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From the Clinical Research Centers |
Comparative Medicine Clinical Research Center (T.B.C., M.S.A.) and Department of Public Health Sciences (T.M.M.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040
Address all correspondence and requests for reprints to: Thomas B. Clarkson, D.V.M., Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040. E-mail: tclarkso{at}wfubmc
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, but
with more than 80% of estradiol’s binding affinity to estrogen
receptor ß (1). Because morbidity and mortality from coronary heart disease and stroke are large public health problems for postmenopausal women, we sought to determine whether soy phytoestrogens (SPEs) inhibited the extent of coronary and cerebral artery atherosclerosis and, if so, their effectiveness relative to traditional estrogen replacement therapy. SPEs should be considered natural selective estrogen receptor modulators, because they appear to be estrogen agonists for the cardiovascular system (2, 3, 4), bone (5, 6, 7), and brain (8), while having either no agonist or, perhaps, antagonist effects for the mammary gland and uterus (9). Soy protein with its phytoestrogens favorably influences plasma lipid and lipoprotein concentrations of both postmenopausal monkeys (10, 11) and postmenopausal women (7, 12) and inhibits the development of coronary artery atherosclerosis in male monkeys (2). We report here the results of a study performed to determine the effect of SPEs on atherosclerosis in the coronary, iliac, and cerebral arteries and to compare those effects to unopposed conjugated equine estrogen (CEE) treatment. This study did not compare the effects of soy protein vs. animal protein; rather, our objective was to determine the effectiveness of SPEs as a component of soy protein.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One hundred and eighty-nine premenopausal cynomolgus monkeys (Macaca fascicularis) were obtained through our collaborative association with the Institut Pertainian Bogor, Indonesia. For the monkeys to be comparable in atherosclerosis extent to 45-yr-old women in the United States (13), they were fed a moderately atherogenic diet, and, in addition, half of the subjects were given an oral contraceptive (Triphasil Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA). The diet contained about 17% of calories from protein, 45% of calories from fat, 38% of calories from carbohydrate, and 0.28 mg cholesterol/Cal. These diets were fed for the entire 26-month premenopausal period (14).
At the end of the 26-month premenopausal period, the animals were
ovariectomized to make them surgically menopausal. At the same time, a
segment of the common iliac artery (
0.5 cm in length) was removed
and perfusion fixed using 10% neutral buffered formalin and prepared
for measurement of atherosclerosis extent (cross-sectional lesion
area).
All procedures involving animals were conducted in compliance with state and federal laws, standards of the U.S. DHHS, and guidelines established by the Wake Forest University animal care and use committee.
Study design
The design of the postmenopausal study was a three-group, parallel arm design, with the treatments lasting for 36 months. A stratified randomization scheme, taking into account premenopausal social group and oral contraceptive exposure, was used to establish the three groups. The control diet contained isolated soy protein that had been alcohol washed to remove the SPEs. The treatments used were either CEE (Premarin, Wyeth-Ayerst Laboratories, Inc.) at a dose comparable to a dose of 0.625 mg/day for women or soy protein isolate containing SPEs at a dose approximately equivalent to 129 mg/day for women, expressed as aglycone units. The doses of CEE and SPEs fed to the monkeys were based on the assumption that women in the United States eat an average of 1800 Cal/day. Thus, a dose of 0.625 mg CEE was added to 1800 Cal of diet. Monkeys were fed 120 Cal of diet/kg BW and, therefore, took in about 0.042 mg CEE/kg BW. There were 129 mg phytoestrogens in 1800 Cal of the SPE diet; thus, the monkeys were fed about 8.6 mg SPEs/kg BW. This type of caloric adjustment of dose accounts for differences in metabolic rates between the monkeys and the human subjects.
To keep the type of protein the same for all groups, both the control and the CEE groups were fed soy protein isolate that had been extracted by an aqueous-alcohol wash to deplete the SPEs. The isolated soy proteins used for this study were generously provided by Protein Technologies International (St. Louis, MO). The unextracted soy protein (SUPRO 670-HG) contained, on the average, 1.105 mg genistein, 0.365 mg daidzein, and 0.08 mg glycitein/g soy protein isolate (expressed in aglycone units). The alcohol-extracted soy protein (SUPRO 670-IF) contained 0.04 mg genistein, 0.01 mg daidzein, and 0.01 mg glycitein/g isolate (expressed in aglycone units).
