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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1428
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 1936-1941
Copyright © 2005 by The Endocrine Society

Dietary Soy Containing Phytoestrogens Does Not Activate the Hemostatic System in Postmenopausal Women

Helena J. Teede, Fabien S. Dalais, Dimitra Kotsopoulos, Barry P. McGrath, Erica Malan, T. Eng Gan and Roger E. Peverill

Department of Vascular Sciences and Medicine (H.J.T., F.S.D., D.K., B.P.M.), Monash University Department of Medicine, Dandenong Hospital, Dandenong, Haematology Unit (E.M., T.E.G.), Monash Medical Centre, Clayton, Centre for Heart and Chest Research (R.E.P.), Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Address all correspondence and requests for reprints to: Dr. Roger Peverill, Cardiology Unit, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, Australia. E-mail: roger.peverill{at}med.monash.edu.au.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The soybean is rich in isoflavone phytoestrogens, which are ligands for estrogen receptors, but it is unknown whether soy/phytoestrogens have similar procoagulant effects to estrogen. In this randomized double-blind trial, 40 healthy postmenopausal women of age 50–75 yr received soy protein isolate (40 g soy protein, 118 mg isoflavones) (n = 19) or casein placebo (n = 21). Plasma markers of coagulation, fibrinolysis, and endothelial dysfunction were measured at baseline and 3 months. The baseline characteristics of the two groups were similar. Compared with casein placebo, soy decreased triglycerides (P < 0.005) and low-density lipoprotein/high-density lipoprotein ratio (P < 0.001) and increased lipoprotein (a) (P < 0.05). Activity of coagulation factor VII (VIIc) decreased similarly in both groups (P < 0.005). Prothrombin fragments 1 + 2 (a marker of thrombin generation) decreased in the soy group (P < 0.005), but the change was not different from the casein group. There was no effect of soy on soluble fibrin (a marker of fibrin production), plasminogen activator inhibitor-1 (a marker of fibrinolytic inhibitory potential), D-dimer (a marker of fibrin turnover), or von Willebrand factor (a marker of endothelial damage).

In conclusion, the results of the current study do not support biologically significant estrogenic effects of soy/phytoestrogens on coagulation, fibrinolysis, or endothelial function.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PHYTOESTROGENS ARE A DIVERSE group of nonsteroidal plant-derived compounds that are structurally similar to estrogenic steroids and have an affinity for estrogen receptors (1). Many foods contain phytoestrogens, but soybeans are particularly rich in isoflavones, one of the common classes of phytoestrogens. Several lines of evidence suggest that soy protein/phytoestrogens may be of potential benefit in preventing cardiovascular disease. First, in the atherogenic monkey model, high soy intake results in a reduction in atherosclerosis in males (2) and ovariectomized females (3). Second, observational studies suggest that subjects with high soy diets have a lower risk of cardiovascular disease (4). Finally, human interventional studies suggest that phytoestrogens have beneficial effects on some cardiovascular risk factors (5, 6). Indeed, we have recently shown that dietary soy containing phytoestrogens improves blood pressure and lipid profiles in healthy men and women, although soy also had the potentially adverse effect of increasing lipoprotein (a) [Lp(a)] (7).

Although the initial interest in phytoestrogens arose in part because of their structural similarity to estrogen and the belief that estrogen had protective effects against cardiovascular disease, recent studies have raised concerns about an early adverse effect of hormone therapy (HT) on cardiovascular risk (8, 9). The mechanism of this increased cardiovascular risk is not known, but one postulate, which also could account for the increased risk of venous thromboembolism reported with estrogen use (9, 10, 11), is that it is a result of a prothrombotic effect of estrogen. Supporting this concept, a number of clinical studies have reported that estrogen causes activation of coagulation, demonstrated by increases in markers of thrombin and fibrin generation (12, 13, 14, 15), an effect that may be partly counterbalanced by a profibrinolytic effect of estrogen (15, 16). Given the structural similarity of phytoestrogens to estrogen and the potential importance of the prothrombotic effects of estrogen, the effect of phytoestrogens on hemostasis is also clearly of interest. Despite this, to date there are no published data about the effects of soy/phytoestrogens on coagulation and fibrinolysis in postmenopausal women.

