Articles |
From Baker Medical Research Institute, Melbourne, Australia (P.J.N., T.Y., T.S., S.P., A.D., P.K.), and CSIRO Division of Human Nutrition, Adelaide, Australia (A.O., M.A.).
Correspondence to Dr P. J. Nestel, Baker Medical Research Institute, Commercial Rd, Prahran VIC 3181, Australia (PO Box 348).
| Abstract |
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Key Words: genistein menopause women flavonoids
| Introduction |
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The effects of soy protein on arterial function are not known in menopausal women, though preliminary reports in female monkeys show enhancement of endothelium-dependent vasodilatation.5 Soybeans contain a number of compounds that have weak estrogenic activity.6 Of these, the isoflavonoids are especially attractive, possessing antioxidant property7 as well as the capacity to occupy estrogen receptors.
We therefore investigated a pure preparation of isoflavones from soybean on several important biomarkers of cardiovascular health in the menopause. These included systemic arterial compliance, a measure of elasticity of the major conduit arteries such as the aorta, the vasodilatory capacity of the microcirculation in the forearm, plasma lipid concentrations, and the oxidizability of LDL.
| Methods |
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Two women dropped out at an early stage, leaving 21 who completed the extended trial.
Exclusion criteria were age >69 years and hormone replacement therapy,
which several women had tried previously or discontinued for 6 weeks
before the start of the trial. Other supplements such as evening
primrose oil and vitamin E, which some women also took, were also
stopped 4 to 6 weeks before the beginning of the study. None took any
regular medication that might have affected plasma lipids or
cardiovascular function. Several had followed a near
vegetarian diet. Smoking and drinking more than 14 standard alcoholic
drinks weekly were other exclusion criteria. Physical examination
showed that all subjects were free of apparent
cardiovascular disease and had been healthy apart from
minor occasional ailments. Relevant details are shown in Table 1
. The
trial was approved by Alfred Hospital Human Ethics Committee and was
carefully explained to obtain informed consent.
Experimental Design
The women were enrolled over a period of 8 weeks so that the
start was staggered over this time (10 women starting together, the
remainder over the next few weeks). A minimum of 4 weeks and up to 6
weeks was the discontinuation period for the women who had been taking
supplements. For the whole group, the 4-week period was used to
familiarize them with dietary principles, including avoiding legumes,
identifying fat content of foods, and maintaining a regular food
pattern with a target of no more than 30% energy from fat. This has
been termed the baseline-diet-only period.
The women were then randomized to commence either one placebo tablet daily for 5 weeks or the isoflavone tablet daily. The intended dose was 40 mg, but when it became apparent that the symptoms of the first 10 women, half of whom would have been receiving active treatment, were not improved (anticipated from other research), the dosage was changed to an 80-mg tablet. Those that had taken only 40 mg in the first phase of the trial (5 women) then took the 80-mg dose after the placebo period. The remaining 16 who received 80 mg either first or after placebo continued for a further 5-week phase taking 80 mg. Thus, all subjects had a 5-week placebo period and two-5 week active treatment periods. Therefore, half the subjects followed an active, placebo, active rotation, and the other half followed a placebo, active, active rotation. Comparisons could therefore be made in all at the end of 5 weeks of placebo and of 5 weeks of active 80 mg treatment; it was also possible to determine whether 10 weeks of treatment outperformed 5 weeks. The nature of these changes was withheld from the subjects who remained blinded; the investigators had been unblinded.
The background diet applied throughout and was supervised closely by the dietitian (S.P.). All subjects were encouraged to compose their diets from whole-grain cereal foods, fruit and vegetables, low-fat dairy products, fish, lean and skinless poultry, and lean meat. Soy-based food products and leguminous vegetables were omitted. Subjects kept 3-day food records during each phase of the trial. The diet was supervised closely by the dietitian, who interviewed each subject and checked each food record to ensure compliance with the protocol. All subjects were encouraged to keep a list of supermarket products containing soy and legume products. These lists were compiled and used as information sheets. Normal exercise routine was encouraged. The subjects attended every two weeks, when tablets were dispensed and compliance with diet and medication was checked. Twenty-four-hour urine samples were collected after the designated active and placebo periods for measurements of isoflavonoid excretion to monitor absorption. This group of women was particularly committed to the study, attended appointments, and complied with the prescribed diet and tablet consumption. They also completed records of their menopausal symptoms, which will be reported elsewhere.
Laboratory Measurements
Measurements were made at the end of each period for baseline
diet only, placebo, and active. Blood for plasma lipid concentrations
was collected on two adjacent days.
The determination of systemic arterial compliance, which measures the elasticity of the main conduit arteries and included frequent automated arterial pressure measurements, was carried out near the end of one period of active treatment (80 mg) and the placebo periods. Forearm venous occlusion plethysmography to test the dilatory capacity of the resistance vessels was performed in nine women; the objective had been to make these measurements in every second person.