The diets were formulated to be isocaloric for the macronutrients [protein (19% of Cal), carbohydrate (37%), and fat (44%)] and comparable for cholesterol (0.28 mg/Cal), calcium (830 mg/1800 Cal), and phosphorus (820 mg/1800 Cal). The monkeys were fed about 120 Cal/kg BW split into two feedings (one third in the morning, two thirds in the afternoon).
Measurements of plasma lipids/lipoproteins
Quarterly, the animals were weighed, and blood for total plasma cholesterol (TPC), high density lipoprotein cholesterol (HDLC), and triglyceride analyses was collected into evacuated tubes containing ethylenediamine tetraacetate (final concentration, 1.0 g/L) after food was withheld for 18 h. TPC was measured by enzymatic techniques based on the methods of Allain et al. (15). Plasma triglycerides were determined by the methods of Fossati and Principe (16). HDLC concentrations were measured using the heparin-manganese precipitation procedure described in the Manual of Laboratory Operations of the Lipid Research Clinics Program (17). Low density lipoprotein cholesterol plus very low density lipoprotein cholesterol (LDL+VLDLC) was calculated as the difference between TPC and HDLC. All analyses were performed on a COBAS FARA II autoanalyzer (Roche, Montclair, NJ). The laboratory subscribes to the Centers for Disease Control (Atlanta, GA) Lipid Standardization Program.
Blood samples to determine concentrations of apolipoprotein (apo) A-I, apo E, and lipoprotein(a) [Lp(a)] were collected into evacuated tubes containing ethylenediamine tetraacetate (1.5 g/L, final concentration) and a protease inhibitor cocktail consisting of sodium azide (1.0 g/L, final concentration), aprotinin (0.4 mg/L, final concentration), and benzamidine (0.15 g/L, final concentration). Food was withheld from the animals for 18 h before blood sample collection. Apo A-I (18) and apo E (19) were quantified by enzyme-linked immunosorbent assay methods previously reported. Lp(a) concentrations were measured using modifications of the enzyme-linked immunosorbent assay for determining apo A-I that was developed at our Lipoprotein Core Laboratory (20). All samples were analyzed in duplicate, and plasma pools were included with all assays.
Measurements of hormones, isoflavones, and isoflavone metabolites
Hormone concentrations were measured three times during the postmenopausal phase. The assays were performed at the Yerkes Regional Primate Research Center Endocrinology Laboratory. Estradiol concentrations were determined using a commercially available RIA kit with a double antibody technique (Diagnostics Products, Los Angeles, CA). Blood samples for estradiol were collected 4 h after the morning meal, around the time of peak blood concentrations. Testosterone, androstenedione, and dehydroepiandrosterone sulfate were quantitated by RIA with commercially available kits using antibody-coated tubes (Coat-A-Count, Diagnostic Products). The androgens were measured on blood samples collected after an 18-h fast.
Blood samples for isoflavone concentrations were collected 4 h after feeding the morning meal (one third of the daily food allotment) at one time during the course of treatment (34 months). Serum isoflavone concentrations (genistein, daidzein, equol, dehydrodaidzein, and o-desmethylangolensin) were measured by high performance liquid chromatography-mass spectrometry (21) in Dr. Stephen Barnes’ laboratory (University of Alabama, Birmingham, AL). Briefly, the isoflavones (as their glucuronide and sulfate conjugates) were extracted from serum using Sep-Pak C18 cartridges (Waters Corp., Milford, MA). They were then hydrolyzed with a mixed ß-glucuronidase/sulfatase preparation to the aglycones, which were again recovered using the Sep-Pak C18 cartridges. Aliquots of the samples were separated by reverse phase high performance liquid chromatography, and the isoflavones were passed into the PE-Sciex API III triple quadruple mass spectrometer via a heated nebulizer-atmospheric pressure chemical ionization interface. Each of the isoflavones was measured by monitoring of unique pairs of parent and daughter fragment ions. Methylumbelliferone glucuronide was added to the samples before extraction to act as an internal check of the efficiency of hydrolysis and recovery throughout this procedure.
Necropsy procedures
After 36 months of postmenopausal treatment, the monkeys were
killed using sodium pentobarbital (100 mg/kg, iv), a method consistent
with the recommendations of the Panel on Euthanasia of the American
Veterinary Medical Association. The remaining common iliac artery
(0.5 cm) was removed, perfusion-fixed with 10% neutral buffered
formalin, and prepared for morphometric evaluation. The heart was
removed, and the coronary arteries were perfused for 1 h at 100 mm
Hg pressure using 10% neutral buffered formalin. The common carotid
arteries, carotid bifurcations, and internal carotid arteries were
removed and fixed flat on cardboard in 10% neutral buffered
formalin.