The aim of this parallel, double-blind, randomized, casein placebo-controlled study, performed in healthy postmenopausal women, was to determine the effect of short-term (3-month) dietary supplementation with soy/phytoestrogens on hemostatic factors previously demonstrated to be affected by short-term estrogen replacement therapy. We measured activity of factor VII (VIIc), a coagulation factor (13, 17, 18, 19); prothrombin fragment 1 + 2 (F1+2), a marker of thrombin generation (12, 13, 14, 15); soluble fibrin, a marker of fibrin production (20); and D-dimer, a marker of fibrin generation and breakdown (fibrin turnover) (14, 16), all of which have been shown to be increased by estrogen. We also measured plasminogen activator inhibitor-1 (PAI-1), a marker of plasma fibrinolytic inhibitory activity, which is decreased by estrogen (15, 16), and von Willebrand factor (vWF), a marker of endothelial dysfunction or damage (21), which may be increased by estrogen (22).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study design

Forty-three healthy postmenopausal women were enrolled in a double-blind, placebo-controlled, randomized trial conducted over 3 months. These women represented a consecutively recruited subgroup enrolled in the larger Phytoestrogen Arterial Reactivity and Lipids (PEARL) study on soy effects on the vascular system (7). Participants aged 50–75 yr were recruited from community advertisements. They had not consumed antibiotics, soy products, or supplements (for 3 months), nor had they taken estrogen therapy (for 12 months) before entry. Postmenopausal status was defined as 12 months of amenorrhea and FSH grater than 20 IU/liter. Exclusion criteria included smoking within last 10 yr, diabetes, alcohol consumption greater than 30 g/d, hypertension (unless controlled on treatment), abnormal uterine bleeding, cervical cytology, or mammogram result, and coexistent major illness. Participants taking lipid-lowering or antihypertensive therapy had to be stable on treatment for 6 months before and throughout the study period. The Southern Health Research Advisory and Ethics Committee approved the study, and all participants gave written informed consent. Randomization was performed independently using computer-generated random numbers, with 20 participants allocated to soy and 23 to casein placebo.

Supplements were presented in identical unmarked sachets of soy protein isolate or casein protein. The soy beverage powder was provided in a single batch by The Solae Company (St. Louis, MO) (AB1.2 HG 70CA 29, lot A161-7). Each sachet of soy isolate powder weighed 28 g, of which 71% was protein, and total isoflavone content was 2.11 mg/g powder. This was composed of genistein 1.35, daidzein 0.66, and glycitein 0.09 (expressed as basic compound plus respective glycosides in milligrams per gram of powder). Overall, this provided 40 g of soy protein and 118 mg of isoflavones (or 69 mg in aglycone weight) per day. Sachets were consumed twice daily after mixing into beverage form and were taken in addition to the usual diet. The only change in dietary intake recommended was the exclusion of dietary items high in phytoestrogens. Dietary stability during the study was confirmed by a 3-d food frequency diary performed at baseline and 3 months. Compliance with supplements was assessed by a count of sachets and by the performance of spot urine phytoestrogen concentrations at baseline and 3 months.

Height, weight, waist circumference, hip circumference, heart rate, and blood pressure were measured at each visit.

Blood collection

Fasting morning blood samples were collected by a single technician (D.K.) trained in nontraumatic phlebotomy at baseline and 3 months. Venepuncture was performed with a 19-gauge needle directly into plain tubes (Vacutainer, Becton Dickinson, Franklin Lakes, NJ) for lipid and hormone assays, then into two 3.8% citrate tubes (9:1 ratio) for coagulation and fibrinolysis studies. The samples were immediately centrifuged at 2500 x g for 12 min, and plasma was separated into 200-µl aliquots, stored at –80 C, and thawed immediately before analysis. FSH and LH were measured in baseline samples. Lipids and hemostatic variables were measured at baseline and 3 months.

