Tài liệu Soy connection fact Sheet by the united Soybean board ppt

1
Soyfoods are a unique dietary source of isoflavones,
a phytoestrogen that may offer women heart health
benefits and may help alleviate hot flashes during
menopause.
Soyfoods offer health benefits for all
consumers, but studies show that
postmenopausal women may reap
particular benefits. This fact sheet
discusses recent research into the benefits
and safety of soy for women, from heart
disease to hot flashes.
Traditional soyfoods such as tofu and miso have been widely used in
many East Asian countries for centuries and have been consumed by
health-conscious individuals in Western countries for several decades. In
recent years, because of the purported health benefits, increased numbers
of Westerners have decided to incorporate soy into their diets. Soyfoods
hold particular appeal for postmenopausal women because they are such
uniquely rich sources of isoflavones, one type of phytoestrogen.
Isoflavones exhibit estrogen-like effects under certain experimental
conditions and are posited to reduce the risk of coronary heart disease,
1

osteoporosis,
2
certain forms of cancer
3
and may alleviate menopause-
related hot flashes.
4
Consequently, many women view soyfoods as natural

alternatives to conventional hormone therapy. Women who use alternative
therapies express a desire to have control over their symptoms and the
way in which their menopause is treated.
5
Not surprisingly, interest in
alternative therapies increased following the publication of results of the
Women’s Health Initiative (WHI) trial in 2002, which showed that the risk
of long-term use of combined hormone therapy (estrogen plus progestin)
outweighed the benefits.
6
In 2010, 11-year follow up data from the WHI trial
found not only that combined hormone therapy increases breast cancer
risk but also breast cancer mortality.
7
However, isoflavones themselves are not without controversy. Their
estrogen-like effects have raised concern that these soybean constituents
possess some of the same undesirable properties as hormone therapy. In
particular, there is controversy over whether soyfoods are contraindicated
for women who have breast cancer or who are at high risk of developing
breast cancer.
8

Overview of Isoflavones
Isoflavones have a limited distribution in nature. In fact, diets that do not
include soyfoods are almost devoid of these compounds.
9
Not surprisingly,
whereas average isoflavone intake among adults ranges from about
30-50 mg/day in Japan and Chinese cities such as Shanghai,
10

intake is less
than 3 mg/day in the United States and other Western countries.
11, 12, 14-17

Using weighted, 2-day food consumption data for the U.S. population from
the National Health and Nutrition Examination Survey (NHANES) 2007-
2008, the United States Department of Agriculture recently estimated that
daily per capita isoflavone intake is 0.68 mg/day.
18

Isoflavones occur in soybeans as glycosides (a sugar molecule is attached
to the isoflavone backbone);
19
upon ingestion, the sugar is hydrolyzed
thereby allowing absorption to occur.
20
In fermented soyfoods such as
miso, tempeh and natto, substantial amounts of the isoflavones occur as
aglycones due to bacterial hydrolysis. The three isoflavones genistein,
daidzein and glycitein and their respective glycosides account for
approximately 50 percent, 40 percent and 10 percent, respectively, of the
total isoflavone content of soybeans.
19

Each gram of soy protein in soybeans and traditional soyfoods is
associated with approximately 3.5 mg of isoflavones.
10
In this document,
isoflavone amounts are expressed in aglycone equivalent weights.
Consequently, one serving of a traditional soyfood, such as 3-4 oz of tofu

or 1 cup of soymilk, typically provides about 25 mg of isoflavones.
Soy protein is present in a wide range of commonly consumed foods in the
U.S. However, isoflavone exposure from these foods is almost negligible
for two reasons. First, the amount of soy protein in these foods is quite
small because it is added for functional (not nutritional) purposes such as
bleaching, moisture retention, oxidation inhibition and improved texture.
And second, the isoflavone concentration of the soy protein used in this
way is generally quite low in comparison to traditional soyfoods. The
isoflavone-to-protein ratio noted above for traditional soyfoods does not
apply to many processed forms of soy.
Soy
WOMEN
Soy connection fact Sheet
by the united Soybean board
2
In most clinical trials, hot flash relief is achieved by
ingesting approximately 50 mg total isoflavones daily.
Soyfoods are unique because they are rich dietary
sources of isoflavones, which are endocrine
active substances but different from the hormone
estrogen.
Isoflavones are diphenolic compounds with a chemical structure similar
to the hormone estrogen; they bind to both estrogen receptors alpha and
beta – ERα and ERβ.
21, 22
For this reason, they are commonly referred to as
phytoestrogens. Their relative binding affinity is lower than that of estrogen
(17β-estradiol), but circulating levels of isoflavones in people consuming
soyfoods are approximately three orders of magnitude higher than levels of
estrogen.

23
While estrogen binds to and transactivates both ERα and ERβ
equally, isoflavones preferentially bind to and transactivate ERβ.
24-27
This
difference in binding and transactivation between isoflavones and estrogen
is important because the two estrogen receptors have different tissue
distributions and, when activated, can have different and sometimes even
opposite physiological effects. This appears to be the case in the breast,
where ERβ transactivation is thought to inhibit the proliferative effects of
ERα transactivation.
28, 29
The preference of isoflavones for ERβ is one reason they exert tissue-
selective effects, and for this reason, isoflavones are classified as selective
estrogen receptor modulators (SERMs).
30-32
In tissues that possess
estrogen receptors, SERMs exert estrogen-like effects in some cases
but no effects or antiestrogenic effects in others. The pharmaceutical
industry has for many years been actively developing SERMs.
33
Widely
used SERMs include tamoxifen, used in breast cancer treatment, and
raloxifene, which is used for treatment of osteoporosis.
34
In addition to
being classified as phytoestrogens and SERMs, the European Food Safety
Authority has recently proposed a new classification for compounds such
as isoflavones, which is “endocrine active substances.”
35

From the above discussion, it is clear that isoflavones should not be
equated with the hormone estrogen. The clinical literature is replete with
examples of differences between these two molecules.
32, 36-56
Furthermore,
isoflavones may exert potentially-relevant hormone-independent
physiological effects. Therefore, the classification related to their hormonal
activity may be an incomplete characterization.
57
Finally, not only should
isoflavones not be equated with estrogen but soyfoods should not be
equated with isoflavones. This is because the soybean, like all foods, is a
collection of hundreds of biologically active molecules.
58

Soy, Isoflavones and Hot Flashes
Hot flashes are the most common reason given by women seeking
treatment for menopausal symptoms. For the majority of women who
experience them, hot flashes begin prior to menopause. Ten to 15 percent
of these women experience hot flashes that are severe and frequent.
59

Although hot flashes usually subside after six months to two years,
59, 60

many women report having them for up to 20 years after menopause.
61

The etiology of hot flashes is not fully understood but the drop in
circulating estrogen levels that occurs during menopause is recognized

as one factor. The low incidence of hot flashes in Japan gave rise to initial
speculation that isoflavones could be useful in their prevention.
62

