Fourth International Symposium on the Role of Soy in
Preventing and Treating Chronic Disease
Gaining Insight into the Health Effects of Soy but a Long Way Still to Go:
Commentary on the Fourth International Symposium on the Role
of Soy in Preventing and Treating Chronic Disease1
Mark Messina,*2Christoper Gardner†and Stephen Barnes**
*Nutrition Matters, Inc., Port Townsend, WA 98368;†Stanford Center for Research in Disease Prevention,
Palo Alto, CA 94304; and the **Department of Pharmacology and Toxicology, University of Alabama at
Birmingham, AL 35294
enal pace over the past decade. This research includes a wide range of areas, such as cancer, coronary heart
disease, osteoporosis, cognitive function, menopausal symptoms and renal function. Importantly, there are an
increasing number of clinical studies being conducted in this field, which was quite evident from the findings
presented at the Fourth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease,
November 4–7, 2001, in San Diego, California. There is no doubt that progress in understanding the health effects
of soy is being made, but much of the data are frustratingly inconsistent. For example, there were conflicting results
presented at the symposium on the role of isoflavones in bone health. Similarly, presentations painted an unclear
picture of the role of isoflavones in cholesterol reduction. The relatively short duration and small sample size of
many of the human studies in this field likely contribute to the inconsistent results. Although there are some
controversies regarding the safety of soy for certain subsets of the population, special sessions at the symposium
on breast cancer and cognitive function did much to alleviate concerns that soy could have detrimental effects in
these areas. Furthermore, published data and new research presented at this meeting suggest that the consump-
tion of even 10 g (typical of Asian intake) of isoflavone-rich soy protein per day may be associated with health
benefits. If this modest amount of soy protein were to be incorporated in the American diet, it would represent only
?15% of total U. S. protein intake.J. Nutr. 132: 547S–551S, 2002.
Research into the health effects of soyfoods and soybean constituents has increased at a phenom-
● soy ● isoflavones ● cancer ● cholesterol intake
The marked increase in soyfood consumption that has
occurred over the past several years can be partially attributed
to the many mainstream food companies, which have taken
ownership of small soyfood companies and begun marketing
their own soy products. The impetus behind these industry
developments is the perception that consumers currently view
and will continue to view soyfoods as healthy. In fact, a recent
U. S. survey found that in 2000, 76% of consumers considered
soy products healthy, up from 59% in 1998 (1).
Not surprisingly, consumer attitudes toward soy have im-
proved as soy has gained recognition by several federal and
private health agencies. In 1999 the Food and Drug Admin-
istration approved a health claim for the cholesterol-lowering
properties of soy protein (2); a year later the American Heart
Association recommended that patients with elevated choles-
terol include soy protein foods in their diets (3,4). As a
testament to the high quality of soy protein, in 2000 the U. S.
Department of Agriculture (USDA)3issued a ruling allowing
soy protein (and other high-quality proteins) to completely
replace animal protein in the Federal School Lunch Program
(5); previous guidelines limited soy to 30% substitution. In
1999 the USDA (in conjunction with Iowa State University)
also created an online database of the isoflavone content of
foods (6,7). That same year, the National Institutes of Health
convened a 3-d workshop on the health effects of isoflavones
(8). Finally, in 2000 the increasing popularity of soyfoods led
1Presented as part of the Fourth International Symposium on the Role of Soy
in Preventing and Treating Chronic Disease held in San Diego, CA, November
4–7, 2001. This conference was supported by Central Soya Company; Monsanto;
Protein Technologies International; SoyLife Nederland BV/Schouten USA SoyLife;
United Soybean Board; Archer Daniels Midland Company; Cargill Soy Protein
Products/Cargill Nutraceuticals; Illinois Soybean Association/Illinois Soybean
Checkoff Board; Indiana Soybean Board; Cyvex Nutrition; Nichimo International,
Inc.; Nutri Pharma Inc.; Revival Soy; Solbar Plant Extracts Ltd.; Soyatech Inc.;
AOCS Press; Dr. Soy Nutrition; Eurofins Scientific/Product Safety Labs; and
Optimum Nutrition. This publication was supported by (in alphabetical order) the
Indiana Soybean Board, the Kentucky Soybean Board, the South Dakota Soy-
bean Research and Promotion Council, Soyfoods Council, Cargill, and the United
Soybean Board. Guest editors for this symposium were Stephen Barnes and
2To whom correspondence should be addressed.
3Abbreviations used: USDA, U. S. Department of Agriculture.
