Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
2006;113;1034-1044; originally published online Jan 17, 2006;
Kris-Etherton, Mary Winston and for the American Heart Association Nutrition
Frank M. Sacks, Alice Lichtenstein, Linda Van Horn, William Harris, Penny
Association Science Advisory for Professionals From the Nutrition Committee
Soy Protein, Isoflavones, and Cardiovascular Health: An American Heart
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
Reprints: Information about reprints can be found online at
Street, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email:
Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden
Subscriptions: Information about subscribing to Circulation is online at
by on May 15, 2006 circ.ahajournals.orgDownloaded from
Soy Protein, Isoflavones, and Cardiovascular Health
An American Heart Association Science Advisory for Professionals
From the Nutrition Committee
Frank M. Sacks, MD; Alice Lichtenstein, DSc; Linda Van Horn, PhD, RD; William Harris, PhD;
Penny Kris-Etherton, PhD; Mary Winston, EdD;
for the American Heart Association Nutrition Committee
Abstract—Soy protein and isoflavones (phytoestrogens) have gained considerable attention for their potential role in
improving risk factors for cardiovascular disease. This scientific advisory assesses the more recent work published on
soy protein and its component isoflavones. In the majority of 22 randomized trials, isolated soy protein with isoflavones,
as compared with milk or other proteins, decreased LDL cholesterol concentrations; the average effect was ?3%. This
reduction is very small relative to the large amount of soy protein tested in these studies, averaging 50 g, about half the
usual total daily protein intake. No significant effects on HDL cholesterol, triglycerides, lipoprotein(a), or blood pressure
were evident. Among 19 studies of soy isoflavones, the average effect on LDL cholesterol and other lipid risk factors
was nil. Soy protein and isoflavones have not been shown to lessen vasomotor symptoms of menopause, and results are
mixed with regard to soy’s ability to slow postmenopausal bone loss. The efficacy and safety of soy isoflavones for
preventing or treating cancer of the breast, endometrium, and prostate are not established; evidence from clinical trials
is meager and cautionary with regard to a possible adverse effect. For this reason, use of isoflavone supplements in food
or pills is not recommended. Thus, earlier research indicating that soy protein has clinically important favorable effects
as compared with other proteins has not been confirmed. In contrast, many soy products should be beneficial to
cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and
low content of saturated fat. (Circulation. 2006;113:1034-1044.)
Key Words: AHA Scientific Statements ? cardiovascular diseases ? soybean proteins ? isoflavones ? cholesterol
disease (CVD). In October 1999, the US Food and Drug
Administration (FDA) approved labeling for foods containing
soy protein as protective against coronary heart disease.1The
FDA based this decision on clinical studies showing that at
least 25 g of soy protein per day lowered total and LDL
cholesterol. The FDA requires for the claim that a serving
contain at least 6.25 g of soy protein, 25% of the necessary
daily amount (25 g), with the expectation that foods contain-
ing soy protein would be eaten at least 4 times per day. The
FDA also stated that “the evidence did not support a signif-
icant role for soy isoflavones in cholesterol-lowering effects
of soy protein.”1
In 2000, the American Heart Association (AHA) Nutrition
Committee released a scientific advisory on soy protein and
oy protein has gained considerable attention for its
potential role in improving risk factors for cardiovascular
CVD.2At that time, the conclusion was that “it is prudent to
recommend including soy protein foods in a diet low in
saturated fat and cholesterol.” Since then, many well-
controlled studies on soy protein and soy-derived isoflavones
substantially added to the knowledge base. For this reason,
the AHA Nutrition Committee decided to reevaluate the
evidence on soy protein and CVD and update its scientific
advisory. Thus, this scientific advisory assesses the more
recent work published on soy protein and its component
isoflavones. The focus is on blood LDL cholesterol because it
is by far the most studied risk factor for CVD, is the primary
criterion on which the National Cholesterol Education Pro-
gram estimates risk and recommends therapy,3and forms the
basis for the FDA-approved health claim. In this advisory, we
also consider the effects of soy protein and isoflavones on
several other CVD risk factors: HDL cholesterol, triglycer-
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside
relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required
to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on August 10, 2005. A single reprint
is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX
75231-4596. Ask for reprint No. 71-0279. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000
or more copies, call 410-528-4121, fax 410-528-4264, or e-mail firstname.lastname@example.org. To make photocopies for personal or educational use, call the
Copyright Clearance Center, 978-750-8400.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development,
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.orgDOI: 10.1161/CIRCULATIONAHA.106.171052
AHA Science Advisory
ides, lipoprotein(a), and blood pressure. The medical litera-
ture was searched comprehensively for original research
publications on the effects of soy protein or isoflavones on
CVD risk factors, and all controlled trials that separately
listed soy protein and isoflavone content were used. In
addition, this advisory reviews the evidence on soy products
in other health conditions, including menopausal symptoms,
osteoporosis, and cancer.
Soy protein, like any other dietary protein, contains calo-
ries and could be used in the diet to replace animal protein or
other vegetable proteins. Soy protein also could replace other
sources of calories such as carbohydrate or fat, raising the
total amount of protein eaten and reducing carbohydrate or fat
intake. Most studies exchanged soy protein for other dietary
proteins, and this evidence is evaluated in the present advi-
sory. Much less is known about the potential impact on risk
factors for CVD of increasing total protein intake by adding
soy or other plant protein in place of carbohydrate or fat; this
important dietary change is currently being studied.
The Soy Protein Hypothesis on
Animal proteins raise blood cholesterol concentrations in
several animal species fed cholesterol-free semisynthetic
diets.4,5Casein, the most prevalent protein in milk, has been
used most often, although other animal proteins such as pork
and beef protein do the same. This is a useful established
nutritional model for studying diet-induced hypercholesterol-
emia and atherosclerosis and an alternative to feeding animals
large amounts of cholesterol. In contrast, when soy protein is
substituted for the animal protein, hypercholesterolemia does
not occur. Thus, either some animal proteins have a direct
hypercholesterolemic action, or soy protein has a cholester-
ol-lowering action. This latter possibility led to intensive
work in the late 1970s and 1980s to test the hypothesis that
soy protein can be a nutritional approach to reducing blood
cholesterol. This concept gained support from epidemiologi-
cal observations on diet and CVD in Japan and other Asian
countries where large amounts of soy products were eaten
and blood cholesterol concentration and CVD incidence were
low.6However, many differences in diet and lifestyle be-
tween Asian and Western countries could explain the differ-
ences in the prevalence of CVD.
Early indications that soy protein had much less effect in
humans than in animals came from direct application of the
animal model to humans. Diets similar to those eaten by
humans, based on either soy protein or casein, were fed to
rabbits, and, as expected, casein produced hypercholesterol-
emia.7However, when the same diets were fed to healthy
people, the protein source did not affect blood cholesterol.7,8
Others studied the effect of casein in strict vegetarians who
ate no dairy or animal proteins to provide a human counter-
part to the mainly vegetarian animal (eg, rabbit) models.
