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Dietary soy containing phytoestrogens does not have detectable estrogenic effects on hepatic protein synthesis in postmenopausal women^1,2,3

¹ From the Vascular Research Group, Department of Medicine, Monash University, Clayton, Australia (HJT and BPM), and the Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Hospital, Prahran, Australia (FSD).

² Supported by a Grant-in-Aid from the National Heart Foundation of Australia (GM98MO139). HJT is a High Blood Pressure Council Research Fellow. The soy protein product was provided by the Solae Company.

³ Reprints not available. Address correspondence to HJ Teede, Vascular Medicine Unit, Dandenong Hospital, PO Box 478, Dandenong, Victoria, 3175, Australia. E-mail: h.teede{at}southernhealth.org.au.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Dietary phytoestrogens are ligands for the estrogen receptor and may mimic estrogenic effects in vivo.

Objective: To assess the biological activity of isoflavone phytoestrogens, we analyzed the effect of dietary soy isoflavone supplementation on in vivo bioassays of estrogenicity.

Design: Fifty healthy postmenopausal women aged 50-75 y participated in a double-blind, placebo-controlled trial in which they received either soy protein isolate (40 g soy protein, 118 mg isoflavones) or casein placebo. Measurements were made at baseline and at 3 mo. Urinary isoflavone excretion was measured to reflect compliance. The bioassays of estrogenicity included measurement of hepatic proteins and gonadotropin concentrations.

Results: Baseline characteristics were not significantly different between the soy and placebo groups. Urinary isoflavone excretion increased in the soy group and at the end of 3 mo was higher in the soy group than in the placebo group. In plasma samples from both groups, C-reactive protein increased significantly over the 3-mo treatment period, whereas sex hormone-binding globulin and thyroid-binding globulin decreased significantly. However, there were no significant differences between the groups in hepatic protein synthesis (change over 3 mo ± SEM in the soy and placebo groups, respectively): C-reactive protein, 0.42 ± 0.2 and 0.48 ± 0.2 U/mL; sex hormone-binding globulin, -6.9 ± 1.5 and -10.0 ± 2.1 µg/mL; thyroid-binding globulin, -16 ± 8 and -26 ± 7 nmol/L. Furthermore, gonadotropin and dehydroepiandrosterone sulfate concentrations did not change significantly in either group.

Conclusions: In healthy postmenopausal women, dietary soy isoflavones do not affect in vivo biological indicators of estrogenicity, including hepatic protein synthesis and gonadotropin concentrations. This suggests that soy isoflavones have little biologically relevant estrogenic effect in vivo in postmenopausal women.

Key Words: Genistein • daidzein • lipids • estrogenic effects • gonadotropins

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Phytoestrogens are ubiquitous, nonsteroidal, plant-derived compounds with a structure similar to that of estrogenic steroids and binding affinity for the estrogen receptor (1, 2). They are classified based on chemical structure as isoflavones, lignans, and coumestans, with much of the human research focusing on isoflavones. The soybean is a rich source of the isoflavones genistein and daidzein, which, of the phytoestrogens, have relatively high binding affinity for the estrogen receptor (2). Compared with 17ß-estradiol (arbitrarily assigned an affinity value of 100), however, their relative affinities are comparatively weak: 0.084 for genistein and 0.013 for daidzein (3).

By virtue of the complexity of the sex steroid receptor system, binding affinities do not equate to hormonal potencies (4), and it is difficult to directly or accurately measure the hormonal potency of synthetic estrogens or related estrogenic compounds (4, 5). Potency not only varies between different estrogenically active compounds but is also both species and tissue specific. With phytoestrogens, the assessment of estrogenicity is further complicated by wide interindividual variations in bioavailability, secondary to variability in intake, absorption, excretion, and metabolism (1).

Nonetheless, there are many reports of estrogenic effects of high-dose phytoestrogens, including the classic report of infertility in sheep grazing on clover (6). Animal studies have also noted phytoestrogen effects on the neuroendocrine system (7), sexual development (8, 9), and uterine growth (6). However, because of the complexity of the steroid receptor system and variations in phytoestrogen bioavailability, estrogenic effects noted in in vitro and animal studies cannot be extrapolated to the human clinical setting. In humans, the estrogenic effects of isoflavones have been assessed in premenopausal women (10); extrapolation to postmenopausal women, however, is limited because the premenopausal endogenous hormonal milieu is different from the hypoestrogenic postmenopausal state. Intervention studies in postmenopausal women are limited, with small sample sizes and conflicting results, and further research is needed (11-13).

