menstrual cycles) than those in previously reported soy studies (one menstrual cycle). As follicular development is known to begin during the previous one to two menstrual cycles, it is difficult to ascribe effects observed in such short studies to the study treatment. Second, our subjects were free living and permitted to consume their habitual diets, in contrast to previous studies performed with controlled diets in metabolic wards. As a result of the addition of soy protein to their diets, our subjects consumed more energy and protein and slightly less dietary fiber during the study than in their habitual diets. However, as there were no differences among the three diet periods, we do not believe that differences in energy or nutrient intakes influenced our results. Third, we focused on isoflavones, whereas most other studies have compared soy to a nonsoy control. It is possible that nonisoflavone components of soy may have contributed to the results observed in other studies. Only one study of three subjects reported effects of an isoflavone-free control, and those results are consistent with ours (15). Fourth, we provided isoflavones relative to body weight, whereas other studies gave the same quantity to each subject regardless of body weight. Although our method introduced some variability into daily isoflavone consumption, it also controlled for differences in body size that might influence isoflavone and hormone metabolism. Finally, we used multiple measures for determination of ovulation, whereas other studies used one measure or ignored the day of ovulation entirely. As we found that urinary LH testing is not accurate in all subjects, it is possible that differences in the methods used to determine the day of ovulation influenced phase length results.
The results of this study suggest weak hormonal effects of isoflavones in premenopausal women, with no evidence of a dose-dependent effect. Although other studies have shown a few additional effects, the physiological relevance of these modest hormonal changes is uncertain, especially as effects on plasma E2 concentrations and the menstrual cycle are inconsistent among studies. Considering all of the available data, effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones prevent cancer in premenopausal women. Our results do not rule out the possibility of important effects of isoflavones on E2-responsive gene activation or effects independent of estrogen receptor binding. It is also possible that the cancer-preventive effects of soy are due to other components, such as saponins, protease inhibitors, phytic acid, phytosterols, or phenolic acids (29).
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Acknowledgments |
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Footnotes |
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Received July 15, 1998.
Revised August 31, 1998.
Accepted September 23, 1998.
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 K. I. Block, A. Constantinou, L. Hilakivi-Clarke, C. Hughes, D. Tripathy, J. A. Tice, K. Block, and K. Block Point-Counterpoint: Soy Intake for Breast Cancer Patients Integr Cancer Ther, March 1, 2002; 1(1): 90 - 100. [PDF]
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M. S. Kurzer Hormonal Effects of Soy in Premenopausal Women and Men J. Nutr., March 1, 2002; 132(3): 570S - 573. [Abstract] [Full Text] [PDF]
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G. Maskarinec, A. E. Williams, J. S. Inouye, F. Z. Stanczyk, and A. A. Franke A Randomized Isoflavone Intervention among Premenopausal Women Cancer Epidemiol. Biomarkers Prev., February 1, 2002; 11(2): 195 - 201. [Abstract] [Full Text] [PDF]
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V. W Persky, M. E Turyk, L. Wang, S. Freels, R. Chatterton Jr, S. Barnes, J. Erdman Jr, D. W Sepkovic, H L. Bradlow, and S. Potter Effect of soy protein on endogenous hormones in postmenopausal women Am. J. Clinical Nutrition, January 1, 2002; 75(1): 145 - 153. [Abstract] [Full Text] [PDF]
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M. J. Messina and C. L. Loprinzi Soy for Breast Cancer Survivors: A Critical Review of the Literature J. Nutr., November 1, 2001; 131(11): 3095S - 3108. [Abstract] [Full Text] [PDF]
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L.-J. W. Lu, K. E. Anderson, J. J. Grady, and M. Nagamani Effects of an Isoflavone-Free Soy Diet on Ovarian Hormones in Premenopausal Women J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3045 - 3052. [Abstract] [Full Text] [PDF]
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