Compared with soy protein, no effect of casein on blood
cholesterol was found.9
In the late 1970s and early 1980s, the soy protein hypoth-
esis was greatly strengthened as a result of studies by Sirtori
et al10and Descovich et al,11who found that diets high in soy
protein, replacing nearly all the animal protein, substantially
reduced blood LDL cholesterol by 20% to 30% in severe
hypercholesterolemia. Because the soy protein diets were also
reduced in saturated fat and cholesterol and increased in
polyunsaturated fat and because the patients also often lost
weight on the dietary protocols, the results were often
confounded. The authors reported that textured soy protein
(50% soy flour, 50% soy protein concentrate) but not soy
protein isolate (90% soy protein) was effective. This raised
the possibilities that, rather than the soy protein itself, the
nonprotein components of the soy protein preparation or the
effect of soy displacing cholesterol-raising fats in the diet
could have had a blood cholesterol–lowering action. Results
of other early studies of soy protein in hypercholesterolemic
subjects showed either cholesterol reduction12or no
A meta-analysis published in 1995 attempted to reconcile
the many divergent findings among studies of soy protein.15
In 29 controlled studies, a trend emerged that soy protein
selectively reduced blood cholesterol in direct proportion to
the degree of hypercholesterolemia. For example, in those
with severely elevated blood cholesterol (?335 mg/dL), soy
protein reduced blood cholesterol by 20%. Only a 7%
reduction occurred in those with cholesterol levels between
259 and 333 mg/dL; if the initial blood cholesterol was ?255
mg/dL, there was no significant effect. Thus, the response to
soy protein was determined more by the initial blood choles-
terol level and, surprisingly, not by the amount of soy protein
eaten, which ranged widely from 18 to 124 g/d. When the
control group was not included in the statistical analysis,
there was a significant correlation between the dose of soy
protein and the degree of cholesterol reduction. However, an
analysis without a control group introduces the effects of
confounding and drift in serum cholesterol that often occur in
experimental situations. This meta-analysis also was limited
by the quality of the studies; studies were less well controlled
in people with hypercholesterolemia than in those with
average cholesterol levels. It is difficult to determine how
much effect this had on the overall results of the meta-anal-
ysis. Thus, the available literature provided some support,
albeit with limitations, for the concept that soy protein is an
effective treatment for severe hypercholesterolemia, that it
produces a mild benefit in people with moderate elevations of
cholesterol, but that it has no effect in those with mildly
elevated or average cholesterol levels. The soy protein
hypothesis culminated in FDA approval of a health claim for
soy protein in foods.
Subsequent to the meta-analysis by Anderson et al,15many
well-controlled studies explored the soy protein hypothesis
with greater specificity. In addition, recognition that soy
protein products contain bioactive molecules called phy-
toestrogens or isoflavones added a fascinating new aspect to
the soy protein hypothesis.16,17,18Isoflavones remain in soy
protein preparations that are not extracted with alcohol.
During the preparation of soy protein isolate, the soy is
washed with alcohol, removing a substantial amount of the
Sacks et alSoy Protein, Isoflavones, and Cardiovascular Health
isoflavones. The soy isoflavones have strong biological
properties in animals, causing arterial vasodilation, lowering
serum cholesterol,18and inhibiting atherosclerosis in post-
menopausal monkeys.19This led to the intriguing idea that the
presence and amount of isoflavones explain the variable
results of soy studies; only those that used high-isoflavone
preparations produced favorable results.18,20Isoflavone con-
tent was not known in many of the earlier studies. Several
subsequent studies tested the effects of soy protein and
The 3 major isoflavones found in soybeans are genistin,
daidzin, and glycitin. Their abundance in soy protein prepa-
rations varies widely and depends on the processing tech-
niques used during production.21,22These compounds have
both estrogenic and antiestrogenic activity23,24and effects that
are unrelated to estrogen activity.25Dehulling, flaking, and
defatting soybeans produces a relatively pure preparation of
protein that is low in isoflavones,26,27whereas methods used
to produce textured soy protein result in a preparation that
retains the isoflavones.21Isoflavone concentrations range
from ?2 mg/g protein in textured soy protein, soy flour, and
soy granules to 0.6 to 1.0 mg/g protein in isolated soy protein.
Intakes of 45 g soy flour have resulted in a 20- to 40-fold
increase and a 50- to 100-fold increase in blood and urinary
isoflavones, respectively,28and there is a dose-dependent
relationship at more moderate intakes.29
Effect of Soy Protein on LDL Cholesterol and
Soy Protein With Isoflavones
First, we summarize studies that tested soy protein that
contained a substantial amount of isoflavones. Because it was
recognized that isoflavones could be the bioactive component
attributed to soy protein, studies published in the late 1990s
and beyond generally stated the amount and type of isofla-
vones in the soy protein. In 22 randomized trials, isolated soy
protein with isoflavones was compared with casein or milk
protein,20,30–46wheat protein,47or mixed animal proteins.48–50
The range of soy protein was 25 to 135 g/d; the range for
isoflavones was 40 to 318 mg. LDL or non-HDL cholesterol
concentrations decreased in most studies, statistically signif-
icantly in 8, with an overall effect of ?3% (weighted
average). A recent meta-analysis that included 10 studies
published from 1995 to 2002 found a similar percentage
reduction in LDL cholesterol with no dose effect.51Over all
studies in Table 1, there is no apparent dose effect; the 8
studies with 50 g of soy protein showed a drop in LDL
cholesterol concentration similar to those using a smaller
amount of soy, ?3% overall (Table 1). This cutpoint for daily
soy protein intake, 50 g, defines a large amount, half or more
of the daily average total protein intake in the United States.
No significant effects were evident for HDL cholesterol or
triglycerides in most of the studies; the weighted average
effects were very small: 1.5% for HDL cholesterol and ?5%
Soy Protein Without Isoflavones
In 7 trials, soy protein, washed with alcohol to remove
isoflavones, was compared with casein or milk pro-
tein20,33,39,43,52or various animal proteins (Table 2).49,50Two
studies showed small significant decreases in LDL cholester-
ol.49,50These studies were very carefully controlled feeding
studies, with all meals formulated according to strict nutri-
tional specifications, and complete meals were provided to
the participants.49,50Specifically designed to sort out the
effects of the protein from the effects of the isoflavones, the
studies showed an effect of protein but not isoflavones on
LDL cholesterol. The declines in LDL cholesterol were
small, 2% to 7%, relative to the large amounts of soy protein
eaten daily, 50 to 55 g. However, other well-controlled
studies did not find significant effects of soy protein on LDL
cholesterol,20,33,39,43,52and the average change across all 7
studies was only a 1% to 2% decrease. Changes in HDL
cholesterol and triglycerides were generally small and were
nonsignificant in 6 of the 7 trials. No dose effect was evident.
Effect of Isoflavones
Some studies compared soy protein that did or did not contain
isoflavones (Table 3),20,30,33,39,43,49,50,52–57whereas other studies
tested isoflavones in pill form as compared with placebo.58–63A
wide range of isoflavone amounts was studied. One study
compared the effect of isoflavones provided with either soy or
animal proteins.49Among these 19 studies,20,30,33,39,43,49,50,52–63
only 3 showed significant reductions in LDL cholesterol con-
centration,52,55,56and the effect among all studies (weighted
average) was nil, 0%. Changes in HDL cholesterol and triglyc-
erides were not significant and showed no trend toward an effect
of isoflavones. Despite large increases in blood isoflavone
concentrations, there is no indication of a dose effect on blood
lipids. A recent meta-analysis concluded that isoflavones do not
affect blood lipid concentrations.51
Influence of Initial Blood LDL Cholesterol Level
In the Anderson et al15meta-analysis, a strong gradient of
LDL cholesterol reduction was found among studies accord-
ing to initial cholesterol level. Lichtenstein et al49and Crouse
et al20found slightly more LDL cholesterol reduction in
people with LDL cholesterol ?160 to 164 mg/dL than in
those with lower levels, although Dent et al33did not find an
effect in women with hypercholesterolemia as compared with
women with average cholesterol levels. However, a larger
percentage reduction in LDL cholesterol in hypercholesterol-
emia is not evident among the 22 recent trials (Table 1).