Several indirect methods have been used to assess the potency of estrogenic compounds in humans (4, 5). Of these, hepatic protein synthesis (4) and gonadotropin concentrations appear to be the most sensitive variables responding to the actions of low-dose oral estrogens, and, as such, have been used as bioassays for estrogenic activity (4).

To systematically investigate the estrogenic effects of soy isoflavones, we conducted a double-blind, randomized, placebo-controlled study of 3 mo of dietary soy protein supplementation compared with casein placebo in healthy postmenopausal women. Endpoints included urinary isoflavone excretion, plasma gonadotropin concentrations [follicle-stimulating hormone (FSH) and lutenizing hormone (LH)] and hepatic proteins [C- reactive protein (CRP), sex hormone-binding globulin (SHBG), and thyroid-binding globulin (TBG)]. Also, plasma concentrations of dehydroepiandrosterone sulfate (DHEAS), a readily convertible source of endogenously synthesized estrogen, were measured because it has been hypothesized that isoflavones alter DHEAS as a mechanism for their effects on the sex steroid system (10).

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study design
The present study involved 50 postmenopausal women selected at random from a larger study of 210 healthy participants that focused on the effects of isoflavones on the cardiovascular system. The present study was a randomized, double blind, placebo-controlled trial of 3 mo duration. Participants aged 50-75 y were recruited through community advertisements. They had not consumed antibiotics or soy products or supplements (for 3 mo) and had not taken estrogen therapy (for 12 mo) before study entry. The participants received dietary counseling on the exclusion of dietary sources rich in phytoestrogens during the study. Dietary habits were stable throughout the study on the basis of a 3-d food-frequency diary completed at baseline and at 3 mo.

Postmenopausal status was defined as 12 mo of amenorrhea and FSH concentrations > 20 IU/L. Exclusion criteria included moderate to severe menopausal symptoms; smoking (past 10 y); diabetes; alcohol consumption > 30 g/d; hypertension; abnormal uterine bleeding, cervical cytology, or mammogram result; and coexistent major illness. The study was approved by the Monash Medical Centre Human Research and Ethics Committee, and all participants gave their written informed consent. Randomization was performed independently by using computer-generated random numbers. The current study is a random sample of 50 women, 30 of whom received soy and 20 of whom received casein placebo.

The participants were screened for dietary phytoestrogen intake at baseline and at the end of the study period on the basis of patient reporting, dietary questionnaire, and urinary isoflavone excretion. Supplements were presented in identical, unmarked powder sachets. They were consumed twice daily after being mixed into beverage form and were taken in addition to the usual diet with no other changes in daily dietary intake. The soy protein isolate powder was prepared by dehulling and defatting soybeans and then blending them for 45 min. The product was then tested before packaging to ensure content uniformity for protein and isoflavones and was provided in a single batch (AB1.2 HG 70CA 29, lot A161-7) by the Solae company (St Louis). Each sachet contained 28 g powdered soy protein isolate, of which 71% was protein. This product was tested for isoflavone content by HPLC with ultraviolet detection and was determined to contain 2.11 mg total isoflavones/g. This was composed specifically of 1.35 g genistein, 0.66 g daidzein, and 0.09 g glycitein (expressed as basic compound + respective glycosides in mg/g product). Overall, this provided 40 g soy protein/d with a total of 118 mg isoflavones daily.

Medical assessments were conducted both at baseline and after 3 mo (14). Dietary adherence was assessed by measuring spot urine isoflavone concentrations at baseline and at the end of 3 mo of dietary supplementation.

Isoflavone assay
Urinary isoflavone excretion was analyzed by HPLC. The principal analytes were genistein and daidzein, as previously described (15). Isoflavone isolation was by reversed-phase HPLC (system LC 10A; Shimadzu Corporation, Kyoto, Japan) according to a method developed by Eldridge (16). Detection was by dual-wavelength ultraviolet absorbance (250 nm for daidzein, 262 nm for genistein) and quantification by comparing the area under the curve with reference standards for genistein (Sigma Chemical Company, St Louis) and daidzein (ICN Biomedicals, Aurora, OH). Samples were processed in one batch.