Systemic Arterial Compliance
Systemic arterial compliance was estimated by using
the "area method" of Liu et al,8 which
requires measurement of volumetric blood flow and associated driving
pressure to derive an estimated compliance over the total
arterial system according to the formula SAC=
Ad[R(Ps -
Pd)], where Ad is the area
under the blood pressure diastolic decay curve from end
systole to end diastole, R is total peripheral
resistance, Ps is end-systolic blood
pressure, and Pd is end-diastolic
blood pressure.
Volume flow was calculated as the product of average systolic flow and aortic root area measured by two-dimensional echocardiography (Hewlett-Packard model 77020A phased array sector scanner). Continuous ascending aortic flow velocity was measured by using a hand-held Doppler flow velocimeter (MD1 Multi-Doplex, Huntleigh Technology) placed on the suprasternal notch. This device provides an analogue signal that is proportional to the instantaneous frequency determined by the number of detected zero crossings per unit time of the backscattered Doppler signal, which can be related via the Doppler equation to flow in the ascending aorta. This technique represents an average (approximately root-mean square) value for flow, which differs from the method used for most clinical applications estimating maximum flow. Because the derived numerical value for flow determined by using zero crossing analysis will be less than that obtained invasively, we have chosen to report our results in arbitrary compliance units (ACU, dimensionally equal to mL/mm Hg).9
Aortic root driving pressure was estimated by applanation tonometry of the proximal right carotid artery using a noninvasive Millar Mikro-Tip pressure transducer (model SPT-301, Millar Instruments). The pressures obtained by this method were calibrated against brachial pressure measurements made simultaneously by using a Dinamap vital signs monitor (1846SX, Critikon). We have previously validated this method against invasively obtained pressure signals.9
Both flow and pressure signals were digitized at 200 Hz by using a Data Translation DT 2801 analogue-to-digital conversion board (Data Translation). Data were acquired and analyzed with purpose-written software (J.D. Cameron) using DAOS version 7.1 (Laboratory Software, Melbourne, Australia). The computation of compliance proceeds automatically; the observer is required only to ensure stable baselines and consistently reproducible pressure-flow traces and to define end-systolic and end-diastolic points. (This is emphasized because the investigators were not blinded.)
Forearm Blood Flow Studies
The brachial artery was cannulated for intraarterial
blood pressure recordings. All of the drugs used were infused
intraarterially at a constant rate of 2 mL/min. Responses
to the vasodilatory agents acetycholine (9.25 and 37 µg/min)
and sodium nitroprusside (400 and 1600 ng/min) were measured.
After an equilibration period of 40 to 60 seconds, the average of three
flow measurements before drug infusion was obtained and used as a
measure of basal flow. Each drug was infused at 2 mL/min over a minimum
of 2 minutes or until the response over three flow measurements reached
a plateau (usually within 2.5 minutes). The average of three flow
measurements at the end of the infusion period was obtained as a
measure of drug-induced flow. Rest periods of 5 minutes between
concentrations and of 15 minutes between drugs were allowed. Basal
blood flows were similar between drug infusions. These drug
concentrations had no effect on either systemic blood pressure
measurement, recorded with an AE 840
physiological pressure transducer (Carlin Medical
Supply P/L), or heart rate, monitored by lead II ECG.
Responses to reactive hyperemia were also measured before drug infusions. Ischemia was achieved by inflation of a blood pressure cuff on the upper arm to a pressure of 200 mm Hg applied for 5 minutes.
Forearm blood flow was measured by venous occlusion using a calibrated, alloy-filled (gallium and indium) double-strain gauge and recorded for 10 out of every 20 seconds. The effect of each concentration of agonist was calculated as a percentage of the basal forearm vascular resistance (arterial pressure divided by blood flow) obtained immediately before each drug addition.
LDL Oxidation Studies
These were carried out only in the first 15 subjects, and
oxidation outcomes were compared at the end of the placebo period and
one active period. LDL were separated from plasma (stored at -80°C)
by rapid isolation using a Beckman OptimaTLX benchtop
ultracentrifuge (Beckman Instruments). LDL for oxidation
experiments was dialyzed at 4°C against phosphate-buffered saline (pH
7.4), which had been purged with N2 and
sterilized by filtration (0.2 µm).
Oxidation of LDL was determined as the production of conjugated dienes by continuously monitoring the change in absorbance at 234 nm as previously described.10 Freshly prepared LDL (50 µg protein/mL) was incubated with 5 µm CuSO4 at 37°C in a Beckman DU65 Spectrophotometer fitted with a peltier heater (Beckman Instruments). Absorbance at 234 nm was automatically recorded at 2-minute intervals for 120 minutes .Lag time and propagation rate were determined as previously described.10
Malondialdehyde (MDA) generated in oxidized LDL and in medium was
measured by the TBARS method as described by Buege and
Aust11 except that the sample volume was 0.1 mL,
the reagent volume was 0.2 mL, and the sample absorbance was measured
at 535 nm in a Cobas-Bio automated centrifugal analyzer. The
concentration of MDA was calculated by using the extinction coefficient
for MDA (1.56 x 105
M-1
cm-1). LDL
-tocopherol was
measured by high-performance liquid
chromatography using the method of Yang and
Lee.12 Total cholesterol
content of isolated LDL was measured as described above for plasma
cholesterol.