Among studies of isoflavones, no relation is evident between
initial cholesterol and cholesterol lowering (Table 3).
Influence of Serum Cholesterol–Lowering Diet
In their meta-analysis, Anderson et al15reported that soy
protein tended to have less effect on LDL cholesterol in trials
in which the participants were eating a low-fat and low-cho-
lesterol diet as compared with a more usual higher-fat and
higher-cholesterol diet. In 11 of the studies listed in Tables 1
through 3, soy protein or isoflavones were tested in combi-
et.20,30,31,34,42,45,47,48,50,58,60The average reduction in LDL in
these studies was 2%, similar to that in the full group. Thus,
the effect on LDL of soy protein or isoflavones does not
appear to be modulated by the saturated fat and cholesterol
content of the diet.
February 21, 2006
Effects on Lipoprotein(a)
Lipoprotein(a), an LDL-like lipoprotein that is an indepen-
dent predictor of CVD,64was increased by soy protein in 2
studies35,65and unchanged in 9 others.20,31,32,36,40,44–46,50
Meinertz et al39found that alcohol-extracted soy protein,
lacking isoflavones, did not raise lipoprotein(a) as found in
their earlier study of intact soy protein,65which suggests an
adverse effect of isoflavones. However, isoflavones had no
effect on lipoprotein(a) in 6 other studies,20,50,55,60,61,63nor did
soy protein that contained isoflavones.20,31,32,36,40,44–46,50
Effects on Blood Pressure
Several studies tested the effect of soy protein with isofla-
vones, as compared with casein or milk protein, on blood
pressure.32,35,40,42,47,50Blood pressure decreased significantly
in 1 study35but not in the other 5 studies.32,40,42,47,50The
TABLE 1.Soy Protein and Blood Lipid Risk Factors: Effects of Soy Protein With Isoflavones
Study and Year Referencen Type Age, yDesignDose Duration
mg/DLTC, % LDL, %HDL, %TG, % Comments
West et al 2005 4532 M, F, HC58 X, DB ISP 25 g IF 90 vs
6 wk 250
et al 2004
44 88 F, HC67 Para, DB ISP 26 g ? IF 99 mg
vs milk protein
et al 2003
43 28 F, Nl55 X, DB ISP 25 g ? IF 107 mg
vs milk protein
Cuevas et al 200342 18F, HC 59X, DB ISP 40 g ? IF 80 mg
Blum et al 20033724F, HC 55X, DB ISP 25 g ? IF 85 mg
vs milk prot
Dalais et al 2003 38 38 F, HC60 Para, DBISP 40 g ? IF 118 mg
Jenkins et al 2002 50 41M, F, HC 62X ISP 50 g ? IF 73 mg vs
dairy ? egg protein
1 mo 260
Tonstad et al 20024630M, F, HC 52 ParaISP 30–50 g ? IF
16 wk 270
23 (NS)No dose
et al 2002
39 12M, F, Nl 30XISP 133 g ? IF 318
mg vs casein
32 d 164
et al 2002
49 42 M, 18; F, 2463X F: ISP 55 g ? IF
6 wk 236
M: ISP 71 g ? IF
139 mg vs dairy
and meat protein
Sirtori et al 20024120M, F, HC60X, DBSoy 25 g ? IF
77 mg vs cow’s milk
Puska et al 2002 36 30 HC 56Para, DB ISP 52 g ? IF 192 mg
6 wk 290
Dent et al 2001 33 24F 50 Para ISP 40 g ? IF 80 mg vs
24 wk 220No effect on
data not shown
Van Horn et al 20013462 F, HC67 ParaISP 29 g ? IF 85 mg vs
6 wk 2400
11 (NS) ND
Teede et al 200135 90M, F61 Para, DBISP 40 g w/IF 118 mg
3 mo 225
et al 2001
4020DM64 X, DBISP 50 g ? IF 165 mg
6 wk 212
Vigna et al 2000 32 40F, Postmen 53 Para, DBISP 60 g ? IF 76 mg
12 wk 2400
Jenkins et al 200047 25M, F, HCXISP 36 g ? IF 168 mg vs
Teixeira et al 20003116M, HC45ParaISP 50 g ? IF 95 mg vs
casein 50 g
6 wk 240
18 (NS) No dose
ISP 20 g ? IF 38 mg vs
casein 50 g
Crouse et al 1999 20 30 M, F52 Para, DBISP 25 g ? IF
62 mg vs casein
9 wk 240
19 (NS)No effect in
High LDL group
Wong et al 1998 48 26 HC, 13 38X ISP 50 g ?IF vs
16 (NS)IF content
Nl, 13 170
Baum et al 1998 30 21F, Postmen 61Para, DBISP 40 g ? IF 90 mg
24 wk 250
22 NSNon-HDL 24*
TC indicates total cholesterol; TG, triglycerides; M, male; F, female; HC, hypercholesterolemic; DM, diabetes mellitus; Nl, normolipidemic; DB, double blind; X,
crossover; Para, parallel group; ISP, isolated soy protein; IF, isoflavones; NS, not significant (P?0.05); and ND, not determined. Percentages are the mean change
in soy protein minus the change in the control group.
*P?0.05 for effect of soy protein vs other protein.
Sacks et al Soy Protein, Isoflavones, and Cardiovascular Health
weighted average change is ?1 mm Hg systolic blood pres-
sure. Several studies that evaluated the effect of soy isofla-
vones also did not find a significant effect on blood
Effects on Health Conditions Related
Menopausal Vasomotor Symptoms
Because of their weak estrogenic activity, soy isoflavones
have been hypothesized to improve several estrogen-
dependent conditions, including perimenopausal vasomotor
symptoms (hot flashes) and postmenopausal bone loss. A
recent review examined 11 clinical trials of soy protein or
isoflavones67for treating hot flashes. Only 3 of 8 studies with
treatment lasting ?6 weeks found modest improvement in
hot flashes, and most benefits disappeared after 6 weeks. Five
additional studies68–72not included in that review showed no
benefit for hot flashes of soy isoflavones. Longer studies
showed no benefit of isoflavones at 24 weeks73or 2 years.71
Substantial reduction in hot flashes, often 40% to 60%,
occurred in the placebo or control group in these studies,
similar to the reduction in the soy group. In contrast, estrogen
replacement markedly reduces hot flashes, more so than
placebo. Thus, it seems unlikely that soy isoflavones have
enough estrogenic activity to have an important impact on
vasomotor symptoms of estrogen deficiency in perimeno-
Another estrogenic effect of soy isoflavones could be to
reduce bone loss after menopause; this hypothesis gains
strength from population studies and certain animal models of
osteoporosis.74However, clinical trials so far have had
insufficient duration and size to be conclusive, and results
have varied.44,74The studies used either direct measurements
of bone mineral content and density in the spine and hip or
biochemical indices of bone resorption or formation to test
the effect of soy isoflavones ranging in amount from 54 to
300 mg, but most studies used 80 to 110 mg. Soy isoflavones
lessened bone loss over 6 to 24 months in some studies,75–78
whereas other trials did not show a benefit over the same
duration.44,57,79There is also inconsistency in the studies
showing favorable effects, with one study showing benefit in
the spine but not hip75and another showing the opposite,77or
improvement in bone mineral content but not bone mineral
density.76,77Diminution of bone loss, indicated by a reduction
in biochemical markers of bone resorption, was found in
some studies78,80,81but not in others.38,44,53,55,82,83The
amounts of isoflavones were similar in studies that found
favorable or no effects. The longest study in any primate
species was in postmenopausal monkeys (cynomolgus ma-
caques); after 3 years, soy isoflavones did not slow bone loss,
whereas estrogen replacement increased bone mineral content
and density, as expected.84These varied results of clinical
trials suggest the need for investigations of isoflavones and
bone health that have substantial sample size and long
duration to provide a definitive result.