Atherosclerosis evaluations
Measurements of plaque progression. To estimate changes in plaque size from baseline for individual monkeys, we used a paired artery, the common iliac artery, shown previously to have essentially the same plaque sizes in the left and right arteries (r = 0.97) and to be highly associated with coronary artery plaque extent (r = 0.86). The artery segment taken at baseline and the contralateral iliac artery taken at necropsy were embedded in paraffin, and five 5-µm sections were made and stained with Verhoeff-van Gieson’s stain. Each of the five sections was projected onto a digitizer plate and quantified using a hand-held stylus with a computer-assisted digitizer. The extent of atherosclerosis was measured as the cross-sectional area of plaque in each of the five sections of the artery segment as described previously (22). Measurements were made blind to treatment by a technician with more than 20 yr experience and were randomly reevaluated by one of us (T.B.C.).
Coronary artery atherosclerosis evaluations. We took 15 blocks (each 3 mm in length) cut perpendicular to the long axis of the arteries. Five of these were serial blocks from the left circumflex, five were from the left anterior descending, and five were from the right coronary artery. Atherosclerosis extent (cross-sectional area of plaques) was measured as described for the iliac arteries and as described previously (22).
Carotid artery atherosclerosis evaluations. Both the left and right common carotid arteries, carotid bifurcations, and internal carotid arteries were removed at necropsy and immersion-fixed in 10% neutral buffered formalin. We examined three blocks of common carotid artery, one block of carotid bifurcation, and two blocks of internal carotid artery from both the left and right sides. The extent of atherosclerosis (cross-sectional area of plaque) was recorded as described for iliac and coronary arteries.
Statistical methods
Analyses were performed using BMDP statistical software (version 7.0, BMDP, Los Angeles, CA) or Statistical Analysis Software (version 6.08, SAS Institute, Inc., Cary, NC). All variables were first evaluated for their distribution and equality of variances between groups. Log transformations were performed for variables that violated the test of equal variances (plasma estradiol, androstenedione, apo E, and plaque area for all arteries).
For data measured at baseline and multiple times during treatment, treatment period averages were used in the analyses, because the data were stable across time. The baseline measure was used as a covariate. Average plaque size was calculated for each artery (mean across blocks) after verifying that treatment effects were consistent for the length of the artery. Average common carotid and internal carotid plaque sizes were calculated by averaging the right and left sides, because treatment effects were comparable. Average coronary artery plaque size was calculated as the mean of the right coronary, left anterior descending, and left circumflex artery means.
Because the data for 
plaque area (i.e. change from
baseline to outcome) were abnormally distributed, a log transformation
of baseline and outcome plaque area was performed, and then the log of
the baseline plaque area was subtracted from the log of the outcome
plaque area. This is equivalent to the log of the ratio of outcome
plaque area to baseline plaque area, and the transformed value has a
natural interpretation. A ratio greater than 1.0 means that there was
progression from baseline to outcome, and a ratio less than 1.0
suggests atherosclerosis regression from baseline to outcome.
Atherosclerosis measurements in each arterial site were analyzed by analysis of covariance (ANCOVA), using baseline variables as covariates that were significantly associated (P < 0.05) with outcome atherosclerosis. These covariates included baseline plasma lipoprotein and apo concentrations, LDL molecular weight, and baseline iliac artery atherosclerosis. After adjusting for these variables measured during the premenopausal treatment period, oral contraceptive treatment status (a randomization factor) was not a significant independent predictor of outcome atherosclerosis; therefore, it was not included in the ANCOVA models. The same covariates were used for all arteries.
The data in this report are the means and calculated SEs
retransformed into original units. One-way ANOVA and ANCOVA were used
to test for differences among groups. t tests were used for
post-hoc between-group comparisons if the ANOVA or ANCOVA
p value was significant. An level of 0.05 or less was
used to determine statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At the end of the 3-yr treatment period, there were no significant differences in the mean body weights of the groups. The control (without soy) group weighed 3.21 ± 0.04 kg compared with 3.25 ± 0.04 kg for the SPE group and 3.16 ± 0.04 for the CEE group (by ANCOVA, P = 0.27).