0022-3166/02 $3.00 © 2002 American Society for Nutritional Sciences.
the USDA for the first time to specifically list calcium-fortified
tofu and soymilk in the Dietary Guidelines as good sources of
Despite this impressive momentum and the ability of in-
dustry to influence consumer attitudes, whether the public will
continue to view soy positively will depend primarily on future
research findings. In this regard, the International Symposium
on the Role of Soy in Preventing and Treating Chronic
Disease, the fourth gathering of which was held this past
November, represents the largest meeting of scientists con-
vened specifically for presenting and discussing research on
soyfoods and soybean constituents. Approximately 150 ab-
stracts were presented at this meeting; these abstracts along
with a few invited reviews form the proceedings in the pages
In this fourth symposium, there was a greater number of
human studies than in previous symposia. This was encourag-
ing. Unfortunately, many of these human studies were pilot
studies or involved small sample sizes. As has been the case
with the previous three symposia, isoflavones were the single
component of soy about which there was the most research
and discussion. Arguably, the most exciting data presented at
the symposium involved a study in which isoflavone supple-
ments seemed to beneficially affect prostate cancer patients. In
this study presented by Omer Kucuk from the Karmanos Can-
cer Institute in Detroit, 41 patients with uncontrolled cancer,
as shown by a rising serum prostate-specific antigen level, were
given isoflavone supplements (?60 mg isoflavones, aglycone
units) daily for 6 mo. Results indicated that more than one-
half of the patients responded to treatment as judged by a
significant decrease in the linear rise in prostate-specific anti-
gen levels. These data add to the impressive case that is
building for soy having a role in reducing prostate cancer risk
Although isoflavones may have dominated discussion, at
the fourth symposium there was relatively more dialogue than
at past symposia about the biologically active nonisoflavone
components of soy, especially the protein component. More
specifically, there was debate about the extent to which pep-
tides and amino acids derived from soy protein might lower
cholesterol and blood pressure, reduce cancer risk, and favor-
ably affect renal function.
Determining the extent to which the effects of soy protein
or whole soyfoods are attributable to specific and individual
soy components is a particularly important issue for several
reasons, not the least of which is because isoflavone supple-
ments are widely available and isoflavones are being used as
food fortificants. Unfortunately, few studies have directly com-
pared the effects of isolated isoflavones with soy. Even if
nutritionists prefer to recommend soyfoods to consumers, es-
tablishing similar short-term health effects of supplements and
foods would allow investigators to justify using supplements for
experimental purposes in human studies. This would make it
easier for researchers to conduct large long-term studies and
might even increase the pool of investigators working on
One of the areas for which the role of isoflavones relative to
the protein has been hotly debated is cholesterol reduction.
The Food and Drug Administration does not require that soy
protein contain a certain level of isoflavones to qualify for the
health claim. At the symposium Mary S. Anthony from Wake
Forest University School of Medicine presented fascinating
data showing that in female and male cynomolgus monkeys
isoflavone-rich soy (soy?) lowers cholesterol to a greater ex-
tent than soy protein from which the isoflavones have been
removed by alcohol extraction (soy?) but that neither adding
pure isoflavones nor the entire alcohol extract fully restored
the hypocholesterolemic effects of soy?. This suggests that
alcohol extraction alters the protein, some other component
of soy, or the protein-isoflavone matrix in a way that disturbs
the cholesterol-lowering properties. Further complicating in-
terpretation of these results were data presented by Thomas B.
Clarkson, also from the Wake Forest University School of
Medicine, showing that in surgically postmenopausal cyno-
molgus monkeys although soy?lowers cholesterol more than
soy?, serum isoflavone levels of animals fed soy?have a
U-shaped response to cholesterol reduction, with higher levels
(? 400 nmol/L) causing the soy-induced cholesterol reduction
to decline. These results do conflict, however, with a recently
published human study (15), although it should be noted that
unlike in most humans, in cynomolgus monkeys, the principal
circulating isoflavone is equol and not genistein and daidzein.
Certainly, there is almost no evidence to suggest that isofla-
vones alone affect serum lipid levels, although they may exert
other antiatherogenic effects, as might soy protein. For exam-
ple, a study presented at the symposium by J. Koudy Williams
from the Wake Forest University School of Medicine found
that genistein enhanced vascular reactivity in aged arteries
from mice. Another study presented by Sheila G. West from
Pennsylvania State University found that compared with ca-
sein, soy protein containing 60 mg isoflavones reduced dia-
stolic blood pressure in response to a 5-min speech stressor or
a cold pressor task in 27 healthy middle-aged men.