Even Chinese-American and Japanese-American women are about
one-third less likely to report experiencing hot flashes than Caucasian
women.
63
Interestingly, among Asian women, chilliness and shoulder
aches are much more commonly reported menopausal symptoms than
hot flashes. Recent evidence suggests, however, that Japanese women are
reluctant to report having hot flashes.
64
To this point, one study found that
hot flash frequency was lower among Japanese compared to Caucasian
women when based on a subjective determination (personal diary), but
not when determined objectively by measuring sternal and nuchal skin
conductance.
65
Sources of Soy Protein
Soyfood Serving size
Grams of
soy protein
Fortified soymilk 1 cup 6-7
Soy cereal
1 ¼ cup 7
Soy yogurt, vanilla
1 cup 6
Soy breakfast patty
2 patties 11

Soy bar
1 bar 14
Soy chips
1 bag 7
Soynut butter
2 Tbsp 7
Soynuts, roasted, unsalted
¼ cup 11
Tofu
½ cup 10
Edamame
½ cup 11
Soy burger
1 patty 13-14
Soy pasta
½ cup (cooked) 13
Soy pudding
½ cup
6
3
isoflavones is consistent with the degree of benefit deemed satisfactory by
women seeking non-hormonal treatments for hot flashes.
76
The amount
of isoflavones providing symptom relief is found in approximately two
servings of traditional soyfoods.
Osteoporosis
In response to declining estrogen levels, women can lose substantial
amounts of bone mass in the decade following menopause, which markedly
increases their fracture risk.

77
Estrogen therapy reduces postmenopausal
bone loss and hip fracture risk by approximately one-third.
6
Recent data
shows that the protective effects against hip fracture are lost within two
years of cessation of estrogen therapy.
78
Initial speculation that soyfoods
might promote bone health in postmenopausal women was based on the
estrogen-like effects of isoflavones and early research showing that the
synthetic isoflavone, ipriflavone, exerted skeletal benefits.
79

Since 1995, more than 50 clinical trials have examined the impact of
isoflavone-rich soyfoods or isoflavone supplements on the alleviation
of menopause-related hot flashes. In recent years, investigators have
gravitated toward the use of supplements rather than soyfoods to enhance
compliance and reduce the complexity of study design. The results of
these trials have produced inconsistent results. Although some recent
reviews and analyses of the literature have concluded that isoflavone-rich
products alleviate hot flashes,
4, 66
most have found that the data does not
allow for definitive conclusions to be made even though more trials than
not showed benefit.
67, 68
Some inconsistency in the literature is expected
given the small sample size of many trials and the variable placebo
response. However, several more specific explanations for the seemingly

inconsistent data have been proposed, including intraindividual differences
in isoflavone metabolism,
69
differences in baseline hot flash frequency (i.e.,
isoflavones are more effective in women with more frequent hot flashes)
66

and differences in the isoflavone content or profile of the intervention
products (i.e., products containing higher amounts of genistein are
deemed to be most effective).
70
In response to the ingestion of the same amount of isoflavones, serum
levels of isoflavones and their metabolites differ by a factor of several
hundred among individuals.
20, 71
Therefore, it is reasonable to speculate
that differences in metabolism can affect the response to soyfoods, at
least for health outcomes thought to be affected by isoflavones. However,
this explanation appears to be more applicable to differences between
individual women’s experiences and less likely to explain why large-scale
studies would report variable outcomes. In contrast, differences in the
isoflavone content of the intervention products appear more applicable
to differences in results among studies. Some of the inconsistency may
also be because the two main soy-derived isoflavone supplements that
are available commercially and that have been used in the clinical trials
have markedly different isoflavone profiles.
72
One is high in genistein and
daidzein but low in glycitein, which is similar to the isoflavone profile of
soyfoods, whereas the other is very low in genistein and high in daidzein

and glycitein. Several lines of evidence, including relative estrogen
receptor binding and transactivation, indicate that genistein is more potent
than daidzein or glycitein and there is evidence that genistein is more
potent than the other isoflavones for alleviating hot flashes.
73, 74
The most comprehensive statistical analysis of the literature, which was
only recently published, clearly supports the efficacy of isoflavones
for alleviating hot flashes.
75
This systematic review and meta-analysis
included 19 and 17 studies, respectively, and included only studies
involving isoflavone supplements derived from soy. The meta-analysis of
the data on hot flash frequency, which included 13 studies involving 1,196
women, found isoflavones were consistently efficacious, reducing the
number of hot flashes per day about 21 percent more than the reduction
in the placebo group. Similarly, in the nine trials involving 988 women
that evaluated hot flash severity, isoflavones reduced symptoms by
about 26 percent more than the reduction in the placebo group. For both
measures, the effect of isoflavones was highly statistically significant.
When considering the combined effect of the placebo and isoflavones,
the overall reduction in frequency and severity was approximately 50
percent. Furthermore, subanalysis indicated that isoflavone supplements
providing at least 18 mg genistein were more than twice as efficacious
as supplements lower in genistein. As noted previously, genistein is the
predominant isoflavone in soybeans.
Collectively, this data makes a convincing case that isoflavones can be of
help to women who experience hot flashes. The level of relief provided by
The relatively low hip-fracture rates in Asian countries have also been cited
as evidence for the skeletal benefits of isoflavones, but other factors may
help explain these rates.

80
For example, Asians have a shorter hip axis
length, which reduces risk for fracture.
81, 82
Also, Japanese women are less
likely than Western women to fall, the precipitating event for hip fracture.
83, 84

However, spinal bone mineral density (BMD) and spinal fracture rates are
similar between Asians and Caucasians.
85-92
Nevertheless, the available
evidence shows that, among Chinese women, high soy consumers are less
likely to report having a fracture.
Fortified soymilk is a good source of isoflavones
and also contains calcium, vitamin D and protein,
which offer additional bone health benefits.
4
Two prospective epidemiologic studies have evaluated the relationship
between soy intake and fracture risk. In both, risk was reduced by
approximately one-third when women in the highest soy intake quintile or
quartile were compared to women in the lowest. This degree of protection
is similar to that noted for estrogen therapy.
6
In one of the prospective
studies, approximately 1,800 fractures of all types occurred in the 24,000
postmenopausal Shanghai women who were followed for 4.5 years.
93
In the
other, there were almost 700 hip fractures (the only site studied) among the

35,000 postmenopausal Singaporean women during the 7-year follow up
period.
94

In a third prospective epidemiologic study involving Seventh-day
Adventists, a religious denomination that includes a high proportion
of vegetarians, soymilk intake was significantly inversely related to
osteoporosis.
95
In this study, which involved 337 postmenopausal women,
participants had their bone health assessed using broadband ultrasound
attenuation of the calcaneus two years after completing a lifestyle and
dietary questionnaire at enrollment. Compared with women who did not
drink soymilk, women drinking soymilk once a day or more had 56 percent
lower odds of osteoporosis (defined as defined as a T-score <-1.8).
However, the protective effect of soymilk was likely due to its calcium
rather than isoflavone content since dairy product intake was similarly
protective. Although the results of these three studies are intriguing,
definitive conclusions about the skeletal effects of soyfoods can only be
based on the results from appropriately designed clinical studies.
Since the first clinical study to examine the effects of an isoflavone-rich
product on bone mineral density (BMD) in postmenopausal women was
published in 1998,
96
more than 25 trials have provided results (for reviews,
see references) although many involved small numbers of subjects and
were conducted for relatively short durations.
97, 9 8
Ideally, studies of bone
health should be at least 2-3 years in duration. The results from the clinical

