- Isoflavones are a class of phytoestrogens — plant-derived compounds with estrogenic activity. Soybeans and soy products are the richest sources of isoflavones in the human diet. (More information)
- Some health effects of soy may be dependent on one’s capacity to convert the isoflavone daidzein to equol during digestion. (More information)
- The results of observational studies suggest that higher intakes of soy foods early in life may decrease the risk of breast cancer in adulthood. There is currently little clinical evidence that taking soy isoflavone supplements decreases the risk of incident and recurrent breast cancer. (More information)
- Current evidence from observational studies and small clinical trials is not robust enough to understand whether soy protein/isoflavone supplements may help prevent or inhibit the progression of prostate cancer. (More information)
- To date, randomized controlled trials examining the effect of soy isoflavones on bone mineral density in postmenopausal women have produced mixed results. Potential benefits of soy isoflavones as an alternative to bone-sparing treatments in women undergoing menopause remain to be determined. (More information)
- Current evidence suggests that whole soy components other than isoflavones may have favorable effects on serum lipid profiles. Yet, two recent meta-analyses of randomized controlled trials indicated that isoflavones might exert cardiovascular benefits by improving vascular function in postmenopausal women. (More information)
- Supplementation with isoflavones appeared to be about 40% less efficient than hormone-replacement therapy in attenuating menopausal hot flashes and required more time to reach its maximum effect. Yet, supplements containing primarily the isoflavone genistein have demonstrated consistent alleviation of menopausal hot flashes. (More information)
- 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 studies, soy isoflavone intake ≥10 mg/day was associated with a 25% reduced risk of tumor recurrence in breast cancer survivors. (More information)
- At present, there is no convincing evidence that infants fed soy-based formula are at greater risk for adverse effects than infants fed cow’s milk-based formula. (More information)
Isoflavones are polyphenolic compounds that possess both estrogen-agonist and estrogen-antagonist properties (see Biological Activities). For this reason, they are classified as phytoestrogens — plant-derived compounds with estrogenic activity (1). Isoflavones are the major flavonoids found in legumes, particularly soybeans. In soybeans, isoflavones 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 molecule from the isoflavone glycoside, leaving an isoflavone aglycone. Soy isoflavone glycosides include genistin, daidzin, and glycitin, while the aglycones are called genistein, daidzein, and glycitein (Figure 1). Unless otherwise indicated, quantities of isoflavones specified in this article refer to aglycones — not glycosides.
[Click to Enlarge]
Metabolism and Bioavailability
The article on Flavonoids describes some of the factors influencing the absorption, metabolic fate, and bioavailability of flavonoid family members, including isoflavones. Pharmacokinetic studies have indicated that plasma concentrations of daidzein and genistein peaked about six hours after isoflavone intake, preceded by a smaller initial peak one hour post-meal (2, 3). The initial peak reflects isoflavone absorption following the hydrolysis of isoflavone glycosides to aglycones by β-glucosidases in the small intestine, while the second peak corresponds to isoflavone aglycones absorbed after the hydrolysis of glycosides by bacterial β-glucosidases in the colon (2).
The composition of one’s colonic microbiota can influence the metabolic fate and biological effects of isoflavones. Indeed, the extent of at least some of the potential health benefits of soy intake are thought to depend on one’s capacity to convert isoflavones to key metabolites during digestion. Specifically, some colonic bacteria can convert the soy isoflavone 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 isoflavone 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 influence the composition of microbiota to include equol-producing bacteria (discussed in 4).
[Click to Enlarge]
Estrogenic and anti-estrogenic activities
Soy isoflavones 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 effects 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 isoflavones can preferentially bind to and transactivate estrogen receptor-β (ER-β) — rather than ER-α — mimicking the effects of estrogen in some tissues and antagonizing (blocking) the effects of estrogen in others (8). Scientists are interested in the tissue-selective activities of phytoestrogens because anti-estrogenic effects in reproductive tissue could help reduce the risk of hormone-associated cancers (breast, uterine, and prostate), while estrogenic effects in other tissues could help maintain bone mineral density and improve blood lipid profiles (see Disease Prevention). The extent to which soy isoflavones exert estrogenic and anti-estrogenic effects in humans is currently the focus of considerable scientific research.