Plasma Lipids
Plasma was separated from chilled blood samples and frozen at
-80°C. Measurements were carried out in batches for plasma glucose,
cholesterol, and triglyceride by enzymatic kits
on a Cobas-Bio automated analyzer (Roche). HDL
cholesterol was separated from plasma by selective
precipitation of other lipoproteins. Plasma insulin was measured by
enzyme immunoassay (Tosoh AIA-PACK IRI).
Isoflavone Content
The tablets supplied by Novogen Pharmaceuticals (North Ryde)
contained mainly the isoflavones genistein and daidzein, with a small
amount of glycitein in the ratio of 1.3:1:0.1, which is similar to that
in soy flour. Each 80-mg tablet therefore contained about 45 mg of
genistein. The isoflavones were aglycones, ie, hydrolyzed
conjugates.
| Results |
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Plasma Lipids and Glucose
None of the lipids that were measured (plasma
cholesterol, plasma triglyceride, HDL
cholesterol) was affected by isoflavones (Table 2
). Mean plasma glucose values were
similar during the three periods (4.98±0.63, 5.17±0.53, and
5.14±0.58 mmol/L).
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Arterial Pressure
Mean arterial pressures were identical during placebo
and isoflavone periods (80±12 and 80±10 mm Hg, respectively)
but significantly higher during baseline (86±10 mm Hg).
Systolic and diastolic pressures and heart rates
showed similar patterns.
Systemic Arterial Compliance
Table 3
compares the values for
systemic arterial compliance at the end of the placebo and
an 80-mg isoflavone period. The mean difference (0.81±0.4 versus
0.99±0.54) was highly significant (P=.011) by paired
t-test analysis. Arterial compliance was
higher with placebo in only three women (the
Figure
). A
2
analysis was carried out on the basis of the proportion of
differences exceeding 15% (more than double the coefficient of
variation of the test). Such a difference was exceeded 13 times on
active treatment and twice on placebo treatment with six equivocal
(P
0.001).
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Systemic arterial compliance was lowest at the end of the baseline dietary period (0.67±0.33 U), which was significantly less than with placebo or isoflavone. However, since arterial pressures were highest during this period (possibly because this was the first period for all women), we draw no conclusions from this period. Arterial compliance and pressure are inversely correlated; in the present study, the correlation coefficient between the two parameters was -0.46 (P<.05) during the baseline measurements. The difference in arterial compliance between placebo and active treatments cannot, however, be attributed to variations in arterial pressure among subjects: percent delta compliance and percent delta pressure were not correlated.
There was no correlation between 24-hour urinary isoflavonoid output and arterial compliance.
Systemic arterial compliance was powerfully correlated with the age of the subjects, inversely (r=-0.766, P<.001). This may partly reflect the menopausal status and duration of menopause, since the younger women were among those with lower FSH values, indicating perimenopausal in six and premenopausal in one. Further, arterial pressure was also inversely correlated with compliance. Stepwise regression analysis followed by multiple regression analysis showed that both age and arterial pressure correlated independently with arterial compliance, together accounting for two-thirds of the variance.
Forearm Blood Flow
Endothelial function (vasodilation following
intrabrachial infusions of acetylcholine and sodium nitroprusside and
immediately after 5 minutes of brachial artery occlusion) is shown in
Table 4
. Of the nine subjects, only three
(numbers 8, 16, and 20) were menopausal; five (numbers 2, 7, 9, 13, and
14) were perimenopausal, and one (number 17) was premenopausal.
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The mean values for basal blood flow, percent decreases in resistance with the vasodilators, acetylcholine, sodium nitroprusside, and ischemia were similar during the placebo and active periods. There was no suggestion in this small group of an effect of menopausal status.
Oxidizability of LDL
The isoflavone supplementation failed to influence LDL
oxidizability in vitro. Table 5
shows
that none of the usual parameters that were measured by
this technique differed between active and placebo treatments.
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| Discussion |
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In the present study, the outstanding finding was the improvement
in arterial compliance which averaged 26% (Fig 1
).
Arterial compliance was higher with isoflavones in thirteen
women but in only two while taking placebo, using a difference of 15%
as cutoff (Table 3
). This is of the order of increase in
arterial compliance observed in this Institute with
estrogen replacement therapy in menopausal
women.19 Arterial compliance has been
reported to be similarly improved by raising physical fitness through
exercise.20 We recently showed that 5 weeks'
consumption of flaxseed oil, which is rich in the n-3 fatty acid
-linolenic acid, increased arterial compliance
by 39% over that measured when subjects ate a saturated fatty
acidrich diet.21
Thus systemic arterial compliance is susceptible to significant improvement within weeks. Since the increasing stiffness of the large conduit arteries, especially the descending aorta, is believed to contribute to cardiovascular disease, including systolic hypertension, coronary artery insufficiency, and left ventricular dysfunction,22 the demonstration of reversibility points to functional causal components. Because endothelial events influence the smooth muscle layer in the artery and because endothelial function is rapidly modifiable, we favor a mechanistic change based on endothelium-related arterial relaxation.
