Next Article in Journal
Effects of Hazelnut Consumption on Blood Lipids and Body Weight: A Systematic Review and Bayesian Meta-Analysis
Next Article in Special Issue
Dietary Fiber Analysis of Four Pulses Using AOAC 2011.25: Implications for Human Health
Previous Article in Journal
Changes in Meat/Poultry/Fish Consumption in Australia: From 1995 to 2011–2012
Previous Article in Special Issue
Beneficial Effects of Pterocarpan-High Soybean Leaf Extract on Metabolic Syndrome in Overweight and Obese Korean Subjects: Randomized Controlled Trial
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature

Nutrition Matters, Inc., 26 Spadina Parkway, Pittsfield, MA 01201, USA
Nutrients 2016, 8(12), 754;
Submission received: 5 October 2016 / Revised: 17 November 2016 / Accepted: 18 November 2016 / Published: 24 November 2016
(This article belongs to the Special Issue Health Benefits of Soybean and other Grain Legumes)


Soyfoods have long been recognized as sources of high-quality protein and healthful fat, but over the past 25 years these foods have been rigorously investigated for their role in chronic disease prevention and treatment. There is evidence, for example, that they reduce risk of coronary heart disease and breast and prostate cancer. In addition, soy alleviates hot flashes and may favorably affect renal function, alleviate depressive symptoms and improve skin health. Much of the focus on soyfoods is because they are uniquely-rich sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor modulators. Despite the many proposed benefits, the presence of isoflavones has led to concerns that soy may exert untoward effects in some individuals. However, these concerns are based primarily on animal studies, whereas the human research supports the safety and benefits of soyfoods. In support of safety is the recent conclusion of the European Food Safety Authority that isoflavones do not adversely affect the breast, thyroid or uterus of postmenopausal women. This review covers each of the major research areas involving soy focusing primarily on the clinical and epidemiologic research. Background information on Asian soy intake, isoflavones, and nutrient content is also provided.

1. Introduction

The health effects of soyfoods have been rigorously investigated for more than 25 years. More than 2000 soy-related peer-reviewed articles are published annually. Much of this research has been conducted because independent of its nutrient content there is evidence that soy exerts a variety of health benefits, especially related to the prevention of chronic disease.
Given the volume of research it is understandably challenging for health professionals to interpret the soy literature, a task that is compounded by the widely divergent results from in vitro and animal studies. However, these types of studies are of doubtful relevance to understanding the effects of soyfoods in humans. Obviously, in vitro conditions do not duplicate the complexity of living organisms, human or otherwise. Also, by necessity, these studies typically examine the effects of isolated compounds, which may be quite different from the effects seen when these compounds are examined in their natural milieu. Furthermore, the biological impact of one food constituent can be affected by the presence of others [1,2]. Studies in mice and rats often have limited value for predicting effects in humans because of the many physiological and anatomical differences between rodents and humans. In the case of soy, there is an additional caveat; most animals, including rodents and non-human primates, metabolize isoflavones very differently than humans [3,4,5,6,7,8,9].
Therefore, the intent of this review is to provide a synopsis of the current understanding of the health effects of soyfoods in the major areas under investigation based primarily upon the clinical and epidemiologic research. Background information on nutrient content and isoflavones, a class of compounds in soybeans that has been widely investigated, is also provided.

2. Nutrient Content

The macronutrient composition of the soybean differs markedly from other legumes as it is much higher in fat, moderately higher in protein and much lower in carbohydrate (Table 1) [10,11].

2.1 Protein

The soybean is notable not only for its total protein content but the quality of soy protein which is higher than that of other plant proteins and similar to animal protein [12]. The protein digestibility corrected amino acid scores (PDCAAS) for soy protein range from 0.9 to 1.0 depending upon the specific soyfood in question [12,13]. Although most work in this area has involved the modern soy products such as isolated soy protein (ISP is by definition at least 90% protein by weight) and soy protein concentrate, evidence indicates that the digestibility of protein from traditional Asian soyfoods is quite good [14,15,16,17,18,19]. Small differences in PDCAASs for soy protein from different soy products exist because of minor differences in amino acid profile and digestibility that result from processing and because of the presence or absence of components such as fiber and phytate [20].
Recently, the Food and Agriculture Organization of the United Nations (FAO) recommended gradually moving from the PDCAAS to another method for determining protein quality, the DIAAS, the digestible indispensable amino acid score [21]. The DIAAS value for soy protein will likely be somewhat lower than the PDCAAS value, as will be true for most proteins because the ileal digestibility of individual amino acids will be used as the measure of digestibility rather than fecal digestibility of the protein overall, but soy protein will still have a DIAAS of approximately 0.9 [13]. This value is well above the value of 0.75 which is the minimum value the FAO recommends should be allowed for nutrient claims to be made for high-quality proteins [21]. Despite recognition of the DIAAS over the PDCAAS, for a number of reasons, but in particular because of the lack of human data, it will likely be years before the former becomes accepted as the single assay of choice by regulatory bodies [22].
Finally, nitrogen conversion factors (NCFs) to determine protein content from Kjeldahl nitrogen measurements have been used for over 100 years [23]. For soy and most other proteins, this factor has traditionally been 6.25. This figure was derived from estimates of the nitrogen content of protein (16%, resulting in 100/16 = 6.25) using a limited number of proteins, but has served as an effective proxy for determining protein concentration for many proteins.
However, in recent years some have suggested that for soy protein a NCF of 5.71 should be used rather than 6.25 [24]. The 5.71 factor that is being proposed originally came from the work of D.B. Jones who published a USDA circular in 1931 on protein conversion factors. He argued that a factor of 6.25 was not appropriate for all proteins and that unique factors should be used based upon the amino acid composition of specific proteins [25]. Jones derived the 5.71 factor for soy protein based on the nitrogen content of one storage protein in soy, glycinin. However, glycinin is not representative of all proteins in soy and it has a relatively high nitrogen content [26]. Morr (1981) estimated that the NCF for different soy proteins using the Factor Method ranged from 6.70 to 6.84 [27].
The use of a NCF of 6.25 for soy is supported by an international consensus of Codex Standards, National and Regional Government Nutrition Labeling Regulations, and globally recognized standards development organizations, including the Association of Official Agricultural Chemists (AOAC) [28], the American Oil Chemist’s Society (AOCS) [29], the American Association of Cereal Chemists International (AACCI) [30] and the International Organization for Standardization (ISO) [31]. Also in the EU legislation 6.25 is the conversion factor used for protein labeling (cfr annex I Regulation 1169/2011).

2.2. Carbohydrate

The low carbohydrate content of the soybean means that many traditional Asian soyfoods are also low in this macronutrient which may make them advantageous for people with diabetes [32].
Also, much of the soybean carbohydrate is comprised of oligosaccharides (predominately stachyose) [33,34,35,36], which, because they are poorly digested by intestinal enzymes, travel to the colon where they are able to stimulate the growth of bacteria such as bifidobacteria, that are considered to be advantageous to the host. For this reason the soybean oligosaccharides are classified as prebiotics [37,38,39]. Twenty-five years ago, a soybean oligosaccharide extract was proposed as being a healthy alternative to table sugar [40].
Although oligosaccharides can lead to flatulence [41], research suggests that concerns about the flatulence-producing effects of beans may be exaggerated [42]. Furthermore, this concern is not applicable to many soy products because as a result of processing the oligosaccharide content is greatly reduced or eliminated. This is true for example for tempeh [43], tofu [43] and ISP [41] but not soy grits and soy protein concentrate [41].

2.3. Fat

The fat content of soybeans is comprised of approximately 10%–15% saturated, 19%–41% monounsaturated and 46% to 62% polyunsaturated fatty acids (PUFA) (per 100 g soybeans that equates to approximately 2.9, 4.4 and 11.3 g saturated, monounsaturated and PUFA, respectively) (Table 2) [44]. As can be seen from Table 2 these figures vary considerably within the same variety and among different varieties. The PUFA is comprised of the omega-6 essential fatty acid linoleic acid and α-linolenic acid, the essential omega-3 fatty acid. The ratio of these two fatty acids is approximately 7–8:1 but the range is from approximately 5–13:1 (Table 2). The soybean and full-fat soyfoods are some of the few foods that are good sources of both essential fatty acids. Because of its widespread use in the United States, soybean oil accounts for over 40% of the intake of both essential fatty acids [45].

2.4. Vitamins and Minerals

The soybean is a good source of a variety of vitamins and minerals, especially for example, potassium (Table 1) [10,11]. The potassium content is notable because intake of this mineral is often suboptimal [46]. It is important to recognize however that the nutrient content of individual soy products, depending upon the manufacturing method employed can differ markedly from one another and from the bean itself. For example, because the traditional Japanese soyfood natto is produced by fermentation using a strain of Bacillus subtilis, it is an extremely rich source of vitamin K2 [47,48].
Soybeans are relatively high in iron (Table 1) which is not surprising because although it is often not recognized, the iron content of plant-based diets is similar to [49] or higher [50] than the iron content of omnivorous diets. Issues surrounding mineral status of those consuming plant-based diets often have more to do with absorption efficiency than intake. The absorption of calcium and iron from soy is an important consideration because soyfoods often replace foods that are good sources of these minerals. Surprisingly, despite the presence of both phytate and oxalate, two compounds that inhibit mineral absorption, calcium absorption from soybeans is quite good [51]. For example, Heaney et al. (1991) found that the fractional calcium absorption from cow’s milk was 0.377 compared with 0.310 and 0.414 for high- and low-phytate soybeans, respectively [51]. Zhao et al. (2005) reported that the fractional calcium absorption from cow’s milk (0.217) did not differ from calcium carbonate-fortified soymilk (0.211) although it was slightly higher than from tricalcium phosphate-fortified soymilk (0.181) [52]. In agreement, Tang et al. (2010) found calcium absorption from soymilk [53] and Weaver et al. (2002) found calcium absorption from tofu made by coagulating soymilk with a calcium salt such as calcium chloride or calcium sulfate was similar to the absorption of calcium from cow’s milk [54].
The traditional view that the iron in soyfoods and in essentially all plant foods is poorly absorbed is contradicted by relatively new research utilizing improved methodology that shows iron absorption from soy may be quite good because most of it is in the form of ferritin [55,56]. Furthermore, in contrast to older understanding [57], there appears to be adaptation to the inhibitory effects of phytate on iron absorption [58]. Therefore, acute absorption studies may underestimate the bioavailability of minerals from plant foods such as soy. It should also be noted that iron status greatly influences nonheme iron absorption with higher absorption rates being observed in individuals with low iron stores [59].