[Click to Enlarge]
Estrogen receptor-independent activities
Soy isoflavones 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 isoflavones may alter the biological activity of endogenous estrogens and androgens (10-13). Soy isoflavones have also been found to inhibit tyrosine kinases (14), enzymes that play critical roles in the signaling pathways that stimulate cell proliferation. Additionally, isoflavones 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 significantly lower after two weeks of daily consumption of soy protein containing 56 mg of isoflavones than after consumption of soy protein providing only 2 mg of isoflavones (16). However, daily supplementation with 50 to 100 mg of isolated soy isoflavones did not significantly alter plasma or urinary F2-isoprostane concentrations (17, 18).
Since soy isoflavones are structurally similar to endogenous estrogens, it has been suggested that they might help protect against hormone-associated cancers.
High isoflavone 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 isoflavone intakes in non-Asian women are generally less than 2 mg/day (20). Nevertheless, several hereditary and lifestyle factors likely also contribute to this difference (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 isoflavones (≥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 isoflavones was reportedly low (0.3 mg/day) and not associated with a decreased risk of breast cancer (22, 23). Moreover, a lifelong exposure to isoflavones may be needed to lower the risk of developing breast cancer later in life (21). This would explain why moderate versus low intakes of isoflavones (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 isoflavone 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 effect of soy isoflavone 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 effect of soy isoflavones (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 effect in postmenopausal women (four studies) but a modest increase in breast density — of unclear clinical significance — in premenopausal women (five studies). Further, in a recent randomized, placebo-controlled trial, soy isoflavone supplementation (50 mg/day for one year) also failed to affect breast density in women (ages, 30 to 75 years) with breast cancer (32).
There is currently little evidence that taking soy isoflavone supplements decreases the risk of incident and recurrent breast 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 isoflavones 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 isoflavone 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 isoflavones (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 isoflavone 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 isoflavones 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 effect of isoflavone 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 isoflavone doses >54 mg/day of isoflavones could significantly 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 isoflavone supplements could decrease the risk of endometrial 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 isoflavone-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 isoflavone 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 isoflavones in limiting the progression of prostate cancer (reviewed in 43).
A number of small, short-term randomized controlled interventions have examined the effect of soy foods/isoflavones on biomarkers of prostate cancer risk (44). Compared to supplementation with milk protein, consumption of a diet supplemented with soy protein isolate high in isoflavones (~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 profile in men at high risk of developing prostate cancer (45). In addition, dietary soy protein supplementation had no effect on prostate-specific antigen (PSA) in serum or markers of cell proliferation and apoptosis in premalignant tissue. Yet, supplemental soy protein isolate — regardless of isoflavone 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 isoflavones (60 mg/day) for one year had no effect 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 significantly lower with isoflavones 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 isoflavones 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 effect of soy food/isoflavones 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 effect of soy isoflavones 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 isoflavone preparations and dosage regimens in short-term interventions (mostly ≤6 months) in small sample-size trials. Therefore, despite a good safety profile for supplemental soy isoflavones and soy proteins in prostate cancer patients, larger randomized controlled trials with longer periods of intervention are required to assess whether soy isoflavones could influence 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.
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 isoflavones 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 isoflavones 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, isoflavone dosages) and target populations (e.g., ethnic and genetic differences, hormonal status) that could explain the conflicting study results.
For instance, the results of short-term (≤6 months) clinical trials assessing the effects 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 isoflavones improved markers of bone resorption and formation (61-64) or attenuated bone loss (64, 65), but other trials have found no significant benefit of increasing soy intakes (66-69). Trials of longer duration also showed conflicting 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 isoflavones resulted in no significant changes in lumbar spine, total hip, or femoral neck BMD of postmenopausal women (70).
Mixed results also emerged from studies conducted in different 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 significant increases in BMD with supplemental soy isoflavones (75-77). In contrast, a meta-analysis of 12 placebo-controlled trials in Caucasian postmenopausal women found no effect of soy isoflavone 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 final menstrual period and is especially increased during the menopausal transition, starting about one year before to two years after the final 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 isoflavone 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 isoflavone 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 effect of supplemental soy isoflavones on BMD in postmenopausal women (70, 75-77). Yet, it remains to be elucidated whether supplementation with soy isoflavones might be of any benefit 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 effect of soy isoflavones 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 isoflavones increased calcium retention capacity in postmenopausal women regardless of their equol-producing capacity (85).
At present, the clinical benefits of soy isoflavones as an alternative to bone-sparing treatments in women undergoing menopause remain to be determined.