Laboratory measurements

Gonadotropins were measured by RIA performed on an automated microparticle enhanced immunoassay using the AxSYM Immunoassay Analyzer (Abbott Laboratories Diagnostics Division, North Chicago, IL). Total cholesterol and triglycerides were measured using enzymatic reagents (DADE Diagnostics, Brisbane, Australia), high-density lipoprotein (HDL) cholesterol was measured by homogeneous assay techniques (HDLC-Plus, DADE Diagnostics) adapted to a DADE Dimension RXL chemistry analyzer (DADE Diagnostics). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation [LDL cholesterol = (total cholesterol –HDL cholesterol) –(triglycerides x 0.20)], adapted to S.I. units. Lp(a) was measured by an immunonephelometric assay on a nephelometric analyzer (Behring, Marburg, Germany) using Dako antiserum (DakoCytomation, Dako, Copenhagen, Denmark). Urinary isoflavone concentrations (genistein and daidzein) were measured as a marker of both compliance and absorption using HPLC and normalized to creatinine, as previously described (23).

All assays for hemostatic factors were performed in duplicate by a single trained medical scientist, and all samples from each individual participant were assayed in the same batch. VIIc was measured with a one-stage assay based on prothrombin time using VIIc-deficient plasma (Helena Laboratories, Beaumont, TX), with thromboplastin from Innovin (Dade/Behring), and performed on the Futura Instrument (ACL Futura Instrumentation Laboratory, Barcelona, Spain). Commercial kits were used to measure F1+2 (Enzygnost F1+2, Behring), soluble fibrin (Soluble Fibrin FM, Roche Molecular Biochemicals, Indianapolis, IN), PAI-1 activity (BerichromPAI, Marburg, Germany) and D-dimer (Dimertest, Agen Biomedical Limited, Brisbane, Australia). vWF antigen (Ag) was measured by a previously described ELISA technique using polyclonal rabbit antihuman vWF Ig and horseradish peroxidase-labeled rabbit anti-vWF sera, both obtained from DakoCytomation (24).

Statistics

Three women, one in the active group and two in the casein group, with F1+2 and soluble fibrin levels greater than 3 SD from the mean, were excluded from the final analysis because of presumed artifactual coagulation activation at the time of sampling. An analysis of the hemostatic variables including these subjects was also performed and resulted in similar findings. The distribution of each variable was examined and triglycerides, Lp(a), and all hemostatic variables other than VIIc were skewed and required normalization by logarithmic transformation. Results are presented as arithmetic mean ± SE, with transformed variables presented after back transformation as geometric mean (95% confidence interval) (25). Baseline characteristics were compared using an unpaired Student’s t test. Changes within groups were analyzed using a paired Student’s t test. Comparison between the soy and casein placebo groups was performed by two-way repeated-measures ANOVA. Regression analysis was performed using Pearson correlation coefficients. Urinary concentrations of daidzein and genistein were not normally distributed and included nondetectable values. These concentrations have been expressed as median (interquartile range) and compared used a Wilcoxon signed rank test. Significance was accepted at the P < 0.05 level.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline hormone, lipid, and hemostatic parameters

All women had gonadotropin levels consistent with their postmenopausal state. Baseline characteristics were similar between the two groups (Table 1Go), and there were no significant differences between the groups in baseline levels of lipids (Table 2Go) or hemostatic variables (Table 3Go). One woman in the soy group was on stable lipid-lowering therapy, and eight women (three soy and five casein) were on stable antihypertensive therapy. No patient within the study had clinical evidence of thrombosis during the treatment period.


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  		TABLE 1. Baseline characteristics of subjects in the soy and casein placebo groups

 

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  		TABLE 2. Lipids at baseline and 3 months in the soy and casein placebo groups

 

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  		TABLE 3. Hemostatic variables at baseline and 3 months in the soy and casein placebo groups

 
Effects of soy on lipids and hemostatic variables

All women in the study used more than 90% of their sachets. Table 2Go demonstrates the lipid levels at baseline and after 3 months of treatment during the study. After 3 months of treatment, there was a fall in triglycerides and the LDL/HDL cholesterol ratio with soy, and these changes were significantly different from the casein group (P = 0.005 and P = 0.001, respectively). There was also a trend toward greater falls in total and LDL cholesterol in the soy group. In contrast, Lp(a) levels increased in the soy compared with the casein group (P < 0.02).