The weak estrogenic action of soy isoflavones and other
phytoestrogens suggested the possibility that they could
lessen the deleterious effects of more potent endogenous
estrogens on breast and endometrial cancer. This hypothesis
came from the low incidence of breast and endometrial
cancers in Asian countries where soy products are prevalent
in the diet and from certain animal models of breast and
endometrial cancer showing benefit of soy isoflavones.85–87
In reality, a host of complexities have emerged that make it
impossible to state a clinical recommendation for the use of
soy isoflavones. In epidemiological studies, associations var-
ied between intake of soy foods and isoflavones and inci-
dence of breast cancer85,88–90; some showed protective asso-
ciations, and others showed no association.85,88–90Clinical
TABLE 2. Effects of Soy Protein With Low or No Isoflavones
Year Referencen Type Age, yDesign Dose, g Duration
mg/dLTC, %LDL, % HDL, %TG, %
et al 2003
et al 2002
et al 2002
43 28 F, Nl55 X,DB ISP 25 vs
ISP 50 vs dairy
and egg protein
ISP 55 F; 71 M
vs dairy and
6 wk 190
50 41 M, F, HC62X 1 mo 260
4942M, F63X6 wk 236
111 (NS) Meinertz
et al 2002
Dent et al
3912 M, F, Nl30XISP 133 vs casein
ISP 40 vs
33 24F 50 Para24 wk 220 No effect
(data not shown)
et al 2001
et al 1999
High LDL group
5231F, Postmen 60 ParaISP 42 vs
ISP 25 vs
20 30 M, F52 Para,DB 9 wk240
Abbreviations as in Table 1. Percentages are the mean change in the soy protein minus the change in the control group.
*P?0.05 for effect of soy protein vs other protein.
February 21, 2006
studies suggested that soy phytoestrogens stimulate epithelial
cell proliferation in breasts of premenopausal women, a
potential precursor of cancer.91,92Animal and cell culture
experiments also found a cancer-stimulating effect.93–95Phy-
toestrogens reduce the activity of enzymes that inactivate
endogenous estrogens, potentially leading to increased active
estrogen concentrations.96Nonlinear dose effects, unique
effects of specific types of isoflavones, changes in isoflavone
composition and structure during the processing of soy foods,
and interperson variation in isoflavone metabolism all could
affect cancer initiation and progression22,86,87and are virtually
unexplored in the clinical arena. It has been hypothesized
from animal experiments that soy isoflavones could be
protective throughout adult life only if eaten in childhood or
puberty.97Case-control studies in Shanghai98and in Asian
Americans99found that high soy intake in adolescence was
associated with low risk for breast cancer in adulthood.
Finally, several recent expert reviews and editorials con-
cluded that the research overall remains insufficient to know
whether certain phytoestrogens are protective or harmful for
breast cancer and at what dose and time period, if any, in a
woman’s life they are active.87,100,101
Concepts with regard to soy isoflavones and breast cancer
are applicable to uterine endometrial cancer, an estrogen-
dependent cancer, although data are much less extensive. Soy
food or isoflavone intake was associated with low risk for
endometrial cancer in case-control studies in Shanghai,102
Hawaii,103and California.104This suggests that soy phy-
toestrogens have antiestrogenic effects on the uterus. How-
ever, a single pilot trial of soy isoflavones given together with
estrogen to perimenopausal or postmenopausal women found
no lessening of estrogen-mediated stimulation of the endo-
metrium.105Several clinical trials found that isoflavones did
not affect the uterine endometrium of perimenopausal or
postmenopausal women.105–110However, these trials may
have had insufficient duration (3 to 6 months) or sample size
to identify an effect. Recently, a relatively large placebo-
controlled trial in postmenopausal women found that isofla-
vone tablets caused endometrial hyperplasia, a precursor to
cancer, after 5 years in 6 of 154 women compared with none
on placebo (P?0.05).111Another 5 women in the phytoestro-
gen group had proliferative endometrium compared with
none in the placebo group after 5 years. These effects were
not found at 21⁄2 years. Thus, some cautionary evidence
indicates that soy phytoestrogens have enough estrogenic
activity to stimulate the endometrium of postmenopausal
women, although the evidence overall is inadequate to draw
conclusions on whether soy protein or isoflavones taken by
perimenopausal or postmenopausal women eventually would
cause endometrial cancer.
Soy isoflavones have estrogenic, antiandrogenic, and other
activities that could prevent prostate cancer or slow its
TABLE 3.Effects of Isoflavones
Study and YearReferencen Type Age, yDesign Dose, mg Duration
mg/dL TC, %LDL, %HDL, %TG, %
Nikander et al 200463 56 F, Nl 55X, DB IF 117 vs 0 pills3 mo226
Gallagher et al 20045717F, Nl55 Para, DB IF 96 vs 4; w/ISP9 mo218
IF 52 vs 4; w/ISP0
Steinberg et al 200343 28 F, Nl55X, DB IF 107 vs 2; w/ISP6 wk 190
Jenkins et al 2002 5041M, F, HC62 X, DB IF 73 vs 10; w/ISP 1 mo 260
Lichtenstein et al 20024942 M, F63XIF 108–139 vs 06 wk 236
w/ISP or animal protein 280
Squadrito et al 2002 5830F, Postmen 56Para, DBIF 54 vs 0 pills 6 mo 207
Sanders et al 2002 5422M, F, Nl 30XIF 56 vs 0; w/ISP 2 wk 170
Dewell et al 2002 59 20F, Postmen70 Para, DBIF 150 vs 0 pills 6 mo2630 Non-HDL 26 (NS)0
Meinertz et al 200239 12M, F, Nl 30XIF 318 vs 0; w/ISP 32 d164
Dent et al 2001 33 24F50 ParaIF 80 vs 0; w/ISP 24 wk220 All NS (data
?220All NS (data
Gardner et al 2001 5231F, Postmen 60ParaIF 80 vs 0; w/ISP 12 wk240
Wangen et al 200155 18F, Postmen57XIF 65 vs 7; w/ISP 3 mo215
IF 132 vs 7; w/ISP
Mackey et al 200053 25F, Postmen 56Para, DB IF 65 vs 4; w/ISP12 wk2850
Merz-Demlow et al 200056 13F, Premen 26XIF129 vs 10; w/ISP 3 mo150NS
IF 65 vs 10; w/ISP All NS
Simons et al 2000 6020 F, Postmen 59 X, DBIF 80 vs 0 pills8 wk 228
Crouse et al 19992030 M, F52Para, DBIF 62 vs 3; w/ISP 9 wk240
High LDL group
Baum et al 1998 3021F, Postmen 61Para, DBIF 90 vs 56; w/ISP24 wk 2500Non-HDL 0
Hodgson et al 199861 30M,F, Postmen 56Para, DB IF 55 vs 0 pills8 wk 210
Nestel et al 1997 6221 F, Postmen 54X IF 80 vs 0 pills5 wk 215
Abbreviations as in Table 1, plus Premen indicates premenopausal. Percentages are the mean change in the isoflavone minus the change in the control group.
*P?0.05 for isoflavone effect.
