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Soy Isoflavones
Contents Summary
Iso avones are a class of phytoestrogens — plant-derived
Summary
compounds with estrogenic activity. Soybeans and soy
Introduction products are the richest sources of iso avones in the
human diet. (More information) 
Metabolism and Bioavailability
Some health e ects of soy may be dependent on one’s
Biological Activities
capacity to convert the iso avone daidzein to equol during
Estrogenic and anti-estrogenic digestion. (More information)
Estrogen receptor-independent The results of observational studies suggest that higher
intakes of soy foods early in life may decrease the risk of Share This Page
Disease Prevention
breast cancer in adulthood. There is currently little clinical
Hormone-associated cancers
evidence that taking soy iso avone supplements decreases
Vitamins
 Osteoporosis the risk of incident and recurrent breast cancer. (More
information) Minerals
Cardiovascular disease
Current evidence from observational studies and small Other Nutrients
Cognitive decline
clinical trials is not robust enough to understand whether
Disease Treatment soy protein/iso avone supplements may help prevent or Dietary Factors
Menopausal symptoms inhibit the progression of prostate cancer. (More
information)  L-Carnitine
Sources
To date, randomized controlled trials examining the e ect
Food  Coenzyme Q10
of soy iso avones on bone mineral density in
Supplements postmenopausal women have produced mixed results.  Lipoic Acid
Potential bene ts of soy iso avones as an alternative to
Infant formulas
bone-sparing treatments in women undergoing  Phytochemicals
Safety menopause remain to be determined. (More information)
 Carotenoids
Adverse e ects Current evidence suggests that whole soy components
Drug interactions other than iso avones may have favorable e ects on
 Chlorophyll and
serum lipid pro les. Yet, two recent meta-analyses of
Authors and Reviewers Chlorophyllin
randomized controlled trials indicated that iso avones
References might exert cardiovascular bene ts by improving vascular  Curcumin
function in postmenopausal women. (More information)
 Fiber
Supplementation with iso avones appeared to be about 40% less e cient than hormone-
replacement therapy in attenuating menopausal hot ashes and required more time to reach its
 Flavonoids
maximum e ect. Yet, supplements containing primarily the iso avone genistein have demonstrated
consistent alleviation of menopausal hot ashes. (More information)
 Garlic
Currently available data suggest that breast cancer survivors should not be further discouraged from
consuming soy foods in moderation. Moreover, in a pooled analysis of three large prospective cohort  Indole-3-Carbinol
studies, soy iso avone intake ≥10 mg/day was associated with a 25% reduced risk of tumor
recurrence in breast cancer survivors. (More information)  Isothiocyanates
 At present, there is no convincing evidence that infants fed soy-based formula are at greater risk for
 Lignans
adverse e ects than infants fed cow’s milk-based formula. (More information)

 Phytosterols
Introduction
Iso avones are polyphenolic compounds that possess both estrogen-agonist and estrogen-antagonist  Resveratrol
properties (see Biological Activities). For this reason, they are classi ed as phytoestrogens — plant-
derived compounds with estrogenic activity (1). Iso avones are the major avonoids found in legumes,  Soy Iso avones
particularly soybeans. In soybeans, iso avones are present as gylcosides, i.e., bound to a sugar
molecule. Digestion or fermentation of soybeans or soy products results in the release of the sugar Food and Beverages
molecule from the iso avone glycoside, leaving an iso avone aglycone. Soy iso avone glycosides
include genistin, daidzin, and glycitin, while the aglycones are called genistein, daidzein, and glycitein Life Stages

(Figure 1). Unless otherwise indicated, quantities of iso avones speci ed in this article refer to
Health and Disease
aglycones — not glycosides.

       

 
  [Click to Enlarge]

Metabolism and Bioavailability

The article on Flavonoids describes some of the factors in uencing the absorption, metabolic fate, and
bioavailability of avonoid family members, including iso avones. Pharmacokinetic studies have
indicated that plasma concentrations of daidzein and genistein peaked about six hours after iso avone
intake, preceded by a smaller initial peak one hour post-meal (2, 3). The initial peak re ects iso avone
absorption following the hydrolysis of iso avone glycosides to aglycones by β-glucosidases in the small
intestine, while the second peak corresponds to iso avone aglycones absorbed after the hydrolysis of
glycosides by bacterial β-glucosidases in the colon (2).

The composition of one’s colonic microbiota can in uence the metabolic fate and biological e ects of
iso avones. Indeed, the extent of at least some of the potential health bene ts of soy intake are thought
to depend on one’s capacity to convert iso avones to key metabolites during digestion. Speci cally,
some colonic bacteria can convert the soy iso avone daidzein to equol, a metabolite that has greater
estrogenic activity than daidzein, and to other metabolites, such as O-desmethylangolensin [O-DMA],
that are less estrogenic (Figure 2) (4, 5). Equol appears in plasma about eight hours after iso avone
intake owing to the transit time of daidzein to the colon and its subsequent conversion to equol by the
microbiota. Studies measuring urinary equol excretion after soy consumption indicated that equol was
produced by about 25%-30% of the adult population in Western countries compared to 50%-60% of
adults living in Asian countries and Western adult vegetarians (4, 6). Note that individuals possessing
equol-producing bacteria are called "equol producers" as opposed to "equol non-producers."

Although prolonged soy food consumption has not been associated with the ability to produce equol,
the type of soy food consumed might in uence the composition of microbiota to include equol-
producing bacteria (discussed in 4).
[Click to Enlarge]
Biological Activities
Estrogenic and anti-estrogenic activities

Soy iso avones are known to have weak estrogenic or hormone-like activity due to their structural
similarity with 17-β-estradiol (Figure 3). Estrogens are signaling molecules that exert their e ects by
binding to estrogen receptors within cells (Figure 3). The estrogen-receptor complex interacts with DNA
to change the expression of estrogen-responsive genes. Estrogen receptors (ER) are present in
numerous tissues other than those associated with reproduction, including bone, liver, heart, and brain
(7). Soy iso avones can preferentially bind to and transactivate estrogen receptor-β (ER-β) — rather than
ER-α — mimicking the e ects of estrogen in some tissues and antagonizing (blocking) the e ects of
estrogen in others (8). Scientists are interested in the tissue-selective activities of phytoestrogens
because anti-estrogenic e ects in reproductive tissue could help reduce the risk of hormone-associated
cancers (breast, uterine, and prostate), while estrogenic e ects in other tissues could help maintain
bone mineral density and improve blood lipid pro les (see Disease Prevention). The extent to which soy
iso avones exert estrogenic and anti-estrogenic e ects in humans is currently the focus of considerable
scienti c research.
  

[Click to Enlarge]

Estrogen receptor-independent activities

Soy iso avones and their metabolites also have biological activities that are unrelated to their
interactions with estrogen receptors (9). By inhibiting the synthesis and activity of certain enzymes
involved in estrogen metabolism, soy iso avones may alter the biological activity of endogenous
estrogens and androgens (10-13). Soy iso avones have also been found to inhibit tyrosine kinases (14),
enzymes that play critical roles in the signaling pathways that stimulate cell proliferation. Additionally,
iso avones can act as antioxidants in vitro (15), but the extent to which they contribute to the
antioxidant status of humans is not yet clear. Plasma F2-isoprostanes, biomarkers of lipid peroxidation
in vivo, were signi cantly lower after two weeks of daily consumption of soy protein containing 56 mg of
iso avones than after consumption of soy protein providing only 2 mg of iso avones (16). However,
daily supplementation with 50 to 100 mg of isolated soy iso avones did not signi cantly alter plasma or
urinary F2-isoprostane concentrations (17, 18).

Disease Prevention
Hormone-associated cancers
Since soy iso avones are structurally similar to endogenous estrogens, it has been suggested that they
might help protect against hormone-associated cancers.

Breast cancer
High iso avone intake from soy foods in Asian countries (average range, 25 to 50 mg/day) has been
suggested to contribute to reducing the risk of breast cancer; in contrast, the incidence of breast cancer
remains elevated in Europe, North America, and Australia/New Zealand (19) where average iso avone
intakes in non-Asian women are generally less than 2 mg/day (20). Nevertheless, several hereditary and
lifestyle factors likely also contribute to this di erence (19, 21). In a meta-analysis of one prospective
cohort study and seven case-control studies conducted in Asian populations and in Asian Americans,
higher versus lower intakes of dietary soy iso avones (≥20 mg/day vs. ≤5 mg/day) were found to be
associated with a 29% reduced risk of breast cancer (22). In observational studies conducted in Western
populations, median intake of soy iso avones was reportedly low (0.3 mg/day) and not associated with a
decreased risk of breast cancer (22, 23). Moreover, a lifelong exposure to iso avones may be needed to
lower the risk of developing breast cancer later in life (21). This would explain why moderate versus low
intakes of iso avones (10.8 mg/day vs. 0.23 mg/day; cohort followed for a median of 7.4 years) during
adulthood was not associated with a reduced risk of breast cancer in British women enrolled in the
European Prospective Investigation into Cancer and Nutrition (EPIC) study (24). A few case-control
studies also reported that early soy exposure — during childhood and adolescence — might be
associated with a lower risk of breast cancer later in life (25-28). Further, a meta-analysis of four
prospective cohort studies suggested that high versus low iso avone intakes might be associated with a
modest reduction in risk of recurrence (RR=0.84, 95% CI: 0.71-0.99) in breast cancer survivors (see Safety
for breast cancer survivors) (23).
While lower circulating estrogen concentrations have been linked to a lower risk of breast cancer in
postmenopausal women (29), a meta-analysis of randomized controlled trials in this population found
no e ect of soy iso avone supplementation on the circulating concentrations of estrogenic hormones,
estradiol (21 studies) and estrone (7 studies), and of sex-hormone binding globulin (SHBG; 17 studies)
(30). Another meta-analysis of seven randomized controlled trials in 1,287 women found no overall
e ect of soy iso avones (40 to 120 mg/day) consumed for six months to three years on mammographic
breast density, used as a surrogate marker of breast cancer risk (31). Subgroup analyses showed no
e ect in postmenopausal women (four studies) but a modest increase in breast density — of unclear
clinical signi cance — in premenopausal women ( ve studies). Further, in a recent randomized, placebo-
controlled trial, soy iso avone supplementation (50 mg/day for one year) also failed to a ect breast
density in women (ages, 30 to 75 years) with breast cancer (32).

There is currently little evidence that taking soy iso avone supplements decreases the risk of incident
and recurrent breast cancer.