3. Isoflavones

Isoflavones are found in many different plant foods but among commonly consumed foods the soybean contains uniquely rich amounts. This point that is illustrated by the difference in isoflavone intake between Asian and non-Asian countries. For example, mean isoflavone intake among adults ranges from about 30–50 mg/day in Japan but is less than 3 mg/day in the United States, Canada and Europe [60,61,62,63,64,65,66,67].
Isoflavones occur in soybeans almost exclusively as glycosides [68] but upon ingestion, the sugar is hydrolyzed thereby allowing absorption to occur [69]. In fermented soyfoods such as miso, tempeh and natto, considerable amounts of the isoflavones, although to varying degrees occur as aglycones due to bacterial hydrolysis [70,71,72,73]. The three isoflavones genistein, daidzein and glycitein and their respective glycosides account for approximately 50%, 40% and 10%, respectively, of the total isoflavone content of soybeans [68]. There is disagreement over whether isoflavone form affects total absorption; some studies show that in comparison to the glycoside, aglycone isoflavones are absorbed faster and to a greater extent [74,75,76] whereas other studies show aglycones are absorbed more quickly but total absorption is the same or even less [77,78,79]. In this document isoflavone amounts are expressed in aglycone equivalent weights.
In regard to isoflavone metabolism, a striking difference among individuals is that only about 25% of non-Asians and 50% of Asians host the intestinal bacteria that convert daidzein into the isoflavonoid equol [80]. In 2002, Setchell et al. (2002) proposed that those individuals who host these bacteria are more likely to benefit from soyfood consumption [81]. Since that time this hypothesis has been hotly debated. Equol does appear to offer health benefits over its precursor daidzein [82,83] in possibly several different areas but especially in the alleviation of hot flashes [84,85,86]. However, it also may be that in some cases it is the equol-producing phenotype (i.e., the ability to produce equol) rather than equol itself, that is responsible for the more beneficial response to isoflavone ingestion [87]. Rodents and non-human primates have been referred to as equol machines because of their ability to so efficiently produce such large amounts of equol in response to daidzein exposure [9]. Several excellent reviews of equol have recently been published [80,82,86,88].
Each gram of soy protein in soybeans and traditional soyfoods is associated with approximately 3.5 mg of isoflavones [89]. Consequently, one serving of a traditional soyfood, such as 100 g of tofu or 250 mL soymilk, typically provides about 25 mg isoflavones. In more refined products, such as ISP, as much as 80% to 90% of the isoflavone content can be lost as a result of processing [68,90,91].
Isoflavones have a chemical structure similar to the hormone estrogen which allows them to bind to both estrogen receptors (ER)—ERα and ERβ [92,93]. For this reason they are able to exert estrogen-like effects under certain experimental conditions and so are referred to as phytoestrogens. Note that although research shows isoflavones bind to ERs much more weakly than estrogen, circulating levels of isoflavones in response to the ingestion of approximately two servings of soyfoods are three orders of magnitude higher than estrogen [94]. More importantly, whereas estrogen binds to and transactivates ERα and ERβ equally, isoflavones preferentially bind to and transactivate ERβ [95,96,97,98]. This difference in binding and transactivation between isoflavones and estrogen is significant because the two ERs have different tissue distributions and, when activated, can have different and sometimes even opposite physiological effects [99,100].
The preference of isoflavones for ERβ is the primary reason that isoflavones are seen as capable of having tissue-selective effects and the reason they are classified as selective estrogen receptor modulators (SERMs) [101,102,103]. In tissues that possess estrogen receptors, SERMs exert estrogen-like effects in some cases but no effects or antiestrogenic effects in others. The pharmaceutical industry has for many years been actively developing SERMs [104]. Widely used SERMs include tamoxifen and raloxifene, both of which are used to treat breast cancer, the latter of which is also used for the treatment of osteoporosis [105]. There is limited clinical evidence to suggest that dietary levels of isoflavones affect immune function although there is interesting in vitro and animal work on this topic [106]. It is notable in this regard that Ryan-Borchers et al. (2006) found an isoflavone intervention (~70 mg/day) in postmenopausal women resulted in higher B cell populations which they interpreted as a heightened humoral response [107].
Although isoflavones are purported to exert a number of health benefits these molecules are not without controversy. Concerns have arisen that because of their estrogen-like properties they may exert untoward effects in some individuals such as postmenopausal women. However, after a comprehensive, multi-year evaluation of the literature, the European Food Safety Authority (EFSA) concluded that in postmenopausal women, isoflavones do not adversely affect the three organs that were investigated, the breast, thyroid and uterus [108]. Recently, the North American Menopause Society also concluded that isoflavones do not increase risk of breast or endometrial cancer.
In any event, it is clear that isoflavones should not be equated with the hormone estrogen. The literature is replete with clinical examples of differences between these two molecules. For example, isoflavones do not stimulate the vaginal maturation index [109] or increase C-reactive protein (CRP) [103] whereas estrogen does [103,109]. Furthermore, isoflavones may exert potentially-relevant hormone-independent physiological effects [110]. Therefore, classification only related to their hormonal activity may be an incomplete characterization [111]. Finally, not only should isoflavones not be equated with estrogen but soyfoods should not be equated with isoflavones. The soybean, like all foods, is a collection of many biologically active molecules [112].

4. Effects of Soy Protein on Cardiovascular Disease Risk Factors

4.1. Lipid Levels

Elevated low-density lipoprotein (LDL)-cholesterol is a well-established risk factor for coronary heart disease (CHD) [113]. As recently articulated by Jarcho and Keaney (2015), data continue to support LDL-cholesterol lowering as a primary strategy to prevent CHD [114].
Clinical research demonstrating the hypocholesterolemic effects of soy protein dates back to 1967 [115]. This benefit of soy protein was first formally recognized by the US Food and Drug Administration (FDA) in 1999 [116]. The FDA established 25 g/day soy protein as the threshold intake for cholesterol reduction. Twenty-five g is certainly more soy protein than is consumed by most Asians but through a combination of soyfoods this threshold can be relatively easily met. Since the FDA claim was approved, more than 10 countries [117] have approved similar claims including Canada, which did so in 2014 [118]. Nevertheless, there exists some controversy about the hypocholesterolemic effect of soy protein.
In general, about 20% of individuals whose cholesterol levels are elevated do not respond to dietary changes [119]. So it is not surprising, especially when considering that many interventions involved small participant numbers and that the effect of soy protein is modest, that not all studies reported soy protein statistically significantly lowered circulating cholesterol levels. In addition, since most studies have intervened with ISP less is known about the hypocholesterolemic effects of soy protein contained in other soy products such as soy flour [120]. The roots of the controversy can in many respects be traced back to 2006, when the American Heart Association (AHA) concluded that soy protein only lowers LDL-cholesterol three percent [121]. One year later, the FDA announced their intention to reevaluate the soy protein health claim.
Often overlooked is that the AHA did not actually conduct a formal statistical analysis of the data. When this was done, Jenkins et al. (2010) found using the 22 studies upon which the AHA based their conclusion, that the AHA had underestimated the cholesterol-lowering effect of soy protein [122]. They determined that soy protein lowered LDL-cholesterol 4.3% (5.2% among the high-quality studies) [122], which is in line with the results of numerous meta-analyses published over the past decade or so, that have found soy protein statistically significantly lowers LDL-cholesterol by approximately 4% to 6% (Table 3) [118,122,123,124,125,126,127,128,129,130]. Evidence indicates that the decrease in LDL-cholesterol in response to soy protein is greater in hypercholesterolemic compared to normocholesterolemic individuals [123,125,126].
In addition to lowering LDL-cholesterol, soy protein also modestly lowers circulating triglyceride levels (~5%) and raises high-density-lipoprotein (HDL)-cholesterol levels (~1%–3%) (Table 3) [123,125].
Although the lipid effects of soy protein are much more modest than initially reported [131] they are still relevant at the clinical and population levels as epidemiologic and intervention data suggest that for every 1% reduction in LDL-cholesterol there is a corresponding 1%–2% reduction in cardiovascular events (CVEs), and for every 2%–3% increase in HDL-cholesterol there is a reduction in CVEs by 2%–4% that is independent of LDL-cholesterol [132,133,134]. It should be noted that despite inverse associations between HDL-cholesterol and CVD risk noted in epidemiologic studies, recent evidence strongly calls into question the value of raising levels of this lipoprotein as means of protection against heart disease [135,136]. The mechanism(s) by which LDL-cholesterol is lowered has not been definitively identified although some work suggests peptides formed from the digestion of soy protein upregulate hepatic LDL receptors [137,138]. Finally, as discussed below, in addition to the direct effect of the protein, soyfoods potentially reduce cholesterol via substitution or replacement effects [122].

4.2. Blood Pressure

Higher-protein diets in general appear to modestly lower blood pressure [139] and there are clinical data suggesting soy protein in particular is hypotensive. The public health benefits of even the modest proposed hypotensive effects of soy protein are relevant as reducing systolic blood pressure by just 2–5 mmHg may reduce stroke and CHD disease by 6%–14% and 5%–9%, respectively [140].
Two trials noted extremely robust reductions in response to soy; one compared the effects of 25 g/day soy protein from soynuts with a diet containing a similar amount of protein in postmenopausal women [141] and the other compared the effects of one liter per day of soymilk with one liter of cow’s milk in men [142]. However, in the vast majority of trials the reductions reported are much more modest. Meta-analyses show systolic and diastolic blood pressure is reduced by approximately 2.5 and 1.5 mmHg, respectively [128,143,144,145]. An important caveat about these data is that in most studies blood pressure was not the primary endpoint of interest. Therefore, additional research is needed before definitive conclusions can be made. The mechanism(s) by which soy protein exerts its hypotensive effects has not been identified.

4.3. Endothelial Function (Vasodilation)

The endothelium is the monolayer of endothelial cells lining the lumen of the vascular beds and is mechanically and metabolically strategically located, separating the vascular wall from the circulation and the blood components. Evidence suggests that endothelial dysfunction is associated with CVEs [146].
Two meta-analyses, one published in 2011 [147] and the other in 2012 [148] found that soybean isoflavones improved endothelial function in postmenopausal women. When the data from one of these were sub-analyzed, the improvement was only found in those women who had impaired endothelial function at baseline [147]. Of course, these women are at greater risk of having or developing CHD. This finding provides at least a partial explanation for the inconsistent literature in that some studies included women with impaired endothelial function and others with normal function. Parenthetically, it may also be that some of the observed anti-inflammatory effects of isoflavones occur only in people at risk of CHD who have elevated levels of inflammatory markers [149]. Interesting, Hoshida et al. (2011) found that isoflavones (50 mg/day) improved endothelial function in pre- and postmenopausal female non-smokers but not smokers [150].

4.4. Arterial Stiffness

Unlike endothelial-mediated vasodilation (primarily nitric oxide-dependent), arterial stiffness relates to the constriction and dilation of arteries associated with systole and diastole. Arterial stiffness is determined by components of the artery wall, such as elastin, proteoglycans and smooth muscle cell function. The most straightforward, valid, and reliable measure of arterial stiffness is pulse wave velocity, which is predictive of future CVEs [151].
In 2011, a systematic review by Pase et al. [152] concluded on the basis of five studies [153,154,155,156,157] that isoflavones reduce arterial stiffness although one of the four that reported benefit intervened with the isoflavone metabolite equol [157]. Three studies not reviewed by Pase et al. [152] are also supportive of the ability of isoflavones to improve arterial stiffness in postmenopausal women [158,159,160]. Conversely, no differences in arterial stiffness were noted in a small trial of hypercholesterolemic men and women when soymilk/soy yogurt was compared with dairy milk/yogurt [161].

4.5. C-Reactive Protein

C-reactive protein, one important indicator of inflammation, is considered to be a risk marker and predictor of CVD [162,163]. A meta-analysis of 14 intervention trials showed a slight, but not significant, reduction of 0.17 mg/L (p = 0.12) in CRP concentrations among postmenopausal women with soy isoflavone intervention compared with controls. Subgroup analyses showed that isoflavones significantly lowered CRP by 0.70 mg/L (p = 0.003) among women with baseline CRP concentrations greater than 2.2 mg/L, which was equivalent to an approximate 22% reduction in levels of this inflammatory marker, whereas no change was noted in women with lower baseline CRP levels [164]. Subsequently published research also reported decreases in CRP in response to various soy interventions (soy protein, soyfoods or isoflavones) including studies involving participants engaged in an exercise program [165], subclinical hypothyroid patients [166], diabetic patients [167,168], patients with liver disease [169] and patients with renal disease [169,170]. Conversely however, soy was without effect in several other studies [120,160,171,172,173,174,175,176].
Given the inconsistency of the data, the different intervention products and experimental designs employed and that in most studies CRP was not the primary outcome of interest, it is not possible to make any definitive conclusions about the impact of different soy products on CRP. A more detailed examination of the data aimed at identifying explanations for the inconsistency is warranted.

4.6. Carotid Intima Media Thickness

Subclinical atherosclerosis can be assessed using ultrasound to measure the thickness of the carotid arteries. Carotid intima-media thickness (CIMT) increases over time; the extent of progression reflects risk of future coronary events. In 2011, a secondary analysis of a large 3-year trial by Hodis et al. [177] involving 350 healthy postmenopausal women (45–92) found that CIMT progression was inhibited in those consuming 25 g/day soy protein (91 mg isoflavones) compared to those women consuming 25 g/day milk protein. However, this benefit was observed primarily only in young postmenopausal women (<5 years since menopause) which is consistent with the “estrogen window” or “estrogen timing” hypothesis [178]. In contrast, a 6-month study involving Chinese postmenopausal women saw no effect of soy flour (40 g/day soy protein, ~50 mg isoflavones) on CIMT [179]. Whether the failure to observe a reduction in CIMT is because of the short study duration, lower dose of isoflavones or because the data were not subanalyzed according to years since menopause is unclear.