Sacks et al Soy Protein, Isoflavones, and Cardiovascular Health
progression.86,87,112,113Prostate cancer incidence is relatively
low in Asian countries where soy products are commonly
eaten, and certain epidemiological studies have shown an
inverse association between soy foods, serum phytoestrogen
levels, and prostate cancer.113,114However, as pointed out by
Messina,113the epidemiological findings are inconsistent, and
there are important limitations in study design. Soy isofla-
vones prevent the development and growth of prostate cancer
in animal models. In prostate cancer cells, genistein reduced
the synthesis of prostate-specific antigen, a marker of prostate
cancer development and progression that is in extensive
clinical use.86However, soy isoflavones did not reduce either
prostate-specific antigen or serum testosterone levels in men
with early-stage prostate cancer112,115,116or in healthy middle-
aged men.117Thus, the effectiveness of soy isoflavones in
preventing or treating human prostate cancer is unknown.
Earlier research indicating that soy protein, as compared with
other proteins, has clinically important favorable effects on
LDL cholesterol and other CVD risk factors has not been
confirmed by many studies reported during the past 10 years.
A very large amount of soy protein, more than half the daily
protein intake, may lower LDL cholesterol by a few percent-
age points when it replaces dairy protein or a mixture of
animal proteins. The evidence favors soy protein rather than
soy isoflavones as the responsible nutrient. However, at this
time, the possibility cannot be ruled out that another
component in soybeans could be the active factor. No
benefit is evident on HDL cholesterol, triglycerides, li-
poprotein(a), or blood pressure. Thus, the direct cardiovas-
cular health benefit of soy protein or isoflavone supple-
ments is minimal at best. Soy protein or isoflavones have
not been shown to improve vasomotor symptoms of
menopause, and results are mixed with regard to the
slowing of postmenopausal bone loss. The efficacy and
safety of soy isoflavones for preventing or treating cancer
of the breast, endometrium, and prostate are not estab-
lished; evidence from clinical trials is meager and caution-
ary with regard to a possible adverse effect. For this
reason, use of isoflavone supplements in food or pills is not
recommended. In contrast, soy products such as tofu, soy
butter, soy nuts, or some soy burgers should be beneficial
to cardiovascular and overall health because of their high
content of polyunsaturated fats, fiber, vitamins, and min-
erals and low content of saturated fat118(Table 4). Using
these and other soy foods to replace foods high in animal
protein that contain saturated fat and cholesterol may
confer benefits to cardiovascular health.119Soy protein
also may be used to increase total dietary protein intake
and to reduce carbohydrate or fat intake. However, much
less is known about the potential impact of high-protein
diets on risk factors for CVD. In the meantime, these
remain dynamic areas for research. The AHA will continue
to monitor the results and modify its advisory statement as
TABLE 4. Nutrient Content of Popular Soy-Containing Foods
Food Item Quantity
Edamame 1/2 cup, 90 g12610 115 0.53 0.5 2.51.50 2254
Miso2 Tbsp, 34 g 71 1042 0.5 1.1 0.11 0.50 12002
Tofu, extra firm79 g 80284 0.5 2.5 0.521001
Tofu, firm79 g 70273 0.52 0.5 1.50.500
Tofu, silken91 g 4524 2.5 0.51.5 0.51 0.5050
Soy burger1 patty, 57 g 606 130000000 2703
Soy hot dog1 link, 42 g 45290000000 3201
Roasted soy butter2 Tbsp, 32 g 170 106 11 1.56 NA NA2.50 1701
Soy milk, plain flavor1 cup, 240 mL 100874 0.52.50.5210 1201
Soy milk, chocolate1 cup, 240 mL 1402353.5 0.52 0.21.810 1002
Soy candy bar, chocolate1 bar, 61.5 g 240 351453NA NANA NA0 2102
Soy nuts, roasted, unsalted 1 oz, 28 g1209 1240NA NANA NA0 105
NA indicates not available. Values derived from Nutritionist Pro, version 2.10.13, First DataBank, Inc, 2004.
February 21, 2006
Writing Group Disclosures
1. Food labeling: health claims: soy protein and coronary heart disease.
Food and Drug Administration, HHS: final rule: soy protein and
coronary heart disease. Fed Reg. 1999;64:57700–57733.
2. Erdman JW Jr. AHA Science Advisory: soy protein and cardiovascular
disease: a statement for healthcare professionals from the Nutrition Com-
mittee of the AHA. Circulation. 2000;102:2555–2559.
3. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
4. Kritchevsky D. Vegetable protein and atherosclerosis. J Am Oil Chemists
5. Carroll KK. Hypercholesterolemia and atherosclerosis: effects of dietary
protein. Fed Proc. 1982;41:2792–2796.
6. Keys A. Seven Countries: A Multivariate Analysis of Death and Coronary
Heart Disease. Cambridge, Mass: Harvard University Press; 1980.
7. van Raaij JM, Katan MB, Hautvast JG, Hermus RJ. Effects of casein versus
soy protein diets on serum cholesterol and lipoproteins in young healthy
volunteers. Am J Clin Nutr. 1981;34:1261–1271.
8. van Raaij JM, Katan MB, West CE, Hautvast JG. Influence of diets con-
taining casein, soy isolate, and soy concentrate on serum cholesterol and
lipoproteins in middle-aged volunteers. Am J Clin Nutr. 1982;35:925–934.
9. Sacks FM, Breslow JL, Wood PG, Kass EH. Lack of an effect of dairy
protein (casein) and soy protein on plasma cholesterol of strict vegetarians:
an experiment and a critical review. J Lipid Res. 1983;24:1012–1020.
10. Sirtori CR, Gatti E, Mantero O, Conti F, Agradi E, Tremoli E, Sirtori M,
Fraterrigo L, Tavazzi L, Kritchevsky D. Clinical experience with the
soybean protein diet in the treatment of hypercholesterolemia. Am J Clin
11. Descovich GC, Ceredi C, Gaddi A, Benassi MS, Mannino G, Colombo L,
Cattin L, Fontana G, Senin U, Mannarino E, Caruzzo C, Bertelli E,
Fragiacomo C, Noseda G, Sirtori M, Sirtori CR. Multicentre study of
soybean protein diet for outpatient hyper-cholesterolaemic patients. Lancet.
12. Goldberg AP, Lim A, Kolar JB, Grundhauser JJ, Steinke FH, Schonfeld G.
Soybean protein independently lowers plasma cholesterol levels in primary
hypercholesterolemia. Atherosclerosis. 1982;43:355–368.
13. Holmes WL, Rubel GB, Hood SS. Comparison of the effect of dietary meat
versus dietary soybean protein on plasma lipids of hyperlipidemic indi-
viduals. Atherosclerosis. 1980;36:379–387.
14. Shorey RL, Bazan B, Lo GS, Steinke FH. Determinants of hypocholester-
olemic response to soy and animal protein–based diets. Am J Clin Nutr.
15. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the
effects of soy protein intake on serum lipids. N Engl J Med. 1995;333:
16. Adlercreutz H, Mazur W. Phyto-oestrogens and Western diseases. Ann
17. Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE,
Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods: their
role in the prevention of cardiovascular disease and cancer. Am J Med.
18. Anthony MS, Clarkson TB, Williams JK. Effects of soy isoflavones on
atherosclerosis: potential mechanisms. Am J Clin Nutr. 1998;68:
19. Clarkson TB, Anthony MS, Morgan TM. Inhibition of postmenopausal
atherosclerosis progression: a comparison of the effects of conjugated
equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab. 2001;
20. Crouse JR 3rd, Morgan T, Terry JG, Ellis J, Vitolins M, Burke GL. 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. 1999;159:2070–2076.
acid, saponins and isoflavones related to soybean processing. J Nutr. 1995;
22. Erdman JW Jr, Badger TM, Lampe JW, Setchell KD, Messina M. Not all
soy products are created equal: caution needed in interpretation of research
results. J Nutr. 2004;134:1229S–1233S.