Hormone and hepatic protein assays
Fasting morning blood samples were collected at baseline and at 3 mo for measurement of gonadotropins, DHEAS, and hepatic proteins and were centrifuged at 2500 x g for 12 min at 22 °C. Plasma was stored at -80 °C and was thawed immediately before analysis. The intra- and interassay CVs for the plasma hepatic protein and DHEAS assays are presented in Table 1.

The SHBG assay is an automated enzyme immunoassay carried out on a Immulite Analyzer (Diagnostic Products Corporation, Los Angeles). Patient samples are diluted 1:21 in a proprietary diluent (from Diagnostic Products Corporation) with a Hamilton Digital Diluter and are then analyzed by using a solid-phase, two-site chemiluminescent immunometric assay. The capture antibody on the polystyrene bead is a monoclonal antibody specific for SHBG, and the second antibody is an alkaline phoshatase-conjugated polyclonal anti-SHBG antibody. Reagents, including calibrators and quality controls, were supplied by Diagnostic Products Corporation.

TBG was measured by a commercial automated chemiluminescent enzyme immunoassay by using an Immulite Analyzer from Diagnostic Products Corporation. This is a competitive immunoassay that uses alkaline phosphatase-labeled TBG as the tracer and adamantyl dioxetane as the luminescent substrate for alkaline phosphatase. All reagents and calibrators are supplied in kit form.

Gonadotropins were measured by the use of an automated microparticle enzyme immunoassay with the Abbott AxSYM Immunoassay Analyzer (Abbott Diagnostics Division, Chicago). Standardization was against the World Health Organization 2nd International Reference Preparation (78/549) for FSH.

DHEAS was measured by a commercial automated chemiluminescent enzyme immunoassay on an Immulite Analyzer from Diagnostic Products Corporation. This is a competitive immunoassay that uses alkaline phosphatase-labeled DHEAS as the tracer and adamantyl dioxetane as the luminescent substrate for alkaline phosphates. All reagents and calibrators are supplied in kit form.

Statistical analysis
The values for urinary isoflavones were positively skewed. The data were analyzed by nonparametric methods and are summarized as geometric means with 95% CIs. The other variables are summarized as arithmetic means ± 1 SE. Significance was accepted at the P 0.05 level. Statistical calculations were performed by using the SPSS statistical package (version 10; SPSS Inc, Chicago).

For the purpose of statistical analysis, the outcomes were defined as the arithmetic difference (change) between baseline observations and those made after 3 mo of treatment. Univariate analyses of variance were completed for each of the independent variables. Then, the outcome variables were analyzed by multivariate analysis of variance on the basis of a model of hepatic protein synthesis including CRP, SHBG, and TBG. The categorical, independent variable was treatment group (soy or casein placebo). Pearson’s correlations were calculated on the basis of changes in hepatic protein concentrations and urinary phytoestrogen excretion.

	RESULTS

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The population was healthy and normotensive, with no significant differences in baseline characteristics between the 2 groups (Table 2), including hepatic protein and gonadotropin concentrations (Table 3). The study participants reported a low intake of phytoestrogen-containing foods, which did not change significantly throughout the study, a finding consistent with the low baseline urinary isoflavone excretion noted in both groups and the lack of significant change in the placebo group over the 3 mo of intervention. On the basis of 3-d food-frequency questionnaires, general dietary intake was also stable (data not presented).

Plasma hepatic protein concentrations
Two sets of CRP values from the soy group were excluded from the analysis, because one of their readings was > 10 SDs outside the mean. Over the 3-mo intervention period in both groups, CRP increased significantly, whereas SHBG and TBG decreased significantly (Table 3). However, individual changes in CRP, SHBG, and TBG with the intervention were not significantly different between the soy and placebo groups (Table 3). The multivariate analysis of variance incorporating change in all hepatic proteins (CRP, SHBG, and TBG) showed no significant differences between the 2 groups (P = 0.5). Also, no significant correlations were observed between changes in urinary phytoestrogen excretion and changes in hepatic proteins.