research thus far has been mixed, as recently published meta-analyses of
the data concluded that isoflavones reduce bone breakdown
99
and increase
both bone formation
99
and spinal BMD
2, 100
in postmenopausal women.
However, a more rigorously-conducted meta-analysis failed to provide
support for the skeletal benefits of isoflavones.
101
Among the many clinical trials, one of the longest (two years) and largest
(304 subjects) published to date found that postmenopausal Italian
women with osteopenia who were assigned to the placebo group lost
approximately 6 percent of their BMD at the spine and hip, whereas those
women in the genistein group (54 mg/day genistein aglycone provided
as a supplement) gained approximately this much bone at both skeletal
sites.
54
Although intended to last only two years, approximately half of
the subjects agreed to continue for a third year; the differences between
groups in the third year were even more striking.
102
However, these results stand in stark contrast to several recently
conducted trials. For example, a 1-year study involving women from three
European countries failed to show that isoflavone supplements (110 mg/
day) inhibited bone loss in early postmenopausal women.
103
In agreement,

another 1-year trial failed to show that either isoflavone supplements or
isoflavone-rich soy protein affected bone loss in U.S. postmenopausal
women.
104
Similarly, a recently published 2-year study found that soy
protein, regardless of isoflavone content, failed to prevent bone loss in
postmenopausal women, although this study had a large dropout rate and
many women were non-compliant with the intervention.
105

According to the American Cancer Society, breast
cancer patients can consume up to 3 servings of
soyfoods daily.
Lastly, the most important results were from three very large studies, two of
which were two years
106, 107
in duration whereas the third was three years in
duration.
108
Two of these were conducted in the U.S.
106, 107
and one in Taiwan.
108

Isoflavone intake from supplements was 80 and 120 mg/day in one study,
109

200 mg/day in another
107
and 300 mg/day in the third.

108
The results from
these trials provide no support for the skeletal benefits of isoflavones
and they agree with those from a trial that utilized a novel methodology
to examine the effects of estrogen and a variety of phytoestrogen
supplements on bone reabsorption. Only at very high doses – doses
exceeding typical isoflavone exposure from soyfoods – was there any
evidence of antiresorptive effects.
73

It is unclear why the previously mentioned Italian study
102
found such
protective effects of genistein, in contrast to other studies using mixed
isoflavones that would have provided similar amounts of genistein. Also
unclear is why the two Chinese prospective epidemiologic studies found
soy intake was so protective against fracture. It is possible that those
subjects who consumed soyfoods also led an overall healthier lifestyle (the
“healthy user effect”). Yet, since soyfoods are traditional foods in Asian
countries, this is less likely to be the explanation than it would be in non-
5
At study termination, progression among the women consuming soy was
16 percent lower than in the milk group. While the difference was not
statistically significant, the results are intriguing. If a 16 percent decrease
in the progression of CIMT translates into a 16 percent decrease in the
risk of future coronary events, the public health implications would be
dramatic. Furthermore, the difference between groups increased steadily
over the 3-year study period. This suggests that after a longer period of
soy exposure, progression would have been reduced to an even greater
extent, and with it, risk of coronary events.

Additionally, subanalysis of the results revealed that among women
who were fewer than 5 years, 5-10 years, and more than 10 years post-
menopause, CIMT progression was reduced by 68 (p=0.05), 17 (p=0.51)
and 9 percent (p=0.77), respectively. It is notable that progression was
reduced so significantly in early postmenopausal women for two reasons.
First, it adds substantially to the biological plausibility of the findings, and
second, it provides clear insight into the soy component responsible for
the beneficial effects. The pronounced effect in early menopausal women
suggests isoflavones were primarily responsible for the reduced CIMT
progression. Over the past 10 years, a hypothesis has emerged, referred
to as the “estrogen timing hypothesis.” This maintains that exposure to
estrogen-like compounds leads to dramatic coronary and cognitive benefits
when begun soon after menopause, but has less effect in later years.
125
Asian countries where soyfoods are generally perceived as health foods.
Another explanation is that in the epidemiologic studies, isoflavone intake
occurred via the consumption of traditional soyfoods, whereas the clinical
studies have generally used soy extracts. However, there is no evidence
that this difference matters with respect to skeletal effects. It may also
be that the effects noted in the epidemiologic studies result from lifelong
intake as opposed to the relatively short-term intervention periods begun
in adulthood in the clinical studies. At the same time, there is no direct
evidence supporting this suggestion.
At this point, the evidence that isoflavones provide skeletal benefits is
unimpressive. Soyfoods have other benefits in this regard, however, since
they provide high quality protein,
110
which may promote bone health.
111, 112

In addition, some are good sources of calcium as well as vitamin D.
113

Importantly, the absorption of calcium from calcium-set tofu
114
and
calcium-fortified soymilk
113, 115
is comparable to the absorption of this
mineral from cow’s milk.
Heart Health
Soyfoods potentially offer protection against heart disease through
several different mechanisms. Soyfoods are low in saturated and high
in polyunsaturated fat.
116
In addition, soy protein directly lowers blood
cholesterol levels, an attribute that was formally recognized by the U.S.
Food and Drug Administration in 1999.
117
Estimates are that, via the fatty
acid profile and soy protein content, when soyfoods replace conventional
sources of protein in Western diets, blood low-density-lipoprotein (LDL)
cholesterol levels will be lowered by about 8 percent. In theory, over a
period of years, this may reduce risk of coronary heart disease (CHD) by
8-16 percent.
118

There is also evidence that, independent of effects on blood cholesterol,
soyfoods may reduce CHD risk. For example, four recently published
meta-analyses found that soy lowered blood pressure.

119-122
Furthermore,
isoflavones improve impaired endothelial function in postmenopausal
women.
123
Lastly, the most important study came from the Women’s
Isoflavone Soy Health (WISH). This 3-year study involved 350 healthy
postmenopausal women ages 45-92, and found that isoflavone-rich soy
protein inhibited the progression of subclinical atherosclerosis.
124

Subclinical atherosclerosis can be assessed using ultrasound to measure
the thickness of the carotid arteries—which are located on both sides
of the neck beneath the jawline and provide the main blood supply to the
brain. The thickness of the carotid artery is referred to as carotid intima-
media thickness or CIMT. Typically, CIMT increases or progresses over
time; the extent of progression reflects risk of future coronary events.
Participants in the WISH study were randomly assigned to groups
consuming either 25 g of isolated soy protein per day or 25g of milk
protein. The soy protein provided 99 mg of isoflavones (expressed in
aglycone equivalent weight).
Soyfoods may offer protection against heart
disease, as they are low in saturated fat and high in
polyunsaturated fats.
6
Breast Cancer
There has been rigorous investigation of the role of soyfoods in
reducing breast cancer risk. A recent meta-analysis found that, in Asian
epidemiologic studies, higher soy intake was associated with a 29
percent decreased risk of breast cancer.