Writing Group MemberEmployment
Linda Van Horn
Pennsylvania State University
St Luke’s Hospital
Harvard School of Public Health
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire that all authors are required to complete and submit.
Neil J. Stone
Pennsylvania State University
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Reviewer
Disclosure Questionnaire that all reviewers are required to complete and submit.
Sacks et al Soy Protein, Isoflavones, and Cardiovascular Health
23. Miksicek RJ. Estrogenic flavonoids: structural requirements for biological
activity. Proc Soc Exp Biol Med. 1995;208:44–50.
24. Cassidy A, Bingham S, Setchell K. Biological effects of isoflavones in
young women: importance of the chemical composition of soyabean prod-
ucts. Br J Nutr. 1995;74:587–601.
25. Barnes S. Soy isoflavones: phytoestrogens and what else? J Nutr. 2004;
26. Dwyer JT, Goldin BR, Saul N, Gualtieri L, Barakat S, Adlercreutz H. Tofu
and soy drinks contain phytoestrogens. J Am Diet Assoc. 1994;94:739–743.
27. Lusas EW, Riaz MN. Soy protein products: processing and use. J Nutr.
28. Morton MS, Wilcox G, Wahlqvist ML, Griffiths K. Determination of
lignans and isoflavonoids in human female plasma following dietary sup-
plementation. J Endocrinol. 1994;142:251–259.
29. Karr SC, Lampe JW, Hutchins AM, Slavin JL. Urinary isoflavonoid
excretion in humans is dose dependent at low to moderate levels of soy-
protein consumption. Am J Clin Nutr. 1997;66:46–51.
30. Baum JA, Teng H, Erdman JW Jr, Weigel RM, Klein BP, Persky VW,
Freels S, Surya P, Bakhit RM, Ramos E, Shay NF, Potter SM. Long-term
intake of soy protein improves blood lipid profiles and increases mono-
nuclear cell low-density-lipoprotein receptor messenger RNA in hypercho-
lesterolemic, postmenopausal women. Am J Clin Nutr. 1998;68:545–551.
31. Teixeira SR, Potter SM, Weigel R, Hannum S, Erdman JW Jr, Hasler CM.
Effects of feeding 4 levels of soy protein for 3 and 6 wk on blood lipids and
apolipoproteins in moderately hypercholesterolemic men. Am J Clin Nutr.
32. Vigna GB, Pansini F, Bonaccorsi G, Albertazzi P, Donega P, Zanotti L, De
Aloysio D, Mollica G, Fellin R. Plasma lipoproteins in soy-treated post-
menopausal women: a double-blind, placebo-controlled trial. Nutr Metab
Cardiovasc Dis. 2000;10:315–322.
33. Dent SB, Peterson CT, Brace LD, Swain JH, Reddy MB, Hanson KB,
Robinson JG, Alekel DL. Soy protein intake by perimenopausal women
does not affect circulating lipids and lipoproteins or coagulation and
fibrinolytic factors. J Nutr. 2001;131:2280–2287.
34. Van Horn L, Liu K, Gerber J, Garside D, Schiffer L, Gernhofer N,
Greenland P. Oats and soy in lipid-lowering diets for women with hyper-
cholesterolemia: is there synergy? J Am Diet Assoc. 2001;101:1319–1325.
35. Teede HJ, Dalais FS, Kotsopoulos D, Liang YL, Davis S, McGrath BP.
Dietary soy has both beneficial and potentially adverse cardiovascular
effects: a placebo-controlled study in men and postmenopausal women.
J Clin Endocrinol Metab. 2001;86:3053–3060.
36. Puska P, Korpelainen V, Hoie LH, Skovlund E, Lahti T, Smerud KT. Soy
in hypercholesterolaemia: a double-blind, placebo-controlled trial. Eur
J Clin Nutr. 2002;56:352–357.
37. Blum A, Lang N, Vigder F, Israeli P, Gumanovsky M, Lupovitz S, Elgazi
A, Peleg A, Ben-Ami M. Effects of soy protein on endothelium-dependent
vasodilatation and lipid profile in postmenopausal women with mild hyper-
cholesterolemia. Clin Invest Med. 2003;26:20–26.
38. Dalais FS, Ebeling PR, Kotsopoulos D, McGrath BP, Teede HJ. The effects
of soy protein containing isoflavones on lipids and indices of bone
resorption in postmenopausal women. Clin Endocrinol (Oxf). 2003;58:
39. Meinertz H, Nilausen K, Hilden J. Alcohol-extracted, but not intact, dietary
soy protein lowers lipoprotein(a) markedly. Arterioscler Thromb Vasc Biol.
40. Hermansen K, Sondergaard M, Hoie L, Carstensen M, Brock B. Beneficial
effects of a soy-based dietary supplement on lipid levels and cardiovascular
risk markers in type 2 diabetic subjects. Diabetes Care. 2001;24:228–233.
41. Sirtori CR, Bosisio R, Pazzucconi F, Bondioli A, Gatti E, Lovati MR,
Murphy P. Soy milk with a high glycitein content does not reduce low-
density lipoprotein cholesterolemia in type II hypercholesterolemic patients.
Ann Nutr Metab. 2002;46:88–92.
42. Cuevas AM, Irribarra VL, Castillo OA, Yanez MD, Germain AM. Isolated
soy protein improves endothelial function in postmenopausal hypercholes-
terolemic women. Eur J Clin Nutr. 2003;57:889–894.
43. Steinberg FM, Guthrie NL, Villablanca AC, Kumar K, Murray MJ. Soy
protein with isoflavones has favorable effects on endothelial function that
are independent of lipid and antioxidant effects in healthy postmenopausal
women. Am J Clin Nutr. 2003;78:123–130.
JW, van der Schouw YT. Effect of soy protein containing isoflavones on
cognitive function, bone mineral density, and plasma lipids in postmeno-
pausal women: a randomized controlled trial. JAMA. 2004;292:65–74.
45. West SG, Hilpery KF, Juturu V, Bordi PL, Lampe JW, Mousa SA, Kris
Etherton PM. Effects of including soy protein in a blood cholesterol
lowering diet on markers of cardiac risk in men, and postmenopausal
women ?/- hormone replacement therapy. J Womens Health (Larchmt).
46. Tonstad S, Smerud K, Hoie L. 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 Clin Nutr. 2002;76:
47. Jenkins DJ, Kendall CW, Vidgen E, Vuksan V, Jackson CJ, Augustin LS,
Lee B, Garsetti M, Agarwal S, Rao AV, Cagampang GB, Fulgoni V 3rd.
Effect of soy-based breakfast cereal on blood lipids and oxidized low-
density lipoprotein. Metabolism. 2000;49:1496–1500.
48. Wong WW, Smith EO, Stuff JE, Hachey DL, Heird WC, Pownell HJ. Cho-
lesterol-lowering effect of soy protein in normocholesterolemic and hyper-
cholesterolemic men. Am J Clin Nutr. 1998;68:1385S–1389S.
49. Lichtenstein AH, Jalbert SM, Adlercreutz H, Goldin BR, Rasmussen H,
Schaefer EJ, Ausman LM. Lipoprotein response to diets high in soy or
animal protein with and without isoflavones in moderately hypercholester-
olemic subjects. Arterioscler Thromb Vasc Biol. 2002;22:1852–1858.
50. Jenkins DJ, Kendall CW, Jackson CJ, Connelly PW, Parker T, Faulkner D,
Vidgen E, Cunnane SC, Leiter LA, Josse RG. Effects of high- and low-
isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and
blood pressure in hyperlipidemic men and women. Am J Clin Nutr. 2002;
51. Weggemans RM, Trautwein EA. Relation between soy-associated
isoflavones and LDL and HDL cholesterol concentrations in humans: a
meta-analysis. Eur J Clin Nutr. 2003;57:940–946.