5. Effects on Cardiovascular Events

CHD and stroke account for over 20% of deaths worldwide but there are striking variations in age-adjusted cardiovascular disease (CVD) mortality rates among countries [180]. These international variations are not due primarily to genetic differences among populations as evidenced from time trends in rates within countries and changes in rates among migrants moving from low-risk to high-risk countries [181].
There has been limited epidemiologic investigation of the relationship between soy intake and CVD. A recently published meta-analysis by Lou et al. (2016) identified five cohort (3 Asian, 2 non-Asian) and three case-control studies that examined the association between soy and CHD [182]. These authors found that when comparing high vs. low intake categories, the summary relative risk (95% confidence intervals, CI) for the three case-control studies [183,184,185] was 0.66 (0.56–0.77).
With respect to the Asian cohort studies, after controlling for numerous potentially confounding variables and when comparing the extremes of intake, two found that among women soy intake was associated with marked reductions in CHD risk. One of these is from China (relative risk [RR]) plus 95% CI; 0.25: 0.10, 0.63) [186] and the other is from Japan (RR, 0.55; 95% CI: 0.26, 1.09) [187]. However, a large Singaporean prospective study failed to find soy intake was protective [188]. The aforementioned meta-analysis found the summary RR (95% CI) for these three studies was 0.57 (0.27–1.19). In contrast to the effects in women, none of the three cohort studies [187,188,189] involving Asian men found soy intake was associated with a reduced risk of CHD although one of these was published only as a letter to the editor [189].
Lou et al. (2016) identified three cohort [65,187,188] and four case-control [185,190,191,192] studies that examined the relationship between soy intake and stroke risk [182]. The summary RR (95% CI) for the case control studies, all of which involved Asian participants, was 0.54 (0.34, 0.87). However, the summary RR (95% CI) for the two of three cohort studies that involved Asian participants was 0.89 (0.71–1.12).
Soyfoods potentially reduce risk of CVD through multiple mechanisms. It is noteworthy that in a recent review, Nabavi et al. (2015) concluded that genistein decreases the chance of ischemic stroke through reduction in ischemic stroke risk factors and ameliorates ischemic stroke induced neuronal damages [193]. Also, as noted previously, soy protein lowers LDL-cholesterol [118,123,124,125] and possibly blood pressure and isoflavones may improve arterial health [128,143,144,145].
In addition, when soyfoods replace protein-rich foods that are sources of saturated fat, which will likely be the case in Western cultures, because of the change in the fatty acid profile of the diet, LDL-cholesterol and CHD risk will likely be reduced. One estimate, based upon the US National Health and Nutrition Examination Survey III population data, is that when 24 g soy protein from soyfoods replace a similar amount of non-soy protein, through displacement effects LDL-cholesterol will be reduced approximately 4% (similar to the direct effect of soy protein) [122].
Although there has been recent controversy about the relationship between dietary fat and CHD [194,195] health agencies and organizations continue to recommend limiting saturated fat intake [196,197]. Recent support for this recommendation comes from a combined analysis of the Nurses' Health Study (study years, 1980 to 2010; n = 84,628) and the Health Professionals Follow-up Study (study years, 1986–2010; n = 42,908 men) which found that replacing 5% of energy intake from saturated fat with equivalent energy intake from PUFA, monounsaturated fat, or carbohydrates from whole grains was associated with a 25%, 15%, and 9% lower risk of CHD, respectively, whereas replacing saturated fat with carbohydrates from refined starches/added sugars was not protective [198].
Claims that the high omega-6 content of soybean oil and other plant oils produce a pro-inflammatory effect are not supported by the clinical evidence [199,200,201,202]. One recently published often-cited but controversial analysis concluded that only trials intervening with oils containing a mix of linoleic acid and omega-3 PUFAs reduce risk [203]. If this observation proves to be correct, soybean oil and full-fat soyfoods will be considered heart-healthy as a result of their fatty acid profile because as previously highlighted, the soybean is one of few foods that provides ample amounts of both omega-6 and omega-3 fatty acids.
The extent to which the hypocholesterolemic and hypotensive effects of soy protein contribute to the reductions in CHD noted in several of the observational studies is not clear. It is notable that the protective effects observed in the previously cited Japanese [187] and Chinese [186] cohort studies were greater than could be expected based on the mean reductions in blood pressure and LDL-cholesterol in response to soy protein observed in clinical trials. Furthermore, even in the upper categories soy protein intake was less than the amounts thought necessary to affect these endpoints.
Since CVD protection was observed in women and not men, it is certainly possible that the isoflavones in soyfoods played an important role in this regard. As previously discussed, in postmenopausal women, these soybean constituents have been shown to improve arterial stiffness [152] and flow mediated dilation [147]. In epidemiologic studies showing soy is protective against CVD, estimated isoflavone exposure is not dissimilar from the doses used in clinical studies which show benefits on arterial health.

6. Bone Health

In response to declining estrogen levels, women can lose substantial amounts of bone mass in the decade following menopause, which markedly increases their fracture risk [204]. Estrogen therapy reduces postmenopausal bone loss and hip fracture risk by approximately one-third [205]. Initial speculation that soyfoods promote bone health in postmenopausal women was based on the estrogen-like effects of isoflavones and early research showing that the synthetic isoflavone, ipriflavone, exerted skeletal benefits [206].
Two large Asian prospective epidemiologic studies found among women soy intake was associated with a one-third reduction in fracture risk [207,208]. A third prospective epidemiologic study, which involved US Seventh-day Adventists (approximately 40% of whom are vegetarians), found that among postmenopausal women soymilk consumption was associated with a significantly lower risk of developing osteoporosis but since the intake of cow’s milk was similarly protective, the benefit of soy may have been due to its calcium rather than isoflavone content [209].
Many short-term clinical studies have found that isoflavones favorably affect bone turnover and/or bone mineral density (BMD) in postmenopausal women [210,211,212]. In contrast, of the four large, long-term clinical trials that have been conducted [213,214,215,216], only one trial, which involved osteopenic women, found isoflavones statistically significantly improved BMD [213]. However, a recently published clinical study which employed novel methodology to assess bone calcium content not only supports the efficacy of isoflavones but provides a possible explanation for the disappointing results from the long-term trials [217].
In this cross-over study, over a 50-day period, isoflavones (105 mg/day) increased bone calcium content by 7.6% (p = 0.0001), approximately half the increase noted in response to risedronate, a bisphosphonate used in the treatment of osteoporosis [218]. Furthermore, doubling the dose of isoflavones to amounts similar to those used in two of the long-term trials [215,216], actually increased bone calcium content to a much lesser extent than the lower dose [217]. Therefore, more mderate doses of isoflavones (50–100 mg/day) may prove to be more efficacious for promoting bone health than more pharmacologic doses.
Although at this point more research is required to establish that isoflavones exert skeletal benefits, the high-quality protein [12,13] and well-absorbed calcium [52,53] provided by many soyfoods certainly can contribute to bone health.

7. Breast Cancer

7.1. Risk Reduction

It is widely recognized that breast cancer incidence rates in soyfood-consuming countries are much lower than in Western countries [219]. Furthermore, as Westernization of Asian cultures has occurred, Asian breast cancer rates have steadily increased [220]. While these observations helped fuel interest in the chemopreventive effects of soy isoflavones, more relevant are Asian epidemiologic studies which show that higher soy consumption is associated with an approximate one-third reduction in breast cancer risk although most data come from case-control not longitudinal studies [221]. However, considerable data suggest that for soy to reduce risk consumption must occur during childhood and/or adolescence [222,223,224,225,226,227,228]. Case-control studies show higher soy intake early in life is associated with 25% to 60% reductions in risk [225,226,227,228].
The “early intake” hypothesis, which was first proposed in 1995 [222,223], is consistent with clinical studies showing that in adults, neither soy protein nor isoflavone supplements affect markers of breast cancer risk including mammographic density [229,230] and breast cell proliferation [231,232,233,234,235,236]. It is also consistent with the recognition of the growing evidence linking childhood and adolescent lifestyle and environmental exposures with subsequent risk of cancers arising in adulthood [237].
The recent results by Baglia et al. (2016) from the Shanghai Women’s Health Study provide interesting insight into the impact of timing of soy intake on breast cancer risk [238]. After a median follow-up period of 13.2 years, 1034 incident breast cancer cases were identified among the >70,000 women enrolled in this study. When women were divided into three soy protein intake groups (low, medium, and high) it was found that high intake during both adolescence and adulthood significantly reduced breast cancer risk (hazard ratio [HR], 0.53; 95% CI: 0.32, 0.88). However, consuming higher amounts of soy only during adolescence (and low soy intake during adulthood) was almost as protective (HR, 0.56; 95% CI: 0.31, 1.00). Thus, these results support the early intake hypothesis. Interestingly, high soy protein intake during adulthood was only protective (HR, 0.63; 95% CI: 0.43, 0.91) against breast cancer among women who consumed little soy during adolescence. Baglia et al. (2016) suggest the reason for this finding is that protective effects would have already been manifest against breast cancer among premenopausal women if they had consumed soy when young [238].
The low intake among non-Asians severely limits the ability of Western epidemiologic studies involving the general population to provide meaningful data about the health effects of soy [239]. However, results from the Oxford arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) have been cited as supporting the early intake hypothesis [240]. This study oversampled for vegetarians so soy intake among a sizeable percentage of the participants was similar to that reported in Japanese studies. It has been argued that the Oxford-EPIC found no association between isoflavone intake and breast cancer risk because the high-soy-consumers in this cohort likely began eating soy only later in life with their adoption of a vegetarian diet [241].
Finally, several mechanisms for the protective effects of early isoflavone exposure have been proposed [242,243,244,245,246]. The protection afforded by isoflavones may be similar to the observed protective effect of early pregnancy against breast cancer [242].

7.2. Breast Cancer Patients

The estrogen-like effects of isoflavones provided a theoretical basis for concern that soyfoods adversely affect the prognosis of breast cancer patients. However, not only as discussed previously, do isoflavones differ from the hormone estrogen but the evidence that estrogen therapy increases breast cancer risk is unimpressive. In fact, in the Women’s Health Initiative trial, which involved over 10,000 women, estrogen therapy statistically significantly reduced risk of developing invasive breast cancer [247].
Nevertheless, in ovariectomized athymic mice implanted with MCF-7 cells, an estrogen-sensitive human breast cancer cell line, isoflavones stimulate the growth of existing mammary tumors [248,249]. However, because rodents metabolize isoflavones differently than humans, the value of these studies for understanding effects in humans is in doubt [3,4,5,6,7,8]. Furthermore, not all rodent models show that soy or isoflavones stimulate the growth of existing mammary tumors [250,251,252] and even in the aforementioned rodent model that does, minimally processed soy does not have this effect [253]. In addition, just slightly tweaking this model in a more physiologic direction causes a complete loss of the stimulatory effects of isoflavones [251].
More importantly, the clinical data show that soy isoflavones, regardless of the source, and even when exposure greatly exceeds Japanese intake, do not exert harmful effects on breast tissue [229,230,231,232,233,234,235,236]. These findings are consistent with the conclusion of the EFSA although their review focused on healthy postmenopausal women not breast cancer patients [108]. In addition to the lack of effect on mammographic density and breast cell proliferation, neither soy nor isoflavone supplements have clinically relevant effects on reproductive hormones in women [254].
Finally, the prospective epidemiologic data show that post-diagnosis soy intake improves prognosis. More specifically, a meta-analysis of five prospective studies, two from the United States [255,256] and three from China [257,258,259], involving over 11,000 women with breast cancer, found soy consumption after a diagnosis of their disease was associated with statistically significant reductions in breast cancer recurrence (HR, 0.85; 95% CI: 0.77, 0.93) and mortality (HR, 0.79; 95% CI: 0.72, 0.87) (Table 4) [260]. Importantly, soy consumption was similarly beneficial in Asian and non-Asian women [261]. Also, in contrast to the results in ovariectomized athymic mice showing genistein negates the inhibitory effect of tamoxifen [262,263] and an aromatase inhibitor [264] on mammary tumor growth, the prospective epidemiologic data suggest that soyfood intake may actually enhance the efficacy of these treatments [258,261].
The positions of the American Cancer Society [265] and the American Institute for Cancer Research [266] are that soyfoods can be safely consumed by women with breast cancer. In addition, an evidence-based conclusion in response to a recent clinical inquiry published in the Journal of Family Practice was that post-diagnosis soy intake improves the prognosis of breast cancer patients [267]. This conclusion is similar to that of the World Cancer Research Fund International that there is a possible link between consuming soyfoods and improved breast cancer prognosis [268].

8. Prostate Cancer

Prostate cancer is the second most commonly diagnosed cancer in men worldwide, and the fourth most commonly diagnosed cancer overall [269]. However, as is the case for breast cancer, prostate cancer incidence and mortality rates vary dramatically throughout the world; rates in Asian countries where soyfoods are commonly consumed are very low relative to Western countries [270]. More relevant are the Asian population studies showing that higher soy consumption is associated with as much as a 50% reduction in prostate cancer risk although most data come from case-control not longitudinal studies [271,272,273,274].
Intervention studies involving prostate cancer patients generally show that isoflavone exposure slows the rise in prostate specific antigen (PSA) levels [275,276,277,278]. In contrast, in long-term trials isoflavone exposure did not affect the biochemical recurrence of prostate cancer after radical prostatectomy [279] or the progression from high-grade prostatic intraepithelial neoplasia to cancer [280]. However, the design weaknesses of each study limit the implications of the findings. In the former, patients were exposed to only 24 mg/day genistein, a relatively low dose for men who had already undergone radical prostatectomy for the treatment of prostate cancer [279]. In the other study, in addition to the treated group consuming isoflavone-rich soy protein, participants were administered supplements of vitamin E and selenium [280]. There is evidence that both of these micronutrients stimulate the development of prostate cancer, although the risk associated with vitamin E is much less clear [281,282].
In regard to possible mechanisms, since neither soy intake nor isoflavone exposure affects testosterone levels in men, effects on this hormone are not a possible explanation for the proposed protective effects of soy against prostate cancer [283]. There is some evidence from animal and clinical studies that isoflavones are able to inhibit metastasis [284,285]. Also, it was suggested more than a decade ago that genistein exerts some of its proposed chemopreventive effects through binding to ERβ [286]. ERβ is expressed in prostate epithelial cells and has a role in cellular homeostasis that is anti-proliferative [287], pro-differentiative [288], and pro-apoptotic [289].