On the other hand, we failed to find evidence of increased
responsiveness to isoflavones in the microcirculation of the forearm
(Table 4
). However, of the nine women, six were either perimenopausal
or premenopausal. All responded with nearly a doubling in blood flow
with acetylcholine and after ischemia during both the placebo
and active treatments. Taddei et al15 have
reported diminishing vasodilatation with acetylcholine with age, so
among women, endothelial dysfunction became evident
after the menopause. The onset of menopause is a significant event,
since the age-related decline in endothelium-dependent
vasodilatation was steeper in women after the menopause than it was in
men.15 That microcirculatory flow is not readily
augmented with estrogen in perimenopausal women has also been reported
by Sudhir et al.3 By contrast, acute
administration of estrogen has induced acetylcholine-mediated
coronary dilation in postmenopausal
women.23
Estrogen supplementation has been reported to raise flow-mediated dilation in the brachial artery, a conduit artery, in menopausal women.24 This has relevance to our finding of improved arterial compliance and suggests that the functional component that contributed to the improvement was endothelium-dependent dilation. Other evidence relating to the in vivo effects of soy on vascular function is confined to female monkeys that are fed atherogenic diets that decreased the capacity of coronary arteries to dilate; long-term dietary soy protein or acute intracoronary injection of genistein reversed such vasoconstriction.5 In the present studies, arterial compliance was inversely correlated with age, blood pressure, and LDL cholesterol, but none of these was a confounding factor in the isoflavone effect.
The effect of dietary soybeans or soy protein on plasma lipids has been controversial. Several well-controlled comparisons of soy protein versus animal protein (generally casein) have shown minimal, if any, differences.14 However, other studies have shown impressive cholesterol lowering,14 raising the question, as yet unanswered, of differences in some active components. Combining many of these studies, but surprisingly omitting at least one major negative study,25 Anderson et al14 concluded that 25 to 50 g of soy protein reduced total cholesterol by an average of 0.23 mmol/L and LDL cholesterol by 0.45 mmol/L; HDL was raised modestly. Kestin et al26 have reported lower LDL cholesterol levels with a soybean-enriched vegetarian diet than when meat protein was substituted for soy protein.
In the present study, we failed to observe any effect on plasma
lipids in women who were marginally
hypercholesterolemic (Table 2
). The dose of isoflavones
was greater than that which would have been contained in the average
amount of soy protein in Anderson et al's
metaanalysis.14 Although genistein was a
favored candidate to explain the LDL-lowering potential of soy protein,
this now seems less likely. How soy protein lowers
cholesterol is clouded by the absence of a clear dose
response and that similar lowering is achievable with different amounts
of protein.
Genistein has also been shown to have antioxidant properties, at least
in vitro.7 The isoflavone is both hydrophilic and
hydrophobic, and it is therefore not clear how much becomes
incorporated into LDL in vivo. Our studies show that the LDL isolated
from subjects when exposed to oxidant copper did not show the delay in
oxidation that is typical of lipid soluble antioxidants such as
-tocopheral (Table 5
). Nor was there less oxidant product
generated from LDL lipids, in vitro. This does not exclude in vivo
antioxidant effects, as with ascorbic acid.
We measured FSH on only one occasion to establish menopausal status. In postmenopausal women, FSH levels remain unaltered after ingestion of soy foods,27 although 60 g of soy protein daily has suppressed midcycle surges of luteinizing hormone (LH) and FSH in premenopausal women.28
In conclusion, moderate consumption of the active isoflavone genistein improved systemic arterial compliance, an important index of the elasticity of large arteries, in postmenopausal and perimenopausal women. Plasma lipids were not changed, a finding suggesting that other constituents of soybean may be responsible for lipid lowering.
| Acknowledgments |
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Received March 27, 1997; accepted June 12, 1997.