52. Gardner CD, Newell KA, Cherin R, Haskell WL. The effect of soy protein
with or without isoflavones relative to milk protein on plasma lipids in
hypercholesterolemic postmenopausal women. Am J Clin Nutr. 2001;73:
53. Mackey R, Ekangaki A, Eden JA. The effects of soy protein in women and
men with elevated plasma lipids. Biofactors. 2000;12:251–257.
54. Sanders TA, Dean TS, Grainger D, Miller GJ, Wiseman H. Moderate
intakes of intact soy protein rich in isoflavones compared with ethanol-
extracted soy protein increase HDL but do not influence transforming
growth factor beta(1) concentrations and hemostatic risk factors for
coronary heart disease in healthy subjects. Am J Clin Nutr. 2002;76:
55. Wangen KE, Duncan AM, Xu X, Kurzer MS. Soy isoflavones improve
plasma lipids in normocholesterolemic and mildly hypercholesterolemic
postmenopausal women. Am J Clin Nutr. 2001;73:225–231.
56. Merz-Demlow BE, Duncan AM, Wangen KE, Xu X, Carr TP, Phipps WR,
Kurzer MS. Soy isoflavones improve plasma lipids in normocholesterol-
emic, premenopausal women. Am J Clin Nutr. 2000;71:1462–1469.
57. Gallagher JC, Satpathy R, Rafferty K, Haynatzka V. The effect of soy
protein isolate on bone metabolism. Menopause. 2004;11:290–298.
58. Squadrito F, Altavilla D, Morabito N, Crisafulli A, D’Anna R, Corrado F,
Ruggeri P, Campo GM, Calapai G, Caputi AP, Squadrito G. The effect of
the phytoestrogen genistein on plasma nitric oxide concentrations,
endothelin-1 levels and endothelium dependent vasodilation in postmeno-
pausal women. Atherosclerosis. 2002;163:339–347.
59. Dewell A, Hollenbeck CB, Bruce B. The effects of soy-derived phy-
toestrogens on serum lipids and lipoproteins in moderately hypercholester-
olemic postmenopausal women. J Clin Endocrinol Metab. 2002;87:
60. Simons LA, von Konigsmark M, Simons J, Celermajer DS. Phytoestrogens
do not influence lipoprotein levels or endothelial function in healthy, post-
menopausal women. Am J Cardiol. 2000;85:1297–1301.
61. Hodgson JM, Puddey IB, Beilin LJ, Mori TA, Croft KD. Supplementation
with isoflavonoid phytoestrogens does not alter serum lipid concentrations:
a randomized controlled trial in humans. J Nutr. 1998;128:728–732.
62. Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P,
Owen A, Abbey M. Soy isoflavones improve systemic arterial compliance
but not plasma lipids in menopausal and perimenopausal women. Arte-
rioscler Thromb Vasc Biol. 1997;17:3392–3398.
63. Nikander E, Tiitinen A, Laitinen K, Tikkanen M, Ylikorkala O. Effects of
isolated isoflavonoids on lipids, lipoproteins, insulin sensitivity, and ghrelin
in postmenopausal women. J Clin Endocrinol Metab. 2004;89:3567–3572.
64. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the
National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and
Cardiovascular Disease: recent advances and future directions. Clin Chem.
65. Nilausen K, Meinertz H. Lipoprotein(a) and dietary proteins: casein lowers
lipoprotein(a) concentrations as compared with soy protein. Am J Clin Nutr.
February 21, 2006
66. Hodgson JM, Puddey IB, Beilin LJ, Mori TA, Burke V, Croft KD, Rogers
PB. Effects of isoflavonoids on blood pressure in subjects with high-normal
ambulatory blood pressure levels: a randomized controlled trial.
Am J Hypertens. 1999;12:47–53.
67. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine
for menopausal symptoms: a review of randomized, controlled trials. Ann
Intern Med. 2002;137:805–813.
68. Kotsopoulos D, Dalais FS, Liang YL, McGrath BP, Teede HJ. The effects
of soy protein containing phytoestrogens on menopausal symptoms in
postmenopausal women. Climacteric. 2000;3:161–167.
69. Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal
symptoms and acceptability of isoflavone-containing soy powder dietary
supplementation. Climacteric. 2001;4:13–18.
70. Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot
flushes: a multicenter, double-blind, randomized, placebo-controlled study.
71. Burke GL, Legault C, Anthony M, Bland DR, Morgan TM, Naughton MJ,
Leggett K, Washburn SA, Vitolins MZ. Soy protein and isoflavone effects
on vasomotor symptoms in peri- and postmenopausal women: the Soy
Estrogen Alternative Study. Menopause. 2003;10:147–153.
72. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, Valerio T,
Marubini E. Soy isoflavones and melatonin for the relief of climacteric
symptoms: a multicenter, double-blind, randomized study. Maturitas. 2004;
73. St Germain A, Peterson CT, Robinson JG, Alekel DL. Isoflavone-rich or
isoflavone-poor soy protein does not reduce menopausal symptoms during
24 weeks of treatment. Menopause. 2001;8:17–26.
74. Setchell KD, Lydeking-Olsen E. Dietary phytoestrogens and their effect on
bone: evidence from in vitro and in vivo, human observational, and dietary
intervention studies. Am J Clin Nutr. 2003;78:593S–609S.
75. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW Jr. Soy
protein and isoflavones: their effects on blood lipids and bone density in
postmenopausal women. Am J Clin Nutr. 1998;68:1375S–1379S.
76. Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T.
Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine
of perimenopausal women. Am J Clin Nutr. 2000;72:844–852.
77. Chen YM, Ho SC, Lam SS, Ho SS, Woo JL. Soy isoflavones have a
favorable effect on bone loss in Chinese postmenopausal women with lower
bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol
78. Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N,
D’Anna R, Corrado F, Pizzoleo MA, Cincotta M, Altavilla D, Ientile R,
Squadrito F. Effects of genistein and hormone-replacement therapy on bone
loss in early postmenopausal women: a randomized double-blind placebo-
controlled study. J Bone Miner Res. 2002;17:1904–1912.
79. Hsu CS, Shen WW, Hsueh YM, Yeh SL. Soy isoflavone supplementation
in postmenopausal women: effects on plasma lipids, antioxidant enzyme
activities and bone density. J Reprod Med. 2001;46:221–226.
80. Nikander E, Metsa-Heikkila M, Ylikorkala O, Tiitinen A. Effects of phy-
toestrogens on bone turnover in postmenopausal women with a history of
breast cancer. J Clin Endocrinol Metab. 2004;89:1207–1212.
M, Nara Y, Taira K, Moriguchi Y. Soybean isoflavones reduce postmeno-
pausal bone resorption in female Japanese immigrants in Brazil: a ten-week
study. J Am Coll Nutr. 2002;21:560–563.
82. Chiechi LM, Secreto G, D’Amore M, Fanelli M, Venturelli E, Cantatore F,
Valerio T, Laselva G, Loizzi P. Efficacy of a soy rich diet in preventing
83. Khalil DA, Lucas EA, Juma S, Smith BJ, Payton ME, Arjmandi BH. Soy
protein supplementation increases serum insulin-like growth factor-I in
young and old men but does not affect markers of bone metabolism. J Nutr.
84. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent
bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:
85. Peeters PH, Keinan-Boker L, van der Schouw YT, Grobbee DE. Phy-
toestrogens and breast cancer risk: review of the epidemiological evidence.