Endometrial cancer
It is thought that the development of endometrial (uterine) cancer could be related to prolonged
exposure to unopposed estrogen, i.e., estrogen not counterbalanced with the hormone progesterone
(33). Excess estrogen relative to progesterone may result in endometrial thickening, a potential
biomarker of estrogen-induced proliferation and a predictor of endometrial carcinomas (34). Whether
high intakes of iso avones with anti-estrogenic activity in uterine tissue could be associated with a lower
risk of endometrial cancer has been examined in a number of observational studies. A recent meta-
analysis of two prospective cohort studies and eight case-control studies found the highest versus
lowest quantile of iso avone intake to be associated with a 19% lower risk of endometrial cancer (35).
One of the two prospective studies included in the meta-analysis found no association between
consumption of total soy foods, legumes, and tofu and risk of endometrial cancer in a cohort of 46,027
multiethnic US women (mean age at cohort entry, 61.6 years) followed for a median 13.6 years (36).
Nevertheless, a 34% lower risk of endometrial cancer was found to be associated with the highest
versus lowest quintile of total iso avones (median intakes, 11.23 mg/1,000 kcal/day vs. 0.87 mg/1,000
kcal/day) in this cohort (36). In the second prospective study, no association was observed between the
top versus bottom tertile of iso avone intakes (median intakes, 63.2 mg/day vs. 17.7 mg/day) and the
risk of endometrial cancer risk in 49,121 Japanese women (ages, 45 to 74 years) (37). Because the
consumption of iso avones is much lower in non-Asian versus Asian cohorts, comparisons among
populations are quite problematic and limit the scope of pooled analyses of observational studies (38).

Finally, a recent meta-analysis of 23 randomized controlled trials found no overall e ect of iso avone
supplementation (5 to 154 mg/day) for up to three years on endometrial thickness in postmenopausal
women (39). Nevertheless, a subgroup analysis of 10 trials showed that supplementation of
postmenopausal women with iso avone doses >54 mg/day of iso avones could signi cantly decrease
endometrial thickness (39).

Although limited evidence from case-control studies showed an inverse relationship between
consumption of soy foods and endometrial cancer, there is little evidence from intervention trials to
suggest that taking soy iso avone supplements could decrease the risk of endometrial cancer.

Prostate cancer
Incidence rates of prostate cancer are much higher in Northern America, Northern and Western Europe,
Australia, and New Zealand compared to Asian countries, such as Japan and China, where iso avone-
rich soybeans are common components of the diet (19). Soy food consumption has been associated
with a reduced risk of prostate cancer in recent pooled analyses of observational studies (40, 41). In a
study of 19 men with prostate cancer, daily soy supplementation resulted in soy iso avone
concentrations six-fold higher in prostate tissue than in serum (42). The results of cell culture and
animal studies have suggested a potential role for soy iso avones in limiting the progression of prostate
cancer (reviewed in 43).

A number of small, short-term randomized controlled interventions have examined the e ect of soy
foods/iso avones on biomarkers of prostate cancer risk (44). Compared to supplementation with milk
protein, consumption of a diet supplemented with soy protein isolate high in iso avones (~107 mg/day)
limited the rise in androgen receptor density in prostate tissue after six months but did not modify
prostatic estrogen receptor-β expression or circulating sex steroid hormone pro le in men at high risk
of developing prostate cancer (45). In addition, dietary soy protein supplementation had no e ect on
prostate-speci c antigen (PSA) in serum or markers of cell proliferation and apoptosis in premalignant
tissue. Yet, supplemental soy protein isolate — regardless of iso avone content — for six months
resulted in a lower cancer incidence compared to milk control (46). In a multicenter, randomized,
double-blind, placebo-controlled trial in 158 Japanese men (ages, 50 to 75 years) with negative prostate
biopsy but rising serum PSA, supplemental iso avones (60 mg/day) for one year had no e ect on
circulating concentrations of PSA and sex steroid hormones, or on the overall incidence of biopsy-
detectable prostate cancer. However, prostate cancer incidence was found to be signi cantly lower with
iso avones compared to placebo in the subset of men aged 65 years and older (47).

Some trials found that supplementation with soy products, soy dietary proteins, or soy iso avones could
reduce or slow down the rising of serum PSA concentration in men with localized prostate cancer prior
to therapy (48-50), as well as in those with PSA biochemical recurrence following radiotherapy and/or
prostatectomy (51-53). However, other trials failed to show an e ect of soy food/iso avones on serum
PSA in prostate cancer patients prior to (54, 55) or after therapy (56-58). Clinical studies have also failed
to show a protective e ect of soy iso avones on circulating concentrations of sex hormones
(testosterone, dihydrotestosterone, and estradiol) and sex hormone-binding globulin (SHBG) in patients
with prostate cancer (44).

Pooled analyses of current data are hindered by the heterogeneity in soy/soy iso avone preparations
and dosage regimens in short-term interventions (mostly ≤6 months) in small sample-size trials.
Therefore, despite a good safety pro le for supplemental soy iso avones and soy proteins in prostate
cancer patients, larger randomized controlled trials with longer periods of intervention are required to
assess whether soy iso avones could in uence the development and/or progression of prostate cancer.

More information about soy foods and prostate cancer risk may be found in the article on Legumes.

Osteoporosis
The decline in estrogen production that accompanies menopause places middle-aged women at risk of
osteopenia and osteoporosis. The measurement of bone mineral density (BMD) loss by dual-energy X-
ray absorptiometry is generally used in the diagnosis of osteoporosis (59). Whether the estrogenic
properties of soy iso avones might play any role in preserving bone health and preventing bone loss is
unclear. To date, the results of observational and intervention studies examining the potential
protection of soy iso avones against BMD loss have been inconsistent. A recent review by Zheng et al.
(60) discussed some potential factors relative to study design (e.g., intervention duration, iso avone
dosages) and target populations (e.g., ethnic and genetic di erences, hormonal status) that could
explain the con icting study results.

For instance, the results of short-term (≤6 months) clinical trials assessing the e ects of increased soy
intake on biochemical markers of bone formation and bone resorption are inconsistent. Some
controlled trials in postmenopausal women have found that increasing intakes of soy foods, soy protein,
or soy iso avones improved markers of bone resorption and formation (61-64) or attenuated bone loss
(64, 65), but other trials have found no signi cant bene t of increasing soy intakes (66-69). Trials of
longer duration also showed con icting results. A meta-analysis of 10 randomized controlled trials (trial
duration, 12 to 24 months) concluded that a mean dose of 87 mg/day of soy iso avones resulted in no
signi cant changes in lumbar spine, total hip, or femoral neck BMD of postmenopausal women (70).

Mixed results also emerged from studies conducted in di erent ethnic populations. Compared to
Caucasian women, the incidence of hip fractures tend to be lower among Asian women who are
habitual soy food consumers (71, 72), suggesting that long-term soy food consumption might protect
against bone loss or osteoporotic fracture (73, 74). Moreover, pooled analyses combining intervention
trials in Caucasian and Asian postmenopausal women reported signi cant increases in BMD with
supplemental soy iso avones (75-77). In contrast, a meta-analysis of 12 placebo-controlled trials in
Caucasian postmenopausal women found no e ect of soy iso avone supplementation (dose range, 52
to 120 mg/day) for six months to three years on lumbar spine BMD (78).

The rate of bone loss is not linear during the 10-year period surrounding the nal menstrual period and
is especially increased during the menopausal transition, starting about one year before to two years
after the nal menstrual period. Surprisingly, the recent US Study of Women’s Health Across the Nation
(SWAN) that followed Black, White, Japanese, and Chinese women reported that Japanese women with
the highest versus lowest tertile of dietary iso avone intakes (median intakes, 36.3 mg/day versus 4
mg/day) had an increased rate of BMD loss during menopause transition (79). In other ethnic groups, no
such associations could be found between habitual dietary iso avone intakes and the rate of bone loss
before, after, or during menopause transition (79). Most meta-analyses of randomized controlled trials
to date have reported a weak, positive e ect of supplemental soy iso avones on BMD in
postmenopausal women (70, 75-77). Yet, it remains to be elucidated whether supplementation with soy
iso avones might be of any bene t to perimenopausal/early postmenopausal women before the acute
loss of estrogen or to older postmenopausal women with established osteoporosis (60).

Finally, some authors have proposed that the e ect of soy iso avones on bone health may be
dependent on whether or not the individual produces the daidzein metabolite, equol (see Metabolism
and Bioavailability) (80-84). However, a recent randomized controlled trial found that supplementation
with soy iso avones increased calcium retention capacity in postmenopausal women regardless of their
equol-producing capacity (85).

At present, the clinical bene ts of soy iso avones as an alternative to bone-sparing treatments in
women undergoing menopause remain to be determined.

Cardiovascular disease
To date, large prospective cohort studies, mainly in Asian populations, investigating whether habitual
soy food/iso avone consumption is related to the incidence of cardiovascular disease (CVD), including
coronary heart disease (CHD), ischemic stroke, and myocardial infarction, have found mixed results. In
the Japan Public Health Center-based Study (mean follow-up, 13.5 years), consumption of soy foods was
associated with a reduced risk of stroke in Japanese women (ages, 40 to 59 years) — but not in men. In
this cohort, the highest versus lowest quintile of soy iso avone intakes was found to be associated with
a 65% lower risk of ischemic stroke and a 63% lower risk of myocardial infarction in women (86). In
addition, an early data analysis of 64,915 Chinese women (ages 40 to 70 years) enrolled in the Shanghai
Women’s Health Study (SWHS) found an inverse relationship between soy food intake and risk of
incident CHD during a 2.5-year follow-up period (87). However, a higher soy protein intake was
associated with a higher risk of incident CHD in 55,474 Chinese men (ages, 40 to 74 years) from the
Shanghai Men’s Health Study (SMHS; mean follow-up of 5.4 years) (88). Moreover, a recent report of the
SWHS cohort followed for 10 years reported a 24% higher risk of ischemic stroke with the highest versus
lowest quintile of iso avone intakes (mean intakes of 59.4 mg/d versus 8.6 mg/day) (89). Nevertheless,
nested case-control studies within both Shanghai prospective studies found no correlations between
soy food intake and incident CVD events when measures of urinary iso avonoids were used as a more
objective estimate of iso avone exposure compared to dietary assessment with food-frequency
questionnaires (89, 90). Further, no signi cant associations were found between long-term soy food, soy
protein, and soy iso avone consumption and CHD-, stroke-, and total CVD-related mortality in a 14.7-
year follow-up of 60,298 participants of the Singapore Chinese Health Study (91).

Low consumption of soy foods in Western cohorts makes it more di cult to analyze possible
longitudinal associations between iso avone intake and CVD incidence or mortality in these populations
(92-95).