3
However, there is solid evidence
indicating that to derive this benefit, soy consumption must occur during
childhood or adolescence.
126-128
In animal studies, when very young
rodents are exposed to isoflavones, breast or mammary cells undergo a
change that makes them permanently less likely to be transformed into
cancer cells later in life.
126, 129-131
This proposed mechanism may be similar
to that proposed for the protective effect of early pregnancy against breast
cancer.
132
Despite the proposed benefits, the relationship between soyfoods and
breast cancer is controversial due to concern, based almost exclusively on
in vitro and rodent data, that isoflavones may be contraindicated for women
with breast cancer or who are at high risk of developing breast cancer.
133

The position of the American Cancer Society is that women with breast
cancer can safely consume up to three servings of traditional soyfoods
daily.
134
However, their review of this issue was rather brief and was
conducted prior to the publication of important clinical and epidemiologic
data. A review of the breast cancer controversy is presented below.
At high concentrations, the isoflavone genistein inhibits the growth of
estrogen-sensitive breast cancer cells in vitro, whereas at lower, more
physiologic concentrations, growth is stimulated.

135
More importantly,
isoflavone-containing products have been found to stimulate the growth
of mammary tumors in ovariectomized athymic mice implanted with
estrogen-sensitive breast cancer cells.
136
Stimulation appears to result
primarily from exposure to the isoflavone genistein.
137
In this model,
genistein was also found to inhibit the efficacy of tamoxifen and the
aromatase inhibitor, letrozole.
138
Interestingly, more highly processed soy
products stimulate tumor growth to a greater extent than less processed
ones, despite containing similar amounts of genistein.
139
In fact, soy flour,
the least processed product to be evaluated, does not result in tumor
stimulation.
However, the relevance of this processing effect is in question because
it has now been established that, in athymic mice, processing affects
genistein pharmacokinetics in a way that leads to greater tumor
stimulation, which is not the case in humans.
140, 141
Also, Japanese
researchers, using the previously described mouse model, found that
genistein did not stimulate tumors.
142
Prior to implantation, the cancer cells

were cultured in estrogen-free media, whereas in the model which found
that genistein stimulated tumors, cells were cultured in media containing
a high concentration of estrogen. The Japanese researchers maintain that
the latter is unphysiologic and makes the cells hypersensitive to estrogenic
molecules. Clearly, there are limitations to animal research and resolving
the soy and breast cancer controversy will require human data.
The pertinent human data suggest that isoflavones do not exert stimulatory
effects on breast tissue. Isoflavones do not increase breast tissue density
or breast cell proliferation in vivo, both of which are markers of breast
cancer risk.
143
In contrast, combined menopausal hormone therapy, which
increases breast cancer risk, increases breast cell proliferation four-fold
within just 12 weeks.
144, 145
Thus, the clinical data are supportive of safety,
but the lack of effects in these studies also argues that adult soy intake
does not reduce breast cancer risk at this point in life.
The lack of harmful effects noted in the clinical studies are consistent
with the results from four prospective epidemiologic investigations. They
examined the impact of post-diagnosis soyfood intake on the prognosis
in women who have had breast cancer. The first study was designed to
specifically examine the soy and breast cancer controversy. Data from the
Shanghai Breast Cancer Survival Study (SBCSS),
146
a population-based
cohort study of breast cancer survivors, were analyzed to investigate the
effect of soy intake after diagnosis on breast cancer prognosis.
147
During

the median follow-up period of approximately 3.9 years, the hazard ratio
associated with the highest quartile of soy protein intake was 0.71 for total
mortality and 0.68 for recurrence compared with the lowest quartile of intake.
In fact, in this study, high soy intake was as protective as tamoxifen use.
In the second study, which was conducted in the U.S. and involved nearly
2,000 breast cancer patients, over the 6-year follow-up period, results
suggested that isoflavone intake may have improved prognosis overall,
and, in particular, among those women taking tamoxifen.
148
However,
among patients who had not previously used tamoxifen, there was an
increased risk associated with higher genistein intake but relatively
few women fell into this category. This raises the possibility that these
findings may have occurred by chance. In a second Chinese study,
Human data suggests that isoflavones do not exert
stimulatory effects on breast tissue, such as tissue
density or cell proliferation in vivo, which are both
markers of breast cancer risk.
Clinical evidence indicates that neither soyfoods nor
isoflavones adversely affect breast tissue.
7
which was conducted in Harbin among postmenopausal women with
estrogen receptor positive and progesterone receptor positive tumors, soy
consumption was associated with an approximate 30 percent decrease
in recurrence although overall mortality was not affected.
149
Interestingly,
although there was no interaction between tamoxifen and soy intake,
which is consistent with the results of the SBCSS, soy intake enhanced
the efficacy of anastrozole, an aromatase inhibitor. These findings are

important in and of themselves, and also because they contradict the
findings in animals.
Finally, the most recently published U.S. study involved 2,736 breast cancer
survivors diagnosed between 1991 and 2000 with early stage breast cancer
who were participants in the Women’s Healthy Eating and Living study.
116

During the median 7.3-year follow-up period, there were 448 new breast
cancer events and 271 deaths. The results showed that as isoflavone intake
increased, risk of death decreased. Women in the highest isoflavone intake
category (cutoff, >16.3 mg/day; median 26.7 mg/day) had a 54 percent
reduction in risk of death (p for trend=0.02). The benefits of isoflavone
intake were most evident in women being treated with tamoxifen.
A recent commentary in the journal Women’s Health concluded that
there is no longer any justification for advising women with breast
cancer to avoid soyfoods.
150
However, the data also does not justify a
recommendation that women should consume soyfoods specifically to
improve prognosis. Rather, the recommendation should be that women
with breast cancer who currently consume soyfoods or wish to consume
them can safely do so. Nevertheless, breast cancer patients should
discuss any dietary changes with their primary healthcare provider.
References
1. Messina M, Lane B. Soy protein, soybean isoflavones, and coronary heart disease risk: Where do we stand? Future Lipidology. 2007;
2: 5 5-74.
2. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women:
Meta-analysis of randomized controlled trials. Clin Nutr. 2008; 27: 57-64.
3. Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures and breast cancer risk. Br J Cancer. 2008; 98: 9-14.
4. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas.

2006; 55: 203-11.
5. Gollschewski S, Kitto S, Anderson D, Lyons-Wall P. Women’s perceptions and beliefs about the use of complementary and
alternative medicines during menopause. Complement Ther Med. 2008; 16: 163-8.
6. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288:
321-33.
7. Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, et al. Estrogen plus
progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010; 304: 1684-92.
8. Helferich WG, Andrade JE, Hoagland MS. Phytoestrogens and breast cancer: a complex story. Inflammopharmacology. 2008; 16:
219-26.
9. Franke AA, Custer LJ, Wang W, Shi CY. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human
fluids. Proc Soc Exp Biol Med. 1998; 217: 263-73.
10. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006; 55: 1-12.
11. Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst.
2003; 95: 1158-64.
12. Goodman-Gruen D, Kritz-Silverstein D. Usual dietary isoflavone intake is associated with cardiovascular disease risk factors in
postmenopausal women. J Nutr. 2001; 131: 1202-6.
13. 2004Q-0151: Qualified Health Claim (QHC): Soy Protein and Cancer ( />dockets/04q0151/04q0151.htm).
14. de Kleijn MJ, van der Schouw YT, Wilson PW, Adlercreutz H, Mazur W, Grobbee DE, Jacques PF. Intake of dietary phytoestrogens is
low in postmenopausal women in the United States: the Framingham study (1-4). J Nutr. 2001; 131: 1826-32.
15. van Erp-Baart MA, Brants HA, Kiely M, Mulligan A, Turrini A, Sermoneta C, Kilkkinen A, Valsta LM. Isoflavone intake in four
different European countries: the VENUS approach. Br J Nutr. 2003; 89 Suppl 1: S25-30.
16. van der Schouw YT, Kreijkamp-Kaspers S, Peeters PH, Keinan-Boker L, Rimm EB, Grobbee DE. Prospective study on usual dietary
phytoestrogen intake and cardiovascular disease risk in Western women. Circulation. 2005; 111: 465-71.
17. Boker LK, Van der Schouw YT, De Kleijn MJ, Jacques PF, Grobbee DE, Peeters PH. Intake of dietary phytoestrogens by Dutch
women. J Nutr. 2002; 132: 1319-28.
18. Haytowitz DB, Bhagwat S. Assessment of sources and dietary intake of isoflavones in the U.S. diet (poster presentation). 9th
international symposium on the role of soy in health promotion and chronic disease prevention and treatment (Washington, DC,
October 16-19, 2010).
19. Murphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. J Chromatogr B Analyt