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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. Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC J. Nutr., March 1, 2007; 137(3): 718S - 737S. [Abstract] [Full Text] [PDF] |
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H. J. Teede, D. Giannopoulos, F. S. Dalais, J. Hodgson, and B. P. McGrath Randomised, Controlled, Cross-Over Trial of Soy Protein with Isoflavones on Blood Pressure and Arterial Function in Hypertensive Subjects J. Am. Coll. Nutr., December 1, 2006; 25(6): 533 - 540. [Abstract] [Full Text] [PDF] |
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F. M. Sacks, A. Lichtenstein, L. Van Horn, W. Harris, P. Kris-Etherton, M. Winston, and for the AHA Nutrition Committee Soy protein, isoflavones, and cardiovascular health: a summary of a statement for professionals from the american heart association nutrition committee. Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1689 - 1692. [Full Text] [PDF] |
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C. N. Bairey Merz, B. D. Johnson, G. D. Braunstein, C. J. Pepine, S. E. Reis, M. Paul-Labrador, G. Hale, B. L. Sharaf, V. Bittner, G. Sopko, et al. Phytoestrogens and Lipoproteins in Women J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2209 - 2213. [Abstract] [Full Text] [PDF] |
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M. Raff, T. Tholstrup, K. Sejrsen, E. M. Straarup, and N. Wiinberg Diets Rich in Conjugated Linoleic Acid and Vaccenic Acid Have No Effect on Blood Pressure and Isobaric Arterial Elasticity in Healthy Young Men J. Nutr., April 1, 2006; 136(4): 992 - 997. [Abstract] [Full Text] [PDF] |
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W. L Hall, K. Vafeiadou, J. Hallund, S. Bugel, M. Reimann, C. Koebnick, H-J F. Zunft, M. Ferrari, F. Branca, T. Dadd, et al. Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production Am. J. Clinical Nutrition, March 1, 2006; 83(3): 592 - 600. [Abstract] [Full Text] [PDF] |
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A. Dewell, P. L. W. Hollenbeck, and C. B. Hollenbeck A Critical Evaluation of the Role of Soy Protein and Isoflavone Supplementation in the Control of Plasma Cholesterol Concentrations J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 772 - 780. [Abstract] [Full Text] [PDF] |
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C. Vlachopoulos, F. Kosmopoulou, N. Alexopoulos, N. Ioakeimidis, G. Siasos, and C. Stefanadis Acute mental stress has a prolonged unfavorable effect on arterial stiffness and wave reflections. Psychosom Med, March 1, 2006; 68(2): 231 - 237. [Abstract] [Full Text] [PDF] |
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G. Douglas, J. A. Armitage, P. D. Taylor, J. R. Lawson, G. E. Mann, and L. Poston Cardiovascular consequences of life-long exposure to dietary isoflavones in the rat J. Physiol., March 1, 2006; 571(2): 477 - 487. [Abstract] [Full Text] [PDF] |
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F. M. Sacks, A. Lichtenstein, L. Van Horn, W. Harris, P. Kris-Etherton, M. Winston, and for the American Heart Association Nutrition Commi Soy Protein, Isoflavones, and Cardiovascular Health: An American Heart Association Science Advisory for Professionals From the Nutrition Committee Circulation, February 21, 2006; 113(7): 1034 - 1044. [Abstract] [Full Text] [PDF] |
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M. K. Melby, M. Lock, and P. Kaufert Culture and symptom reporting at menopause Hum. Reprod. Update, September 1, 2005; 11(5): 495 - 512. [Abstract] [Full Text] [PDF] |
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Y. Ma, D. Chiriboga, B. C. Olendzki, R. Nicolosi, P. A. Merriam, and I. S. Ockene Effect of Soy Protein Containing Isoflavones on Blood Lipids in Moderately Hypercholesterolemic Adults: A Randomized Controlled Trial J. Am. Coll. Nutr., August 1, 2005; 24(4): 275 - 285. [Abstract] [Full Text] [PDF] |
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J. B. Keogh, J. A. Grieger, M. Noakes, and P. M. Clifton Flow-Mediated Dilatation Is Impaired by a High-Saturated Fat Diet but Not by a High-Carbohydrate Diet Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1274 - 1279. [Abstract] [Full Text] [PDF] |
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G. Yang, X.-O. Shu, F. Jin, X. Zhang, H.-L. Li, Q. Li, Y.-T. Gao, and W. Zheng Longitudinal study of soy food intake and blood pressure among middle-aged and elderly Chinese women Am. J. Clinical Nutrition, May 1, 2005; 81(5): 1012 - 1017. [Abstract] [Full Text] [PDF] |
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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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D. Liu, H. Jiang, and R. W. Grange Genistein Activates the 3',5'-Cyclic Adenosine Monophosphate Signaling Pathway in Vascular Endothelial Cells and Protects Endothelial Barrier Function Endocrinology, March 1, 2005; 146(3): 1312 - 1320. [Abstract] [Full Text] [PDF] |
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F. M. Sacks Dietary Phytoestrogens to Prevent Cardiovascular Disease: Early Promise Unfulfilled Circulation, February 1, 2005; 111(4): 385 - 387. [Full Text] [PDF] |
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Y. T. van der Schouw, S. Kreijkamp-Kaspers, P. H.M. Peeters, L. Keinan-Boker, E. B. Rimm, and D. E. Grobbee Prospective Study on Usual Dietary Phytoestrogen Intake and Cardiovascular Disease Risk in Western Women Circulation, February 1, 2005; 111(4): 465 - 471. [Abstract] [Full Text] [PDF] |