9. Kidney Function

The potential renal benefits of soy have considerable public health significance because of the increasing worldwide prevalence of renal disease, which is largely a consequence of the increasing prevalence of diabetes [290]. There is preliminary evidence that soy protein places less stress on the kidneys in comparison to other high-quality proteins, which over time could reduce the risk of developing renal disease in susceptible individuals, such as those with diabetes [291,292]. More specifically, it has been proposed that replacing animal protein with soy protein leads to a decrease in hyperfiltration and glomerular hypertension, with resultant protection from diabetic nephropathy [291,293].
However, a recent meta-analysis of 12 clinical studies involving 280 patients with chronic renal disease found that dietary soy protein did not affect glomerular filtration rate although it significantly decreased serum creatinine, serum phosphorus, inflammation (assessed by CRP) and proteinuria in predialysis patients [294]. In individuals whose renal function is compromised serum phosphorus levels often become abnormally high so replacing animal protein with soy protein could be helpful [295]. For more detailed information about the renal effects of soyfoods the reader is referred to the reference [296].

10. Menopausal Symptoms

Hot flashes are the most common reason given by women seeking treatment for menopausal symptoms. Although hot flashes usually subside within six months to two years [297,298], many women report having them for up to 20 years after menopause [299]. It is notable that in the Study of Women’s Health Across the Nation, a multiracial/multiethnic observational study of the menopausal transition involving 3302 women enrolled at seven US sites, among women who began having hot flashes during the pre- or perimenopausal period, the average duration of hot flashes was 11.8 years [300].
The low prevalence of hot flashes among native Japanese women combined with the knowledge that isoflavones interact with ERs led to the hypothesis that soyfoods prevent the onset of hot flashes and/or are capable of alleviating existing hot flashes [301]. The first trial to test this hypothesis was published more than two decades ago [302]. Since then at least 25 trials have evaluated the effects of a variety of soy products on menopause-related hot flashes although in recent years most trials have intervened with isoflavone supplements [303,304]. These trials have produced inconsistent results. However, a meta-analysis published in 2012 provides strong support for the efficacy of isoflavones as well as an explanation for the inconsistent data [305].
This analysis found that soybean isoflavones statistically significantly reduced the frequency and severity of hot flashes by 20.6% (p < 0.00001) and 26.2% (p = 0.001), respectively, above and beyond the reduction that occurred in the placebo group (total reduction in response to isoflavones, i.e., placebo plus isoflavones, ~50%). However, sub-analysis of the data revealed that in the trials in which the intervention supplement provided >18.8 mg genistein (the median for all trials) the reduction in hot flash frequency was more than twice that observed in those trials involving supplements providing lesser amounts of genistein (Table 5). Approximately 40 mg total isoflavones derived from whole soybeans provides the amount of genistein shown to be efficacious.
Failure to differentiate between low-genistein (typically derived from soy germ) and high-genistein (typically derived from the whole soybean) supplements, as is the case for all other narrative reviews and meta-analyses of data with one exception [306], leads to erroneous conclusions about the efficacy of isoflavones.

11. Cognitive Function

The impact of both cumulative estrogen exposure and estrogen therapy on cognitive function and Alzheimer’s disease (AD) is controversial although most recent work does not support the notion that estrogen affords significant benefits in this regard [307,308,309,310].
An intriguing theory proposed more than a decade ago is that exposure to estrogenic molecules soon, but not late after menopause, produces pronounced cognitive benefits [178]. Since isoflavones interact with ERs there has been interest in understanding the impact of isoflavone exposure on cognitive function. Unexpectedly, an early epidemiologic study that was designed to study heart disease, raised concern about soy adversely affecting cognition [311], a finding that was supported by more recent research from Indonesia [312]. However, follow up research from Indonesia produced opposite results [313] and epidemiologic studies overall that have evaluated the impact of soy intake on cognition have produced very mixed findings [314,315,316,317].
In contrast to the epidemiologic data, a meta-analysis of 10 placebo-controlled randomized clinical trials involving 1024 participants found that soy isoflavones favorably affected summary cognitive function and visual memory in postmenopausal women [318]. However, a 3-year trial involving over 300 postmenopausal women failed to show that isoflavone-rich soy protein affects global cognition [319]. More recently, a six-month study found that 100 mg/day isoflavones did not benefit cognition in older men and women with AD [320]. After comprehensively evaluating the animal, clinical and epidemiologic data, Soni et al. (2014) recently concluded that “the evidence to date is not sufficient to make any recommendations about the association between dietary intake of soy isoflavones and cognition in older adults” [321]. It seems reasonable to assume that at this point this conclusion will be valid for the foreseeable future.

12. Mental Health

There are several areas in relation to the impact of soy intake that have been investigated to only a limited extent but that based upon preliminary results warrant additional research. One such area is mental health and specifically depression. Depression is a commonly occurring disorder associated with diminished quality of life and increased morbidity and mortality [322,323]. Strikingly, there is an approximate two-fold female-male disparity in the prevalence of depression [324]. The higher prevalence of depression among women compared to men suggests that reproductive hormones may be involved in the etiology of this disease. Also, longitudinal studies suggest that menopause is a period of risk for new onset or recurrent depression for some women [325,326,327]. Importantly, there is a growing recognition that diet affects mental health; in fact, a group of academics recently concluded that “diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology” [328].
With this background in mind the emerging evidence suggesting that isoflavones may function as antidepressants is particularly intriguing [329]. For example, over a two-year period, an Italian study that was evaluating mood effects, found that postmenopausal women taking 54 mg/day genistein showed a decline in depressive symptoms as measured by the Zung Self-rating Depression Scale whereas no change occurred in the placebo group [330]. Also, a Japanese study involving peri- and postmenopausal women found that a very moderate dose (25 mg/day) of isoflavones consumed in aglycone form reduced depressive symptoms as assessed by the Hospital Anxiety and Depression Scale and also reduced anxiety as assessed by the Athens Insomnia Scale [331]. In contrast to the benefit of this dose, this eight-week trial found that a very low dose of isoflavones (12.5 mg/day) lacked efficacy. Finally, Estrella et al. (2014) found that over a three-month period 100 mg/day isoflavones reduced depressive symptoms in clinically depressed postmenopausal women to a similar extent as Zoloft (50 mg/day) and Prozac (10 mg/day) [332]. In addition, the combination of Zoloft and isoflavones resulted in a greater reduction in symptoms than the other three individual treatments.

13. Skin Health

The impact of soy and more specifically isoflavones, on skin health including wrinkles, is another area for which encouraging preliminary data exist. Interest in the effects of isoflavones on overall skin health is not surprising given that they bind to ERs, which are present in the skin [333,334]—and that estrogen therapy is thought to improve a number of skin parameters [335,336,337,338] including skin elasticity [339], water-holding capacity [340], pigmentation [341] and vascularity [342]. Skin appendages, such as hair follicles, are also influenced by estrogens [343].
Several trials suggest that isoflavones help to reduce wrinkles but all of them have design limitations. In one study, which lacked a true control group, two groups of 20 healthy postmenopausal women aged 50 to 65 years were instructed to consume their usual diet with or without 20 g/day of an isoflavone-rich soy protein for three months [344]. There were statistically significant improvements in facial-skin wrinkling, discoloration and overall appearance in the supplemented group. In another study, which involved only 26 premenopausal Japanese women, over a 3-month period, use of supplements that provided 40 mg/day isoflavones led to a statistically significant decrease in fine wrinkles, whereas no change occurred in the placebo group [345]. Finally, a 14-week trial conducted by Jenkins et al. (2013) involving 159 postmenopausal women found that a beverage containing isoflavones (plus other bioactives) statistically significantly reduced wrinkles by on average 10%; there was also a positive correlation between baseline wrinkles and the response to the isoflavone-containing beverage; that is, the greater the wrinkle depth at baseline, the greater the improvement [346]. There was also a statistically significant increase in collagen synthesis.

14. Developmental Effects

Establishing healthy eating habits early in life is important because childhood eating habits track into adulthood, and changing adult dietary behavior is difficult [347,348,349,350,351]. Also, evidence suggests that healthy behaviors during childhood and adolescence can affect the risk of developing certain chronic diseases later in life [352,353,354,355]. Not surprisingly, compared to adults, relatively little soy research has involved children. Nonetheless, research has shown that as in adults, soy protein lowers LDL-cholesterol [356,357,358,359,360]. As discussed previously, evidence also suggests that eating soy early in life reduces risk of breast cancer [222,223,224,225,226,227,228].
The classification of isoflavones as phytoestrogens has led to investigation of the possible hormonal effects of soy consumption in children. Although only very limited clinical research addressing this issue has been conducted the evidence suggests neither soy nor isoflavone intake affects endogenous hormone levels [361,362,363].
There is also interest in understanding the impact of diet on pubertal development because pubertal characteristics are occurring at an earlier age [364,365]. Many factors likely contribute to this trend such as increasing adiposity. Epidemiologic studies have found that both total and animal protein intake is associated with earlier menarche and the development of early pubertal characteristics [366,367].
Two small Korean epidemiologic studies noted that urinary isoflavones in children with precocious puberty were higher than in children serving as controls [368,369]. However, a US cross-sectional study involving Seventh-day Adventist (SDA) girls (n = 327; age range 12 to 18 years; mean age, 15 years) found that soy intake was unrelated to the age of onset of menses [370]. The mean number of servings of soyfoods among the adolescent girls was 12.9 per week and 21.1% of the girls consumed soyfoods ≥4 times/week [370].

15. Fertility/Reproduction

There are number of issues involving soyfoods that have given rise to quite lively discussions in the peer-reviewed literature. One of those somewhat ironically, given the large populations of Asian countries that have historically consumed soy, is the possible adverse impact of soy on fertility On the other hand, breeding problems have been noted in some animal species in response to isoflavone ingestion [371,372,373,374] although it was subsequently shown that these issues arose because of either excessive intake [375] or because of differences in isoflavone metabolism between animals and humans [69,81,376,377].
In women, soyfoods appear to increase the length of the menstrual cycle although ovulation is not prevented it is simply delayed by one day [254]. According to limited epidemiologic data, this minor effect on menstrual cycle length could help to decrease breast cancer risk [378]. There is actually some evidence that isoflavones aid fertility. A prospective study found that among 315 women who collectively underwent 520 assisted reproductive technology cycles soy isoflavone intake was positively related to live birth rates [379]. Similarly, among women undergoing in vitro fertilization, soy consumption appeared to negate the adverse reproductive effects of the endocrine disruptor bisphenol A (BPA) [380]. Although the low isoflavone intake among the soy-consumers (mean intake, 3.4 mg/day) in this study raises doubt about the plausibility of these findings, they do agree with animal data [381,382].
In men, a small pilot cross-sectional study found that very modest soy consumption was associated with lower sperm concentration (sperm count was not decreased) but there were many weaknesses to this study [383]. In fact, much of the decreased sperm concentration occurred because there was an increase in ejaculate volume in men consuming higher amounts of soy, a finding which seems biologically implausible. Furthermore, this same research group subsequently found in a cross-sectional study involving 184 men from couples undergoing in vitro fertilization that male partner's intake of soyfoods and soy isoflavones was unrelated to fertilization rates, proportions of poor quality embryos, accelerated or slow embryo cleavage rate, and implantation, clinical pregnancy and live births [384].
Finally, and most importantly, all three of the clinical studies conducted show that isoflavones have no effect on sperm concentration or quality [385,386,387]. Interestingly, a case report indicated that daily isoflavone supplementation for six months in the male partner of an infertile couple with initially low sperm count led to normalization of sperm quality and quantity [388].

16. Male Feminization

Two case reports describing feminizing effects that allegedly occurred as a result of soyfood consumption have been published [389,390]. However, in both cases the individuals were said to have consumed 360 mg/day isoflavones (~9-fold greater than the mean intake among older Japanese men) in the context of unbalanced and likely nutrient-deficient diets since soyfoods accounted for the vast majority of calories consumed. Furthermore, in contrast to the rise in circulating estrogen levels noted in one case [389], no effects on estrogen levels have been noted in numerous clinical studies in which men were exposed to as much as 150 mg/day isoflavones [391].
Similarly, the drop in testosterone levels noted in the other case [390] is as already noted, inconsistent with the preponderance of the clinical data showing neither soy nor isoflavone supplements affect testosterone levels [283]. More specifically, a systematic review and meta-analysis that included 15 placebo-controlled treatment groups with baseline and ending measures and an additional 32 reports involving 36 treatment groups found no effects of soy protein or isoflavone intake on testosterone, sex hormone binding globulin, free testosterone or the free androgen index [283]. Studies published subsequent to this meta-analysis have reached similar conclusions [168,392,393,394]. The two aforementioned case reports simply illustrate that consuming excessive amounts of essentially any food can potentially lead to abnormalities [389,390].