Cardiometabolic risk factors

A number of intervention studies have examined soy intake in relation to several cardiometabolic risk
factors. A recent meta-analysis of randomized controlled trials concluded that intake of either soy
products (i.e., whole soybeans, soy milk, nuts, oil, and our), soy protein isolate, or soy iso avones for
one month to one year could signi cantly improve serum lipid pro les in healthy and
hypercholesterolemic individuals by lowering circulating triglycerides, total cholesterol, and LDL-
cholesterol, and by increasing HDL-cholesterol (96). Further analyses suggested that soy protein without
iso avones was more e ective at lowering total and LDL-cholesterol than soy protein containing
iso avones, and the consumption of soy iso avones alone (as supplements or extracts) showed no
signi cant e ects on serum lipid pro les (96). In addition, a meta-analysis of 18 randomized controlled
studies indicated that neither soy foods nor soy iso avones could lower blood homocysteine
concentrations, a known risk factor for CVD, in high-risk middle-aged and older adults (97). Another
meta-analysis of 14 randomized controlled studies reported a reduction in circulating C-reactive protein
(CRP) — an in ammation marker associated with increased cardiovascular risk — following soy
iso avone intake (from soy foods or iso avone extracts) in postmenopausal women with elevated
baseline CRP concentrations (>2.2 mg/L) (98). In a recent six-month placebo-controlled intervention
study in 253 postmenopausal equol-producing women with prehypertension, supplementation with
whole soy — but not daidzein — improved lipid pro les and lowered the concentrations of CRP (99).
Whether potential cardiovascular bene ts of soy iso avone intake depend on individuals’ capacity to
produce iso avone metabolites (like equol) needs to be more closely examined.
Current evidence suggests that whole soy components other than iso avones may have favorable
e ects on cardiometabolic risk factors.

Vascular function
The preservation of normal arterial function plays an important role in cardiovascular disease
prevention. The ability of all types of blood vessels, including arteries, to dilate in response to nitric
oxide (NO) produced by the endothelial cells that line their inner surface is compromised in people at
high risk for cardiovascular disease (100). In the presence of cardiovascular risk factors (e.g.,
hypertension, hypercholesterolemia, hyperglycemia), impaired endothelial function results in
widespread vasodilation and coagulation abnormalities and is considered to be an early step in the
development of atherosclerosis. Measures of brachial ow-mediated dilation (FMD), a surrogate marker
of endothelial function, have been found to be inversely associated with risk of future cardiovascular
events (101). A meta-analysis of nine small randomized, placebo-controlled trials found that
supplementation with soy iso avones (50 to 99 mg/day; isolated or from iso avone-containing soy
protein) for a median eight-week period signi cantly increased brachial FMD, especially in
postmenopausal women with low FMD levels (102). A more inclusive meta-analysis of 17 trials in either
healthy individuals or in individuals with hyperlipidemia showed an increase of FMD with the intake of
isolated iso avones but not of iso avones-containing soy protein (103).  

Arterial sti ness or impaired arterial distensibility, another marker of vascular damage and an indicator
of cardiovascular disease risk, is generally assessed using measures of aortic pulse-wave velocity (PWV)
(104). Some, but not all, placebo-controlled clinical trials have suggested that supplementation with
iso avone-containing soy protein or iso avone extracts might signi cantly decrease arterial sti ness
(105-107). A recent randomized, double-blind, placebo-controlled study found that carotid-femoral PWV
could be signi cantly reduced 24 hours after a single oral intake of 80 mg of soy iso avones but only in
participants able to produce equol (3). Long-term interventions are needed to evaluate the clinical
relevance of such a result.

Finally, whether whole soy or iso avones reduce the burden of subclinical atherosclerosis (99, 108) and
lower blood pressure (109) in individuals at high CVD risk requires further examination.
Cognitive decline
Scienti c research on the e ect of soy iso avones on cognitive function has been recently reviewed by
Soni et al. (110). An observational study — the Honolulu-Asia Asian Study — that examined the
relationship between soy intake and cognitive function found that Hawaiian men who reported
consuming tofu (non-fermented soy product) at least twice weekly during midlife were more likely to
have poor cognitive test scores 20 to 25 years later than those who reported consuming tofu less than
twice a week (111). In an Indonesian study of elderly men and women, consumption of tofu was
associated with worse memory, while consumption of tempeh (fermented soy) was associated with
improved memory (112). In the multicenter, prospective, SWAN phytoestrogen ancillary study, the
highest versus lowest tertile of iso avone intakes was found to be associated with better scores in the
processing speed test but worse scores in the verbal memory test in late perimenopausal and
postmenopausal Asian women (79).

The results of several randomized controlled trials have been mixed. In a review of 12 trials, only half
reported an improvement in cognitive function with soy iso avone supplementation (110).
Postmenopausal women given soy extracts, providing 60 mg/day of soy iso avones for 6 to 12 weeks,
performed better on cognitive tests of picture recall (short-term memory), learning rule reversals
(mental exibility), and a planning task compared to women given a placebo (113, 114). In a longer trial,
postmenopausal women given supplements that provided 110 mg/day of soy iso avones for six months
performed better on a test of verbal uency than women given placebos (115). In a cross-over trial
lasting six months, women receiving 60 mg/day of soy iso avones experienced signi cant
improvements in cognitive performance and overall mood compared to when the women were given a
placebo (116). However, in larger placebo-controlled trials, 80 mg/day of iso avones for six months (117)
or 99 mg/day of iso avones for one year (118) did not a ect performance on a battery of cognitive
function tests, including tests for memory, attention, verbal uency, motor control, and dementia in
postmenopausal women. In addition, in the 30-month Women’s Iso avone Soy Health trial in 313
postmenopausal women, daily supplementation with 91 mg of soy iso avones signi cantly improved
visual memory but failed to improve other aspects of cognition or global cognition (119). Nevertheless, a
recent meta-analysis of 10 randomized controlled trials found a signi cant improvement in the pooled
summary of cognitive function tests in healthy postmenopausal women supplemented with 60 to 160
mg/day of soy iso avones for 6 to 30 months (120).

There has been little investigation regarding the potential e ects of soy iso avones in individuals with
cognitive impairments (121).

Disease Treatment
Menopausal symptoms
Menopause-related vasomotor symptoms, including hot ashes ( ushes) and night sweats, a ect over
75% of middle-aged US women (122). Concern over potential adverse e ects of hormone replacement
therapy (123, 124) has led to an increased interest in the use of phytoestrogen supplements in the
management of menopausal symptoms (125).

To date, the e ects of increasing soy iso avone intake on the frequency and severity of menopausal
symptoms have been examined in over 60 randomized controlled trials of small sample size (126). The
results of these trials have been mixed, as re ected by the conclusions of several systematic reviews
and meta-analyses published in the last decade (125, 127-134). However, a systematic Cochrane review
published in 2013 concluded that supplements containing primarily genistein (four studies; 30 to 60
mg/day for 12 weeks to one year) — but not dietary soy (13 studies), soy iso avone extracts (12 studies),
or red clover extracts (nine studies) — signi cantly reduced the frequency of hot ashes (131). This
result was consistent with previous analyses reporting alleviation of hot ashes in higher- rather than
lower-genistein supplementation trials (126, 133, 134). Nevertheless, in a meta-analysis by Taku et al.
(133), supplemental soy iso avone extract (30 to 80 mg/day for six weeks to one year) was found to
result in a net 17.4% reduction in hot ash frequency in 13 placebo-controlled trials (1,196 women). In
addition, the meta-analysis of nine trials (988 women) showed a 30.5% reduction in hot ash severity
with soy iso avone extracts (30 to 135 mg/day for 12 weeks to one year) (133). Moreover, the
observation that longer trials showed a greater e cacy of soy iso avones was con rmed in a recent
model-based meta-analysis by Li et al. (135). In this analysis of 16 studies, the authors estimated that
supplementation with soy iso avones required 48 weeks of treatment, compared to only 12 weeks for
estradiol, in order to achieve close to 80% of its maximum e ect (135). Besides, the maximum e ect of
soy iso avones was found to account for only 57% of the maximum e ect of estradiol (135).

Evidence from observational studies suggested that one’s ability to produce equol might contribute to
reducing the occurrence or severity of menopausal symptoms in postmenopausal women (see
Metabolism and Bioavailability) (136, 137). Several relatively small intervention studies have examined
the potential of equol to relieve these symptoms (reviewed in 138). A recent study in Chinese
postmenopausal and equol-producing women showed no bene ts of daily supplementation with soy
our (40 g) or daidzein (63 mg) for six months on the frequency or severity of menopausal symptoms
(139). Yet, an earlier randomized controlled study found that, compared to equol non-producing
women, those able to produce equol experienced improvements in menopausal symptoms like hot
ashes following soy iso avone supplementation (135 mg/day) for six months (140). In addition, the 12-
week administration of 10 mg/day of equol to equol non-producing Japanese women experiencing three
or more daily hot ashes signi cantly reduced the frequency and severity of hot ashes and neck and
shoulder muscle sti ness compared to a placebo (141). In another study, daily supplementation with
soy iso avone (containing 24 mg of daidzein and 22 mg of genistein) or equol (10, 20, or 40 mg)
supplements over an eight-week period resulted in equivalent reductions of the frequency of hot
ashes in postmenopausal women with ve or more daily hot ashes; however, 20 mg/day and 40
mg/day of equol supplements proved to be more e ective than soy iso avone supplements in the
subgroup of women experiencing eight or more hot ashes per day (142). Nevertheless, because this
study lacked an inert placebo control group, the results should be viewed with caution.

At present, supplements containing su cient amounts of genistein may help alleviate vasomotor
symptoms in women transitioning through menopause (126, 143).

Sources
Food sources
Iso avones are found in small amounts in a number of legumes, grains, and vegetables, but soybeans
are by far the most concentrated source of iso avones in the human diet (144, 145). Average dietary
iso avone intakes in Japan, China, and other Asian countries range from 25 to 50 mg/day (20). Dietary
iso avone intakes are considerably lower in Western countries. Twenty-four-hour dietary recall data
collected from 36,037 individuals in 10 countries (participating in the EPIC study) showed average
iso avone intakes to be lower than 1 mg/day (146). Compared to other European countries, the
iso avone intake was slightly higher in the British general population (2.3 mg/day) and health-conscious
cohort (19.4 mg/day) (146).

Traditional Asian foods made from soybeans include tofu, tempeh, miso, and natto. Edamame refers to
varieties of soybeans that are harvested and eaten in their green phase. Soy products that are gaining
popularity in Western countries include soy-based meat substitutes, soy milk, soy cheese, and soy
yogurt. The iso avone content of a soy protein isolate depends on the method used to isolate it. Soy
protein isolates prepared by an ethanol wash process generally lose most of their associated
iso avones, while those prepared by aqueous wash processes tend to retain them (147). Some foods
that are rich in soy iso avones are listed in Table 1, along with their iso avone content. Because the
iso avone content of soy foods can vary considerably among brands and among di erent lots of the
same brand (147), these values should be viewed only as a guide. Given the potential health implications
of diets rich in soy iso avones, accurate and consistent labeling of the soy iso avone content of soy
foods is needed. Of note, foods of animal origin also contain low levels of iso avones (and other
phytoestrogens), derived from animal feeds and pastures (148). More information on the iso avone
content of foods is available from the USDA Food Composition Database website and the USDA
Database for the Iso avone Content of Selected Foods report (149).