Breast Cancer Res Treat. 2003;77:171–183.
86. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest.
87. Magee PJ, Rowland IR. Phyto-oestrogens, their mechanism of action:
current evidence for a role in breast and prostate cancer. Br J Nutr. 2004;
88. Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S, for the Japan
Public Health Center-Based Prospective Study on Cancer Cardiovascular
Diseases Group. Soy, isoflavones, and breast cancer risk in Japan. J Natl
Cancer Inst. 2003;95:906–913.
89. Keinan-Boker L, van Der Schouw YT, Grobbee DE, Peeters PH. Dietary
phytoestrogens and breast cancer risk. Am J Clin Nutr. 2004;79:282–288.
90. Linseisen J, Piller R, Hermann S, Chang-Claude J, for the German Case-
Control Study. Dietary phytoestrogen intake and premenopausal breast
cancer risk in a German case-control study. Int J Cancer. 2004;110:
91. Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike
R, Kirk M, Coward L. Stimulatory influence of soy protein isolate on breast
secretion in pre- and postmenopausal women. Cancer Epidemiol
Biomarkers Prev. 1996;5:785–794.
92. McMichael-Phillips DF, Harding C, Morton M, Roberts SA, Howell A,
proliferation in the histologically normal human breast. Am J Clin Nutr.
93. Allred CD, Allred KF, Ju YH, Goeppinger TS, Doerge DR, Helferich WG.
Soy processing influences growth of estrogen-dependent breast cancer
tumors. Carcinogenesis. 2004;25:1649–1657.
94. Murata M, Midorikawa K, Koh M, Umezawa K, Kawanishi S. Genistein
and daidzein induce cell proliferation and their metabolites cause oxidative
DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive
organs. Biochemistry. 2004;43:2569–2577.
95. Luijten M, Thomsen AR, van den Berg JA, Wester PW, Verhoef A,
Nagelkerke NJ, Adlercreutz H, van Kranen HJ, Piersma AH, Sorensen IK,
Rao GN, van Kreijl CF. Effects of soy-derived isoflavones and a high-fat
diet on spontaneous mammary tumor development in Tg.NK (MMTV/
c-neu) mice. Nutr Cancer. 2004;50:46–54.
RH, Kirk CJ. Phytoestrogens are potent inhibitors of estrogen sulfation:
implications for breast cancer risk and treatment. J Clin Endocrinol Metab.
97. Lamartiniere CA. Timing of exposure and mammary cancer risk. J
Mammary Gland Biol Neoplasia. 2002;7:67–76.
98. Shu XO, Jin F, Dai Q, Wen W, Potter JD, Kushi LH, Ruan Z, Gao YT,
Zheng W. Soyfood intake during adolescence and subsequent risk of breast
cancer among Chinese women. Cancer Epidemiol Biomarkers Prev. 2001;
99. Wu AH, Wan P, Hankin J, Tseng CC, Yu MC, Pike MC. Adolescent and
adult soy intake and risk of breast cancer in Asian-Americans. Carcino-
100. Ziegler RG. Phytoestrogens and breast cancer. Am J Clin Nutr. 2004;79:
troubling data. Cancer Invest. 2003;21:817–818.
102. Xu WH, Zheng W, Xiang YB, Ruan ZX, Cheng JR, Dai Q, Gao YT, Shu
XO. Soya food intake and risk of endometrial cancer among Chinese
women in Shanghai: population based case-control study. BMJ. 2004;
103. Goodman MT, Wilkens LR, Hankin JH, Lyu LC, Wu AH, Kolonel LN.
Association of soy and fiber consumption with the risk of endometrial
cancer. Am J Epidemiol. 1997;146:294–306.
104. Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phy-
toestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 2003;95:
105. Murray MJ, Meyer WR, Lessey BA, Oi RH, DeWire RE, Fritz MA. Soy
protein isolate with isoflavones does not prevent estradiol-induced endo-
metrial hyperplasia in postmenopausal women: a pilot trial. Menopause.
106. Duncan AM, Merz BE, Xu X, Nagel TC, Phipps WR, Kurzer MS. Soy
isoflavones exert modest hormonal effects in premenopausal women. J Clin
Endocrinol Metab. 1999;84:192–197.
107. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized
placebo-controlled trial of an isoflavone supplement and menopausal
symptoms in women. Climacteric. 1999;2:85–92.
108. Scambia G, Mango D, Signorile PG, Anselmi Angeli RA, Palena C, Gallo
D, Bombardelli E, Morazzoni P, Riva A, Mancuso S. Clinical effects of a
standardized soy extract in postmenopausal women: a pilot study.
109. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA.
Vasomotor symptom relief by soy isoflavone extract tablets in postmeno-
pausal women: a multicenter, double-blind, randomized, placebo-controlled
study. Menopause. 2000;7:236–242.
Sacks et al Soy Protein, Isoflavones, and Cardiovascular Health
110. Hale GE, Hughes CL, Robboy SJ, Agarwal SK, Bievre M. A double-blind
randomized study on the effects of red clover isoflavones on the endo-
metrium. Menopause. 2001;8:338–346.
111. Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Di Renzo GC.
Endometrial effects of long-term treatment with phytoestrogens: a ran-
domized, double-blind, placebo-controlled study. Fertil Steril. 2004;82:
145–148, quiz 265.
112. Kumar NB, Cantor A, Allen K, Riccardi D, Besterman-Dahan K, Seigne J,
Helal M, Salup R, Pow-Sang J. The specific role of isoflavones in reducing
prostate cancer risk. Prostate. 2004;59:141–147.
113. Messina MJ. Emerging evidence on the role of soy in reducing prostate
cancer risk. Nutr Rev. 2003;61:117–131.
114. Ozasa K, Nakao M, Watanabe Y, Hayashi K, Miki T, Mikami K, Mori M,
Sakauchi F, Washio M, Ito Y, Suzuki K, Wakai K, Tamakoshi A, for the
JACC Study Group. Serum phytoestrogens and prostate cancer risk in a
115. Spentzos D, Mantzoros C, Regan MM, Morrissey ME, Duggan S, Flickner-
Garvey S, McCormick H, DeWolf W, Balk S, Bubley GJ. Minimal effect of
a low-fat/high soy diet for asymptomatic, hormonally naive prostate cancer
patients. Clin Cancer Res. 2003;9:3282–3287.
116. Urban D, Irwin W, Kirk M, Markiewicz MA, Myers R, Smith M, Weiss H,
Grizzle WE, Barnes S. The effect of isolated soy protein on plasma
biomarkers in elderly men with elevated serum prostate specific antigen.
J Urol. 2001;165:294–300.
117. Jenkins DJ, Kendall CW, D’Costa MA, Jackson CJ, Vidgen E, Singer W,
Silverman JA, Koumbridis G, Honey J, Rao AV, Fleshner N, Klotz L. Soy
consumption and phytoestrogens: effect on serum prostate specific antigen
when blood lipids and oxidized low-density lipoprotein are reduced in
hyperlipidemic men. J Urol. 2003;169:507–511.
118. Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ,
Mitch WE, Mullis R, Robinson K, Wylie-Rosett J, St Jeor S, Suttie J,
Tribble DL, Bazzarre TL. AHA Dietary Guidelines: revision 2000: a
statement for healthcare professionals from the Nutrition Committee of the
American Heart Association. Stroke. 2000;31:2751–2766.
119. Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Wong JM, de Souza R,
Emam A, Parker TL, Vidgen E, Lapsley KG, Trautwein EA, Josse RG,
Leiter LA, Connelly PW. Effects of a dietary portfolio of cholesterol-
lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA.
February 21, 2006