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S. Vega-Lopez, K.-J. Yeum, J. L Lecker, L. M Ausman, E. J Johnson, S. Devaraj, I. Jialal, and A. H Lichtenstein Plasma antioxidant capacity in response to diets high in soy or animal protein with or without isoflavones Am. J. Clinical Nutrition, January 1, 2005; 81(1): 43 - 49. [Abstract] [Full Text] [PDF] |
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D. Liu, L. L. Homan, and J. S. Dillon Genistein Acutely Stimulates Nitric Oxide Synthesis in Vascular Endothelial Cells by a Cyclic Adenosine 5'-Monophosphate-Dependent Mechanism Endocrinology, December 1, 2004; 145(12): 5532 - 5539. [Abstract] [Full Text] [PDF] |
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Y. T. van der Schouw, D. E. Grobbee, L. Kok, and S. Kreijkamp-Kaspers Isoflavones and Postmenopausal Women--Reply JAMA, November 17, 2004; 292(19): 2337 - 2337. [Full Text] [PDF] |
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M. S Rosell, P. N Appleby, E. A Spencer, and T. J Key Soy intake and blood cholesterol concentrations: a cross-sectional study of 1033 pre- and postmenopausal women in the Oxford arm of the European Prospective Investigation into Cancer and Nutrition Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1391 - 1396. [Abstract] [Full Text] [PDF] |
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X.-G. Zhuo, M. K. Melby, and S. Watanabe Soy Isoflavone Intake Lowers Serum LDL Cholesterol: A Meta-Analysis of 8 Randomized Controlled Trials in Humans J. Nutr., September 1, 2004; 134(9): 2395 - 2400. [Abstract] [Full Text] [PDF] |
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M. Messina Western soy intake is too low to produce health effects Am. J. Clinical Nutrition, August 1, 2004; 80(2): 528 - 529. [Full Text] [PDF] |
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E. Nikander, A. Tiitinen, K. Laitinen, M. Tikkanen, and O. Ylikorkala Effects of Isolated Isoflavonoids on Lipids, Lipoproteins, Insulin Sensitivity, and Ghrelin in Postmenopausal Women J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3567 - 3572. [Abstract] [Full Text] [PDF] |
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S. Desroches, J.-F. Mauger, L. M. Ausman, A. H. Lichtenstein, and B. Lamarche Soy Protein Favorably Affects LDL Size Independently of Isoflavones in Hypercholesterolemic Men and Women J. Nutr., March 1, 2004; 134(3): 574 - 579. [Abstract] [Full Text] [PDF] |
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L. W. Lissin, R. Oka, S. Lakshmi, and J. P Cooke Isoflavones improve vascular reactivity in post-menopausal women with hypercholesterolemia Vascular Medicine, February 1, 2004; 9(1): 26 - 30. [Abstract] [PDF] |
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C. Atkinson, J. E Compston, N. E Day, M. Dowsett, and S. A Bingham The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial Am. J. Clinical Nutrition, February 1, 2004; 79(2): 326 - 333. [Abstract] [Full Text] [PDF] |
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Y. Lin, G. W. Meijer, M. A. Vermeer, and E. A. Trautwein Soy Protein Enhances the Cholesterol-Lowering Effect of Plant Sterol Esters in Cholesterol-Fed Hamsters J. Nutr., January 1, 2004; 134(1): 143 - 148. [Abstract] [Full Text] [PDF] |
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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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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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J. W. Anderson Diet First, Then Medication for Hypercholesterolemia JAMA, July 23, 2003; 290(4): 531 - 533. [Full Text] [PDF] |
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F. M Steinberg, N. L Guthrie, A. C Villablanca, K. Kumar, and M. J Murray Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women Am. J. Clinical Nutrition, July 1, 2003; 78(1): 123 - 130. [Abstract] [Full Text] [PDF] |
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C. E. Piersen Phytoestrogens in Botanical Dietary Supplements: Implications for Cancer Integr Cancer Ther, June 1, 2003; 2(2): 120 - 138. [Abstract] [PDF] |
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H. J. Teede, B. P. McGrath, L. DeSilva, M. Cehun, A. Fassoulakis, and P. J. Nestel Isoflavones Reduce Arterial Stiffness: A Placebo-Controlled Study in Men and Postmenopausal Women Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1066 - 1071. [Abstract] [Full Text] [PDF] |
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M. S. Kurzer Phytoestrogen Supplement Use by Women J. Nutr., June 1, 2003; 133(6): 1983S - 1986. [Abstract] [Full Text] [PDF] |
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J. W. Lampe Isoflavonoid and Lignan Phytoestrogens as Dietary Biomarkers J. Nutr., March 1, 2003; 133(3): 956S - 964. [Abstract] [Full Text] [PDF] |
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R. M. Blair, S. E. Appt, C. Bennetau-Pelissero, T. B. Clarkson, M. S. Anthony, V. Lamothe, and S. M. Potter Dietary Soy and Soy Isoflavones Have Gender-Specific Effects on Plasma Lipids and Isoflavones in Golden Syrian F1B Hybrid Hamsters J. Nutr., December 1, 2002; 132(12): 3585 - 3591. [Abstract] [Full Text] [PDF] |