Table 1. Total Iso avone, Daidzein, Genistein, and Glycitein Content of Selected Foods*
 Total Iso avones Daidzein Genistein Glycitein
Food Serving
(mg) (mg) (mg) (mg)

Soy protein concentrate,

3.5 oz 94.6 38.2 52.8 4.9
aqueous washed

Soy protein concentrate,

3.5 oz 11.5 5.8 5.3 1.5
alcohol washed

Miso ½ cup 57 22.6 32 4.1

Soybeans, mature seeds,

½ cup 56 26.5 26.9 3.2
boiled

3
Tempeh 51.5 19.3 30.7 3.2
ounces

3
Tempeh, cooked 30.3 11.1 18 1.2
ounces

1
Soybeans, dry roasted 41.6 17.4 21.2 3.7
ounce

Soy milk, low-fat 1 cup 6.2 2.4 3.7 0.1

Tofu yogurt ½ cup 21.3 7.5 12.3 1.6

3
Tofu, avone
*Iso soft content of soy foods can vary considerably
19.2 between brands
8.1 and between10.1 di erent 1.4
lots of
ounces
the same brand (147); therefore, these values should be viewed only as a guide.
Soybeans, green, boiled
½ cup 16.1 6.7 6.3 4.1
(Edamame)
 Meatless (soy) burger,
1 patty 4.5 1.6 3.5 0.4
unprepared

Meatless (soy) sausage 3 links 10.8 3.3 6.9 1.7

Soy cheese, cheddar 1 oz 1.9 0.5 0.6 0.8

*Iso avone content of soy foods can vary considerably between brands and between di erent lots of
the same brand (147); therefore, these values should be viewed only as a guide.

Supplements
Soy iso avone extracts and supplements are available as dietary supplements without a prescription in
the US. These products are not standardized, and the amounts of soy iso avones they provide may vary
considerably. Moreover, quality control may be an issue with some of these products (150). When
iso avone supplements available in the US were tested for their iso avone content by an independent
laboratory, the iso avone content in the product di ered by more than 10% from the amount claimed
on the label in approximately 50% of the products tested (151).

Infant formulas
Soy protein-based infant formulas are made from soy protein isolate and contain signi cant amounts of
soy iso avones (Table 2). In 1997, the total iso avone content of soy-based infant formulas that were
commercially available in the US ranged from 32 to 47 mg/liter (~34 uid ounces) (152).

Table 2. Total Iso avone, Daidzein, Genistein, and Glycitein Content of Selected Soy-based Infant
Formulas

Total Iso avones Daidzein Genistein Glycitein

Soy-based Formula Serving
(mg) (mg) (mg) (mg)

Mead Johnson Prosobee,

8 oz. 9.4 4.1 5.3 —
ready to feed
 Abbott Nutrition, Similac,
8 oz. 5.4 1.8 3.3 0.3
Isomil, ready to feed

PBM products, soy, ready to

8 oz. 6.4 1.8 3.9 0.7
feed (formerly Wyeth-Ayerst)

Safety
Soy iso avones have been consumed by humans as part of soy-based diets for many years without any
evidence of adverse e ects (145). The 75th percentile of dietary iso avone intake has been reported to
be as high as 65 mg/day in some Asian populations (153). Although diets rich in soy or soy-containing
products appear safe and potentially bene cial, the long-term safety of very high supplemental doses of
soy iso avones is not yet known. One study in older men and women found that 100 mg/day of soy
iso avones for six months was well tolerated (154). Yet, longer-term studies are needed to evaluate the
safety of iso avones.

Adverse effects
Safety for breast cancer survivors
The safety of high intakes of soy iso avones and other phytoestrogens for breast cancer survivors is an
area of concern among scientists and clinicians. The results of cell culture and animal studies have been
con icting; some preclinical studies showed that soy iso avones might stimulate the growth of estrogen
receptor-positive (ER+) breast cancer cells (155, 156), while others suggested that they might either
potentiate (157, 158) or abrogate the anticancer e ects of tamoxifen on breast tissue (159, 160).

Very limited data from clinical trials suggested that increased consumption of soy iso avones (38 to 45
mg/day) may show weak estrogenic e ects in human breast tissue (161, 162). However, a study in
women with biopsy-con rmed breast cancer found that supplementation with 200 mg/day of soy
iso avones did not increase breast cell proliferation — a marker of breast cancer risk — over the two to
six weeks before surgery when compared to a control group that did not take soy iso avones (163). A
few large prospective cohort studies have examined the association between soy iso avone intake and
breast cancer recurrence and survival. In the Shanghai Breast Cancer Survival Study that followed 5,042
female breast cancer survivors for a median of 3.9 years, consumption of iso avone-rich soy foods was
signi cantly associated with a 29% lower risk of death and a 32% lower risk of cancer recurrence (164).
In this study, soy iso avone intake was associated with a signi cant 23% reduced risk of cancer
recurrence and a nonsigni cant 21% reduced risk of death (164). A pooled analysis of data from 9,514
breast cancer survivors from the Shanghai Breast Cancer Survival Study (164), the Life After Cancer
Epidemiology study (165), and the Women’s Healthy Eating and Living study (166) found a 25% reduced
risk of recurrence with soy iso avone intakes ≥10 mg/day (compared to intakes of <4 mg/day) (167). A
subgroup analysis showed that the inverse association between soy iso avone intake and recurrence
was signi cant only among women taking the anticancer drug, tamoxifen. No inverse association was
reported between soy iso avone intake and the risks of all-cause and breast cancer-speci c mortality
(167).

Given the available data, some experts think that women with a history of breast cancer, particularly ER+
breast cancer, should not increase their consumption of phytoestrogens, including soy iso avones (168).
Nevertheless, there is not enough evidence to discourage breast cancer survivors from consuming soy
foods in moderation (143, 169).

Safety of soy protein-based infant formulas

Infant formula made from soy protein isolate has been commercially available since the mid-1960s
(170). As much as 25% of the infant formula sold in the US is soy protein-based formula (171). The
American Academy of Pediatrics (AAP) supports the use of soy protein isolate-based formula for normal
growth and development of term infants whose needs are not being met by human milk or cow’s milk-
based formulas (171). Soy protein-based formulas are especially indicated for infants with galactosemia
and hereditary lactase de ciency, but they have no proven value in the prevention or management of
infantile colic and fussiness (171).

Since infants fed soy-based formulas are exposed to relatively high levels of iso avones (152), which
they can absorb and metabolize, concern has been raised regarding potential long-term e ects on
anthropometric growth, bone health, as well as reproductive, endocrine, and immune functions (152,
172). In addition to the AAP review (171), a recent systematic review and meta-analysis of data published
between 1909 and 2013 found no clinical concerns regarding nutritional adequacy, sexual development,
thyroid disease, immune function, and neurodevelopment in infants fed soy protein-fed formulas (173).
Speci cally, this review identi ed 14 clinical trials comparing infants fed soy-based formula with infants
fed human milk or cow’s milk-based formula and found that soy-based formula adequately supported
growth and development in the rst year of life (173). In addition, the results of three observational
studies suggested no adverse e ects of soy protein-based formula on the neurodevelopment of
children (174-176). Two of these observational studies of low-to-moderate quality also reported
associations between soy protein-based formula intake and marginal adverse events, including early
menarche (176, 177) and increased duration of menstrual bleeding (176). A recent prospective cohort
study (the Beginnings study) examining the e ects of early infant feeding on reproductive organ
development during childhood found no di erences in the volume and structure of the reproductive
organs of 101 ve-year-old boys and girls who were either breastfed or fed soy protein- or cow’s milk-
based formula as infants (178). Finally, no adverse health e ects have been associated with the
presence of phytates and aluminum in soy protein-based formulas fed to full-term infants (reviewed in
173).

At present, there is no convincing evidence that infants fed soy protein-based formula are at greater risk
for adverse e ects than infants fed cow’s milk-based formula. Nonetheless, if current evidence shows a
safety pro le for use of soy protein-based formulas in term infants, they are not designed or
recommended for preterm infants (171). Also, recent preliminary ndings suggesting potential links
between consumption of soy protein-based formulas and adverse e ects in autistic children deserve
further investigation (179, 180).

Male reproductive health

Claims that soy food/iso avone consumption can have adverse e ects on male reproductive function,
including feminization, erectile dysfunction, and infertility, are primarily based on animal studies and
case reports (181). Exposure to iso avones (including at levels above typical Asian dietary intakes) has
not been shown to a ect either the concentrations of estrogen and testosterone, or the quality of
sperm and semen (181, 182). Thorough reviews of the literature found no basis for concern but
emphasized the need for long-term, large scale comprehensive human studies (181, 183).

Thyroid function
In cell culture and animal studies, soy iso avones have been found to inhibit the activity of thyroid
peroxidase, an enzyme required for thyroid hormone synthesis (184, 185). However, high intakes of soy
iso avones do not appear to increase the risk of hypothyroidism as long as dietary iodine consumption
is adequate (186). Since the addition of iodine to soy-based formulas in the 1960s, there have been no
further reports of hypothyroidism in soy formula-fed infants (187). Several clinical trials, mostly in
women with su cient iodine intakes, have not found increased consumption of soy iso avones to result
in clinically signi cant changes in circulating thyroid hormone concentrations (188-192).

Pregnancy
To date, studies have not examined the e ect of an iso avone-rich diet on fetal development or
pregnancy outcomes in humans, and the safety of iso avone supplements during pregnancy has not
been established.

Drug interactions
Fermented soy foods contain highly variable amounts of the biologically active amine, tyramine, which is
catabolized in the body by monoamine oxidase enzyme (MAO) and excreted in the urine. The ingestion
of very high amount of tyramine may saturate the detoxi cation system and lead to clinical symptoms
of intoxication. Because individuals taking MAO inhibitors (MAOIs; phenelzine, tranylcypromine) are at
greater risk of adverse e ects, they should avoid consuming fermented soy products (193, 194).
Because colonic bacteria play an important role in the metabolism of soy iso avones, antibiotic therapy
could decrease their biological activity (193). Some evidence from animal studies suggested that high
intakes of soy iso avones, particularly genistein, could interfere with the antitumor e ects of tamoxifen
(Nolvadex) (159). Yet, a recent pooled analysis of three prospective cohort studies found that the risk of
recurrence in breast cancer survivors was reduced to a greater extent with soy iso avone intake in
tamoxifen users than in nonusers (see Safety for breast cancer survivors) (167). Nonetheless, until more
is known about potential interactions in humans, those taking tamoxifen or other selective estrogen
receptor modulators (SERMs) to treat or prevent breast cancer should be cautious and seek medical
advice regarding the use of soy protein supplements or iso avone extracts (193).
High intakes of soy protein may interfere with the e cacy of the anticoagulant medication warfarin.
There is one case report of an individual on warfarin who developed subtherapeutic international
normalized ratio (INR; prothrombin time) values upon consuming ~16 ounces of soy milk daily for four
weeks (195). INR values returned to therapeutic levels two weeks after discontinuing soy milk.