17. Thyroid Function

Concerns about the anti-thyroid effects of soy are based primarily on in vitro research [395,396] and studies in rodents administered isolated isoflavones [397,398]. Although several cases of goiter were attributed to the use of soy infant formula, this problem was eliminated in the mid-1960s with the advent of iodine fortification of the formula [399,400,401]. A comprehensive review published in 2006 that included 14 clinical trials found that the totality of the evidence showed that neither soyfoods nor isoflavones adversely affect thyroid function in euthyroid men or women [402]. Studies published since this review [403,404,405,406,407], which include two that were three years in duration [408,409], are supportive of this conclusion as is the conclusion of the EFSA that isoflavone supplements do not affect thyroid function in postmenopausal women [108].
Soyfoods may increase the amount of thyroid medication needed by hypothyroid patients, not because of an effect on the thyroid, but because soy protein may interfere to some extent with the absorption of levothyroxine [410,411,412,413]. Soy is not unique in this regard however as many herbs and drugs and fiber and calcium supplements have similar effects [414,415,416,417,418,419,420,421,422]. In any event, it is not necessary for thyroid patients (with the exception of infants with congenital hypothyroidism) to avoid soyfoods since thyroid medication is taken on an empty stomach and dosages can easily be adjusted to compensate for any effects of soy [423].
Finally, there is concern that soy may worsen thyroid function in those whose thyroid function is compromised such as subclinical hypothyroid patients and those whose iodine intake is marginal. The concern about the latter is based on the potential for isoflavones rather than the amino acid tyrosine to be iodinated, thereby inhibiting the synthesis of thyroid hormone [424]. However, clinical research published in 2012 indicates that the iodination of isoflavones is negligible and clinically irrelevant [425]. One small British study did find that modest isoflavone exposure (16 mg/day) increased the likelihood of progressing from subclinical to overt hypothyroidism [166]. These results are surprising because the progression of subclinical to overt hypothyroidism among Japanese patients is not elevated [426] nor are rates of hypothyroidism elevated in Japan [427]. It is notable that in the British study isoflavone exposure caused marked and statistically significant reductions in systolic and diastolic blood pressure, insulin resistance and CRP.

18. Effects on Endometrial Tissue

Endometrial cancer (cancer of the corpus uteri) represents the most common gynecological malignancy in the industrialized world and is the seventh most common cancer among females although incidence and mortality rates vary markedly among geographical regions and countries [428]. The highest rates are in the United States and Europe and the lowest in Asia and Africa [429]. There is concern that because of the presence of isoflavones soyfoods could increase risk of developing endometrial cancer and stimulate the growth of existing endometrial tumors. Ever users of unopposed estrogen therapy are about two to three times more likely to develop endometrial cancer as never users [430,431,432].
However, after reviewing 25 clinical studies that measured endometrial thickness and nine that measured histopathological changes the EFSA concluded that isoflavones do not adversely affect the endometrium [108]. Interestingly, a recently published meta-analysis of the clinical data found that when all studies (n = 23; 2167 participants) were included in the analysis there was no effect of isoflavones on endometrial thickness overall whereas there was a significant (p = 0.04) decrease in thickness when considering only the seven North American trials which involved 726 women [433]. On the other hand, there was small increase in thickness among women involved in the three Asian trials but none of these studies actually intervened with soybean-derived isoflavones.
Furthermore, a recent meta-analysis of 10 observational studies (8 case-control, 2 prospective) found soy intake was inversely associated with endometrial cancer risk with an overall risk estimate (RE) of 0.81 (95% CI: 0.72, 0.91) [434]. Subgroup analyses found statistically significant protective effects for both Asian (RE: 0.79, 95% CI: 0.66, 0.95) and non-Asian (RE: 0.83, 95% CI: 0.71, 0.96) populations. Finally, Bitto et al. (2010) found that in a group of premenopausal women with non-atypical endometrial hyperplasia, genistein (54 mg/day) improved symptoms after six months to approximately the same degree as norethisterone [435]. Hence, Bitto et al. (2010) concluded that genistein might be useful for the management of endometrial hyperplasia without atypia in women that cannot be treated with progestin [435].

19. Conclusions

Soyfoods have become increasingly popular in non-Asian countries. Their versatility allows them to easily be incorporated into Western diets and therefore provides a convenient way to exploit the nutritional advantages of legumes, which often play an underutilized role in North America and many European countries. However, the macronutrient composition of the soybean is different from other legumes. Also, soy protein is higher in quality than other legume proteins and the soybean is a good source of both essential fatty acids. Soy protein also directly lowers circulating LDL-cholesterol levels and may also modestly lower blood pressure. Replacement of commonly-consumed sources of protein in Western diets by soyfoods may also lead to a favorable change in the fatty acid content of the diet.
The most distinctive aspect of the soybean is its high isoflavone content. Isoflavones are proposed as having a number of health benefits although not surprisingly, the degree to which the evidence supports these claims varies. For example, there is solid evidence in support of isoflavones alleviating hot flashes and improving arterial health in menopausal women whereas the evidence that they reduce risk of breast and prostate cancer, not surprisingly, is more preliminary. Concerns that the estrogen-like properties of isoflavones produce untoward effects in some subpopulations, such as postmenopausal women, are not supported by the clinical and epidemiologic research. Evidence indicates soyfoods can be safely consumed by all individuals except those who are allergic to soy protein, which is relatively uncommon in comparison to the number of individuals allergic to many other commonly-consumed foods [436,437,438].
When adding soy to the diet it is important to consider the overall nutritional quality of a particular soyfood since many Westernized soyfoods include a variety of non-soy ingredients. There are no formal recommendations for soy intake beyond the 25 g/day soy protein established by the US FDA as the threshold intake for cholesterol reduction. However, population and clinical studies involving adults suggest benefits are associated with approximately two to four servings per day. Ideally, soyfoods are incorporated into the diet by displacing less healthy foods and as part of an overall healthy diet designed to lower risk of chronic disease such as the approach represented by the portfolio diet [439].


The European Soy and Plant-based Foods Manufacturers Association paid for the costs of publication.

Author Contributions

The author was solely responsible for the writing of this manuscript.

Conflicts of Interest

The author is the executive director of the Soy Nutrition Institute, an organization funded by the United Soybean Board and its soy industry members.