To date, large prospective cohort studies, mainly in Asian populations, investigating whether habitual soy food/isoflavone 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 isoflavone 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 isoflavone 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 isoflavonoids were used as a more objective estimate of isoflavone exposure compared to dietary assessment with food-frequency questionnaires (89, 90). Further, no significant associations were found between long-term soy food, soy protein, and soy isoflavone 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 difficult to analyze possible longitudinal associations between isoflavone 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 flour), soy protein isolate, or soy isoflavones for one month to one year could significantly improve serum lipid profiles 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 isoflavones was more effective at lowering total and LDL-cholesterol than soy protein containing isoflavones, and the consumption of soy isoflavones alone (as supplements or extracts) showed no significant effects on serum lipid profiles (96). In addition, a meta-analysis of 18 randomized controlled studies indicated that neither soy foods nor soy isoflavones 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 inflammation marker associated with increased cardiovascular risk — following soy isoflavone intake (from soy foods or isoflavone 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 profiles and lowered the concentrations of CRP (99). Whether potential cardiovascular benefits of soy isoflavone intake depend on individuals’ capacity to produce isoflavone metabolites (like equol) needs to be more closely examined.
Current evidence suggests that whole soy components other than isoflavones may have favorable effects on cardiometabolic risk factors.
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 flow-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 isoflavones (50 to 99 mg/day; isolated or from isoflavone-containing soy protein) for a median eight-week period significantly 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 isoflavones but not of isoflavones-containing soy protein (103).
Arterial stiffness 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 isoflavone-containing soy protein or isoflavone extracts might significantly decrease arterial stiffness (105-107). A recent randomized, double-blind, placebo-controlled study found that carotid-femoral PWV could be significantly reduced 24 hours after a single oral intake of 80 mg of soy isoflavones 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 isoflavones reduce the burden of subclinical atherosclerosis (99, 108) and lower blood pressure (109) in individuals at high CVD risk requires further examination.
Scientific research on the effect of soy isoflavones 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 isoflavone 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 isoflavone supplementation (110). Postmenopausal women given soy extracts, providing 60 mg/day of soy isoflavones for 6 to 12 weeks, performed better on cognitive tests of picture recall (short-term memory), learning rule reversals (mental flexibility), 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 isoflavones for six months performed better on a test of verbal fluency than women given placebos (115). In a cross-over trial lasting six months, women receiving 60 mg/day of soy isoflavones experienced significant 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 isoflavones for six months (117) or 99 mg/day of isoflavones for one year (118) did not affect performance on a battery of cognitive function tests, including tests for memory, attention, verbal fluency, motor control, and dementia in postmenopausal women. In addition, in the 30-month Women’s Isoflavone Soy Health trial in 313 postmenopausal women, daily supplementation with 91 mg of soy isoflavones significantly 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 significant improvement in the pooled summary of cognitive function tests in healthy postmenopausal women supplemented with 60 to 160 mg/day of soy isoflavones for 6 to 30 months (120).
There has been little investigation regarding the potential effects of soy isoflavones in individuals with cognitive impairments (121).
Menopause-related vasomotor symptoms, including hot flashes (flushes) and night sweats, affect over 75% of middle-aged US women (122). Concern over potential adverse effects 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 effects of increasing soy isoflavone 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 reflected 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 isoflavone extracts (12 studies), or red clover extracts (nine studies) — significantly reduced the frequency of hot flashes (131). This result was consistent with previous analyses reporting alleviation of hot flashes in higher- rather than lower-genistein supplementation trials (126, 133, 134). Nevertheless, in a meta-analysis by Taku et al. (133), supplemental soy isoflavone extract (30 to 80 mg/day for six weeks to one year) was found to result in a net 17.4% reduction in hot flash 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 flash severity with soy isoflavone extracts (30 to 135 mg/day for 12 weeks to one year) (133). Moreover, the observation that longer trials showed a greater efficacy of soy isoflavones was confirmed 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 isoflavones required 48 weeks of treatment, compared to only 12 weeks for estradiol, in order to achieve close to 80% of its maximum effect (135). Besides, the maximum effect of soy isoflavones was found to account for only 57% of the maximum effect 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 benefits of daily supplementation with soy flour (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 flashes following soy isoflavone 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 flashes significantly reduced the frequency and severity of hot flashes and neck and shoulder muscle stiffness compared to a placebo (141). In another study, daily supplementation with soy isoflavone (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 flashes in postmenopausal women with five or more daily hot flashes; however, 20 mg/day and 40 mg/day of equol supplements proved to be more effective than soy isoflavone supplements in the subgroup of women experiencing eight or more hot flashes per day (142). Nevertheless, because this study lacked an inert placebo control group, the results should be viewed with caution.