Perhaps the most striking illustrations of conflicting results
were the findings from three studies presented at the sympo-
sium that focused on bone health. The area of bone research
is a good example of the need for research directly comparing
isoflavone supplements with soy protein or soyfoods. In one
2-y study, which was presented by Eva Lydeking-Olsen from
the Institute for Optimum Nutrition in Denmark, 23 post-
menopausal women given soy?(100 mg isoflavones/d) expe-
rienced a statistically significant increase in spinal bone min-
eral density compared with 22 women given soy?, although
the combination of soy?and progesterone (22 women) pro-
duced the most spinal bone loss, despite progesterone admin-
istration by itself (22 women) increasing bone mineral density
in this study. The findings showing that soy?favorably affects
bone health compared with soy?agrees with some (16,17) but
not all previously published data (18). However, a similarly
designed study, also 2 y long, that was presented by Mara Z.
Vitolins from Wake Forest School of Medicine, found no
differences in spinal bone mineral density among 241 peri-
menopausal and postmenopausal women who received soy
protein (25 g/d) that provided ? 5, 42 or 58 mg isoflavones.
One obvious difference between these two studies was that the
highest dose of isoflavones used in the latter study was only 58
mg/d, considerably less than the 100 mg used in the former
study, but this lower level still exceeds that typically consumed
in Japan (19).
Consistent with the lack of isoflavone effect are the results
from a short-term study in which the effects of protein sup-
plements (40 g/d) on calcium metabolism were examined over
1-mo periods in 15 postmenopausal women. Treatments had
no effect on calcium absorption, but soy protein reduced
urinary calcium excretion compared with a casein-whey mix-
ture; however, no differences were noted between soy?and
soy?. The lower sulfur amino acid content of soy protein and
the resulting reduction in acid ash have been suggested as
explanations for these results and for previous observations
showing reductions in urinary calcium excretion when soy
protein is substituted for animal proteins, such as meat (20)
and whey protein (21). All other factors being equal, these
data suggest, but by no means prove, that replacing some
animal protein with soy protein would have a desirable effect
on bones. However, it is not possible to conclude that isofla-
vones exert bone-protective effects. This will undoubtedly
remain the case until the results of several long-term studies
currently planned or about to be undertaken are known. The
disappointing results from the 3-y ipriflavone-osteoporosis
trial, despite impressive supporting data, attest to the need for
large long-term studies (22).
Two studies in a relatively underresearched area regarding
soy and potential health benefits found that soy protein, when
substituted for animal protein, favorably affected renal func-
tion in diabetic patients with diabetic nephropathy. These
studies, one from the University of Illinois and the other from
the University of Kentucky, are consistent with most but not
all of the published research in this area (23). The renal effects
of soy are not insignificant given the rising incidence of
diabetes that is occurring in many parts of the world (24,25).
Longer-term studies are warranted.
One matter that arose on several occasions during the
symposium was the importance of determining the relevance
of equol. Approximately one-third of subjects fed soy produce
equol, a bacterial metabolite of the isoflavone daidzein (26–
28). The ability to synthesize equol is determined by the
composition and the enzymatic capability of the intestinal
microflora. Some studies suggest that equol production may be
advantageous but this is not known for certain. Equol produc-
tion may simply be a marker for some other attribute that
affects health (27). Interestingly, the request for applications
issued by the Diet and Cancer Branch of the National Cancer
Institute in 1991, when that agency first became interested in
the anticancer effects of soy, called for research on isoflavone
metabolism primarily to establish whether future trials should
be limited to or exclude equol producers.
Two controversial areas related to the health effects of soy
were addressed at the symposium: breast cancer and cognitive
function. Despite some evidence suggesting that soy intake
reduces the risk of developing breast cancer, concern has
arisen that soy consumption could stimulate the growth of
estrogen-dependent tumors. Genistein and soy protein isolate
stimulate tumor growth in athymic ovariectomized mice that
have been subcutaneously implanted with estrogen-dependent
(MCF-7) breast cancer cells (29–31), but this model has been
criticized on methodological grounds and the results from this
model are opposite to those that occur in intact mice ortho-
topically implanted with MCF-7 cells and exposed to genistein
via injection (32) or the diet (J.-R. Zhou, Beth Israel Deacon-
ess Medical Center, Boston, unpublished results, 2001). Still,
two previously published studies did find that soy seems to
exert weak estrogen-like effects on breast tissue in premeno-
pausal women (33,34).