Concentrations of gonadotropin and DHEAS
The changes in plasma FSH and LH concentrations were not significantly different between the soy and placebo groups (Table 4). Likewise, the changes in plasma DHEAS concentrations were not significantly different between the 2 groups (Table 3).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Phytoestrogens are present as inactive glycosides in plants (genistin and daidzin and their respective methyl ethers, biochanin A and formononetin) that require gastrointestinal metabolism to genistein and daidzein before absorption, after which they are excreted in the urine (17, 18). Despite individual variability, urinary isoflavone excretion in clinical trials is a useful measure of dietary compliance and is a crude reflection of isoflavone dose in each individual (19). In the current study, 3 mo of soy isoflavones significant increased urinary isoflavone excretion. Absorption was variable; however, this was unlikely to have been a major contributor to the negative results because no correlation was noted between isoflavone excretion and hepatic protein synthesis.

Ligand-estrogen receptor interactions are inherently complex, and our understanding of the biological activity of the isoflavones remains limited. Within this complex system, it is not possible to directly study the "estrogenicity" of a compound; therefore, we studied the effect of soy isoflavones on the more sensitive available bioassays used to study conventional oral synthetic estrogens (4, 20). A pharmacodynamic study noted that hepatic protein changes were the most sensitive indicators of the effects of oral estrogens (20). SHBG and TBG are hepatically synthesized proteins that bind to circulating sex steroids and thyroid hormones, respectively, reducing free hormone concentrations. Oral estrogen given for 6 wk [conjugated equine estrogen (CEE) doses of 0.15, 0.3, 0.625 (standard dose of hormone replacement therapy), and 1.25 mg] was shown to alter SHBG (detectable at a CEE dose of 0.15 mg), TBG (detectable at a CEE dose of 0.3 mg), and gonadotropin concentrations, including those of FSH (detectable at a CEE dose of 0.3 mg) and LH (detectable at a CEE dose of 0.625 mg) (4). However, there was no significant effect of soy isoflavones on these estrogen-sensitive proteins and gonadotropins in the current trial.

The effect of isoflavones on TBG has not been previously documented. In contrast, previous trials have focused on the effects of soy isoflavones on SHBG. In vitro, isoflavones induce human HepG2 hepatoblastoma cells to increase SHBG synthesis and secretion (21); however, human dietary studies in postmenopausal women have yielded inconsistent results (12, 13, 22, 23). An uncontrolled study of 69 mg isoflavones (soy milk) daily for 10 wk in 20 women showed an increase in SHBG, which was correlated with the increase in isoflavone concentrations (22). Duncan et al (13) studied 18 postmenopausal women given control soy protein without isoflavones and a low- and a high-isoflavone soy protein preparation in a crossover study. Compared with baseline, SHBG was lower during all 3 soy protein treatments, although concentrations were higher during the high-isoflavone treatment than during the control period (13). Mackey et al (23) noted a reduction in SHBG with soy protein both with and without isoflavones in 54 postmenopausal women over 3 mo. Consistent with this finding, Baird et al (12) showed in 94 postmenopausal women that both the active (165 mg isoflavones in soyfoods) and the control (standard diet) group had a small decrease in SHBG over 4 wk and concluded that longer-term controlled trials are needed. Consistent with these findings, with 3 mo of treatment, we noted a small decrease in SHBG in both the soy and placebo groups, despite a stable diet throughout the study. However, there were no significant differences between the 2 treatment groups, suggesting that the increased protein ingestion from the dietary supplements in both groups may have altered SHBG synthesis.

CRP is also a hepatically synthesized protein that is an acute phase reactant with the potential to increase 1000-fold in inflammatory disorders. Recently, automated high-sensitivity assays have allowed the detection of lower CRP concentrations. In this setting, CRP in the upper range of the sensitive assay has been identified as an independent risk factor for cardiovascular disease and appears to increase by up to 84% with conventional oral estrogen replacement doses (0.625 mg CEE) (24-26). In the current study, no significant effect of soy isoflavones on highly sensitive CRP was noted. This is consistent with a study using soy diet supplements in 41 subjects (men and postmenopausal women) over 4 wk, which also showed no change in CRP (27).