Plasma lipid/lipoprotein concentrations
The plasma lipid/lipoprotein concentration data are summarized in
Table 1
. Both SPE and CEE treatment
resulted in significantly lower TPC concentrations compared with
control values, and the two treatment groups were not different. Plasma
triglyceride concentrations were significantly higher in the CEE group,
but not in the SPE group. SPE treatment resulted in significantly
higher concentrations of HDLC compared with the control values, but
such an effect was not observed for CEE treatment. Both SPE and CEE
groups had significantly lower LDL+VLDLC compared with the control
group. The magnitude of the effect was comparable for both treatment
groups. Although there is a trend showing improvement in the total
cholesterol to HDL cholesterol ratio with SPE treatment, the effect was
not statistically significant. There were no significant differences
among the groups for Lp(a) concentrations. SPE treatment, but not CEE
treatment, resulted in significantly higher Apo A-1 concentrations
compared with the control values. The CEE group had significantly lower
plasma concentrations of Apo E compared with the control group, but SPE
treatment showed no effect.
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The results of measurements of plasma hormone concentrations are
summarized in Table 2. Treatment with CEE
resulted in significantly higher plasma concentrations of
17ß-estradiol. SPE treatment had no effect on 17ß-estradiol
concentrations. There were no differences among the groups for plasma
testosterone concentrations. Treatment with SPE resulted in
significantly higher androstenedione concentrations, whereas the CEE
group was not different from the control group. Neither treatment had a
statistically significant effect on plasma concentrations of
dehydroepiandrosterone sulfate.
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. The total plasma isoflavone
concentration of the SPE group was 776 ± 85 nmol/L. The
proportions of the total isoflavones that were genistein, daidzein, and
their metabolites are shown in Fig. 1.
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Atherosclerosis progression was considered the change in plaque
size from baseline to the end of the 3-yr trial. In Fig. 2 are presented the change in plaque size
of all the animals in the trial. Equivalent numbers of animals in the
three groups appeared to have regressed their plaque sizes (less than
-0.1 mm2). Among the animals with little or no
change in plaque size (-0.1 to +0.1 mm2), there
was a major treatment effect, with SPE and CEE treatment being about
equally effective. Fourteen percent of the control group had little or
no change in plaque size, whereas 46% of the SPE group and 44% of the
CEE group had no change. Conversely, 63% of the control group had
significant atherosclerosis progression (change greater than +0.1
mm2), whereas only 39% of the SPE group and 35%
of the CEE group were in this category. The SPE effects and CEE effects
were comparable, except that among the SPE-treated animals there was
more plaque progression in three of the animals. In Fig. 3 are presented the group means for
atherosclerosis progression (expressed as the plaque size at the
outcome divided by plaque size at baseline). The difference between the
control group and the SPE group was of borderline statistical
significance (P = 0.10), whereas the difference between
the control group and the CEE group was significant (P
= 0.0001).
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The effects of the interventions on mean coronary artery plaque
size are presented in Fig. 4. The
estimate of the amount of coronary artery atherosclerosis in the
SPE-treated group was intermediate between that in the control group
and that in the CEE group and was of borderline statistical
significance (control vs. SPE, P = 0.12).
CEE treatment was significantly more effective than SPE treatment
(P = 0.02). The largest difference in the extent of
coronary artery atherosclerosis was between the control group and the
CEE-treated group, which was statistically significant
(P = 0.0002).
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Both SPE and CEE had a significant effect on inhibiting
atherosclerosis development in the common carotid arteries and the
internal carotid arteries (Fig. 5). The
effect size was slightly larger for the CEE group than for the SPE
group. There was no effect of the interventions on carotid bifurcation
atherosclerosis (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The atherosclerosis-inhibiting effects of SPEs appear to be largely mediated through their beneficial effects on plasma lipid/lipoprotein concentrations (24, 25, 26) and perhaps through their ability to protect LDL particles from oxidation (27). There are some plasma lipid-independent mechanisms that are also thought to contribute to their cardiovascular benefits. Mäkelä et al. (28) found genistein and 17ß-estradiol to be equivalent in preventing intimal proliferation in response to vascular injury of rats. Such an effect is consistent with reports that genistein inhibits the proliferation and migration of smooth muscle cells (28, 29, 30). SPEs have been shown to improve flow-mediated arterial dilation in both nonhuman and human primates (4, 31). SPEs also have beneficial effects on platelets (32, 33).