Technol Biomed Life Sci. 2002; 777: 129-38.
20. Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, Cassidy A. Bioavailability of phyto-oestrogens. Br J Nutr. 2003; 89 Suppl
1: S45-58.
21. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity
and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997; 138: 863-70.
22. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction of estrogenic
chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998; 139: 4252-63.
23. Nagata C, Iwasa S, Shiraki M, Ueno T, Uchiyama S, Urata K, Sahashi Y, Shimizu H. Associations among maternal soy intake,
isoflavone levels in urine and blood samples, and maternal and umbilical hormone concentrations (Japan). Cancer Causes Control.
2006; 17: 1107-13.
24. An J, Tzagarakis-Foster C, Scharschmidt TC, Lomri N, Leitman DC. Estrogen Receptor Beta -Selective Transcriptional Activity and
Recruitment of Coregulators by Phytoestrogens. J Biol Chem. 2001; 276: 17808-14.
25. Margeat E, Bourdoncle A, Margueron R, Poujol N, Cavailles V, Royer C. Ligands Differentially Modulate the Protein Interactions of
the Human Estrogen Receptors alpha and beta. J Mol Biol. 2003; 326: 77-92.
26. Kostelac D, Rechkemmer G, Briviba K. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the
estrogen response element. J Agric Food Chem. 2003; 51: 7632-5.
Soyfoods provide high quality protein and are good
sources of well-absorbed protein.
Summary and Conclusions
Soyfoods are unique because they are rich dietary sources of isoflavones,
which are endocrine active substances but different from the hormone
estrogen. Epidemiologic and clinical data suggest that soyfoods can
make important contributions to the health of women, particularly
postmenopausal women. Soyfoods potentially reduce coronary heart
disease through multiple mechanisms and may be especially beneficial
when consumed by young postmenopausal women. Clinical research
indicates that isoflavones alleviate hot flashes although the evidence that
they reduce bone loss is unimpressive. Nevertheless, soyfoods can be part
of a bone-healthy diet as they provide high quality protein and many are
good sources of well-absorbed calcium. Adult soy intake does not appear to

reduce breast cancer risk although evidence suggests that soy consumption
during childhood and adolescence does. As there remains a controversy
over whether soyfoods are contraindicated for breast cancer patients, the
clinical evidence indicates that neither soyfoods nor isoflavones adversely
affect breast tissue. Recent epidemiologic evidence indicates that soy
consumption improves the prognosis of breast cancer patients.
27. Pike AC, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, Ljunggren J, Gustafsson JA, Carlquist M. Structure of
the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J. 1999; 18:
4608-18.
28. Lindberg MK, Moverare S, Skrtic S, Gao H, Dahlman-Wright K, Gustafsson JA, Ohlsson C. Estrogen receptor (ER)-beta reduces ER
alpha-regulated gene transcription, supporting a “ying yang” relationship between ER alpha and ER beta in mice. Mol Endocrinol.
2003; 17: 203-8.
29. Maehle BO, Collett K, Tretli S, Akslen LA, Grotmol T. Estrogen receptor beta an independent prognostic marker in estrogen
receptor alpha and progesterone receptor-positive breast cancer? APMIS. 2009; 117: 644-50.
30. Brzezinski A, Adlercreutz H, Shaoul R, Rösler R, Shmueli A, Tanos V, Schenker JG. Short-term effect of phytoestrogen-rich diet on
postmenopausal women. Menopause. 1997; 4: 89-94.
31. Diel P, Geis RB, Caldarelli A, Schmidt S, Leschowsky UL, Voss A, Vollmer G. The differential ability of the phytoestrogen genistein
and of estradiol to induce uterine weight and proliferation in the rat is associated with a substance specific modulation of uterine
gene expression. Mol Cell Endocrinol. 2004; 221: 21-32.
32. Yildiz MF, Kumru S, Godekmerdan A, Kutlu S. Effects of raloxifene, hormone therapy, and soy isoflavone on serum high-sensitive
C-reactive protein in postmenopausal women. Int J Gynaecol Obstet. 2005; 90: 128-33.
33. Schmidt C. Third-generation SERMs may face uphill battle. J Natl Cancer Inst. 2010; 102: 1690-1692.
34. Jordan VC. Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell. 2004; 5: 207-13.
35. European Food Safety Authority. Scientific report of the endocrine active substances task force. EFSA J. 2010; 8: 1-59.
36. Ho JY, Chen MJ, Sheu WH, Yi YC, Tsai AC, Guu HF, Ho ES. Differential effects of oral conjugated equine estrogen and transdermal
estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Hum Reprod.
2006; 21: 2715-20.
37. Lakoski SG, Brosnihan B, Herrington DM. Hormone therapy, C-reactive protein, and progression of atherosclerosis: data from the
Estrogen Replacement on Progression of Coronary Artery Atherosclerosis (ERA) trial. Am Heart J. 2005; 150: 907-11.
38. Helgason S, Damber JE, Damber MG, von Schoultz B, Selstam G, Sodergard R. A comparative longitudinal study on sex hormone