Table 3Go shows the baseline and 3-month levels of hemostatic variables by treatment group. Within-group comparisons of baseline and 3-month values (Table 3Go) demonstrated a significant reduction in VIIc in both the soy and casein groups (P < 0.005 for both), changes that did not differ between the groups. Linear regression analysis was performed to investigate the cause of the decrease in VIIc. In the combined group at baseline, VIIc was correlated with total cholesterol (r = 0.43; P = 0.005), LDL cholesterol (r= 0.38; P < 0.02), and triglycerides (r = 0.60; P < 0.0001). In the casein group, the change in VIIc over 3 months correlated with the changes in total cholesterol (r = 0.56; P = 0.008) and triglycerides (r = 0.75; P < 0.0001), and on multivariate analysis, the changes in cholesterol and triglycerides accounted for 60% of the change in VIIc. By contrast, there were no significant correlations between changes in lipids and VIIc in the soy group.

Within-group comparisons of baseline and 3-month values also revealed a significant reduction in F1+2 in the soy group, although there was no significant difference in F1+2 between the soy and casein groups. On linear regression analysis, F1+2 was not related to any of the lipids at baseline and the reduction in F1+2 in the soy group was not related to any of the lipid changes in that group. There was no difference between the soy and casein groups in levels of soluble fibrin, D-dimer, PAI-1, or vWF Ag during the study.

Individual urinary isoflavone concentrations were examined in the soy group to take into account the possibilities of noncompliance or inadequate isoflavone absorption. There were two subjects who had little or no change in urinary isoflavone concentrations after 3 months of treatment and additional analysis was performed after exclusion of these subjects. In the remaining 17 subjects, the urinary daidzein concentration (ng/µmol creatinine) increased from 13.6 (0.00, 40.7) to 272.1 (137.68, 464.6); the urinary genistein concentration (ng/µmol creatinine) increased from 4.45 (0.00, 10.5) to 107.73 (59.49, 248.3) (P < 0.002 for both); and there were significant reductions in total cholesterol (P < 0.001), triglycerides (P = 0.006), and LDL cholesterol (P < 0.001). There were no differences in the effect of soy on hemostatic variables compared with the main group, with similar decreases observed in both F1+2 (P = 0.003) and VIIc (P = 0.001).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Despite beneficial effects on LDL and HDL cholesterol, randomized controlled trials of oral HT have found an increased early risk of coronary heart disease (8, 9) as well as an increased risk of stroke (9, 26) and venous thromboembolism (9, 10, 11). Clinical studies have demonstrated that a dose-dependent increase in in vivo coagulation activity accompanies estrogen use (12, 13, 14, 15), suggesting that the adverse cardiovascular effects of HT may be at least partly a result of a procoagulant effect of estrogen. Phytoestrogens share a structural similarity with estrogen, and soy has beneficial effects on lipids; however, the prothrombotic potential of soy/phytoestrogens has not previously been studied in postmenopausal women. The main finding of this casein-controlled, double-blind study is that 3-month dietary supplementation with soy/phytoestrogens did not increase VIIc, F1+2, soluble fibrin, or D-dimer. This finding suggests that a high dietary intake of soy/phytoestrogens does not have the same procoagulant effect as oral estrogen and therefore implies that soy/phytoestrogens may not be prothrombotic.

Factor VII is a vitamin K-dependent coagulation factor that is a key enzyme in the clotting cascade, combining with tissue factor and, when activated, converting factor X to factor Xa (27). A causal role for factor VII in cardiovascular disease was proposed after VIIc was found to be an independent predictor of cardiovascular disease in the Northwick Park Heart Study (28), although this association was not confirmed by subsequent studies (29, 30, 31, 32). A possible confounding feature in the epidemiological studies was the existence of a positive association between VIIc and triglycerides, LDL cholesterol and total cholesterol (31, 33, 34, 35, 36, 37, 38), relationships also observed in the present study. On the other hand, a recent study found VIIc to be an independent predictor of cardiovascular mortality in a low-risk group of elderly women but not men, suggesting not only that there may be gender-related differences in the effects of factor VII but also that factor VII may have significance independent of lipids (38). Most studies of HT with estrogen alone in postmenopausal women have demonstrated the potentially adverse effect of an increase in VIIc (13, 17, 18, 19). By contrast, in the current study, a decrease in VIIc was observed in both the soy and casein placebo groups, and no difference was found between the groups, suggesting that soy does not have the same effect as estrogen on VIIc. The explanation for the decrease in VIIc in both groups is not clear, but the positive correlations present between VIIc and lipids at baseline and between changes in VIIc and lipids with treatment in the casein group suggest that the decrease is at least partly related to the lipid changes. On the other hand, differences in the relationships between the changes in VIIc and lipids in the soy and casein groups raise the possibility that the mechanism for the decrease in VIIc in the soy group may not be the same. Nevertheless, there was no evidence that soy had an adverse effect on VIIc.