At present, supplements containing sufficient amounts of genistein may help alleviate vasomotor symptoms in women transitioning through menopause (126, 143).
Isoflavones are found in small amounts in a number of legumes, grains, and vegetables, but soybeans are by far the most concentrated source of isoflavones in the human diet (144, 145). Average dietary isoflavone intakes in Japan, China, and other Asian countries range from 25 to 50 mg/day (20). Dietary isoflavone 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 isoflavone intakes to be lower than 1 mg/day (146). Compared to other European countries, the isoflavone 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 isoflavone 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 isoflavones, while those prepared by aqueous wash processes tend to retain them (147). Some foods that are rich in soy isoflavones are listed in Table 1, along with their isoflavone content. Because the isoflavone content of soy foods can vary considerably among brands and among different 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 isoflavones, accurate and consistent labeling of the soy isoflavone content of soy foods is needed. Of note, foods of animal origin also contain low levels of isoflavones (and other phytoestrogens), derived from animal feeds and pastures (148). More information on the isoflavone content of foods is available from the USDA Food Composition Database website and the USDA Database for the Isoflavone Content of Selected Foods report (149).
Table 1. Total Isoflavone, Daidzein, Genistein, and Glycitein Content of Selected Foods*
||Total Isoflavones (mg)
|Soy protein concentrate, aqueous washed
|Soy protein concentrate, alcohol washed
|Soybeans, mature seeds, boiled
|Soybeans, dry roasted
|Soy milk, low-fat
|Soybeans, green, boiled (Edamame)
|Meatless (soy) burger, unprepared
|Meatless (soy) sausage
|Soy cheese, cheddar
|*Isoflavone content of soy foods can vary considerably between brands and between different lots of the same brand (147); therefore, these values should be viewed only as a guide.
Soy isoflavone extracts and supplements are available as dietary supplements without a prescription in the US. These products are not standardized, and the amounts of soy isoflavones they provide may vary considerably. Moreover, quality control may be an issue with some of these products (150). When isoflavone supplements available in the US were tested for their isoflavone content by an independent laboratory, the isoflavone content in the product differed by more than 10% from the amount claimed on the label in approximately 50% of the products tested (151).
Soy protein-based infant formulas are made from soy protein isolate and contain significant amounts of soy isoflavones (Table 2). In 1997, the total isoflavone content of soy-based infant formulas that were commercially available in the US ranged from 32 to 47 mg/liter (~34 fluid ounces) (152).
Table 2. Total Isoflavone, Daidzein, Genistein, and Glycitein Content of Selected Soy-based Infant Formulas
||Total Isoflavones (mg)
|Mead Johnson Prosobee, ready to feed
||8 fl oz.
|Abbott Nutrition, Similac, Isomil, ready to feed
||8 fl oz.
|PBM products, soy, ready to feed (formerly Wyeth-Ayerst)
||8 fl oz.
Soy isoflavones have been consumed by humans as part of soy-based diets for many years without any evidence of adverse effects (145). The 75th percentile of dietary isoflavone 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 beneficial, the long-term safety of very high supplemental doses of soy isoflavones is not yet known. One study in older men and women found that 100 mg/day of soy isoflavones for six months was well tolerated (154). Yet, longer-term studies are needed to evaluate the safety of isoflavones.
Safety for breast cancer survivors
The safety of high intakes of soy isoflavones 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 conflicting; some preclinical studies showed that soy isoflavones 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 effects of tamoxifen on breast tissue (159, 160).
Very limited data from clinical trials suggested that increased consumption of soy isoflavones (38 to 45 mg/day) may show weak estrogenic effects in human breast tissue (161, 162). However, a study in women with biopsy-confirmed breast cancer found that supplementation with 200 mg/day of soy isoflavones 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 isoflavones (163). A few large prospective cohort studies have examined the association between soy isoflavone 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 isoflavone-rich soy foods was significantly associated with a 29% lower risk of death and a 32% lower risk of cancer recurrence (164). In this study, soy isoflavone intake was associated with a significant 23% reduced risk of cancer recurrence and a nonsignificant 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 isoflavone intakes ≥10 mg/day (compared to intakes of <4 mg/day) (167). A subgroup analysis showed that the inverse association between soy isoflavone intake and recurrence was significant only among women taking the anticancer drug, tamoxifen. No inverse association was reported between soy isoflavone intake and the risks of all-cause and breast cancer-specific 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 isoflavones (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 deficiency, 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 isoflavones (152), which they can absorb and metabolize, concern has been raised regarding potential long-term effects 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). Specifically, this review identified 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 first year of life (173). In addition, the results of three observational studies suggested no adverse effects 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 effects of early infant feeding on reproductive organ development during childhood found no differences in the volume and structure of the reproductive organs of 101 five-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 effects 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 effects than infants fed cow’s milk-based formula. Nonetheless, if current evidence shows a safety profile for use of soy protein-based formulas in term infants, they are not designed or recommended for preterm infants (171). Also, recent preliminary findings suggesting potential links between consumption of soy protein-based formulas and adverse effects in autistic children deserve further investigation (179, 180).