The SPEs in this experiment had beneficial effects on plasma lipid/lipoprotein concentrations, i.e. a reduction in LDL+VLDL cholesterol and an increase in HDL cholesterol. These changes are consistent with our previous findings with male and female monkeys (2, 3), observations by Crouse et al. (24) in studies of both men and women, and the data reported by Baum et al. (34) based on studies of postmenopausal women. Generally, the effect of the SPEs on plasma lipid and lipoprotein profiles was somewhat better than the effect of CEE treatment (lack of hypertriglyceridemia and a significant increase in HDLC and Apo A-1 concentrations).
The only unexpected finding in hormone concentrations concerns
androstenedione. Plasma concentrations of androstenedione were
increased by SPE treatment and decreased by CEE treatment. The
physiological significance, if any, is not known to us.
Androstenedione, the 4 analog of
dehydroepiandrosterone, is a circulating prohormone and has no specific
receptors or target tissue activity (35). After
ovariectomy, plasma concentrations of androstenedione have been
reported to decrease (36). Bernini et al.
(37) reported recently that there was a strong inverse
association between plasma androstenedione concentrations and carotid
artery intima-media thickness in postmenopausal women. The discordant
effects of SPE and CEE on plasma androstenedione could relate to the
finding that soy phytoestrogens, not CEE, inhibit aromatase (estrogen
synthetase) (38).
Plasma isoflavone concentrations in this study are intermediate between those of Japanese men eating a typical Asian diet (39) and women fed comparable amounts of isoflavones in soy milk (40). Equol makes up a much larger proportion of total isoflavone concentrations in the nonhuman primates, possibly because of differences in gut flora between species. Although the isoflavone values were generally lower than those in women eating similar amounts of isoflavones, it is difficult to compare isoflavone values measured in different laboratories using different methodologies. However, as higher isoflavone concentrations appear to be associated with higher HDLC and lower LDLC and plasma triglyceride concentrations (25, 26), one could speculate that this amount of isoflavones might have a more beneficial effect in women.
The data obtained on plaque progression represent our first attempt to determine the effect of an intervention on the progression of preexisting atherosclerosis within an individual. When one views the data on all the animals in the study, the effect of the SPE and CEE interventions on change in plaque size are generally comparable.
The effect of SPE treatment on coronary artery atherosclerosis appears to be intermediate between that in the control group given soy lacking isoflavones/phytoestrogens and that in the group given CEE. Based on the plasma lipid and lipoprotein profiles of the two intervention groups, a more robust effect in the prevention of progression of coronary artery atherosclerosis was expected. There are two important considerations in the interpretation of this observation. First, the control group was fed a soy-containing diet depleted of SPE. Had there been a control group fed animal protein (i.e. casein/lactalbumin), we perhaps would have seen a modest effect of phytoestrogen-depleted soy and a larger effect of the soy containing the SPEs. Such was the case in our study of male monkeys, which included phytoestrogen-depleted soy and phytoestrogen-containing soy groups, and a casein/lactalbumin reference group (2). The other consideration is that the comparison here is with unopposed CEE. Had the comparison been with CEE given continuously with medroxyprogesterone acetate, the results might have been different (41). We also cannot rule out the possibility of some favorable interactions between soy protein and CEE.
Stroke ranks third as a cause of death for middle-aged and older women (42). A 50-yr-old white woman has a 20% lifetime probability of developing stroke (43). Whether and to what extent HRT reduces the risk for stroke in the postmenopausal population is uncertain. Paganini-Hill (44) reviewed seven studies of death from stroke and found the wide range of a 20–60% reduction in risk among postmenopausal estrogen users relative to nonusers. On the other hand, Thompson et al. (45) found no benefit of HRT for the prevention of stroke in a study conducted in England. Given the uncertainties surrounding the effects of estrogens on stroke and stroke risk, we believed it important to evaluate the carotid arteries, especially the internal carotid arteries, because atherosclerotic lesions at that site are most commonly associated with cerebral vascular disorders in humans (46). Postmenopausal therapy with either SPE or CEE markedly reduced the occurrence and extent of both common carotid and internal carotid artery atherosclerosis. We found no effect of either intervention on carotid bifurcation atherosclerosis. That finding was expected, because plaque progression at that site is more related to increased blood pressure than to increased plasma lipids (47).
SPEs, administered as a soy protein supplement, may be a useful alternative to traditional hormone replacement therapy. As natural selective estrogen receptor modulators, there is some evidence that they may affect cognitive function favorably, provide some protection against breast cancer, and inhibit bone loss. Evidence presented in this report supports the conclusion that SPEs may also inhibit the progression of postmenopausal atherosclerosis. There is a need in future studies to define better the optimum dose of the SPEs and to determine whether there are therapeutic benefits to be gained from altering the ratios of genistein and daidzein.