We found no difference between the soy and casein groups in the change in either F1+2 levels, a marker of thrombin generation, or soluble fibrin, a marker of fibrin production. Indeed, F1+2 levels actually fell in the soy group, making the likelihood that soy/phytoestrogens result in activation of coagulation even less likely. By contrast, a number of studies have found that oral estrogen replacement therapy results in increases in F1+2 levels, with reported increases in F1+2 levels of between 15 and 98% (12, 13, 14, 15). Although no studies have measured the effects of estrogen alone on soluble fibrin, oral estrogen has been found to increase fibrinopeptide A, which is also a marker of fibrin formation (12), and combined oral HT has been shown to result in a 76% increase in soluble fibrin levels (20). F1+2 and soluble fibrin provide a serial and complementary assessment of coagulation activity, because thrombin generation immediately precedes fibrin production in the coagulation cascade (39). This interdependency is reflected in the positive correlation between F1+2 and soluble fibrin levels at baseline found in the present (results not shown) and previous studies (20). The observed lack of increase in soluble fibrin in the soy group is therefore expected given the absence of an increase in F1+2.

Previous studies of between 4 wk and 6 months duration have consistently demonstrated that estrogen, either alone or in combination with progestin, decreases levels of PAI-1 by up to 50% (14, 15, 16, 20). Such a decrease in PAI-1, which is an inhibitor of tissue plasminogen activator, implies an increase in fibrinolytic potential and has been proposed as a beneficial effect of estrogen (16). We did not find any effect of soy on PAI-1 activity, and thus there is no evidence for soy having a beneficial or adverse effect on fibrinolytic potential.

D-dimer is a product of plasmin-mediated breakdown of cross-linked fibrin, which is dependent on both fibrin generation and fibrinolysis and is thus best thought of as a marker of fibrin turnover (40). D-dimer levels are elevated in thrombosis and atherosclerosis, and elevated levels are predictive of subsequent cardiovascular events (41). Estrogen-alone HT has been shown to result in increases in D-dimer levels after 2–12 wk (14, 16), although it remains controversial whether this is a result of an increase in fibrin production (20), a reduction in PAI-1, with resultant enhanced fibrinolysis (16), or a combination of both processes. In the present study, no effect on D-dimer levels was evident after 3 months of dietary soy/phytoestrogens, which is consistent with the absence of an effect of soy on either soluble fibrin or PAI-1.

vWF has been proposed as a marker of endothelial damage (21), and increased levels are found in patients with cardiovascular disease (42, 43, 44). vWF has also been found to be an independent predictor of cardiovascular mortality in cohorts of patients with known cardiovascular disease (43, 44, 45, 46) as well as in a population-based cohort (47). Rabbani et al. (22) reported that oral estrogen therapy for 1 month resulted in a 23% increase in vWF Ag levels and proposed that this may have relevance for the early increase in cardiovascular events seen with HT. In the present study, there were no effects of soy on vWF Ag, consistent with the absence of an adverse or beneficial effect of soy on this hemostatic marker. We have previously reported that soy supplementation in postmenopausal women has no effect on brachial flow-mediated vasodilation (7), a test of endothelial nitric oxide production that may improve with estrogen therapy (48).

The results of the current study do not support biologically significant estrogenic effects of soy/phytoestrogens on coagulation, fibrinolytic potential, or endothelial function. The negative results are consistent with our previous work that found that soy/phytoestrogens did not affect other biological markers of estrogenicity, including gonadotropin levels (7), markers of bone turnover (49), and markers of hepatic protein synthesis (50). The absence of a demonstrable effect of soy was despite a relatively high isoflavone intake of 118 mg, which is close to the maximum intake that is feasible from dietary sources. Furthermore, neither noncompliance nor inadequate absorption of isoflavones is an explanation for the negative findings because substantial increases in the urinary excretion of genistein and daidzein were observed in the soy group.