Male reproductive health
Claims that soy food/isoflavone consumption can have adverse effects on male reproductive function, including feminization, erectile dysfunction, and infertility, are primarily based on animal studies and case reports (181). Exposure to isoflavones (including at levels above typical Asian dietary intakes) has not been shown to affect 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).
In cell culture and animal studies, soy isoflavones have been found to inhibit the activity of thyroid peroxidase, an enzyme required for thyroid hormone synthesis (184, 185). However, high intakes of soy isoflavones 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 sufficient iodine intakes, have not found increased consumption of soy isoflavones to result in clinically significant changes in circulating thyroid hormone concentrations (188-192).
To date, studies have not examined the effect of an isoflavone-rich diet on fetal development or pregnancy outcomes in humans, and the safety of isoflavone supplements during pregnancy has not been established.
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 detoxification system and lead to clinical symptoms of intoxication. Because individuals taking MAO inhibitors (MAOIs; phenelzine, tranylcypromine) are at greater risk of adverse effects, they should avoid consuming fermented soy products (193, 194). Because colonic bacteria play an important role in the metabolism of soy isoflavones, antibiotic therapy could decrease their biological activity (193). Some evidence from animal studies suggested that high intakes of soy isoflavones, particularly genistein, could interfere with the antitumor effects 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 isoflavone 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 isoflavone extracts (193).
High intakes of soy protein may interfere with the efficacy 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 isoflavone extracts or isoflavone 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.
Department of Human Health and Nutritional Sciences
University of Guelph
Guelph, Ontario, Canada
Copyright 2004-2016 Linus Pauling Institute
1. Lampe JW. Isoflavonoid 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 isoflavonoids after soy intake. Arch Biochem Biophys. 2014;559:24-28. (PubMed)
3. Hazim S, Curtis PJ, Schar MY, et al. Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness 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 isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr. 2005;81(5):1072-1079. (PubMed)
6. Setchell KD, Cole SJ. Method of defining 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. Isoflavonoids 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 flavone and isoflavone 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 effects 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 isoflavone 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 specific inhibitor of tyrosine-specific 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 isoflavones. Free Radic Res. 1997;26(1):63-70. (PubMed)
16. Wiseman H, O'Reilly JD, Adlercreutz H, et al. Isoflavone 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. Isoflavonoids 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. Effect of soy isoflavone 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 isoflavone 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 effects 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 isoflavones 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 isoflavone 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. Effects of soy protein and isoflavones 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. Effects of isoflavones 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 effects on breast MRI fibroglandular tissue density or mammographic density. Cancer Prev Res (Phila). 2015;8(10):942-951. (PubMed)
33. Key TJ, Pike MC. The dose-effect 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, Pfeiffer 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 isoflavone 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 isoflavone 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 isoflavone 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 isoflavone concentrations exceed serum levels after dietary supplementation. Prostate. 2009;69(7):719-726. (PubMed)
43. Mahmoud AM, Yang W, Bosland MC. Soy isoflavones 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 isoflavones 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. Isoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum hormonal profiles 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. Effects 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 purified isoflavones in men with rising prostate-specific antigen. Cancer Sci. 2012;103(1):125-130. (PubMed)
48. Dalais FS, Meliala A, Wattanapenpaiboon N, et al. Effects of a diet rich in phytoestrogens on prostate-specific 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 isoflavones in the treatment of prostate cancer. Nutr Cancer. 2003;47(2):111-117. (PubMed)
50. Lazarevic B, Boezelijn G, Diep LM, et al. Efficacy 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 specific 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-specific 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 isoflavone in prostate-specific 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. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone 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 specific role of isoflavones in reducing prostate cancer risk. Prostate. 2004;59(2):141-147. (PubMed)
56. Bosland MC, Kato I, Zeleniuch-Jacquotte A, et al. Effect 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. Effects 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 isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer. J Androl. 2011;32(1):40-48. (PubMed)
59. Cosman F, de Beur SJ, LeBoff 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 isoflavones 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. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis 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 significant 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 effect 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 isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13(9):1000-1007. (PubMed)
65. Ye YB, Tang XY, Verbruggen MA, Su YX. Soy isoflavones 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. Effects of soy isoflavones 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. Isoflavone-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 effects of soy protein containing isoflavones 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 isoflavones do not affect 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. Effect of long-term intervention of soy isoflavones 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-specific 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 isoflavone 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. 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(1):33-42. (PubMed)