The amount of levothyroxine required for adequate thyroid hormone replacement has been found to
increase in infants with congenital hypothyroidism fed soy formula (187, 196). Taking levothyroxine at
the same time as a soy protein supplement also increased the levothyroxine dose required for adequate
thyroid hormone replacement in an adult with hypothyroidism (197).

Regular consumption of a diet high in soy — rather than supplementation with iso avone extracts or
iso avone containing isolated soy protein — may help lower fasting glucose concentrations (198). It is
unknown whether individuals taking antidiabetic agents might be at risk of hypoglycemia if they follow a
soy-based meal replacement plan rather than a diet plan recommended by the American Diabetes
Association (199).

Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2006 by:

Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in December 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2016 by:

Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in October 2016 by:

Alison M. Duncan, Ph.D., R.D.
Professor
Department of Human Health and Nutritional Sciences
University of Guelph
Guelph, Ontario, Canada

Copyright 2004-2018  Linus Pauling Institute

References
1.  Lampe JW. Iso avonoid and lignan phytoestrogens as dietary biomarkers. J Nutr. 2003;133 Suppl
3:956S-964S.  (PubMed)

2.  Franke AA, Lai JF, Halm BM. Absorption, distribution, metabolism, and excretion of iso avonoids after
soy intake. Arch Biochem Biophys. 2014;559:24-28.  (PubMed)

3.  Hazim S, Curtis PJ, Schar MY, et al. Acute bene ts of the microbial-derived iso avone metabolite
equol on arterial sti ness in men prospectively recruited according to equol producer phenotype: a
double-blind randomized controlled trial. Am J Clin Nutr. 2016;103(3):694-702.  (PubMed)
4.  Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr. 2010;140(7):1355S-1362S. 
(PubMed)

5.  Setchell KD, Clerici C, Lephart ED, et al. S-equol, a potent ligand for estrogen receptor beta, is the
exclusive enantiomeric form of the soy iso avone metabolite produced by human intestinal bacterial
ora. Am J Clin Nutr. 2005;81(5):1072-1079.  (PubMed)

6.  Setchell KD, Cole SJ. Method of de ning equol-producer status and its frequency among vegetarians. J
Nutr. 2006;136(8):2188-2193.  (PubMed)

7.  National Cancer Institute. Understanding Estrogen Receptors/SERMs. National Cancer Institute.

January 2005. http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors. Accessed
7/12/09.

8.  Wang LQ. Mammalian phytoestrogens: enterodiol and enterolactone. J Chromatogr B Analyt Technol
Biomed Life Sci. 2002;777(1-2):289-309.  (PubMed)

9.  Barnes S, Boersma B, Patel R, et al. Iso avonoids and chronic disease: mechanisms of action.
Biofactors. 2000;12(1-4):209-215.  (PubMed)

10.  Holzbeierlein JM, McIntosh J, Thrasher JB. The role of soy phytoestrogens in prostate cancer. Curr
Opin Urol. 2005;15(1):17-22.  (PubMed)

11.  Kao YC, Zhou C, Sherman M, Laughton CA, Chen S. Molecular basis of the inhibition of human
aromatase (estrogen synthetase) by avone and iso avone phytoestrogens: A site-directed mutagenesis
study. Environ Health Perspect. 1998;106(2):85-92.  (PubMed)

12.  Whitehead SA, Cross JE, Burden C, Lacey M. Acute and chronic e ects of genistein, tyrphostin and
lavendustin A on steroid synthesis in luteinized human granulosa cells. Hum Reprod. 2002;17(3):589-
594.  (PubMed)

13.  Ye L, Chan MY, Leung LK. The soy iso avone genistein induces estrogen synthesis in an
extragonadal pathway. Mol Cell Endocrinol. 2009;302(1):73-80.  (PubMed)
14.  Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a speci c inhibitor of tyrosine-speci c protein
kinases. J Biol Chem. 1987;262(12):5592-5595.  (PubMed)

15.  Ruiz-Larrea MB, Mohan AR, Paganga G, Miller NJ, Bolwell GP, Rice-Evans CA. Antioxidant activity of
phytoestrogenic iso avones. Free Radic Res. 1997;26(1):63-70.  (PubMed)

16.  Wiseman H, O'Reilly JD, Adlercreutz H, et al. Iso avone phytoestrogens consumed in soy decrease
F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in
humans. Am J Clin Nutr. 2000;72(2):395-400.  (PubMed)

17.  Hodgson JM, Puddey IB, Croft KD, Mori TA, Rivera J, Beilin LJ. Iso avonoids do not inhibit in vivo lipid
peroxidation in subjects with high-normal blood pressure. Atherosclerosis. 1999;145(1):167-172. 
(PubMed)

18.  Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O. E ect of soy iso avone supplementation on
markers of oxidative stress in men and women. Cancer Lett. 2001;172(1):1-6.  (PubMed)

19.  Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA
Cancer J Clin. 2015;65(2):87-108.  (PubMed)

20.  Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and iso avone intakes. Nutr Cancer.
2006;55(1):1-12.  (PubMed)

21.  Messina M, Hilakivi-Clarke L. Early intake appears to be the key to the proposed protective e ects of
soy intake against breast cancer. Nutr Cancer. 2009;61(6):792-798.  (PubMed)

22.  Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures and breast cancer risk. Br J
Cancer. 2008;98(1):9-14.  (PubMed)

23.  Dong JY, Qin LQ. Soy iso avones consumption and risk of breast cancer incidence or recurrence: a
meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;125(2):315-323.  (PubMed)
24.  Travis RC, Allen NE, Appleby PN, Spencer EA, Roddam AW, Key TJ. A prospective study of
vegetarianism and iso avone intake in relation to breast cancer risk in British women. Int J Cancer.
2008;122(3):705-710.  (PubMed)

25.  Korde LA, Wu AH, Fears T, et al. Childhood soy intake and breast cancer risk in Asian American
women. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1050-1059.  (PubMed)

26.  Shu XO, Jin F, Dai Q, et al. Soyfood intake during adolescence and subsequent risk of breast cancer
among Chinese women. Cancer Epidemiol Biomarkers Prev. 2001;10(5):483-488.  (PubMed)

27.  Thanos J, Cotterchio M, Boucher BA, Kreiger N, Thompson LU. Adolescent dietary phytoestrogen
intake and breast cancer risk (Canada). Cancer Causes Control. 2006;17(10):1253-1261.  (PubMed)

28.  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. Carcinogenesis. 2002;23(9):1491-1496.  (PubMed)

29.  Eliassen AH, Hankinson SE. Endogenous hormone levels and risk of breast, endometrial and ovarian
cancers: prospective studies. Adv Exp Med Biol. 2008;630:148-165.  (PubMed)

30.  Hooper L, Ryder JJ, Kurzer MS, et al. E ects of soy protein and iso avones on circulating hormone
concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum
Reprod Update. 2009;15(4):423-440.  (PubMed)

31.  Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A. E ects of iso avones on breast density in pre-
and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials.
Hum Reprod Update. 2010;16(6):745-760.  (PubMed)

32.  Wu AH, Spicer D, Garcia A, et al. Double-blind randomized 12-month soy intervention had no e ects
on breast MRI broglandular tissue density or mammographic density. Cancer Prev Res (Phila).
2015;8(10):942-951.  (PubMed)
33.  Key TJ, Pike MC. The dose-e ect relationship between 'unopposed' oestrogens and endometrial
mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer.
1988;57(2):205-212.  (PubMed)

34.  Felix AS, Weissfeld JL, Pfei er RM, et al. Endometrial thickness and risk of breast and endometrial
carcinomas in the prostate, lung, colorectal and ovarian cancer screening trial. Int J Cancer.
2014;134(4):954-960.  (PubMed)

35.  Zhang GQ, Chen JL, Liu Q, Zhang Y, Zeng H, Zhao Y. Soy intake is associated with lower endometrial
cancer risk: a systematic review and meta-analysis of observational studies. Medicine (Baltimore).
2015;94(50):e2281.  (PubMed)

36.  Ollberding NJ, Lim U, Wilkens LR, et al. Legume, soy, tofu, and iso avone intake and endometrial
cancer risk in postmenopausal women in the multiethnic cohort study. J Natl Cancer Inst.
2012;104(1):67-76.  (PubMed)

37.  Budhathoki S, Iwasaki M, Sawada N, et al. Soy food and iso avone intake and endometrial cancer
risk: the Japan Public Health Center-based prospective study. BJOG. 2015;122(3):304-311.  (PubMed)

38.  Wan YL, Crosbie EJ. Soy intake and endometrial cancer risk varies according to study population.
BJOG. 2015;122(3):311.  (PubMed)

39.  Liu J, Yuan F, Gao J, et al. Oral iso avone supplementation on endometrial thickness: a meta-analysis
of randomized placebo-controlled trials. Oncotarget. 2016;7(14):17369-17379.  (PubMed)

40.  Hwang YW, Kim SY, Jee SH, Kim YN, Nam CM. Soy food consumption and risk of prostate cancer: a
meta-analysis of observational studies. Nutr Cancer. 2009;61(5):598-606.  (PubMed)

41.  Zhang M, Wang K, Chen L, Yin B, Song Y. Is phytoestrogen intake associated with decreased risk of
prostate cancer? A systematic review of epidemiological studies based on 17,546 cases. Andrology.
2016;4(4):745-756.  (PubMed)
42.  Gardner CD, Oelrich B, Liu JP, Feldman D, Franke AA, Brooks JD. Prostatic soy iso avone
concentrations exceed serum levels after dietary supplementation. Prostate. 2009;69(7):719-726. 
(PubMed)

43.  Mahmoud AM, Yang W, Bosland MC. Soy iso avones and prostate cancer: a review of molecular
mechanisms. J Steroid Biochem Mol Biol. 2014;140:116-132.  (PubMed)

44.  van Die MD, Bone KM, Williams SG, Pirotta MV. Soy and soy iso avones in prostate cancer: a
systematic review and meta-analysis of randomized controlled trials. BJU Int. 2014;113(5b):E119-130. 
(PubMed)

45.  Hamilton-Reeves JM, Rebello SA, Thomas W, Slaton JW, Kurzer MS. Iso avone-rich soy protein isolate
suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum
hormonal pro les in men at high risk of prostate cancer. J Nutr. 2007;137(7):1769-1775.  (PubMed)

46.  Hamilton-Reeves JM, Rebello SA, Thomas W, Kurzer MS, Slaton JW. E ects of soy protein isolate
consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer.
Nutr Cancer. 2008;60(1):7-13.  (PubMed)