  1. Rozen, P.; Lubin, F.; Papo, N.; Knaani, J.; Farbstein, H.; Farbstein, M.; Zajicek, G. Calcium supplements interact significantly with long-term diet while suppressing rectal epithelial proliferation of adenoma patients. Cancer 2001, 91, 833–840. [Google Scholar] [CrossRef]
  2. Bolca, S.; Wyns, C.; Possemiers, S.; Depypere, H.; De Keukeleire, D.; Bracke, M.; Verstraete, W.; Heyerick, A. Cosupplementation of isoflavones, prenylflavonoids, and lignans alters human exposure to phytoestrogen-derived 17beta-estradiol equivalents. J. Nutr. 2009, 139, 2293–2300. [Google Scholar] [CrossRef] [PubMed]
  3. Wisniewski, A.B.; Klein, S.L.; Lakshmanan, Y.; Gearhart, J.P. Exposure to genistein during gestation and lactation demasculinizes the reproductive system in rats. J. Urol. 2003, 169, 1582–1586. [Google Scholar] [CrossRef] [PubMed]
  4. Fielden, M.R.; Samy, S.M.; Chou, K.C.; Zacharewski, T.R. Effect of human dietary exposure levels of genistein during gestation and lactation on long-term reproductive development and sperm quality in mice. Food Chem. Toxicol. 2003, 41, 447–454. [Google Scholar] [CrossRef]
  5. Ojeda, S.R.; Andrews, W.W.; Advis, J.P.; White, S.S. Recent advances in the endocrinology of puberty. Endocr. Rev. 1980, 1, 228–257. [Google Scholar] [CrossRef] [PubMed]
  6. Robinson, J.D.; Judd, H.L.; Young, P.E.; Jones, O.W.; Yen, S.S. Amniotic fluid androgens and estrogens in midgestation. J. Clin. Endocrinol. Metab. 1977, 45, 755–761. [Google Scholar] [CrossRef] [PubMed]
  7. Gu, L.; House, S.E.; Prior, R.L.; Fang, N.; Ronis, M.J.; Clarkson, T.B.; Wilson, M.E.; Badger, T.M. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J. Nutr. 2006, 136, 1215–1221. [Google Scholar] [PubMed]
  8. Setchell, K.D.; Brown, N.M.; Zhao, X.; Lindley, S.L.; Heubi, J.E.; King, E.C.; Messina, M.J. Soy isoflavone phase II metabolism differs between rodents and humans: Implications for the effect on breast cancer risk. Am. J. Clin. Nutr. 2011, 94, 1284–1294. [Google Scholar] [CrossRef] [PubMed]
  9. Soukup, S.T.; Helppi, J.; Muller, D.R.; Zierau, O.; Watzl, B.; Vollmer, G.; Diel, P.; Bub, A.; Kulling, S.E. Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: A cross-species and sex comparison. Arch. Toxicol. 2016, 90, 1335–1347. [Google Scholar] [CrossRef] [PubMed]
  10. Messina, M.J. Legumes and soybeans: Overview of their nutritional profiles and health effects. Am. J. Clin. Nutr. 1999, 70, 439S–450S. [Google Scholar] [PubMed]
  11. U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory. USDA National Nutrient Database for Standard Reference, Release 28. Version Current: September 2015. Available online: (accessed on 17 August 2016).
  12. Hughes, G.J.; Ryan, D.J.; Mukherjea, R.; Schasteen, C.S. Protein digestibility-corrected amino acid scores (PDCAAS) for soy protein isolates and concentrate: Criteria for evaluation. J. Agric. Food Chem. 2011, 59, 12707–12712. [Google Scholar] [CrossRef] [PubMed]
  13. Rutherfurd, S.M.; Fanning, A.C.; Miller, B.J.; Moughan, P.J. Protein digestibility-corrected amino acid scores and digestible indispensable amino acid scores differentially describe protein quality in growing male rats. J. Nutr. 2015, 145, 372–379. [Google Scholar] [CrossRef] [PubMed]
  14. Takahashi, T.; Muramatsu, S.; Muramatsu, Y. Comparison of nutritive values between soy protein isolate and tofu. Nutr. Sci. Soy Protein 1983, 4, 93–98. [Google Scholar]
  15. Cheng, L.T.; Li, H.C.; Lan, T.H. Biological values of soybean protein and mixed soybean-pork and soybean-egg proteins in human subjects. Chin. J. Physiol. 1941, 16, 83–90. [Google Scholar]
  16. Cahill, W.M.; Schroeder, L.J.; Smith, A.H. Digestibility and biological value of soybean protein in whole soybeans, soybean flour, and soybean milk. J. Nutr. 1944, 28, 209–218. [Google Scholar]
  17. Adolph, W.H.; Wan, Y.-L. The digestibility of the protein of soybean milk. Chin. J. Physiol. 1934, 8, 171–178. [Google Scholar]
  18. Babji, A.S.; Fatimah, S.; Ghassem, M.; Abolhassani, Y. Protein quality of selected edible animal and plant protein sources using rat bio-assay. Int. Food Res. J. 2010, 17, 303–308. [Google Scholar]
  19. Pian, J.H.-C. Biological value of the proteins of mung bean, peanut and bean curd. Chin. J. Physiol. 1930, 4, 431–436. [Google Scholar]
  20. Gilani, G.S.; Cockell, K.A.; Sepehr, E. Effects of antinutritional factors on protein digestibility and amino acid availability in foods. J. AOAC Int. 2005, 88, 967–987. [Google Scholar] [PubMed]
  21. World Health Organization. Dietary Protein Quality Evaluation in Human Nutrition; Report of an FAO Expert Consultation; FAO: Rome, Italy, 2013. [Google Scholar]
  22. Lee, W.T.; Weisell, R.; Albert, J.; Tome, D.; Kurpad, A.V.; Uauy, R. Research approaches and methods for evaluating the protein quality of human foods proposed by an FAO Expert Working Group in 2014. J. Nutr. 2016, 146, 929–932. [Google Scholar] [CrossRef] [PubMed]
  23. Kjeldahl, J. En ny Methode til Kvaelstofvestemmelse i organiske Stoffer. Z. Anal. Chem. 1883, 22, 366–382. [Google Scholar] [CrossRef]
  24. Maubois, J.L.; Lorient, D. Dairy proteins and soy proteins in infant foods nitrogen-to-protein conversion factors. Dairy Sci. Technol. 2016, 96, 15–25. [Google Scholar] [CrossRef] [PubMed]
  25. Jones, D.B. Factors for Converting Percentages of Nitrogen in Foods and Feeds into Percentages of Protein; U.S. Department of Agriculture Circular: Washington, DC, USA, 1931.
  26. Murphy, P.; Resurreccion, A.P. Varietal and environmental differences in soybean glycinin and B-conglycinin content. J. Agric. Food Chem. 1984, 32, 911–915. [Google Scholar] [CrossRef]
  27. Morr, C.V. Nitrogen conversion factors for several soybean protein products. J. Food Sci. 1981, 46, 1362–1363. [Google Scholar] [CrossRef]
  28. Association of Official Analytical Chemists (AOAC). Official Method 992.23. Crude Protein in Cereal Grains and Oilseeds: Generic Combustion Method, 18th ed.; AOAC International: Rockville, MD, USA, 2005. [Google Scholar]
  29. The American Oil Chemists’ Society (AOCS). AOCS Official Method Ba 4a-38. Nitrogen-Ammonia-Protein Modified Kjeldahl Method; AOCS: Urbana, IL, USA, 2009. [Google Scholar]
  30. American Association of Cereal Chemists (AACC). AACCI Method 46-30.01. Crude Protein—Combustion Method; AACC International: St. Paul, MN, USA, 1999. [Google Scholar]
  31. ISO 16634-1:2008. Food Products: Determination of the Total Nitrogen Content by Combustion According to the Dumas Principle and Calculation of the Crude Protein Content. Part 1: Oilseeds and Animal Feeding Stuffs. Available online: (accessed on 12 June 2015).
  32. Feinman, R.D.; Pogozelski, W.K.; Astrup, A.; Bernstein, R.K.; Fine, E.J.; Westman, E.C.; Accurso, A.; Frassetto, L.; Gower, B.A.; McFarlane, S.I.; et al. Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base. Nutrition 2015, 31, 1–13. [Google Scholar] [CrossRef] [PubMed]
  33. Karr-Lilienthal, L.K.; Grieshop, C.M.; Spears, J.K.; Fahey, G.C., Jr. Amino acid, carbohydrate, and fat composition of soybean meals prepared at 55 commercial U.S. soybean processing plants. J. Agric. Food Chem. 2005, 53, 2146–2150. [Google Scholar] [CrossRef] [PubMed]
  34. Kuo, T.M.; VanMiddlesworth, J.F.; Wolf, W.J. Content of raffinose oligosaccharides and sucrose in various plant seeds. J. Agric. Food Chem. 1988, 36, 32–36. [Google Scholar] [CrossRef]
  35. Grieshop, C.M.; Kadzere, C.T.; Clapper, G.M.; Flickinger, E.A.; Bauer, L.L.; Frazier, R.L.; Fahey, G.C., Jr. Chemical and nutritional characteristics of United States soybeans and soybean meals. J. Agric. Food Chem. 2003, 51, 7684–7691. [Google Scholar] [CrossRef] [PubMed]
  36. De Lourdes, M.; Silva, H.C.B. Oligosaccharide content of ten varieties of dark-coated soybeans. J. Agric. Food Chem. 1984, 32, 355–357. [Google Scholar]
  37. Inoguchi, S.; Ohashi, Y.; Narai-Kanayama, A.; Aso, K.; Nakagaki, T.; Fujisawa, T. Effects of non-fermented and fermented soybean milk intake on faecal microbiota and faecal metabolites in humans. Int. J. Food Sci. Nutr. 2012, 63, 402–410. [Google Scholar] [CrossRef] [PubMed]
  38. Bang, M.H.; Chio, O.S.; Kim, W.K. Soyoligosaccharide increases fecal bifidobacteria counts, short-chain fatty acids, and fecal lipid concentrations in young Korean women. J. Med. Food 2007, 10, 366–370. [Google Scholar] [CrossRef] [PubMed]
  39. Hayakawa, K.; Mizutani, J.; Wada, K.; Masa, T.; Yoshihara, I.; Mitsuoka, T. Effects of soybean oligosaccharides on human faecal flora. Microb. Ecol. Health Dis. 1990, 3, 292–303. [Google Scholar] [CrossRef]
  40. Hata, Y.; Yamamoto, M.; Nakajima, K. Effects of soybean oligosaccharides on human digestive organs: Estimate of fifty percent effective dose and maximum non-effective dose based on diarrhea. J. Clin. Biochem. Nutr. 1991, 10, 135–144. [Google Scholar] [CrossRef] [PubMed]
  41. Suarez, F.L.; Springfield, J.; Furne, J.K.; Lohrmann, T.T.; Kerr, P.S.; Levitt, M.D. Gas production in human ingesting a soybean flour derived from beans naturally low in oligosaccharides. Am. J. Clin. Nutr. 1999, 69, 135–139. [Google Scholar] [PubMed]
  42. Winham, D.M.; Hutchins, A.M. Perceptions of flatulence from bean consumption among adults in 3 feeding studies. Nutr. J. 2011, 10, 128. [Google Scholar] [CrossRef] [PubMed]
  43. Calloway, D.H.; Hickey, C.A.; Murphy, E.L. Reduction of intestinal gas-forming of legumes by traditional and experimental food processing methods. J. Food Sci. 1971, 36, 251–255. [Google Scholar] [CrossRef]
  44. Slavin, M.; Kenworthy, W.; Yu, L.L. Antioxidant properties, phytochemical composition, and antiproliferative activity of Maryland-grown soybeans with colored seed coats. J. Agric. Food Chem. 2009, 57, 11174–11185. [Google Scholar] [CrossRef] [PubMed]
  45. Blasbalg, T.L.; Hibbeln, J.R.; Ramsden, C.E.; Majchrzak, S.F.; Rawlings, R.R. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am. J. Clin. Nutr. 2011, 93, 950–962. [Google Scholar] [CrossRef] [PubMed]
  46. O’Neil, C.E.; Keast, D.R.; Fulgoni, V.L.; Nicklas, T.A. Food sources of energy and nutrients among adults in the US: NHANES 2003–2006. Nutrients 2012, 4, 2097–2120. [Google Scholar] [CrossRef] [PubMed]
  47. Kamao, M.; Suhara, Y.; Tsugawa, N.; Uwano, M.; Yamaguchi, N.; Uenishi, K.; Ishida, H.; Sasaki, S.; Okano, T. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J. Nutr. Sci. Vitaminol. 2007, 53, 464–470. [Google Scholar] [CrossRef] [PubMed]
  48. Katsuyama, H.; Ideguchi, S.; Fukunaga, M.; Saijoh, K.; Sunami, S. Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. J. Nutr. Sci. Vitaminol. 2002, 48, 207–215. [Google Scholar] [CrossRef] [PubMed]
  49. Rizzo, N.S.; Jaceldo-Siegl, K.; Sabate, J.; Fraser, G.E. Nutrient profiles of vegetarian and nonvegetarian dietary patterns. J. Acad. Nutr. Diet. 2013, 113, 1610–1619. [Google Scholar] [CrossRef] [PubMed]
  50. Davey, G.K.; Spencer, E.A.; Appleby, P.N.; Allen, N.E.; Knox, K.H.; Key, T.J. EPIC-Oxford: Lifestyle characteristics and nutrient intakes in a cohort of 33,883 meat-eaters and 31,546 non meat-eaters in the UK. Public Health Nutr. 2003, 6, 259–269. [Google Scholar] [CrossRef] [PubMed]
  51. Heaney, R.P.; Weaver, C.M.; Fitzsimmons, M.L. Soybean phytate content: Effect on calcium absorption. Am. J. Clin. Nutr. 1991, 53, 745–747. [Google Scholar] [PubMed]
  52. Zhao, Y.; Martin, B.R.; Weaver, C.M. Calcium bioavailability of calcium carbonate fortified soymilk is equivalent to cow’s milk in young women. J. Nutr. 2005, 135, 2379–2382. [Google Scholar] [PubMed]
  53. Tang, A.L.; Walker, K.Z.; Wilcox, G.; Strauss, B.J.; Ashton, J.F.; Stojanovska, L. Calcium absorption in Australian osteopenic post-menopausal women: An acute comparative study of fortified soymilk to cows milk. Asia Pac. J. Clin. Nutr. 2010, 19, 243–249. [Google Scholar] [PubMed]
  54. Weaver, C.M.; Heaney, R.P.; Connor, L.; Martin, B.R.; Smith, D.L.; Nielsen, E. Bioavailability of calcium from tofu vs. milk in premenopausal women. J. Food Sci. 2002, 68, 3144–3147. [Google Scholar] [CrossRef]