Gonadotropins have also been used as bioassays of estrogenic activity (4, 20). In the current study, we found no significant effect of soy or casein supplements on FSH and LH concentrations. This is consistent with a previous study showing no effect of marginally higher isoflavone intakes in soy food (12), whereas Mackey et al (23) noted no effect of soy + isoflavones compared with soy - isoflavones on FSH and LH.

DHEAS, which is produced in the adrenal glands, is a precursor for endogenous estrogen production. Isoflavones may alter DHEAS concentrations as a mechanism for their effects on the sex steroid system (10). In the current randomized controlled study in 50 women, no significant effect of soy containing 118 mg isoflavones on DHEAS concentrations was noted. A crossover study in 18 postmenopausal women over 1 y with 7 mg, 65 mg, and 132 mg isoflavones in soy protein noted that DHEAS concentrations were lower with soy protein plus all 3 isoflavone doses than at baseline. DHEAS concentrations after the soy protein + 132 mg isoflavone dose were statistically greater than after soy protein + 7 mg isoflavone dose (10); however, the differences were not physiologically important (10). Overall, it appears unlikely that isoflavones affect the sex steroid system by increasing DHEAS concentrations.

The negative results of the current study occurred despite apparently adequate isoflavone intake. This may have been attributable to low bioavailability. However, even if this was the responsible factor, it remains that the high dietary intake in postmenopausal women did not have a significant effect on markers of estrogenicicty. Alternatively, the lack of estrogenic effects may have been attributable to the low potency of the soy isoflavones, because their binding affinities for the estrogen receptor (2) are relatively weak (0.05-0.1% of conjugated estrogen) compared with those of 17ß-estradiol (3, 12). Hence, the high dietary intake of 40 g soy protein with 118 mg isoflavones would equate to 0.118 mg conjugated estrogen. Effects on hepatic proteins have been noted with lower doses of oral estrogens (4, 20). The variability of isoflavone bioavailability may have masked any estrogenic effects; however, it would be difficult to achieve a dose higher than 118 mg from dietary sources. The negative findings are also consistent with studies focusing on other estrogen-responsive endpoints, which also showed no estrogenic effects of dietary soy isoflavones (28-31). We have suggested that soy does not activate coagulation or fibrinolysis (31), affect the hypothalamic pituitary gonadal axis in males and females (30), improve menopausal symptoms (28), or alter bone turnover markers (29), all of which are altered by estrogen (32). We have also shown that soy isoflavones alter lipid profiles (30), but the changes differ from those induced with oral estrogen. It has been postulated that the lipid effects are related to the soy protein and not to the isoflavones (30). Along with the current results showing no effect on hepatic protein synthesis and gonadotropin concentrations, these findings suggest that dietary soy isoflavones have little biologically relevant estrogenic effect in vivo in postmenopausal women.

In conclusion, 3 mo of a high intake of isoflavones provided as dietary soy protein in healthy postmenopausal women did not have biologically detectable estrogenic effects on sensitive variables of in vivo oral estrogen activity, hepatic protein synthesis, and gonadotropin concentrations. With the inherent complexity of the estrogen receptor system, however, estrogenic effects on other estrogenic endpoints cannot be excluded. Further research is needed to elucidate whether higher pharmacologic doses of isoflavones have biologically relevant estrogenic activity, although the safety of this approach needs to be established.

	ACKNOWLEDGMENTS

 
We thank the Department of Clinical Biochemistry, Southern Health Care, for the plasma lipid measurements and hormone and hepatic protein assays.

HJT conceptualized the project with FSD and advice from BPM. HJT and FSD were integrally involved in the ethics, grant funding process, recruitment of subjects, and conduct of the study. HJT analyzed the data. All authors were involved in manuscript preparation. None of the authors had any advisory board affiliations or financial interests in any organization sponsoring the research.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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				H. J. Teede, F. S. Dalais, D. Kotsopoulos, B. P. McGrath, E. Malan, T. E. Gan, and R. E. Peverill Dietary Soy Containing Phytoestrogens Does Not Activate the Hemostatic System in Postmenopausal Women J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1936 - 1941. [Abstract] [Full Text] [PDF]

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