47.  Miyanaga N, Akaza H, Hinotsu S, et al. Prostate cancer chemoprevention study: an investigative
randomized control study using puri ed iso avones in men with rising prostate-speci c antigen. Cancer
Sci. 2012;103(1):125-130.  (PubMed)

48.  Dalais FS, Meliala A, Wattanapenpaiboon N, et al. E ects of a diet rich in phytoestrogens on
prostate-speci c antigen and sex hormones in men diagnosed with prostate cancer. Urology.
2004;64(3):510-515.  (PubMed)

49.  Hussain M, Banerjee M, Sarkar FH, et al. Soy iso avones in the treatment of prostate cancer. Nutr
Cancer. 2003;47(2):111-117.  (PubMed)

50.  Lazarevic B, Boezelijn G, Diep LM, et al. E cacy and safety of short-term genistein intervention in
patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled,
double-blind Phase 2 clinical trial. Nutr Cancer. 2011;63(6):889-898.  (PubMed)
51.  Grainger EM, Schwartz SJ, Wang S, et al. A combination of tomato and soy products for men with
recurring prostate cancer and rising prostate speci c antigen. Nutr Cancer. 2008;60(2):145-154. 
(PubMed)

52.  Kwan W, Duncan G, Van Patten C, Liu M, Lim J. A phase II trial of a soy beverage for subjects without
clinical disease with rising prostate-speci c antigen after radical radiation for prostate cancer. Nutr
Cancer. 2010;62(2):198-207.  (PubMed)

53.  Pendleton JM, Tan WW, Anai S, et al. Phase II trial of iso avone in prostate-speci c antigen recurrent
prostate cancer after previous local therapy. BMC Cancer. 2008;8:132.  (PubMed)

54.  deVere White RW, Tsodikov A, Stapp EC, Soares SE, Fujii H, Hackman RM. E ects of a high dose,
aglycone-rich soy extract on prostate-speci c antigen and serum iso avone concentrations in men with
localized prostate cancer. Nutr Cancer. 2010;62(8):1036-1043.  (PubMed)

55.  Kumar NB, Cantor A, Allen K, et al. The speci c role of iso avones in reducing prostate cancer risk.
Prostate. 2004;59(2):141-147.  (PubMed)

56.  Bosland MC, Kato I, Zeleniuch-Jacquotte A, et al. E ect of soy protein isolate supplementation on
biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial. JAMA.
2013;310(2):170-178.  (PubMed)

57.  deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y, Sun B. E ects of a genistein-rich extract
on PSA levels in men with a history of prostate cancer. Urology. 2004;63(2):259-263.  (PubMed)

58.  Napora JK, Short RG, Muller DC, et al. High-dose iso avones do not improve metabolic and
in ammatory parameters in androgen-deprived men with prostate cancer. J Androl. 2011;32(1):40-48. 
(PubMed)

59.  Cosman F, de Beur SJ, LeBo MS, et al. Clinician's guide to prevention and treatment of
osteoporosis. Osteoporos Int. 2014;25(10):2359-2381.  (PubMed)
60.  Zheng X, Lee SK, Chun OK. Soy iso avones and osteoporotic bone loss: a review with an emphasis
on modulation of bone remodeling. J Med Food. 2016;19(1):1-14.  (PubMed)

61.  Chiechi LM, Secreto G, D'Amore M, et al. E cacy of a soy rich diet in preventing postmenopausal
osteoporosis: the Men s randomized trial. Maturitas. 2002;42(4):295-300.  (PubMed)

62.  Scheiber MD, Liu JH, Subbiah MT, Rebar RW, Setchell KD. Dietary inclusion of whole soy foods results
in signi cant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal
postmenopausal women. Menopause. 2001;8(5):384-392.  (PubMed)

63.  Arjmandi BH, Khalil DA, Smith BJ, et al. Soy protein has a greater e ect on bone in postmenopausal
women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary
calcium excretion. J Clin Endocrinol Metab. 2003;88(3):1048-1054.  (PubMed)

64.  Harkness LS, Fiedler K, Sehgal AR, Oravec D, Lerner E. Decreased bone resorption with soy
iso avone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13(9):1000-
1007.  (PubMed)

65.  Ye YB, Tang XY, Verbruggen MA, Su YX. Soy iso avones attenuate bone loss in early postmenopausal
Chinese women : a single-blind randomized, placebo-controlled trial. Eur J Nutr. 2006;45(6):327-334. 
(PubMed)

66.  Wangen KE, Duncan AM, Merz-Demlow BE, et al. E ects of soy iso avones on markers of bone
turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab. 2000;85(9):3043-
3048.  (PubMed)

67.  Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T. Iso avone-rich soy protein
isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr.
2000;72(3):844-852.  (PubMed)

68.  Dalais FS, Ebeling PR, Kotsopoulos D, McGrath BP, Teede HJ. The e ects of soy protein containing
iso avones on lipids and indices of bone resorption in postmenopausal women. Clin Endocrinol (Oxf).
2003;58(6):704-709.  (PubMed)
69.  Cheong JM, Martin BR, Jackson GS, et al. Soy iso avones do not a ect bone resorption in
postmenopausal women: a dose-response study using a novel approach with 41Ca. J Clin Endocrinol
Metab. 2007;92(2):577-582.  (PubMed)

70.  Liu J, Ho SC, Su YX, Chen WQ, Zhang CX, Chen YM. E ect of long-term intervention of soy iso avones
on bone mineral density in women: a meta-analysis of randomized controlled trials. Bone.
2009;44(5):948-953.  (PubMed)

71.  Lauderdale DS, Jacobsen SJ, Furner SE, Levy PS, Brody JA, Goldberg J. Hip fracture incidence among
elderly Asian-American populations. Am J Epidemiol. 1997;146(6):502-509.  (PubMed)

72.  Silverman SL, Madison RE. Decreased incidence of hip fracture in Hispanics, Asians, and blacks:
California Hospital Discharge Data. Am J Public Health. 1988;78(11):1482-1483.  (PubMed)

73.  Koh WP, Wu AH, Wang R, et al. Gender-speci c associations between soy and risk of hip fracture in
the Singapore Chinese Health Study. Am J Epidemiol. 2009;170(7):901-909.  (PubMed)

74.  Zhang X, Shu XO, Li H, et al. Prospective cohort study of soy food consumption and risk of bone
fracture among postmenopausal women. Arch Intern Med. 2005;165(16):1890-1895.  (PubMed)

75.  Ma DF, Qin LQ, Wang PY, Katoh R. Soy iso avone intake increases bone mineral density in the spine
of menopausal women: meta-analysis of randomized controlled trials. Clin Nutr. 2008;27(1):57-64. 
(PubMed)

76.  Taku K, Melby MK, Takebayashi J, et al. E ect of soy iso avone extract supplements on bone mineral
density in menopausal women: meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr.
2010;19(1):33-42.  (PubMed)

77.  Wei P, Liu M, Chen Y, Chen DC. Systematic review of soy iso avone supplements on osteoporosis in
women. Asian Pac J Trop Med. 2012;5(3):243-248.  (PubMed)
78.  Ricci E, Cipriani S, Chia arino F, Malvezzi M, Parazzini F. Soy iso avones and bone mineral density in
perimenopausal and postmenopausal Western women: a systematic review and meta-analysis of
randomized controlled trials. J Womens Health (Larchmt). 2010;19(9):1609-1617.  (PubMed)

79.  Greendale GA, Tseng CH, Han W, et al. Dietary iso avones and bone mineral density during midlife
and the menopausal transition: cross-sectional and longitudinal results from the Study of Women's
Health Across the Nation Phytoestrogen Study. Menopause. 2015;22(3):279-288.  (PubMed)

80.  Frankenfeld CL, McTiernan A, Thomas WK, et al. Postmenopausal bone mineral density in relation to
soy iso avone-metabolizing phenotypes. Maturitas. 2006;53(3):315-324.  (PubMed)

81.  Ishimi Y. Soybean iso avones in bone health. Forum Nutr. 2009;61:104-116.  (PubMed)

82.  Kuhnle GG, Ward HA, Vogiatzoglou A, et al. Association between dietary phyto-oestrogens and bone
density in men and postmenopausal women. Br J Nutr. 2011;106(7):1063-1069.  (PubMed)

83.  Vatanparast H, Chilibeck PD. Does the e ect of soy phytoestrogens on bone in postmenopausal
women depend on the equol-producing phenotype? Nutr Rev. 2007;65(6 Pt 1):294-299.  (PubMed)

84.  Wu J, Oka J, Ezaki J, et al. Possible role of equol status in the e ects of iso avone on bone and fat
mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial. Menopause.
2007;14(5):866-874.  (PubMed)

85.  Pawlowski JW, Martin BR, McCabe GP, et al. Impact of equol-producing capacity and soy-iso avone
pro les of supplements on bone calcium retention in postmenopausal women: a randomized crossover
trial. Am J Clin Nutr. 2015;102(3):695-703.  (PubMed)

86.  Kokubo Y, Iso H, Ishihara J, et al. Association of dietary intake of soy, beans, and iso avones with risk
of cerebral and myocardial infarctions in Japanese populations: the Japan Public Health Center-based
(JPHC) study cohort I. Circulation. 2007;116(22):2553-2562.  (PubMed)

87.  Zhang X, Shu XO, Gao YT, et al. Soy food consumption is associated with lower risk of coronary heart
disease in Chinese women. J Nutr. 2003;133(9):2874-2878.  (PubMed)
88.  Yu D, Zhang X, Xiang YB, et al. Association of soy food intake with risk and biomarkers of coronary
heart disease in Chinese men. Int J Cardiol. 2014;172(2):e285-287.  (PubMed)

89.  Yu D, Shu XO, Li H, et al. Dietary iso avones, urinary iso avonoids, and risk of ischemic stroke in
women. Am J Clin Nutr. 2015;102(3):680-686.  (PubMed)

90.  Zhang X, Gao YT, Yang G, et al. Urinary iso avonoids and risk of coronary heart disease. Int J
Epidemiol. 2012;41(5):1367-1375.  (PubMed)

91.  Talaei M, Koh WP, van Dam RM, Yuan JM, Pan A. Dietary soy intake is not associated with risk of
cardiovascular disease mortality in Singapore Chinese adults. J Nutr. 2014;144(6):921-928.  (PubMed)

92.  McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and
cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr. 2012;95(2):454-
464.  (PubMed)

93.  Mink PJ, Scra ord CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a
prospective study in postmenopausal women. Am J Clin Nutr. 2007;85(3):895-909.  (PubMed)

94.  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(4):465-471.  (PubMed)

95.  Zamora-Ros R, Jimenez C, Cleries R, et al. Dietary avonoid and lignan intake and mortality in a
Spanish cohort. Epidemiology. 2013;24(5):726-733.  (PubMed)

96.  Tokede OA, Onabanjo TA, Yansane A, Gaziano JM, Djousse L. Soya products and serum lipids: a
meta-analysis of randomised controlled trials. Br J Nutr. 2015;114(6):831-843.  (PubMed)

97.  Song X, Zeng R, Ni L, Liu C. The e ect of soy or iso avones on homocysteine levels: a meta-analysis
of randomised controlled trials. J Hum Nutr Diet. 2016;29(6):797-804.  (PubMed)
98.  Dong JY, Wang P, He K, Qin LQ. E ect of soy iso avones on circulating C-reactive protein in
postmenopausal women: meta-analysis of randomized controlled trials. Menopause. 2011;18(11):1256-
1262.  (PubMed)

99.  Liu ZM, Ho SC, Chen YM, et al. Whole soy, but not puri ed daidzein, had a favorable e ect on
improvement of cardiovascular risks: a 6-month randomized, double-blind, and placebo-controlled trial
in equol-producing postmenopausal women. Mol Nutr Food Res. 2014;58(4):709-717.  (PubMed)

100.  Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis?