  55. Murray-Kolb, L.E.; Welch, R.; Theil, E.C.; Beard, J.L. Women with low iron stores absorb iron from soybeans. Am. J. Clin. Nutr. 2003, 77, 180–184. [Google Scholar] [PubMed]
  56. Lonnerdal, B.; Bryant, A.; Liu, X.; Theil, E.C. Iron absorption from soybean ferritin in nonanemic women. Am. J. Clin. Nutr. 2006, 83, 103–107. [Google Scholar] [PubMed]
  57. Brune, M.; Rossander, L.; Hallberg, L. Iron absorption: No intestinal adaptation to a high-phytate diet. Am. J. Clin. Nutr. 1989, 49, 542–545. [Google Scholar] [PubMed]
  58. Armah, S.M.; Boy, E.; Chen, D.; Candal, P.; Reddy, M.B. Regular consumption of a high-phytate diet reduces the inhibitory effect of phytate on nonheme-iron absorption in women with suboptimal iron stores. J. Nutr. 2015, 145, 1735–1739. [Google Scholar] [CrossRef] [PubMed]
  59. Dainty, J.R.; Berry, R.; Lynch, S.R.; Harvey, L.J.; Fairweather-Tait, S.J. Estimation of dietary iron bioavailability from food iron intake and iron status. PLoS ONE 2014, 9, e111824. [Google Scholar] [CrossRef] [PubMed]
  60. Horn-Ross, P.L.; John, E.M.; Canchola, A.J.; Stewart, S.L.; Lee, M.M. Phytoestrogen intake and endometrial cancer risk. J. Natl. Cancer Inst. 2003, 95, 1158–1164. [Google Scholar] [CrossRef] [PubMed]
  61. Goodman-Gruen, D.; Kritz-Silverstein, D. Usual dietary isoflavone intake is associated with cardiovascular disease risk factors in postmenopausal women. J. Nutr. 2001, 131, 1202–1206. [Google Scholar] [PubMed]
  62. Bai, W.; Wang, C.; Ren, C. Intakes of total and individual flavonoids by US adults. Int. J. Food Sci. 2014, 65, 9–14. [Google Scholar] [CrossRef] [PubMed]
  63. De Kleijn, M.J.; van der Schouw, Y.T.; Wilson, P.W.; Adlercreutz, H.; Mazur, W.; Grobbee, D.E.; Jacques, P.F. Intake of dietary phytoestrogens is low in postmenopausal women in the United States: The Framingham study (1–4). J. Nutr. 2001, 131, 1826–1832. [Google Scholar] [PubMed]
  64. Van Erp-Baart, M.A.; Brants, H.A.; Kiely, M.; Mulligan, A.; Turrini, A.; Sermoneta, C.; Kilkkinen, A.; Valsta, L.M. Isoflavone intake in four different European countries: The VENUS approach. Br. J. Nutr. 2003, 89, S25–S30. [Google Scholar] [CrossRef] [PubMed]
  65. Van der Schouw, Y.T.; Kreijkamp-Kaspers, S.; Peeters, P.H.; Keinan-Boker, L.; Rimm, E.B.; Grobbee, D.E. Prospective study on usual dietary phytoestrogen intake and cardiovascular disease risk in Western women. Circulation 2005, 111, 465–471. [Google Scholar] [CrossRef] [PubMed]
  66. Boker, L.K.; Van der Schouw, Y.T.; De Kleijn, M.J.; Jacques, P.F.; Grobbee, D.E.; Peeters, P.H. Intake of dietary phytoestrogens by Dutch women. J. Nutr. 2002, 132, 1319–1328. [Google Scholar] [PubMed]
  67. Faulkner-Hogg, K.B.; Selby, W.S.; Loblay, R.H. Dietary analysis in symptomatic patients with coeliac disease on a gluten-free diet: The role of trace amounts of gluten and non-gluten food intolerances. Scand. J. Gastroenterol. 1999, 34, 784–789. [Google Scholar] [CrossRef] [PubMed]
  68. Murphy, P.A.; Barua, K.; Hauck, C.C. Solvent extraction selection in the determination of isoflavones in soy foods. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2002, 777, 129–138. [Google Scholar] [CrossRef]
  69. Rowland, I.; Faughnan, M.; Hoey, L.; Wahala, K.; Williamson, G.; Cassidy, A. Bioavailability of phyto-oestrogens. Br. J. Nutr. 2003, 89, S45–S58. [Google Scholar] [CrossRef] [PubMed]
  70. Murphy, P.A.; Song, T.; Buseman, G.; Barua, K.; Beecher, G.R.; Trainer, D.; Holden, J. Isoflavones in retail and institutional soy foods. J. Agric. Food Chem. 1999, 47, 2697–2704. [Google Scholar] [CrossRef] [PubMed]
  71. Nakajima, N.; Nozaki, N.; Ishihara, K.; Ishikawa, A.; Tsuji, H. Analysis of isoflavone content in tempeh, a fermented soybean, and preparation of a new isoflavone-enriched tempeh. J. Biosci. Bioeng. 2005, 100, 685–687. [Google Scholar] [CrossRef] [PubMed]
  72. Yen, G.C.; Lai, H.H. Inhibition of reactive nitrogen species effects in vitro and in vivo by isoflavones and soy-based food extracts. J. Agric. Food Chem. 2003, 51, 7892–7900. [Google Scholar] [CrossRef] [PubMed]
  73. Chan, S.G.; Murphy, P.A.; Ho, S.C.; Kreiger, N.; Darlington, G.; So, E.K.; Chong, P.Y. Isoflavonoid content of Hong Kong soy foods. J. Agric. Food Chem. 2009, 57, 5386–5390. [Google Scholar] [CrossRef] [PubMed]
  74. Nagino, T.; Kano, M.; Masuoka, N.; Kaga, C.; Anbe, M.; Miyazaki, K.; Kamachi, K.; Isozaki, M.; Suzuki, C.; Kasuga, C.; et al. Intake of a fermented soymilk beverage containing moderate levels of isoflavone aglycones enhances bioavailability of isoflavones in healthy premenopausal Japanese women: A double-blind, placebo-controlled, single-dose, crossover trial. Biosci. Microb. Food Health 2016, 35, 9–17. [Google Scholar] [CrossRef] [PubMed]
  75. Izumi, T.; Piskula, M.K.; Osawa, S.; Obata, A.; Tobe, K.; Saito, M.; Kataoka, S.; Kubota, Y.; Kikuchi, M. Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans. J. Nutr. 2000, 130, 1695–1699. [Google Scholar] [PubMed]
  76. Chang, Y.; Choue, R. Plasma pharmacokinetics and urinary excretion of isoflavones after ingestion of soy products with different aglycone/glucoside ratios in South Korean women. Nutr. Res. Pract. 2013, 7, 393–399. [Google Scholar] [CrossRef] [PubMed]
  77. Yuan, B.; Zhen, H.; Jin, Y.; Xu, L.; Jiang, X.; Sun, S.; Li, C.; Xu, H. Absorption and plasma disposition of genistin differ from those of genistein in healthy women. J. Agric. Food Chem. 2012, 60, 1428–1436. [Google Scholar] [CrossRef] [PubMed]
  78. Zubik, L.; Meydani, M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am. J. Clin. Nutr. 2003, 77, 1459–1465. [Google Scholar] [PubMed]
  79. Setchell, K.D.; Brown, N.M.; Desai, P.; Zimmer-Nechemias, L.; Wolfe, B.E.; Brashear, W.T.; Kirschner, A.S.; Cassidy, A.; Heubi, J.E. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 2001, 131, 1362S–1375S. [Google Scholar] [PubMed]
  80. Setchell, K.D.; Clerici, C. Equol: Pharmacokinetics and biological actions. J. Nutr. 2010, 140, 1363S–1368S. [Google Scholar] [CrossRef] [PubMed]
  81. Setchell, K.D.; Brown, N.M.; Lydeking-Olsen, E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J. Nutr. 2002, 132, 3577–3584. [Google Scholar] [PubMed]
  82. Utian, W.H.; Jones, M.; Setchell, K.D. S-equol: A potential nonhormonal agent for menopause-related symptom relief. J. Womens Health 2015, 24, 200–208. [Google Scholar] [CrossRef] [PubMed]
  83. Usui, T.; Tochiya, M.; Sasaki, Y.; Muranaka, K.; Yamakage, H.; Himeno, A.; Shimatsu, A.; Inaguma, A.; Ueno, T.; Uchiyama, S.; et al. Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status. Clin. Endocrinol. 2013, 78, 365–372. [Google Scholar] [CrossRef] [PubMed]
  84. Aso, T. Equol improves menopausal symptoms in Japanese women. J. Nutr. 2010, 140, 1386S–1389S. [Google Scholar] [CrossRef] [PubMed]
  85. Ishiwata, N.; Melby, M.K.; Mizuno, S.; Watanabe, S. New equol supplement for relieving menopausal symptoms: Randomized, placebo-controlled trial of Japanese women. Menopause 2009, 16, 141–148. [Google Scholar] [CrossRef] [PubMed]
  86. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause 2015, 22, 1155–1172.
  87. Hazim, S.; Curtis, P.J.; Schar, M.Y.; Ostertag, L.M.; Kay, C.D.; Minihane, A.M.; Cassidy, A. 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, 694–702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Setchell, K.D.; Clerici, C. Equol: History, chemistry, and formation. J. Nutr. 2010, 140, 1355S–1362S. [Google Scholar] [CrossRef] [PubMed]
  89. Messina, M.; Nagata, C.; Wu, A.H. Estimated Asian adult soy protein and isoflavone intakes. Nutr. Cancer 2006, 55, 1–12. [Google Scholar] [CrossRef] [PubMed]
  90. Wang, H.-J.; Murphy, P.A. Mass balance study of isoflavones during soybean processing. J. Agric. Food Chem. 1996, 44, 2377–2383. [Google Scholar] [CrossRef]
  91. Pandjaitan, N.H.; Ju, Z.Y.; Crandall, P.; Sneller, C.; Dombek, D. Evaluation of genistin and genistein contents in soybean varieties and soy protein concentrate prepared with 3 basic methods. J. Food Sci. 2000, 65, 399–402. [Google Scholar] [CrossRef]
  92. Kuiper, G.G.; Carlsson, B.; Grandien, K.; Enmark, E.; Haggblad, J.; Nilsson, S.; Gustafsson, J.A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997, 138, 863–870. [Google Scholar] [PubMed]
  93. Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998, 139, 4252–4263. [Google Scholar] [PubMed]
  94. Van der Velpen, V.; Hollman, P.C.; van Nielen, M.; Schouten, E.G.; Mensink, M.; Van’t Veer, P.; Geelen, A. Large inter-individual variation in isoflavone plasma concentration limits use of isoflavone intake data for risk assessment. Eur. J. Clin. Nutr. 2014, 68, 1141–1147. [Google Scholar] [CrossRef] [PubMed]
  95. An, J.; Tzagarakis-Foster, C.; Scharschmidt, T.C.; Lomri, N.; Leitman, D.C. Estrogen Receptor beta -Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens. J. Biol. Chem. 2001, 276, 17808–17814. [Google Scholar] [CrossRef] [PubMed]
  96. Margeat, E.; Bourdoncle, A.; Margueron, R.; Poujol, N.; Cavailles, V.; Royer, C. Ligands Differentially Modulate the Protein Interactions of the Human Estrogen Receptors alpha and beta. J. Mol. Biol. 2003, 326, 77–92. [Google Scholar] [CrossRef]
  97. Kostelac, D.; Rechkemmer, G.; Briviba, K. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J. Agric. Food Chem. 2003, 51, 7632–7635. [Google Scholar] [CrossRef] [PubMed]
  98. Pike, A.C.; Brzozowski, A.M.; Hubbard, R.E.; Bonn, T.; Thorsell, A.G.; Engstrom, O.; Ljunggren, J.; Gustafsson, J.A.; Carlquist, M. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J. 1999, 18, 4608–4618. [Google Scholar] [CrossRef] [PubMed]
  99. Speirs, V.; Carder, P.J.; Lane, S.; Dodwell, D.; Lansdown, M.R.; Hanby, A.M. Oestrogen receptor beta: What it means for patients with breast cancer. Lancet Oncol. 2004, 5, 174–181. [Google Scholar] [CrossRef]
  100. Pons, D.G.; Nadal-Serrano, M.; Torrens-Mas, M.; Oliver, J.; Roca, P. The phytoestrogen genistein affects breast cancer cells treatment depending on the ERalpha/ERbeta ratio. J. Cell Biochem. 2016, 117, 218–229. [Google Scholar] [CrossRef] [PubMed]
  101. Brzezinski, A.; Adlercreutz, H.; Shaoul, R.; Rösler, R.; Shmueli, A.; Tanos, V.; Schenker, J.G. Short-term effect of phytoestrogen-rich diet on postmenopausal women. Menopause 1997, 4, 89–94. [Google Scholar] [CrossRef]
  102. Diel, P.; Geis, R.B.; Caldarelli, A.; Schmidt, S.; Leschowsky, U.L.; Voss, A.; Vollmer, G. The differential ability of the phytoestrogen genistein and of estradiol to induce uterine weight and proliferation in the rat is associated with a substance specific modulation of uterine gene expression. Mol. Cell Endocrinol. 2004, 221, 21–32. [Google Scholar] [CrossRef] [PubMed]
  103. Yildiz, M.F.; Kumru, S.; Godekmerdan, A.; Kutlu, S. Effects of raloxifene, hormone therapy, and soy isoflavone on serum high-sensitive C-reactive protein in postmenopausal women. Int. J. Gynaecol. Obstet. 2005, 90, 128–133. [Google Scholar] [CrossRef] [PubMed]
  104. Schmidt, C. Third-generation SERMs may face uphill battle. J. Natl. Cancer Inst. 2010, 102, 1690–1692. [Google Scholar] [CrossRef] [PubMed]
  105. Jordan, V.C. Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell 2004, 5, 207–213. [Google Scholar] [CrossRef]
  106. Masilamani, M.; Wei, J.; Sampson, H.A. Regulation of the immune response by soybean isoflavones. Immunol. Res. 2012, 54, 95–110. [Google Scholar] [CrossRef] [PubMed]
  107. Ryan-Borchers, T.A.; Park, J.S.; Chew, B.P.; McGuire, M.K.; Fournier, L.R.; Beerman, K.A. Soy isoflavones modulate immune function in healthy postmenopausal women. Am. J. Clin. Nutr. 2006, 83, 1118–1125. [Google Scholar] [PubMed]
  108. Panel on Food Additives and Nutrient Sources added to Food. Scientific opinion on the risk assessment for peri- and post-menopausal women taking food supplements containing isolated isoflavones. EFSA J. 2015, 13, 4246. [Google Scholar]