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P. Nestel Role of Soy Protein in Cholesterol-Lowering: How Good Is It? Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1743 - 1744. [Full Text] [PDF] |
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A. H. Lichtenstein, S. M. Jalbert, H. Adlercreutz, B. R. Goldin, H. Rasmussen, E. J. Schaefer, and L. M. Ausman Lipoprotein Response to Diets High in Soy or Animal Protein With and Without Isoflavones in Moderately Hypercholesterolemic Subjects Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1852 - 1858. [Abstract] [Full Text] [PDF] |
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D. A.J.M. Kerckhoffs, F. Brouns, G. Hornstra, and R. P. Mensink Effects on the Human Serum Lipoprotein Profile of {beta}-Glucan, Soy Protein and Isoflavones, Plant Sterols and Stanols, Garlic and Tocotrienols J. Nutr., September 1, 2002; 132(9): 2494 - 2505. [Abstract] [Full Text] [PDF] |
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D. J. Jenkins, C. W. Kendall, C.-J. C Jackson, P. W Connelly, T. Parker, D. Faulkner, E. Vidgen, S. C Cunnane, L. A Leiter, and R. G Josse Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women Am. J. Clinical Nutrition, August 1, 2002; 76(2): 365 - 372. [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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N. Tsunoda, S. Pomeroy, and P. Nestel Absorption in Humans of Isoflavones from Soy and Red Clover Is Similar J. Nutr., August 1, 2002; 132(8): 2199 - 2201. [Abstract] [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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S. Tonstad, K. Smerud, and L. Hoie A comparison of the effects of 2 doses of soy protein or casein on serum lipids, serum lipoproteins, and plasma total homocysteine in hypercholesterolemic subjects Am. J. Clinical Nutrition, July 1, 2002; 76(1): 78 - 84. [Abstract] [Full Text] [PDF] |
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T. B. Clarkson Soy, Soy Phytoestrogens and Cardiovascular Disease J. Nutr., March 1, 2002; 132(3): 566S - 569. [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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A. Dewell, C. B. Hollenbeck, and B. Bruce The Effects of Soy-Derived Phytoestrogens on Serum Lipids and Lipoproteins in Moderately Hypercholesterolemic Postmenopausal Women J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 118 - 121. [Abstract] [Full Text] [PDF] |
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M. R. Adams, D. L. Golden, M. S. Anthony, T. C. Register, and J. K. Williams The Inhibitory Effect of Soy Protein Isolate on Atherosclerosis in Mice Does Not Require the Presence of LDL Receptors or Alteration of Plasma Lipoproteins J. Nutr., January 1, 2002; 132(1): 43 - 49. [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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V. Burke, J. M. Hodgson, L. J. Beilin, N. Giangiulioi, P. Rogers, and I. B. Puddey Dietary Protein and Soluble Fiber Reduce Ambulatory Blood Pressure in Treated Hypertensives Hypertension, October 1, 2001; 38(4): 821 - 826. [Abstract] [Full Text] [PDF] |
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S. B. Dent, C. T. Peterson, L. D. Brace, J. H. Swain, M. B. Reddy, K. B. Hanson, J. G. Robinson, and D. L. Alekel Soy Protein Intake by Perimenopausal Women Does Not Affect Circulating Lipids and Lipoproteins or Coagulation and Fibrinolytic Factors J. Nutr., September 1, 2001; 131(9): 2280 - 2287. [Abstract] [Full Text] [PDF] |
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H. J. Teede, F. S. Dalais, D. Kotsopoulos, Y.-L. Liang, S. Davis, and B. P. McGrath Dietary Soy Has Both Beneficial and Potentially Adverse Cardiovascular Effects: A Placebo-Controlled Study in Men and Postmenopausal Women J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3053 - 3060. [Abstract] [Full Text] [PDF] |
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M. G. Glazier and M. A. Bowman A Review of the Evidence for the Use of Phytoestrogens as a Replacement for Traditional Estrogen Replacement Therapy Arch Intern Med, May 14, 2001; 161(9): 1161 - 1172. [Abstract] [Full Text] [PDF] |
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A. H Lichtenstein Got soy? Am. J. Clinical Nutrition, April 1, 2001; 73(4): 667 - 668. [Full Text] [PDF] |
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C. D Gardner, K. A Newell, R. Cherin, and W. L Haskell The effect of soy protein with or without isoflavones relative to milk protein on plasma lipids in hypercholesterolemic postmenopausal women Am. J. Clinical Nutrition, April 1, 2001; 73(4): 728 - 735. [Abstract] [Full Text] [PDF] |
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D. Goodman-Gruen and D. Kritz-Silverstein Usual Dietary Isoflavone Intake Is Associated with Cardiovascular Disease Risk Factors in Postmenopausal Women J. Nutr., April 1, 2001; 131(4): 1202 - 1206. [Abstract] [Full Text] |
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K. D. R. Setchell, N. M. Brown, P. Desai, L. Zimmer-Nechemias, B. E. Wolfe, W. T. Brashear, A. S. Kirschner, A. Cassidy, and J. E. Heubi Bioavailability of Pure Isoflavones in Healthy Humans and Analysis of Commercial Soy Isoflavone Supplements J. Nutr., April 1, 2001; 131(4): 1362S - 1375. [Abstract] [Full Text] |
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A. M. Dart and B. A. Kingwell Pulse pressure--a review of mechanisms and clinical relevance J. Am. Coll. Cardiol., March 15, 2001; 37(4): 975 - 984. [Abstract] [Full Text] [PDF] |