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Acknowledgments |
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Footnotes |
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Received February 8, 2000.
Revised August 10, 2000.
Accepted October 1, 2000.
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J. D. Wagner, D. C. Schwenke, K. A. Greaves, L. Zhang, M. S. Anthony, R. M. Blair, M. K. Shadoan, and J. K. Williams Soy Protein With Isoflavones, but not an Isoflavone-Rich Supplement, Improves Arterial Low-Density Lipoprotein Metabolism and Atherogenesis Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2241 - 2246. [Abstract] [Full Text] [PDF]
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T. C. Register, M. J. Jayo, and M. S. Anthony Soy Phytoestrogens Do Not Prevent Bone Loss in Postmenopausal Monkeys J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4362 - 4370. [Abstract] [Full Text] [PDF]
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X. Zhang, X. O. Shu, Y.-T. Gao, G. Yang, Q. Li, H. Li, F. Jin, and W. Zheng Soy Food Consumption Is Associated with Lower Risk of Coronary Heart Disease in Chinese Women J. Nutr., September 1, 2003; 133(9): 2874 - 2878. [Abstract] [Full Text] [PDF]
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 H. N. Hodis, W. J. Mack, S. P. Azen, R. A. Lobo, D. Shoupe, P. R. Mahrer, D. P. Faxon, L. Cashin-Hemphill, M. E. Sanmarco, W. J. French, et al. Hormone Therapy and the Progression of Coronary-Artery Atherosclerosis in Postmenopausal Women N. Engl. J. Med., August 7, 2003; 349(6): 535 - 545. [Abstract] [Full Text] [PDF]
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R. M. Blair, S. E. Appt, A. A. Franke, and T. B. Clarkson Treatment with Antibiotics Reduces Plasma Equol Concentration in Cynomolgus Monkeys (Macaca fascicularis) J. Nutr., July 1, 2003; 133(7): 2262 - 2267. [Abstract] [Full Text] [PDF]
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 F. L. Bellino and P. M. Wise Nonhuman Primate Models of Menopause Workshop Biol Reprod, January 1, 2003; 68(1): 10 - 18. [Abstract] [Full Text] [PDF]
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 J. B. Hodgin and N. Maeda Minireview: Estrogen and Mouse Models of Atherosclerosis Endocrinology, December 1, 2002; 143(12): 4495 - 4501. [Abstract] [Full Text] [PDF]
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 J. J. B. Anderson, X. Chen, A. Boass, M. Symons, M. Kohlmeier, J. B. Renner, and S. C. Garner Soy Isoflavones: No Effects on Bone Mineral Content and Bone Mineral Density in Healthy, Menstruating Young Adult Women after One Year J. Am. Coll. Nutr., October 1, 2002; 21(5): 388 - 393. [Abstract] [Full Text] [PDF]
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M. S. Anthony Phytoestrogens and Cardiovascular Disease: Where's the Meat? Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1245 - 1247. [Full Text] [PDF]
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Y. T. van der Schouw, A. Pijpe, C. E.I. Lebrun, M. L. Bots, P. H.M. Peeters, W. A. van Staveren, S. W.J. Lamberts, and D. E. Grobbee Higher Usual Dietary Intake of Phytoestrogens Is Associated With Lower Aortic Stiffness in Postmenopausal Women Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1316 - 1322. [Abstract] [Full Text] [PDF]
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E. A. Lucas, R. D. Wild, L. J. Hammond, D. A. Khalil, S. Juma, B. P. Daggy, B. J. Stoecker, and B. H. Arjmandi Flaxseed Improves Lipid Profile without Altering Biomarkers of Bone Metabolism in Postmenopausal Women J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1527 - 1532. [Abstract] [Full Text] [PDF]
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 T. S Mikkola and T. B Clarkson Estrogen replacement therapy, atherosclerosis, and vascular function Cardiovasc Res, February 15, 2002; 53(3): 605 - 619. [Abstract] [Full Text] [PDF]
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 S. R Davis Phytoestrogen therapy for menopausal symptoms? BMJ, August 18, 2001; 323(7309): 354 - 355. [Full Text] [PDF]
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B. Anderson; Soy Phytoestrogens, Lipid Reductions, and Atherosclerosis Delay in Ovariectomized Primates J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 39 - 40. [Full Text]
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