Circulation. 2004;109(21 Suppl 1):II27-33.  (PubMed)

101.  Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction:
a systematic review with meta-analysis. Int J Cardiol. 2013;168(1):344-351.  (PubMed)

102.  Li SH, Liu XX, Bai YY, et al. E ect of oral iso avone supplementation on vascular endothelial
function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials. Am J Clin
Nutr. 2010;91(2):480-486.  (PubMed)

103.  Beavers DP, Beavers KM, Miller M, Stamey J, Messina MJ. Exposure to iso avone-containing soy
products and endothelial function: a Bayesian meta-analysis of randomized controlled trials. Nutr Metab
Cardiovasc Dis. 2012;22(3):182-191.  (PubMed)

104.  Bots ML, Dijk JM, Oren A, Grobbee DE. Carotid intima-media thickness, arterial sti ness and risk of
cardiovascular disease: current evidence. J Hypertens. 2002;20(12):2317-2325.  (PubMed)

105.  Nestel PJ, Yamashita T, Sasahara T, et al. Soy iso avones improve systemic arterial compliance but
not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol.
1997;17(12):3392-3398.  (PubMed)

106.  Teede HJ, Dalais FS, Kotsopoulos D, Liang YL, Davis S, McGrath BP. Dietary soy has both bene cial
and potentially adverse cardiovascular e ects: a placebo-controlled study in men and postmenopausal
women. J Clin Endocrinol Metab. 2001;86(7):3053-3060.  (PubMed)
107.  Teede HJ, Giannopoulos D, Dalais FS, Hodgson J, McGrath BP. Randomised, controlled, cross-over
trial of soy protein with iso avones on blood pressure and arterial function in hypertensive subjects. J
Am Coll Nutr. 2006;25(6):533-540.  (PubMed)

108.  Chan YH, Lau KK, Yiu KH, et al. Iso avone intake in persons at high risk of cardiovascular events:
implications for vascular endothelial function and the carotid atherosclerotic burden. Am J Clin Nutr.
2007;86(4):938-945.  (PubMed)

109.  Liu XX, Li SH, Chen JZ, et al. E ect of soy iso avones on blood pressure: a meta-analysis of
randomized controlled trials. Nutr Metab Cardiovasc Dis. 2012;22(6):463-470.  (PubMed)

110.  Soni M, Rahardjo TB, Soekardi R, et al. Phytoestrogens and cognitive function: a review. Maturitas.
2014;77(3):209-220.  (PubMed)

111.  White LR, Petrovitch H, Ross GW, et al. Brain aging and midlife tofu consumption. J Am Coll Nutr.
2000;19(2):242-255.  (PubMed)

112.  Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. High tofu intake is associated with
worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord. 2008;26(1):50-57. 
(PubMed)

113.  Du y R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12
weeks of consumption of a soya extract containing iso avones. Pharmacol Biochem Behav.
2003;75(3):721-729.  (PubMed)

114.  File SE, Hartley DE, Elsabagh S, Du y R, Wiseman H. Cognitive improvement after 6 weeks of soy
supplements in postmenopausal women is limited to frontal lobe function. Menopause. 2005;12(2):193-
201.  (PubMed)

115.  Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA. Iso avones and cognitive function
in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause.
2003;10(3):196-202.  (PubMed)
116.  Casini ML, Marelli G, Papaleo E, Ferrari A, D'Ambrosio F, Unfer V. Psychological assessment of the
e ects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind,
crossover, placebo-controlled study. Fertil Steril. 2006;85(4):972-978.  (PubMed)

117.  Ho SC, Chan AS, Ho YP, et al. E ects of soy iso avone supplementation on cognitive function in
Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause. 2007;14(3
Pt 1):489-499.  (PubMed)

118.  Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. E ect of soy protein containing iso avones on
cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized
controlled trial. JAMA. 2004;292(1):65-74.  (PubMed)

119.  Henderson VW, St John JA, Hodis HN, et al. Long-term soy iso avone supplementation and
cognition in women: a randomized, controlled trial. Neurology. 2012;78(23):1841-1848.  (PubMed)

120.  Cheng PF, Chen JJ, Zhou XY, et al. Do soy iso avones improve cognitive function in postmenopausal
women? A meta-analysis. Menopause. 2015;22(2):198-206.  (PubMed)

121.  Gleason CE, Fischer BL, Dowling NM, et al. Cognitive E ects of Soy Iso avones in Patients with
Alzheimer's Disease. J Alzheimers Dis. 2015;47(4):1009-1019.  (PubMed)

122.  Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position

statement of The North American Menopause Society. Menopause. 2015;22(11):1155-1172; quiz 1173-
1154.  (PubMed)

123.  Farquhar C, Marjoribanks J, Lethaby A, Suckling JA, Lamberts Q. Long term hormone therapy for
perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2009(2):CD004143. 
(PubMed)

124.  Hardie C, Bain C, Walters M. Hormone replacement therapy: the risks and bene ts of treatment. J R
Coll Physicians Edinb. 2009;39(4):324-326.  (PubMed)
125.  Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot ashes:
systematic review and meta-analysis. JAMA. 2006;295(17):2057-2071.  (PubMed)

126.  Messina M. Soy foods, iso avones, and the health of postmenopausal women. Am J Clin Nutr.
2014;100 Suppl 1:423S-430S.  (PubMed)

127.  Bolanos R, Del Castillo A, Francia J. Soy iso avones versus placebo in the treatment of climacteric
vasomotor symptoms: systematic review and meta-analysis. Menopause. 2010;17(3):660-666.  (PubMed)

128.  Chen MN, Lin CC, Liu CF. E cacy of phytoestrogens for menopausal symptoms: a meta-analysis
and systematic review. Climacteric. 2015;18(2):260-269.  (PubMed)

129.  Franco OH, Chowdhury R, Troup J, et al. Use of Plant-Based Therapies and Menopausal Symptoms:
A Systematic Review and Meta-analysis. JAMA. 2016;315(23):2554-2563.  (PubMed)

130.  Howes LG, Howes JB, Knight DC. Iso avone therapy for menopausal ushes: a systematic review
and meta-analysis. Maturitas. 2006;55(3):203-211.  (PubMed)

131.  Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for

menopausal vasomotor symptoms. Cochrane Database Syst Rev. 2013(12):CD001395.  (PubMed)

132.  North American Menopause Society. The role of soy iso avones in menopausal health: report of
The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL
(October 2010). Menopause. 2011;18(7):732-753.  (PubMed)

133.  Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean
iso avones reduce menopausal hot ash frequency and severity: systematic review and meta-analysis
of randomized controlled trials. Menopause. 2012;19(7):776-790.  (PubMed)

134.  Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Iso avone supplements containing
predominantly genistein reduce hot ash symptoms: a critical review of published studies. Menopause.
2006;13(5):831-839.  (PubMed)
135.  Li L, Xu L, Wu J, Dong L, Zhao S, Zheng Q. Comparative e cacy of nonhormonal drugs on
menopausal hot ashes. Eur J Clin Pharmacol. 2016;72(9):1051-1058.  (PubMed)

136.  Melby MK, Lock M, Kaufert P. Culture and symptom reporting at menopause. Hum Reprod Update.
2005;11(5):495-512.  (PubMed)

137.  Newton KM, Reed SD, Uchiyama S, et al. A cross-sectional study of equol producer status and self-
reported vasomotor symptoms. Menopause. 2015;22(5):489-495.  (PubMed)

138.  Utian WH, Jones M, Setchell KD. S-equol: a potential nonhormonal agent for menopause-related
symptom relief. J Womens Health (Larchmt). 2015;24(3):200-208.  (PubMed)

139.  Liu ZM, Ho SC, Woo J, Chen YM, Wong C. Randomized controlled trial of whole soy and iso avone
daidzein on menopausal symptoms in equol-producing Chinese postmenopausal women. Menopause.
2014;21(6):653-660.  (PubMed)

140.  Jou HJ, Wu SC, Chang FW, Ling PY, Chu KS, Wu WH. E ect of intestinal production of equol on
menopausal symptoms in women treated with soy iso avones. Int J Gynaecol Obstet. 2008;102(1):44-
49.  (PubMed)

141.  Aso T, Uchiyama S, Matsumura Y, et al. A natural S-equol supplement alleviates hot ushes and
other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Womens
Health (Larchmt). 2012;21(1):92-100.  (PubMed)

142.  Jenks BH, Iwashita S, Nakagawa Y, et al. A pilot study on the e ects of S-equol compared to soy
iso avones on menopausal hot ash frequency. J Womens Health (Larchmt). 2012;21(6):674-682. 
(PubMed)

143.  Schmidt M, Arjomand-Wolkart K, Birkhauser MH, et al. Consensus: soy iso avones as a rst-line
approach to the treatment of menopausal vasomotor complaints. Gynecol Endocrinol. 2016;32(6):427-
430.  (PubMed)
144.  Fletcher RJ. Food sources of phyto-oestrogens and their precursors in Europe. Br J Nutr. 2003;89
Suppl 1:S39-43.  (PubMed)

145.  Munro IC, Harwood M, Hlywka JJ, et al. Soy iso avones: a safety review. Nutr Rev. 2003;61(1):1-33. 
(PubMed)

146.  Zamora-Ros R, Knaze V, Lujan-Barroso L, et al. Dietary intakes and food sources of phytoestrogens
in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort.
Eur J Clin Nutr. 2012;66(8):932-941.  (PubMed)

147.  Setchell KD, Cole SJ. Variations in iso avone levels in soy foods and soy protein isolates and issues
related to iso avone databases and food labeling. J Agric Food Chem. 2003;51(14):4146-4155.  (PubMed)

148.  Kuhnle GG, Dell'Aquila C, Aspinall SM, Runswick SA, Mulligan AA, Bingham SA. Phytoestrogen
content of foods of animal origin: dairy products, eggs, meat, sh, and seafood. J Agric Food Chem.
2008;56(21):10099-10104.  (PubMed)

149.  US Department of Agriculture. USDA Database for the Iso avone Content of Selected Foods,
Release 2. Available at: http://www.ars.usda.gov/News/docs.htm?docid=6382. Accessed 8/9/16.