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K. E Wangen, A. M Duncan, X. Xu, and M. S Kurzer Soy isoflavones improve plasma lipids in normocholesterolemic and mildly hypercholesterolemic postmenopausal women Am. J. Clinical Nutrition, February 1, 2001; 73(2): 225 - 231. [Abstract] [Full Text] [PDF] |
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J. W. Erdman Jr Soy Protein and Cardiovascular Disease : A Statement for Healthcare Professionals From the Nutrition Committee of the AHA Circulation, November 14, 2000; 102(20): 2555 - 2559. [Full Text] [PDF] |
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S. Lamon-Fava Genistein Activates Apolipoprotein A-I Gene Expression in the Human Hepatoma Cell Line Hep G2 J. Nutr., October 1, 2000; 130(10): 2489 - 2492. [Abstract] [Full Text] |
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Y. Arai, S. Watanabe, M. Kimira, K. Shimoi, R. Mochizuki, and N. Kinae Dietary Intakes of Flavonols, Flavones and Isoflavones by Japanese Women and the Inverse Correlation between Quercetin Intake and Plasma LDL Cholesterol Concentration J. Nutr., September 1, 2000; 130(9): 2243 - 2250. [Abstract] [Full Text] |
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M. R. Peluso, T. A. Winters, M. F. Shanahan, and W. J. Banz A Cooperative Interaction between Soy Protein and Its Isoflavone-Enriched Fraction Lowers Hepatic Lipids in Male Obese Zucker Rats and Reduces Blood Platelet Sensitivity in Male Sprague-Dawley Rats J. Nutr., September 1, 2000; 130(9): 2333 - 2342. [Abstract] [Full Text] |
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J. Yamakoshi, M. K. Piskula, T. Izumi, K. Tobe, M. Saito, S. Kataoka, A. Obata, and M. Kikuchi Isoflavone Aglycone-Rich Extract without Soy Protein Attenuates Atherosclerosis Development in Cholesterol-Fed Rabbits J. Nutr., August 1, 2000; 130(8): 1887 - 1893. [Abstract] [Full Text] |
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B. E Merz-Demlow, A. M Duncan, K. E Wangen, X. Xu, T. P Carr, W. R Phipps, and M. S Kurzer Soy isoflavones improve plasma lipids in normocholesterolemic, premenopausal women Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1462 - 1469. [Abstract] [Full Text] [PDF] |
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E. L. Ashton, F. S. Dalais, and M. J. Ball Effect of Meat Replacement by Tofu on CHD Risk Factors Including Copper Induced LDL Oxidation J. Am. Coll. Nutr., June 1, 2000; 19(6): 761 - 767. [Abstract] [Full Text] [PDF] |
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K. A. Greaves, M. D. Wilson, L. L. Rudel, J. K. Williams, and J. D. Wagner Consumption of Soy Protein Reduces Cholesterol Absorption Compared to Casein Protein Alone or Supplemented with an Isoflavone Extract or Conjugated Equine Estrogen in Ovariectomized Cynomolgus Monkeys J. Nutr., April 1, 2000; 130(4): 820 - 826. [Abstract] [Full Text] |
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M. S. Anthony Soy and Cardiovascular Disease: Cholesterol Lowering and Beyond J. Nutr., March 1, 2000; 130(3): 662 - 662. [Full Text] |
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Oral Presentation Abstracts J. Nutr., March 1, 2000; 130(3): 666 - 666. [Full Text] |
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Poster Presentation Abstracts J. Nutr., March 1, 2000; 130(3): 680 - 680. [Full Text] |
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K. Sudhir and P. A. Komesaroff Cardiovascular Actions of Estrogens in Men J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3411 - 3415. [Full Text] [PDF] |
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J. R. Crouse III, T. Morgan, J. G. Terry, J. Ellis, M. Vitolins, and G. L. Burke A Randomized Trial Comparing the Effect of Casein With That of Soy Protein Containing Varying Amounts of Isoflavones on Plasma Concentrations of Lipids and Lipoproteins Arch Intern Med, September 27, 1999; 159(17): 2070 - 2076. [Abstract] [Full Text] [PDF] |
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K. A. Greaves, J. S. Parks, J. K. Williams, and J. D. Wagner Intact Dietary Soy Protein, but Not Adding an Isoflavone-Rich Soy Extract to Casein, Improves Plasma Lipids in Ovariectomized Cynomolgus Monkeys J. Nutr., August 1, 1999; 129(8): 1585 - 1592. [Abstract] [Full Text] |
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J. W. Anderson and T. J. Hanna Impact of Nondigestible Carbohydrates on Serum Lipoproteins and Risk for Cardiovascular Disease J. Nutr., July 1, 1999; 129(7): 1457 - 1457. [Abstract] [Full Text] |
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P. FANTI, B. P. SAWAYA, L. J. CUSTER, and A. A. FRANKE Serum Levels and Metabolic Clearance of the Isoflavones Genistein and Daidzein in Hemodialysis Patients J. Am. Soc. Nephrol., April 1, 1999; 10(4): 864 - 871. [Abstract] [Full Text] |
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P. J. Nestel, S. Pomeroy, S. Kay, P. Komesaroff, J. Behrsing, J. D. Cameron, and L. West Isoflavones from Red Clover Improve Systemic Arterial Compliance But Not Plasma Lipids in Menopausal Women J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 895 - 898. [Abstract] [Full Text] |
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A. H. Lichtenstein Soy Protein, Isoflavones and Cardiovascular Disease Risk J. Nutr., October 1, 1998; 128(10): 1589 - 1592. [Abstract] [Full Text] |
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