binding globulin capacity during estrogen replacement therapy. Acta Obstet Gynecol Scand. 1982; 61: 97-100.
39. Serin IS, Ozcelik B, Basbug M, Aygen E, Kula M, Erez R. Long-term effects of continuous oral and transdermal estrogen replacement
therapy on sex hormone binding globulin and free testosterone levels. Eur J Obstet Gynecol Reprod Biol. 2001; 99: 222-5.
40. Reid IR, Eastell R, Fogelman I, Adachi JD, Rosen A, Netelenbos C, Watts NB, Seeman E, Ciaccia AV, et al. A comparison of the
effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women. Arch Intern Med. 2004;
164: 871-9.
41. Shulman LP. Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in
postmenopausal women. Am J Cardiol. 2002; 89: 47E-54E; discussion 54E-55E.
42. Marqusee E, Braverman LE, Lawrence JE, Carroll JS, Seely EW. The effect of droloxifene and estrogen on thyroid function in
postmenopausal women. J Clin Endocrinol Metab. 2000; 85: 4407-10.
43. Abech DD, Moratelli HB, Leite SC, Oliveira MC. Effects of estrogen replacement therapy on pituitary size, prolactin and thyroid-
stimulating hormone concentrations in menopausal women. Gynecol Endocrinol. 2005; 21: 223-6.
44. Davies GC, Huster WJ, Shen W, Mitlak B, Plouffe L, Jr., Shah A, Cohen FJ. Endometrial response to raloxifene compared with
placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause. 1999; 6: 188-95.
45. Meuwissen JH, van Langen H. Monitoring endometrial thickness during estrogen replacement therapy with vaginosonography.
Radiology. 1992; 183: 284.
46. Kaari C, Haidar MA, Junior JM, Nunes MG, Quadros LG, Kemp C, Stavale JN, Baracat EC. Randomized clinical trial comparing
conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas. 2006; 53: 49-58.
47. D’Anna R, Baviera G, Corrado F, Cancellieri F, Crisafulli A, Squadrito F. The effect of the phytoestrogen genistein and hormone
replacement therapy on homocysteine and C-reactive protein level in postmenopausal women. Acta Obstet Gynecol Scand. 2005;
84: 474-7.
48. Garrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma
lipids in menopausal women. Maturitas. 2006; 54: 270-6.
49. Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, Blackburn GL. Daidzein-rich isoflavone aglycones are potentially
effective in reducing hot flashes in menopausal women. Menopause. 2008; 15: 125-32.
50. Hall WL, Vafeiadou K, Hallund J, Bugel S, Reimann M, Koebnick C, Zunft HJ, Ferrari M, Branca F, et al. Soy-isoflavone-enriched
foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production.
Am J Clin Nutr. 2006; 83: 592-600.
51. Katz DL, Evans MA, Njike VY, Hoxley ML, Nawaz H, Comerford BP, Sarrel PM. Raloxifene, soy phytoestrogens and endothelial
function in postmenopausal women. Climacteric. 2007; 10: 500-7.

8
2322-081512-1500
52. Cheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM. Isoflavone treatment for acute menopausal symptoms. Menopause.
2007; 14: 468-73.
53. Bruce B, Messina M, Spiller GA. Isoflavone supplements do not affect thyroid function in iodine-replete postmenopausal women. J
Med Food. 2003; 6: 309-16.
54. Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A, Mazzaferro S, Frisina A, et al. Effects of the phytoestrogen
genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007; 146: 839-47.
55. Sammartino A, Di Carlo C, Mandato VD, Bifulco G, Di Stefano M, Nappi C. Effects of genistein on the endometrium:
ultrasonographic evaluation. Gynecol Endocrinol. 2003; 17: 45-9.
56. Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and
placebo on menopausal symptoms: a randomized controlled trial. Maturitas. 2010; 67: 262-9.
57. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest. 2003; 21: 744-57.
58. Fang N, Yu S, Badger TM. Comprehensive phytochemical profile of soy protein isolate. J Agric Food Chem. 2004; 52: 4012-20.
59. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci. 1990; 592: 52-86; discussion 123-33.
60. Berg G, Gottwall T, Hammar M, Lindgren R, Gottgall T. Climacteric symptoms among women aged 60-62 in Linkoping, Sweden, in
1986. Maturitas. 1988; 10 : 193-9.
61. Rodstrom K, Bengtsson C, Lissner L, Milsom I, Sundh V, Bjorkelund C. A longitudinal study of the treatment of hot flushes: the
population study of women in Gothenburg during a quarter of a century. Menopause. 2002; 9: 156-61.
62. Adlercreutz H, Hamalainen E, Gorbach S, Goldin B. Dietary phyto-oestrogens and the menopause in Japan. Lancet. 1992; 339:
1233.
63. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, Salamone L, Stellato R. Relation of demographic and lifestyle factors
to symptoms in a multi- racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000; 152: 463-73.
64. Maki PM, Rubin LH, Fornelli D, Drogos L, Banuvar S, Shulman LP, Geller SE. Effects of botanicals and combined hormone therapy
on cognition in postmenopausal women. Menopause. 2009; 16:1167-77.
65. Brown DE, Sievert LL, Morrison LA, Reza AM, Mills PS. Do Japanese American women really have fewer hot flashes than European
Americans? The Hilo Women’s Health Study. Menopause. 2009; 16:870-6.
66. Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively
related to initial hot flush frequency. J Med Food. 2003; 6: 1-11.
67. Jacobs A, Wegewitz U, Sommerfeld C, Grossklaus R, Lampen A. Efficacy of isoflavones in relieving vasomotor menopausal

symptoms - A systematic review. Mol Nutr Food Res. 2009; 53: 1084-97.
68. Lethaby A, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms.
Cochrane Database Syst Rev. 2007: CD001395.
69. Wiseman H, Casey K, Bowey EA, Duffy R, Davies M, Rowland IR, Lloyd AS, Murray A, Thompson R, et al. Influence of 10 wk of soy
consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults. Am J
Clin Nutr. 2004; 80: 692-9.
70. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein
reduce hot flash symptoms: a critical review of published studies. Menopause. 2006; 13: 831-9.
71. Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. Interindividual variation in metabolism of soy isoflavones and
lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000; 36: 27-32.
72. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein
reduce hot flash symptoms: a critical review of published studies. Menopause. 2006; 13: 831-9.
73. Weaver CM, Martin BR, Jackson GS, McCabe GP, Nolan JR, McCabe LD, Barnes S, Reinwald S, Boris ME, et al. Antiresorptive
effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca
methodology. J Clin Endocrinol Metab. 2009; 94: 3798-805.
74. Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG, Katzenellenbogen JA. Equol, a natural
estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding
and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem. 2004; 12: 1559-67.
75. Taku K, Melby M, Kronenberg F, Kurzer M, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash
frequency and severity: Systematic review and meta-analysis of randomized controlled trials. Menopause. 2012.
76. Butt DA, Deng LY, Lewis JE, Lock M. Minimal decrease in hot flashes desired by postmenopausal women in family practice.
Menopause. 2007; 14: 203-7.
77. Finkelstein JS, Brockwell SE, Mehta V, Greendale GA, Sowers MR, Ettinger B, Lo JC, Johnston JM, Cauley JA, et al. Bone Mineral
Density Changes During the Menopause Transition in a Multi-Ethnic Cohort of Women. J Clin Endocrinol Metab. 2008; 93:861-8.
78. LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, et al. Health
outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized
controlled trial. JAMA. 2011; 305: 1305-14.
79. Brandi ML, Gennari C. Ipriflavone: new insights into its mechanisms of action on bone remodeling. Calcif Tissue Int. 1993; 52:
151-2.
80. Ross PD, Norimatsu H, Davis JW, Yano K, Wasnich RD, Fujiwara S, Hosoda Y, Melton LJ. A comparison of hip fracture incidence

