© 1997 American Heart Association, Inc.
Articles |
Soy Isoflavones Improve Systemic Arterial Compliance but Not Plasma Lipids in Menopausal and Perimenopausal Women
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).
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Abstract |
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Abstract The possibility that the heightened cardiovascular risk associated with the menopause, which is said to be ameliorated by soybeans, can be reduced with soy isoflavones was tested in 21 women. Although several were perimenopausal, all have been included. A placebo-controlled crossover trial tested the effects of 80-mg daily isoflavones (45 mg genistein) over 5- to 10-week periods. Systemic arterial compliance (arterial elasticity), which declined with age in this group, improved 26% (P<.001) compared with placebo. Arterial pressure and plasma lipids were unaffected. The vasodilatory capacity of the microcirculation was measured in nine women; high acetylcholine-mediated dilation in the forearm vasculature was similar with active and placebo treatments. LDL oxidizability measured in vitro was unchanged. Thus, one important measure of arterial health, systemic arterial compliance, was significantly improved in perimenopausal and menopausal women taking soy isoflavones to about the same extent as is achieved with conventional hormone replacement therapy.
Key Words: genistein • menopause • women • flavonoids
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Introduction |
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The high consumption of soybean products has been credited with the relative protection that Japanese women enjoy from complications of the menopause. Fewer symptoms and less cardiovascular disease resemble the likely benefits of hormone replacement therapy in menopausal Western women.1 The mechanisms have not been previously defined. The lipoprotein profile is more clearly improved with estrogen,2 and a direct beneficial effect on arterial vasculature has also been established for estrogen.3 4
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.
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Methods |
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Test Subjects
Women were invited through newspaper advertisements to take part in a clinical trial of the purified soybean extract that might alleviate menopausal symptoms and reduce measurable cardiovascular risk. Respondents all claimed that they were experiencing some menopausal discomfort. The majority had been clearly postmenopausal for several years; others considered themselves perimenopausal because symptoms had appeared during the preceding year and menstruation had become infrequent and reduced. Objective measurements of FSH were not available until later. Of the 23 women who apparently fulfilled the criteria of being menopausal or perimenopausal, two resumed regular menses during the trial, and in the opinion of the endocrinologist (P.K.), and on the basis of subsequent FSH values, six have been classified perimenopausal and one premenopausal (Table 1
).
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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.
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Results |
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General Results
Three intervention periods were planned, an initial baseline-diet-only period to establish a regular low-legume diet and to "wash out" previous supplements (eg, vitamins and primrose oil) and then a crossed-over, randomly initiated placebo versus isoflavone trial. A second isoflavone period, also of about 5 weeks' duration, was added at the end. This led to a continuous 10 weeks of active treatment in those who were randomly assigned to isoflavones to follow placebo. The results include the baseline data as a reference point, but interpretation and conclusions will be limited to placebo versus active treatment. The data have been examined in the first instance for effects of time and order of treatment, including possible carryover. None of these was found to be a confounder: 10 weeks continuous active treatment did not differ from 5 weeks treatment, and the order of active and placebo did not affect results, so a carryover effect from active into placebo was unlikely. There were too few women to compare the effects of 40 mg and 80 mg. Urinary isoflavones showed satisfactory absorption, but since only one 24-hour sample was available, no conclusions have been attempted. Isoflavonoid output varied from 11 mg to 59 mg, average (±SD), 32±12mg comprising mainly genistein and daidzein. This equates to at least 40% absorption, which may be unreliable on single measurements and takes no account of intestinal reexcretion. Isoflavonoid excretion during placebo averaged <1 mg daily. Average group body weights did not change during the baseline (70±12 kg), placebo (70±12 kg), and active (70±12 kg) interventions.
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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This study was undertaken with the assumption that dietary soybeans as consumed by Asian women afforded protection from coronary heart disease (CHD) through mechanisms that might also explain the reduced prevalence of CHD among menopausal women in Western cultures who take estrogen replacement therapy.13 Soy protein, like estrogen, has been reported to lower LDL cholesterol,14 to inhibit oxidizability of LDL,7 and to exert direct vasodilatory effects on the arterial circulation in monkeys.5 Since the menopause, untreated, leads to a rise in LDL cholesterol,2 13 to endothelial dysfunction,15 and to reduced carotid arterial pulsatility,16 these were some of the parameters that were chosen as appropriate biomarkers for the postulated cardiovascular benefits from eating soybean. Soybeans contain several promising candidate compounds, of which isoflavones, especially genistein, have been favored by a number of investigators. We chose a purified source of soy isoflavones in preference to soybeans because of the variability in the isoflavone content of soybeans17 and the uncertainty of the degree of absorption.17 The dosage (80 mg total isoflavone distributed 1.3:1:0.1 as genistein, daidzein, and glycetin) provided about 45 mg of genistein daily, of which at least 40% was absorbed. Absorption was almost certainly greater because reexcretion of absorbed genistein in feces is an additional process. This approximates to 60 g of green soybean or a little less of soy flour. Although this represents a high intake for omnivorous Western women, it resembles that present in the traditional Japanese cuisine,18 but of the order that is said to have lowered LDL cholesterol.14
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
acid–rich 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.
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Acknowledgments |
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The isoflavones were provided by Novogen Limited, North Ryde, NSW, Australia, and we thank Dr Erin Mander for the supplies and advice. The study was supported by Novogen Limited, Grains Research Development Corporation, and National Heart Foundation of Australia. Alice Owen, a graduate student, is enrolled in the Department of Physiology, University of Adelaide.
Received March 27, 1997; accepted June 12, 1997.
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