77. Wei P, Liu M, Chen Y, Chen DC. Systematic review of soy isoflavone supplements on osteoporosis in women. Asian Pac J Trop Med. 2012;5(3):243-248. (PubMed)
78. Ricci E, Cipriani S, Chiaffarino F, Malvezzi M, Parazzini F. Soy isoflavones 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 isoflavones 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 isoflavone-metabolizing phenotypes. Maturitas. 2006;53(3):315-324. (PubMed)
81. Ishimi Y. Soybean isoflavones 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 effect 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 effects of isoflavone 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-isoflavone profiles 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 isoflavones 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 isoflavones, urinary isoflavonoids, 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 isoflavonoids 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, Scrafford 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 flavonoid 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 effect of soy or isoflavones 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. Effect of soy isoflavones 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 purified daidzein, had a favorable effect 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. 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(2):480-486. (PubMed)
103. Beavers DP, Beavers KM, Miller M, Stamey J, Messina MJ. Exposure to isoflavone-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 stiffness 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 isoflavones 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 beneficial and potentially adverse cardiovascular effects: 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 isoflavones 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. Isoflavone 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. Effect of soy isoflavones 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. Duffy R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacol Biochem Behav. 2003;75(3):721-729. (PubMed)
114. File SE, Hartley DE, Elsabagh S, Duffy 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. Isoflavones 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 effects 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. Effects of soy isoflavone 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. Effect of soy protein containing isoflavones 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 isoflavone 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 isoflavones 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 Effects of Soy Isoflavones 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 benefits 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 flashes: systematic review and meta-analysis. JAMA. 2006;295(17):2057-2071. (PubMed)
126. Messina M. Soy foods, isoflavones, 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 isoflavones 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. Efficacy 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. Isoflavone therapy for menopausal flushes: 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 isoflavones 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 isoflavones reduce menopausal hot flash 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. Isoflavone supplements containing predominantly genistein reduce hot flash 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 efficacy of nonhormonal drugs on menopausal hot flashes. 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 isoflavone 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. Effect of intestinal production of equol on menopausal symptoms in women treated with soy isoflavones. 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 flushes 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 effects of S-equol compared to soy isoflavones on menopausal hot flash frequency. J Womens Health (Larchmt). 2012;21(6):674-682. (PubMed)
143. Schmidt M, Arjomand-Wolkart K, Birkhauser MH, et al. Consensus: soy isoflavones as a first-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 isoflavones: 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 isoflavone levels in soy foods and soy protein isolates and issues related to isoflavone 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, fish, and seafood. J Agric Food Chem. 2008;56(21):10099-10104. (PubMed)
149. US Department of Agriculture. USDA Database for the Isoflavone 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 purified soy isoflavonoid products. J Altern Complement Med. 2004;10(6):1053-1060. (PubMed)
151. Setchell KD, Brown NM, Desai P, et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr. 2001;131(4 Suppl):1362S-1375S. (PubMed)
152. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. Isoflavone 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 isoflavonoids 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 efficacy of soy isoflavone 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 effects of soy protein and purified soy isoflavones 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 effects 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 effect 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 influence 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 effect 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 isoflavone 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 effect 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. Duffy 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 influence 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 affect 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 isoflavone exposure does not have feminizing effects 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 effects of soy protein or isoflavones 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 isoflavones 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 isoflavones. Environ Health Perspect. 2002;110 Suppl 3:349-353. (PubMed)
186. Messina M, Redmond G. Effects of soy protein and soybean isoflavones 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. Isoflavone supplements do not affect 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. Effect 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 isoflavones exert modest hormonal effects 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 effects of soy isoflavones 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 isoflavone content do not influence 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. Effect of soy milk on warfarin efficacy. 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 influence 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. Effects 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 efficacy of soy-based meal replacements vs an individualized diet plan in obese type II DM patients: relative effects on weight loss, metabolic parameters, and C-reactive protein. Eur J Clin Nutr. 2005;59(3):411-418. (PubMed)