among native Japanese, Japanese Americans, and American Caucasians. Am J Epidemiol. 1991; 133: 801-9.
81. Chin K, Evans MC, Cornish J, Cundy T, Reid IR. Differences in hip axis and femoral neck length in premenopausal women of
Polynesian, Asian and European origin. Osteoporos Int. 1997; 7: 344-7.
82. Cummings SR, Cauley JA, Palermo L, Ross PD, Wasnich RD, Black D, Faulkner KG. Racial differences in hip axis lengths might
explain racial differences in rates of hip fracture. Study of Osteoporotic Fractures Research Group. Osteoporos Int. 1994; 4: 226-9.
83. Aoyagi K, Ross PD, Davis JW, Wasnich RD, Hayashi T, Takemoto T. Falls among community-dwelling elderly in Japan. J Bone Miner
Res. 1998; 13: 1468-74.
84. Davis JW, Ross PD, Nevitt MC, Wasnich RD. Incidence rates of falls among Japanese men and women living in Hawaii. J Clin
Epidemiol. 1997; 50: 589-94.
85. Ross PD, He Y, Yates AJ, Coupland C, Ravn P, McClung M, Thompson D, Wasnich RD. Body size accounts for most differences in
bone density between Asian and Caucasian women. The EPIC (Early Postmenopausal Interventional Cohort) Study Group. Calcif
Tissue Int. 1996; 59: 339-43.
86. Russell-Aulet M, Wang J, Thornton JC, Colt EW, Pierson RN, Jr. Bone mineral density and mass in a cross-sectional study of white
and Asian women. J Bone Miner Res. 1993; 8: 575-82.
87. Nomura A, Wasnich RD, Heilbrun LK, Ross PD, Davis JW. Comparison of bone mineral content between Japan-born and US-born
Japanese subjects in Hawaii. Bone Miner. 1989; 6: 213-23.
88. Ross PD, Fujiwara S, Huang C, Davis JW, Epstein RS, Wasnich RD, Kodama K, Melton LJ, 3rd. Vertebral fracture prevalence in
women in Hiroshima compared to Caucasians or Japanese in the US. Int J Epidemiol. 1995; 24: 1171-7.
89. Lau EM, Chan HH, Woo J, Lin F, Black D, Nevitt M, Leung PC. Normal ranges for vertebral height ratios and prevalence of vertebral
fracture in Hong Kong Chinese: a comparison with American Caucasians. J Bone Miner Res. 1996; 11: 1364-8.
90. Dennison E, Yoshimura N, Hashimoto T, Cooper C. Bone loss in Great Britain and Japan: a comparative longitudinal study. Bone.
1998; 23: 379-82.
91. Tsai K, Huang K, Chieng P, Su C. Bone mineral density of normal Chinese women in Taiwan. Calcif Tissue Inter. 1991; 48: 161-166.
92. Tsai K, Twu S, Chieng P, Yang R, Lee T. Prevalence of vertebral fractures in chinese men and women in urban Taiwanese
communities. Calcif Tissue Int. 1996; 59: 249-53.
93. Zhang X, Shu XO, Li H, Yang G, Li Q, Gao YT, Zheng W. Prospective cohort study of soy food consumption and risk of bone fracture
among postmenopausal women. Arch Intern Med. 2005; 165: 1890-5.
94. Koh WP, Wu AH, Wang R, Ang LW, Heng D, Yuan JM, Yu MC. Gender-specific associations between soy and risk of hip fracture in
the Singapore Chinese Health Study. Am J Epidemiol. 2009; 170: 901-9.
95. Matthews VL, Knutsen SF, Beeson WL, Fraser GE. Soymilk and dairy consumption is independently associated with ultrasound

attenuation of the heel bone among postmenopausal women: the Adventist Health Study-2. Nutr Res. 2011; 31: 766-75.
96. 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.
97. Atmaca A, Kleerekoper M, Bayraktar M, Kucuk O. Soy isoflavones in the management of postmenopausal osteoporosis. Menopause.
2008; 15:748-57.
98. Messina M, Ho S, Alekel DL. Skeletal benefits of soy isoflavones: a review of the clinical trial and epidemiologic data. Curr Opin Clin
Nutr Metab Care. 2004; 7: 649-658.
99. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal
women: meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2008; 62:155-61.
100. Taku K, Melby MK, Takebayashi J, Mizuno S, Ishimi Y, Omori T, Watanabe S. Effect of soy isoflavone extract supplements on bone
mineral density in menopausal women: meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr. 2010; 19: 33-42.
101. Liu J, Ho SC, Su YX, Chen WQ, Zhang CX, Chen YM. Effect of long-term intervention of soy isoflavones on bone mineral density in
women: A meta-analysis of randomized controlled trials. Bone. 2009; 44:948-53.
102. Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano V, Minutoli L, Atteritano M, Levy RM, et al. Breast safety and efficacy of
genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab. 2008; 93: 4787-96.
103. Brink E, Coxam V, Robins S, Wahala K, Cassidy A, Branca F. Long-term consumption of isoflavone-enriched foods does not affect
bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo
controlled study. Am J Clin Nutr. 2008; 87: 761-70.
104. Kenny AM, Mangano KM, Abourizk RH, Bruno RS, Anamani DE, Kleppinger A, Walsh SJ, Prestwood KM, Kerstetter JE. Soy proteins
and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr. 2009; 90: 234-42.
105. Vupadhyayula PM, Gallagher JC, Templin T, Logsdon SM, Smith LM. Effects of soy protein isolate on bone mineral density and
physical performance indices in postmenopausal women-a 2-year randomized, double-blind, placebo-controlled trial. Menopause.
2009; 16: 320-8.
106. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, Kurzer MS, Peterson CT. The Soy Isoflavones for
Reducing Bone Loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr. 2010; 91: 218-30.
107. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss
and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med. 2011; 171: 1363-9.
108. Tai TY, Tsai KS, Tu ST, Wu JS, Chang CI, Chen CL, Shaw NS, Peng HY, Wang SY, et al. The effect of soy isoflavone on bone mineral
density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study.
Osteoporos Int. 2012; 23: 1571-80.

109. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, Kurzer MS, Peterson CT. The Soy Isoflavones for
Reducing Bone Loss (SIRBL) Study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr. 2010; 91: 218-30.
110. Rand WM, Pellett PL, Young VR. Meta-analysis of nitrogen balance studies for estimating protein requirements in healthy adults.
Am J Clin Nutr. 2003; 77: 109-27.
111. Darling AL, Millward DJ, Torgerson DJ, Hewitt CE, Lanham-New SA. Dietary protein and bone health: a systematic review and
meta-analysis. Am J Clin Nutr. 2009; 90: 1674-92.
112. Jesudason D, Clifton P. The interaction between dietary protein and bone health. J Bone Miner Metab. 2011; 29: 1-14.
113. Zhao Y, Martin BR, Weaver CM. Calcium bioavailability of calcium carbonate fortified soymilk is equivalent to cow’s milk in young
women. J Nutr. 2005; 135: 2379-82.
114. Weaver CM, Heaney RP, Connor L, Martin BR, Smith DL, Nielsen E. Bioavailability of calcium from tofu vs. milk in premenopausal
women. J Food Sci. 2002; 68: 3144-3147.
115. Tang AL, Walker KZ, Wilcox G, Strauss BJ, Ashton JF, Stojanovska L. Calcium absorption in Australian osteopenic post-menopausal
women: an acute comparative study of fortified soymilk to cows’ milk. Asia Pac J Clin Nutr. 2010; 19: 243-9.
116. Slavin M, Kenworthy W, Yu LL. Antioxidant properties, phytochemical composition, and antiproliferative activity of Maryland-grown
soybeans with colored seed coats. J Agric Food Chem. 2009 ; 57:111740-85.
117. Food labeling: health claims; soy protein and coronary heart disease. Food and Drug Administration, HHS. Final rule. Fed Regist.
1999; 64: 57700-33.
118. Jenkins DJ, Mirrahimi A, Srichaikul K, Berryman CE, Wang L, Carleton A, Abdulnour S, Sievenpiper JL, Kendall CW, et al. Soy
protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr. 2010; 140: 2302S-2311S.
119. Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, Ryder JJ, Hall WL, Cassidy A. Flavonoids, flavonoid-rich foods,
and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008; 88: 38-50.
120. Dong JY, Tong X, Wu ZW, Xun PC, He K, Qin LQ. Effect of soya protein on blood pressure: a meta-analysis of randomised controlled
trials. Br J Nutr. 2011; 106: 317-26.
121. Liu XX, Li SH, Chen JZ, Sun K, Wang XJ, Wang XG, Hui RT. Effect of soy isoflavones on blood pressure: A meta-analysis of
randomized controlled trials. Nutr Metab Cardiovasc Dis. 2012; 22: 463-70.
122. Taku K, Lin N, Cai D, Hu J, Zhao X, Zhang Y, Wang P, Melby MK, Hooper L, et al. Effects of soy isoflavone extract supplements on
blood pressure in adult humans: systematic review and meta-analysis of randomized placebo-controlled trials. J Hypertens. 2010;
28: 1971-82.
123. Li SH, Liu XX, Bai YY, Wang XJ, Sun K, Chen JZ, Hui RT. Effect of oral isoflavone supplementation on vascular endothelial function
in postmenopausal women: a meta-analysis of randomized placebo-controlled trials. Am J Clin Nutr. 2010; 91: 480-6.

124. Hodis HN, Mack WJ, Kono N, Azen SP, Shoupe D, Hwang-Levine J, Petitti D, Whitfield-Maxwell L, Yan M, et al. Isoflavone soy
protein supplementation and atherosclerosis progression in healthy postmenopausal women: a randomized controlled trial. Stroke.
2011; 42: 3168-75.
125. Hodis HN, Mack WJ. A “window of opportunity:” The reduction of coronary heart disease and total mortality with menopausal
therapies is age- and time-dependent. Brain Res. 2011; 1379: 244-52.
126. Lamartiniere CA, Zhao YX, Fritz WA. Genistein: mammary cancer chemoprevention, in vivo mechanisms of action, potential for
toxicity and bioavailability in rats. J Women’s Cancer. 2000; 2: 11-19.
127. 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; 10: 483-8.
128. Wu AH, Yu MC, Tseng CC, Stanczyk FZ, Pike MC. Dietary patterns and breast cancer risk in Asian American women. Am J Clin Nutr.
2009; 89: 1145-54.
129. Peng JH, Zhang F, Zhang HX, Fan HY. Prepubertal octylphenol exposure up-regulate BRCA1 expression, down-regulate ER alpha
expression and reduce rat mammary tumorigenesis. Cancer Epidemiol. 2009; 33: 51-5.
130. Messina M, Hilakivi-Clarke L. Early intake appears to be the key to the proposed protective effects of soy intake against breast
cancer. Nutr Cancer. 2009; 61: 792-798.
131. Mishra P, Kar A, Kale RK. Prepubertal daidzein exposure enhances mammary gland differentiation and regulates the expression of
estrogen receptor-alpha and apoptotic proteins. ISRN oncology. 2011; 896826.
132. Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, Russo IH. Breast differentiation and its implication in cancer prevention. Clin Cancer
Res. 2005; 11: 931s-6s.
133. Messina M, McCaskill-Stevens W, Lampe JW. Addressing the soy and breast cancer relationship: review, commentary, and
workshop proceedings. J Natl Cancer Inst. 2006; 98: 1275-84.
134. Doyle C, Kushi LH, Byers T, Courneya KS, Demark-Wahnefried W, Grant B, McTiernan A, Rock CL, Thompson C, et al. Nutrition and
physical activity during and after cancer treatment: an american cancer society guide for informed choices. CA Cancer J Clin. 2006;
56: 323-53.
135. Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor- positive human
breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 1998; 58: 3833-8.
136. Allred CD, Ju YH, Allred KF, Chang J, Helferich WG. Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors
similar to that observed with genistein. Carcinogenesis. 2001; 22: 1667-73.
137. Ju YH, Fultz J, Allred KF, Doerge DR, Helferich WG. Effects of dietary daidzein and its metabolite, equol, at physiological
concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic

mice. Carcinogenesis. 2006; 27: 856-63.
138. Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Dietary genistein negates the inhibitory effect of letrozole on
the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. 2008; 29:
2162-8.
139. Allred CD, Twaddle NC, Allred KF, Goeppinger TS, Churchwell MI, Ju YH, Helferich WG, Doerge DR. Soy processing affects
metabolism and disposition of dietary isoflavones in ovariectomized BALB/c mice. J Agric Food Chem. 2005; 53: 8542-50.
140. 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: 1649-57.
141. Setchell KD, Brown NM, Zhao X, Lindley SL, Heubi JE, King EC, Messina MJ. Soy isoflavone phase II metabolism differs between
rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011; 94: 1284-94.
142. Onoda A, Ueno T, Uchiyama S, Hayashi SI, Kato K, Wake N. Effects of S-equol and natural S-equol supplement (SE5-OH) on the
growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice. Food Chem Toxicol. 2011; 49: 2279-84.
143. Messina MJ, Wood CE. Soy isoflavones, estrogen therapy, and breast cancer risk: Analysis and commentary. Nutr J. 2008; 7: 17.
144. Conner P, Skoog L, Soderqvist G. Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration
cytology. Climacteric. 2001; 4: 7-12.
145. Conner P, Soderqvist G, Skoog L, Graser T, Walter F, Tani E, Carlstrom K, von Schoultz B. Breast cell proliferation in
postmenopausal women during HRT evaluated through fine needle aspiration cytology. Breast Cancer Res Treat. 2003; 78: 159-65.
146. Messina M, Watanabe S, Setchell KD. Report on the 8th International Symposium on the Role of Soy in Health Promotion and
Chronic Disease Prevention and Treatment. J Nutr. 2009; 139: 796S-802S.
147. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009; 302: 2437-43.
148. Guha N, Kwan ML, Quesenberry CP, Jr., Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort
of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009; 118: 395-405.
149. Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving
adjuvant endocrine therapy. CMAJ. 2010; 182: 1857-62.
150. Messina M, Abrams DI, Hardy M. Can clinicians now assure their breast cancer patients that soyfoods are safe? Women’s Health
(Lond Engl). 2010; 6: 335-8.
The 69 farmer-directors of USB oversee the investments of the soy checkoff to maximize profit opportunities for all U.S. soybean farmers. These volunteers invest
and leverage checkoff funds to increase the value of U.S. soy meal and oil, to ensure U.S. soybean farmers and their customers have the freedom and infrastructure
to operate, and to meet the needs of U.S. soy’s customers. As stipulated in the federal Soybean Promotion, Research and Consumer Information Act, the USDA
Agricultural Marketing Service has oversight responsibilities for USB and the soy checkoff. For more information, please visit SoyConnection.com.