Although an affinity of phytoestrogens for the estrogen receptor has been established (51), ligand-estrogen receptor interactions are complex, and our understanding of the biological effects of phytoestrogens remains limited. Most phytoestrogens are significantly less potent in bioassays than 17ß-estradiol (52). Although soy protein may have effects on lipids (53), such lipid effects are unlikely to be estrogenically mediated. Thus, the pattern of lipid change with soy differs from that induced by oral estrogens with regard to the opposite effects on triglycerides (7, 54) and Lp(a) (7). Furthermore, isolated phytoestrogen supplements without the protein component of soy appear to have minimal effects on lipids (54, 55). Alternative explanations for the lipid effects of soy are the individual or combined effects of the saponins, polyunsaturated oils or vegetable proteins contained in soy, as well as displacement of fatty foods from the diet because of increased protein intake (54).

In this study in postmenopausal women, consumption of soy/phytoestrogens was accompanied by reductions in triglyceride and the LDL/HDL cholesterol ratio and an increase in Lp(a) compared with casein placebo, whereas reductions in total and LDL cholesterol were seen with both soy and casein and were not significantly different between the groups. These lipid changes are similar to those reported in the main study of 213 men and women (7) but contrast with a recently reported study in postmenopausal women by Kreijkamp-Kaspers et al. (56) that compared soy and total milk protein supplements and found no effect of soy on lipids. Given the potential mechanisms by which soy may cause cholesterol lowering mentioned above, important differences between our study and that of Kreijkamp-Kaspers et al. are the higher soy protein intake in our study (56 vs. 25 g) and the different advice given regarding dietary protein intake. Thus, no change in diet was advised for subjects in our study, whereas subjects in the study of Kreijkamp-Kaspers et al. were advised to decrease protein intake to compensate for the extra protein in the supplement.

Post hoc power calculations for hemostatic variables that did not significantly change in the soy group indicated that the present study had 80% power to detect the following changes: 60% for soluble fibrin, 100% for D-dimer, 70% for PAI-1, and 15% for vWF Ag. Such changes are less than or equal to the increases in soluble fibrin, D-dimer, and vWF Ag observed with oral HT in previous studies (20, 22). However, the present study may have been underpowered to detect an effect of soy on PAI-1. Moreover, we cannot exclude the possibility of false negative findings or that we could have missed detecting a procoagulant effect of soy of a lesser degree than that seen with oral HT.

Conclusion

Soy protein supplementation containing phytoestrogens for 3 months in healthy postmenopausal women significantly reduced triglycerides and the LDL/HDL cholesterol ratio and increased Lp(a) but did not result in activation of the coagulation cascade, fibrinolytic potential, or endothelial damage. This study suggests that soy containing phytoestrogens does not have biologically significant estrogenic effects on the hemostatic system. However, additional mechanistic research, as well as clinical endpoint trials, will be necessary to definitively assess the safety and efficacy of soy containing phytoestrogens.


   Acknowledgments
 
We thank the Department of Biochemistry, Monash Medical Centre, for performing the hormone and lipid assays.


   Footnotes
 
This study was supported in part by a Grant-in-Aid from the National Heart Foundation of Australia G98M0139. Soy supplements were provided by Protein Technologies Inc. H.J.T. was a National Health and Medical Research Council (NH&MRC) Ph.D. Fellow and subsequently a High Blood Pressure Research Foundation Fellow during the study and is currently an NH&MRC CDA Research Fellow.

First Published Online January 18, 2005

Abbreviations: Ag, Antigen; F1+2, prothrombin fragment 1 + 2; HDL, high-density lipoprotein; HT, hormone treatment; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); PAI-1, plasminogen activator inhibitor-1; VIIc, activity of coagulation factor VII; vWF, von Willebrand factor.

Received July 20, 2004.

Accepted January 12, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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J. W. Erdman Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. Hollman, C. L. Keen, G. Mazza, et al.
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