150.  Chua R, Anderson K, Chen J, Hu M. Quality, labeling accuracy, and cost comparison of puri ed soy
iso avonoid products. J Altern Complement Med. 2004;10(6):1053-1060.  (PubMed)

151.  Setchell KD, Brown NM, Desai P, et al. Bioavailability of pure iso avones in healthy humans and
analysis of commercial soy iso avone supplements. J Nutr. 2001;131(4 Suppl):1362S-1375S.  (PubMed)

152.  Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. Iso avone content of infant formulas and the
metabolic fate of these phytoestrogens in early life. Am J Clin Nutr. 1998;68(6 Suppl):1453S-1461S. 
(PubMed)

153.  Chen Z, Zheng W, Custer LJ, et al. Usual dietary consumption of soy foods and its correlation with
the excretion rate of iso avonoids in overnight urine samples among Chinese women in Shanghai. Nutr
Cancer. 1999;33(1):82-87.  (PubMed)
154.  Gleason CE, Carlsson CM, Barnet JH, et al. A preliminary study of the safety, feasibility and cognitive
e cacy of soy iso avone supplements in older men and women. Age Ageing. 2009;38(1):86-93. 
(PubMed)

155.  Allred CD, Allred KF, Ju YH, Virant SM, Helferich WG. Soy diets containing varying amounts of
genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer
Res. 2001;61(13):5045-5050.  (PubMed)

156.  Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WG. Physiological concentrations of
dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer
(MCF-7) tumors implanted in athymic nude mice. J Nutr. 2001;131(11):2957-2962.  (PubMed)

157.  Constantinou AI, Lantvit D, Hawthorne M, Xu X, van Breemen RB, Pezzuto JM. Chemopreventive
e ects of soy protein and puri ed soy iso avones on DMBA-induced mammary tumors in female
Sprague-Dawley rats. Nutr Cancer. 2001;41(1-2):75-81.  (PubMed)

158.  Tanos V, Brzezinski A, Drize O, Strauss N, Peretz T. Synergistic inhibitory e ects of genistein and
tamoxifen on human dysplastic and malignant epithelial breast cells in vitro. Eur J Obstet Gynecol
Reprod Biol. 2002;102(2):188-194.  (PubMed)

159.  Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Dietary genistein negates the inhibitory e ect
of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic
mice. Cancer Res. 2002;62(9):2474-2477.  (PubMed)

160.  Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated
mammary tumor prevention. Cancer Res. 2005;65(3):879-886.  (PubMed)

161.  Petrakis NL, Barnes S, King EB, et al. Stimulatory in uence of soy protein isolate on breast secretion
in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev. 1996;5(10):785-794.  (PubMed)

162.  Hargreaves DF, Potten CS, Harding C, et al. Two-week dietary soy supplementation has an
estrogenic e ect on normal premenopausal breast. J Clin Endocrinol Metab. 1999;84(11):4017-4024. 
(PubMed)
163.  Sartippour MR, Rao JY, Apple S, et al. A pilot clinical study of short-term iso avone supplements in
breast cancer patients. Nutr Cancer. 2004;49(1):59-65.  (PubMed)

164.  Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302(22):2437-
2443.  (PubMed)

165.  Caan B, Sternfeld B, Gunderson E, Coates A, Quesenberry C, Slattery ML. Life After Cancer
Epidemiology (LACE) Study: a cohort of early stage breast cancer survivors (United States). Cancer
Causes Control. 2005;16(5):545-556.  (PubMed)

166.  Pierce JP, Faerber S, Wright FA, et al. A randomized trial of the e ect of a plant-based dietary
pattern on additional breast cancer events and survival: the Women's Healthy Eating and Living (WHEL)
Study. Control Clin Trials. 2002;23(6):728-756.  (PubMed)

167.  Nechuta SJ, Caan BJ, Chen WY, et al. Soy food intake after diagnosis of breast cancer and survival:
an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin
Nutr. 2012;96(1):123-132.  (PubMed)

168.  Du y C, Perez K, Partridge A. Implications of phytoestrogen intake for breast cancer. CA Cancer J
Clin. 2007;57(5):260-277.  (PubMed)

169.  Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer
survivors. CA Cancer J Clin. 2012;62(4):243-274.  (PubMed)

170.  American Academy of Pediatrics. Committee on Nutrition. Soy protein-based formulas:

recommendations for use in infant feeding. Pediatrics. 1998;101(1 Pt 1):148-153.  (PubMed)

171.  Bhatia J, Greer F. Use of soy protein-based formulas in infant feeding. Pediatrics. 2008;121(5):1062-
1068.  (PubMed)

172.  Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. Exposure of infants to phyto-oestrogens from
soy-based infant formula. Lancet. 1997;350(9070):23-27.  (PubMed)
173.  Vandenplas Y, Castrellon PG, Rivas R, et al. Safety of soya-based infant formulas in children. Br J
Nutr. 2014;111(8):1340-1360.  (PubMed)

174.  Andres A, Cleves MA, Bellando JB, Pivik RT, Casey PH, Badger TM. Developmental status of 1-year-
old infants fed breast milk, cow's milk formula, or soy formula. Pediatrics. 2012;129(6):1134-1140. 
(PubMed)

175.  Malloy MH, Berendes H. Does breast-feeding in uence intelligence quotients at 9 and 10 years of
age? Early Hum Dev. 1998;50(2):209-217.  (PubMed)

176.  Strom BL, Schinnar R, Ziegler EE, et al. Exposure to soy-based formula in infancy and
endocrinological and reproductive outcomes in young adulthood. JAMA. 2001;286(7):807-814.  (PubMed)

177.  Adgent MA, Daniels JL, Rogan WJ, et al. Early-life soy exposure and age at menarche. Paediatr
Perinat Epidemiol. 2012;26(2):163-175.  (PubMed)

178.  Andres A, Moore MB, Linam LE, Casey PH, Cleves MA, Badger TM. Compared with feeding infants
breast milk or cow-milk formula, soy formula feeding does not a ect subsequent reproductive organ
size at 5 years of age. J Nutr. 2015;145(5):871-875.  (PubMed)

179.  Westmark CJ. Soy Infant Formula may be Associated with Autistic Behaviors. Autism Open Access.
2013;3.  (PubMed)

180.  Westmark CJ. Soy infant formula and seizures in children with autism: a retrospective study. PLoS
One. 2014;9(3):e80488.  (PubMed)

181.  Messina M. Soybean iso avone exposure does not have feminizing e ects on men: a critical
examination of the clinical evidence. Fertil Steril. 2010;93(7):2095-2104.  (PubMed)

182.  Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ. Clinical studies show
no e ects of soy protein or iso avones on reproductive hormones in men: results of a meta-analysis.
Fertil Steril. 2010;94(3):997-1007.  (PubMed)
183.  Cederroth CR, Zimmermann C, Nef S. Soy, phytoestrogens and their impact on reproductive
health. Mol Cell Endocrinol. 2012;355(2):192-200.  (PubMed)

184.  Divi RL, Chang HC, Doerge DR. Anti-thyroid iso avones from soybean: isolation, characterization,
and mechanisms of action. Biochem Pharmacol. 1997;54(10):1087-1096.  (PubMed)

185.  Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy iso avones. Environ Health
Perspect. 2002;110 Suppl 3:349-353.  (PubMed)

186.  Messina M, Redmond G. E ects of soy protein and soybean iso avones on thyroid function in
healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid. 2006;16(3):249-
258.  (PubMed)

187.  Chorazy PA, Himelhoch S, Hopwood NJ, Greger NG, Postellon DC. Persistent hypothyroidism in an
infant receiving a soy formula: case report and review of the literature. Pediatrics. 1995;96(1 Pt 1):148-
150.  (PubMed)

188.  Bruce B, Messina M, Spiller GA. Iso avone supplements do not a ect thyroid function in iodine-
replete postmenopausal women. J Med Food. 2003;6(4):309-316.  (PubMed)

189.  Persky VW, Turyk ME, Wang L, et al. E ect of soy protein on endogenous hormones in
postmenopausal women. Am J Clin Nutr. 2002;75(1):145-153.  (PubMed)

190.  Duncan AM, Merz BE, Xu X, Nagel TC, Phipps WR, Kurzer MS. Soy iso avones exert modest
hormonal e ects in premenopausal women. J Clin Endocrinol Metab. 1999;84(1):192-197.  (PubMed)

191.  Duncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR, Kurzer MS. Modest hormonal e ects of soy
iso avones in postmenopausal women. J Clin Endocrinol Metab. 1999;84(10):3479-3484.  (PubMed)

192.  Dillingham BL, McVeigh BL, Lampe JW, Duncan AM. Soy protein isolates of varied iso avone
content do not in uence serum thyroid hormones in healthy young men. Thyroid. 2007;17(2):131-137. 
(PubMed)
193.  Natural Medicines. Soy: interactions with drugs - Professional handout. 2016. Available at:
https://naturalmedicines-therapeuticresearch-
com.ezproxy.proxy.library.oregonstate.edu/databases/food,-herbs-supplements/professional.aspx?
productid=975 - interactionsWithDrugs. Accessed 8/8/16.

194.  Toro-Funes N, Bosch-Fuste J, Latorre-Moratalla ML, Veciana-Nogues MT, Vidal-Carou MC.

Biologically active amines in fermented and non-fermented commercial soybean products from the
Spanish market. Food Chem. 2015;173:1119-1124.  (PubMed)

195.  Cambria-Kiely JA. E ect of soy milk on warfarin e cacy. Ann Pharmacother. 2002;36(12):1893-
1896.  (PubMed)

196.  Jabbar MA, Larrea J, Shaw RA. Abnormal thyroid function tests in infants with congenital
hypothyroidism: the in uence of soy-based formula. J Am Coll Nutr. 1997;16(3):280-282.  (PubMed)

197.  Bell DS, Ovalle F. Use of soy protein supplement and resultant need for increased dose of
levothyroxine. Endocr Pract. 2001;7(3):193-194.  (PubMed)

198.  Liu ZM, Chen YM, Ho SC. E ects of soy intake on glycemic control: a meta-analysis of randomized
controlled trials. Am J Clin Nutr. 2011;93(5):1092-1101.  (PubMed)

199.  Li Z, Hong K, Saltsman P, et al. Long-term e cacy of soy-based meal replacements vs an
individualized diet plan in obese type II DM patients: relative e ects on weight loss, metabolic
parameters, and C-reactive protein. Eur J Clin Nutr. 2005;59(3):411-418.  (PubMed)

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