Symposium findings from two 1-y human studies provided
some measure of reassurance that detrimental effects were
unlikely. In one, presented by Gertraud Maskarinec from the
Cancer Research Center of Hawaii, isoflavone (100 mg/d)
supplements had no effect on breast tissue density in 34
premenopausal women, and in the other, presented by Char-
lotte Atkinson from MRC Biostatistics Unit in Cambridge,
isoflavone (40 mg/d) supplements derived from red clover had
no effect on breast tissue density in 175 perimenopausal and
postmenopausal women overall. Furthermore, in post-hoc sub-
group analysis of the latter study, when women were divided
into age groups, breast tissue density was significantly de-
creased in those aged 56–65 y. Notably, these two studies were
conducted in healthy women, not in breast cancer patients.
Breast tissue density is regarded as an excellent marker of
breast cancer risk; agents such as hormone replacement ther-
apy that increase breast cancer risk also increase density (35),
whereas agents that decrease risk, such as tamoxifen, also
decrease density (36,37).
In regard to cognitive function, data from a prospective
epidemiological study presented at the Third International
Symposium in 1999 and published 1 y later showed that tofu
consumption was associated with impaired cognitive function
in Japanese men and women (38). Previously published animal
studies do not support this finding (39–44) and two human
studies presented at this symposium suggested that soy and
isoflavones might beneficially affect cognitive function. In one
study, presented by Rosanna Duffy from King’s College in
London, 27 healthy young male and female subjects (average
age: ?25 y) who consumed a high-soy diet that provided 100
mg isoflavones/d for 10 wk experienced an improvement in
short-term and long-term memory and mental flexibility (45).
In the other study, presented by Donna Kritz-Silverstein from
the University of California, San Diego, 53 postmenopausal
women who were given a daily isoflavone supplement (110
mg) for 6 mo experienced an improvement in verbal memory
in comparison with the placebo group. Although these studies
do not directly refute the epidemiological study cited above
because they did not examine the effect of long-term or
lifetime soy consumption, they help to allay fears that soy has
adverse effects on cognition.
The symposium findings left no doubt that soy contains a
number of scientifically interesting constituents. In fairness,
though, it is likely that many plant foods when investigated as
intensely as soy has been would be found to contain multiple
biologically active components. It is, therefore, important to
compare the biological data on these soy components with the
epidemiological and dietary intake data on which many of the
soy-related hypotheses are based. This will provide more in-
sight into the extent to which these biologically active com-
ponents are pharmacologically or nutritionally related to soy.
Important strides in our understanding of soy have been
made especially as a result of moving from rodents to human
subjects and from epidemiological to human intervention
studies. Unfortunately, this transition has not allowed many of
the proposed hypotheses to be confirmed or rejected. Al-
though much of the data continues to intrigue and even
excite, research is still relatively limited and results are frus-
All scientists, but especially nutritionists, are familiar with
having to deal with conflicting data, especially when those
data relate to chronic disease. The etiology of all chronic
disease is multifactorial and risk is likely affected by a lifetime
of subtle influences. Add to this mix the effect of genetic
heterogeneity, and it is easy to understand the snail’s pace at
which understanding proceeds and why seemingly similarly
designed studies often produce inconsistent findings. Demon-
strating statistically significant changes in human studies in-
volving dietary interventions is often hindered by the short
duration and small sample sizes typical of many of the studies
presented at this meeting.
It will be some time before definitive conclusions can be
reached about the many hypothesized health effects of soy, but
the available data do suggest that the American public would
benefit if soy protein made a larger contribution to total U. S.
dietary protein intake than it currently does. At the turn of the
past century, the ratio of plant to animal protein was ?1:1;
today that ratio is ?1:2 (46). Replacing some of the animal
protein in the U. S. diet with soy protein would help to restore
the balance of animal to plant protein to a more favorable
ratio. Consuming soyfoods in amounts that provide ?10 g/d of
COMMENTARY ON THE FOURTH INTERNATIONAL SYMPOSIUM
soy protein—which is similar to Asian intake (19,47–49) and
consistent with the amount of soy associated with decreases in
coronary heart disease (19,47), certain cancers (13,14,50,51)
and improved bone health (52–55) in many epidemiological
studies—holds the potential to exert health benefits while still
only representing no ? 10–15% of total U. S. protein intake
Finally, although progress in understanding the effects of
soy on chronic disease risk has been made, this is still a
relatively new field; in fact, most researchers have been work-
ing in this area for ? 5 y. However, a few investigators have
been at it for quite a bit longer. At the third symposium, six
such investigators were recognized. At the fourth symposium,
three more researchers were recognized by their peers for their
substantial contribution to this field, each having worked in
this area for ? 20 y. These researchers are John Erdman, JR.,
from the University of Illinois; Patricia Murphy, from Iowa
State University; and Masataro Nishimura, from Fugi Oil, in
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