  109. Carmignani, L.O.; Pedro, A.O.; Costa-Paiva, L.H.; Pinto-Neto, A.M. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: A randomized controlled trial. Maturitas 2010, 67, 262–269. [Google Scholar] [CrossRef] [PubMed]
  110. Russo, M.; Russo, G.L.; Daglia, M.; Kasi, P.D.; Ravi, S.; Nabavi, S.F.; Nabavi, S.M. Understanding genistein in cancer: The “good” and the “bad” effects: A review. Food Chem. 2016, 196, 589–600. [Google Scholar] [CrossRef] [PubMed]
  111. Sarkar, F.H.; Li, Y. Soy isoflavones and cancer prevention. Cancer Investig. 2003, 21, 744–757. [Google Scholar] [CrossRef]
  112. Fang, N.; Yu, S.; Badger, T.M. Comprehensive phytochemical profile of soy protein isolate. J. Agric. Food Chem. 2004, 52, 4012–4020. [Google Scholar] [CrossRef] [PubMed]
  113. Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005, 366, 1267–1278. [Google Scholar] [PubMed]
  114. Jarcho, J.A.; Keaney, J.F., Jr. Proof that lower is better—LDL cholesterol and IMPROVE-IT. N. Engl. J. Med. 2015, 372, 2448–2450. [Google Scholar] [CrossRef] [PubMed]
  115. Hodges, R.E.; Krehl, W.A.; Stone, D.B.; Lopez, A. Dietary carbohydrates and low cholesterol diets: Effects on serum lipids on man. Am. J. Clin. Nutr. 1967, 20, 198–208. [Google Scholar] [PubMed]
  116. Food labeling: Health claims; soy protein and coronary heart disease. Food and Drug Administration, HHS. Final rule. Fed. Regist. 1999, 64, 57700–57733.
  117. Xiao, C.W. Health effects of soy protein and isoflavones in humans. J. Nutr. 2008, 138, 1244S–1249S. [Google Scholar]
  118. Benkhedda, K.B.; Sinclair, S.E.; Marles, R.J.; Xiao, C.W.; Underhill, L. Food risk analysis communication. issued by health canada’s food directorate. Health Canada’s proposal to accept a health claim about soy products and cholesterol lowering. Int. Food Risk Anal. J. 2014, 4. [Google Scholar] [CrossRef]
  119. Denke, M.A.; Adams-Huet, B.; Nguyen, A.T. Individual cholesterol variation in response to a margarine- or butter- based diet: A study in families. JAMA 2000, 284, 2740–2747. [Google Scholar] [CrossRef] [PubMed]
  120. Padhi, E.M.; Blewett, H.J.; Duncan, A.M.; Guzman, R.P.; Hawke, A.; Seetharaman, K.; Tsao, R.; Wolever, T.M.; Ramdath, D.D. Whole soy flour incorporated into a muffin and consumed at 2 doses of soy protein does not lower LDL cholesterol in a randomized, double-blind controlled trial of hypercholesterolemic adults. J. Nutr. 2015, 145, 2665–2674. [Google Scholar] [CrossRef] [PubMed]
  121. Sacks, F.M.; Lichtenstein, A.; Van Horn, L.; Harris, W.; Kris-Etherton, P.; Winston, M. Soy protein, isoflavones, and cardiovascular health: An American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006, 113, 1034–1044. [Google Scholar] [CrossRef] [PubMed]
  122. Jenkins, D.J.; Mirrahimi, A.; Srichaikul, K.; Berryman, C.E.; Wang, L.; Carleton, A.; Abdulnour, S.; Sievenpiper, J.L.; Kendall, C.W.; Kris-Etherton, P.M. Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J. Nutr. 2010, 140, 2302S–2311S. [Google Scholar] [CrossRef] [PubMed]
  123. Zhan, S.; Ho, S.C. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am. J. Clin. Nutr. 2005, 81, 397–408. [Google Scholar] [PubMed]
  124. Harland, J.I.; Haffner, T.A. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis 2008, 200, 13–27. [Google Scholar] [CrossRef] [PubMed]
  125. Anderson, J.W.; Bush, H.M. Soy protein effects on serum lipoproteins: A quality assessment and meta-analysis of randomized, controlled studies. J. Am. Coll. Nutr. 2011, 30, 79–91. [Google Scholar] [CrossRef] [PubMed]
  126. Tokede, O.A.; Onabanjo, T.A.; Yansane, A.; Gaziano, J.M.; Djousse, L. Soya products and serum lipids: A meta-analysis of randomised controlled trials. Br. J. Nutr. 2015, 114, 831–843. [Google Scholar] [CrossRef] [PubMed]
  127. Yang, B.; Chen, Y.; Xu, T.; Yu, Y.; Huang, T.; Hu, X.; Li, D. Systematic review and meta-analysis of soy products consumption in patients with type 2 diabetes mellitus. Asia Pac. J. Clin. Nutr. 2011, 20, 593–602. [Google Scholar] [PubMed]
  128. Hooper, L.; Kroon, P.A.; Rimm, E.B.; Cohn, J.S.; Harvey, I.; Le Cornu, K.A.; Ryder, J.J.; Hall, W.L.; Cassidy, A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2008, 88, 38–50. [Google Scholar] [PubMed]
  129. Reynolds, K.; Chin, A.; Lees, K.A.; Nguyen, A.; Bujnowski, D.; He, J. A meta-analysis of the effect of soy protein supplementation on serum lipids. Am. J. Cardiol. 2006, 98, 633–640. [Google Scholar] [CrossRef] [PubMed]
  130. Weggemans, R.M.; Trautwein, E.A. Relation between soy-associated isoflavones and LDL and HDL cholesterol concentrations in humans: A meta-analysis. Eur. J. Clin. Nutr. 2003, 57, 940–946. [Google Scholar] [CrossRef] [PubMed]
  131. Anderson, J.W.; Johnstone, B.M.; Cook-Newell, M.E. Meta-analysis of the effects of soy protein intake on serum lipids. N. Engl. J. Med. 1995, 333, 276–282. [Google Scholar] [CrossRef] [PubMed]
  132. Pedersen, T.R.; Olsson, A.G.; Faergeman, O.; Kjekshus, J.; Wedel, H.; Berg, K.; Wilhelmsen, L.; Haghfelt, T.; Thorgeirsson, G.; Pyorala, K.; et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998, 97, 1453–1460. [Google Scholar] [CrossRef] [PubMed]
  133. Gotto, A.M., Jr.; Grundy, S.M. Lowering LDL cholesterol: Questions from recent meta-analyses and subset analyses of clinical trial DataIssues from the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, ninth Council meeting. Circulation 1999, 99, E1–E7. [Google Scholar] [CrossRef] [PubMed]
  134. Charland, S.L.; Malone, D.C. Prediction of cardiovascular event risk reduction from lipid changes associated with high potency dyslipidemia therapy. Curr. Med. Res. Opin. 2010, 26, 365–375. [Google Scholar] [CrossRef] [PubMed]
  135. Toth, P.P.; Barter, P.J.; Rosenson, R.S.; Boden, W.E.; Chapman, M.J.; Cuchel, M.; D’Agostino, R.B.; Davidson, M.H.; Davidson, W.S.; Heinecke, J.W.; et al. High-density lipoproteins: A consensus statement from the National Lipid Association. J. Clin. Lipidol. 2013, 7, 484–525. [Google Scholar] [CrossRef] [PubMed]
  136. Voight, B.F.; Peloso, G.M.; Orho-Melander, M.; Frikke-Schmidt, R.; Barbalic, M.; Jensen, M.K.; Hindy, G.; Holm, H.; Ding, E.L.; Johnson, T.; et al. Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 2012, 380, 572–580. [Google Scholar] [CrossRef]
  137. Lammi, C.; Zanoni, C.; Arnoldi, A.; Vistoli, G. Two peptides from soy beta-conglycinin induce a hypocholesterolemic effect in HepG2 cells by a statin-like mechanism: Comparative in vitro and in silico modeling studies. J. Agric. Food Chem. 2015, 63, 7945–7951. [Google Scholar] [CrossRef] [PubMed]
  138. Lovati, M.R.; Manzoni, C.; Gianazza, E.; Arnoldi, A.; Kurowska, E.; Carroll, K.K.; Sirtori, C.R. Soy protein peptides regulate cholesterol homeostasis in Hep G2 cells. J. Nutr. 2000, 130, 2543–2549. [Google Scholar] [PubMed]
  139. Santesso, N.; Akl, E.A.; Bianchi, M.; Mente, A.; Mustafa, R.; Heels-Ansdell, D.; Schunemann, H.J. Effects of higher- versus lower-protein diets on health outcomes: A systematic review and meta-analysis. Eur. J. Clin. Nutr. 2012, 66, 780–788. [Google Scholar] [CrossRef] [PubMed]
  140. Stamler, R. Implications of the INTERSALT study. Hypertension 1991, 17, 116–120. [Google Scholar] [CrossRef]
  141. Welty, F.K.; Lee, K.S.; Lew, N.S.; Zhou, J.R. Effect of soy nuts on blood pressure and lipid levels in hypertensive, prehypertensive, and normotensive postmenopausal women. Arch. Intern. Med. 2007, 167, 1060–1067. [Google Scholar] [CrossRef] [PubMed]
  142. Rivas, M.; Garay, R.P.; Escanero, J.F.; Cia, P., Jr.; Cia, P.; Alda, J.O. Soy milk lowers blood pressure in men and women with mild to moderate essential hypertension. J. Nutr. 2002, 132, 1900–1902. [Google Scholar] [PubMed]
  143. Dong, J.Y.; Tong, X.; Wu, Z.W.; Xun, P.C.; He, K.; Qin, L.Q. Effect of soya protein on blood pressure: A meta-analysis of randomised controlled trials. Br. J. Nutr. 2011, 106, 317–326. [Google Scholar] [CrossRef] [PubMed]
  144. Taku, K.; Lin, N.; Cai, D.; Hu, J.; Zhao, X.; Zhang, Y.; Wang, P.; Melby, M.K.; Hooper, L.; Kurzer, M.S.; et al. Effects of soy isoflavone extract supplements on blood pressure in adult humans: Systematic review and meta-analysis of randomized placebo-controlled trials. J. Hypertens. 2010, 28, 1971–1982. [Google Scholar] [CrossRef] [PubMed]
  145. Liu, X.X.; Li, S.H.; Chen, J.Z.; Sun, K.; Wang, X.J.; Wang, X.G.; Hui, R.T. Effect of soy isoflavones on blood pressure: A meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 463–470. [Google Scholar] [CrossRef] [PubMed]
  146. Versari, D.; Daghini, E.; Virdis, A.; Ghiadoni, L.; Taddei, S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 2009, 32, S314–S321. [Google Scholar] [CrossRef] [PubMed]
  147. Li, S.H.; Liu, X.X.; Bai, Y.Y.; Wang, X.J.; Sun, K.; Chen, J.Z.; Hui, R.T. Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: A meta-analysis of randomized placebo-controlled trials. Am. J. Clin. Nutr. 2010, 91, 480–486. [Google Scholar] [CrossRef] [PubMed]
  148. Beavers, D.P.; Beavers, K.M.; Miller, M.; Stamey, J.; Messina, M.J. Exposure to isoflavone-containing soy products and endothelial function: A Bayesian meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 182–191. [Google Scholar] [CrossRef] [PubMed]
  149. Fuchs, D.; Vafeiadou, K.; Hall, W.L.; Daniel, H.; Williams, C.M.; Schroot, J.H.; Wenzel, U. Proteomic biomarkers of peripheral blood mononuclear cells obtained from postmenopausal women undergoing an intervention with soy isoflavones. Am. J. Clin. Nutr. 2007, 86, 1369–1375. [Google Scholar] [PubMed]
  150. Hoshida, S.; Miki, T.; Nakagawa, T.; Shinoda, Y.; Inoshiro, N.; Terada, K.; Adachi, T. Different effects of isoflavones on vascular function in premenopausal and postmenopausal smokers and nonsmokers: NYMPH study. Heart Vessels 2011, 26, 590–595. [Google Scholar] [CrossRef] [PubMed]
  151. Vlachopoulos, C.; Aznaouridis, K.; Stefanadis, C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. J. Am. Coll. Cardiol. 2010, 55, 1318–1327. [Google Scholar] [CrossRef] [PubMed]
  152. Pase, M.P.; Grima, N.A.; Sarris, J. The effects of dietary and nutrient interventions on arterial stiffness: A systematic review. Am. J. Clin. Nutr. 2011, 93, 446–454. [Google Scholar] [CrossRef] [PubMed]
  153. Teede, H.J.; Dalais, F.S.; Kotsopoulos, D.; Liang, Y.L.; Davis, S.; McGrath, B.P. Dietary soy has both beneficial and potentially adverse cardiovascular effects: A placebo-controlled study in men and postmenopausal women. J. Clin. Endocrinol. Metab. 2001, 86, 3053–3060. [Google Scholar] [CrossRef] [PubMed]
  154. Teede, H.J.; McGrath, B.P.; DeSilva, L.; Cehun, M.; Fassoulakis, A.; Nestel, P.J. Isoflavones reduce arterial stiffness: A placebo-controlled study in men and postmenopausal women. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1066–1071. [Google Scholar] [CrossRef] [PubMed]
  155. Tormala, R.; Appt, S.; Clarkson, T.B.; Groop, P.H.; Ronnback, M.; Ylikorkala, O.; Mikkola, T.S. Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation. Atherosclerosis 2008, 198, 174–178. [Google Scholar] [CrossRef] [PubMed]
  156. Nestel, P.J.; Yamashita, T.; Sasahara, T.; Pomeroy, S.; Dart, A.; Komesaroff, P.; Owen, A.; Abbey, M. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 3392–3398. [Google Scholar] [CrossRef] [PubMed]
  157. Nestel, P.; Fujii, A.; Zhang, L. An isoflavone metabolite reduces arterial stiffness and blood pressure in overweight men and postmenopausal women. Atherosclerosis 2007, 192, 184–189. [Google Scholar] [CrossRef] [PubMed]
  158. Nestel, P.J.; Pomeroy, S.; Kay, S.; Komesaroff, P.; Behrsing, J.; Cameron, J.D.; West, L. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J. Clin. Endocrinol. Metab. 1999, 84, 895–898. [Google Scholar] [CrossRef] [PubMed]
  159. Curtis, P.J.; Potter, J.; Kroon, P.A.; Wilson, P.; Dhatariya, K.; Sampson, M.; Cassidy, A. Vascular function and atherosclerosis progression after 1 y of flavonoid intake in statin-treated postmenopausal women with type 2 diabetes: A double-blind randomized controlled trial. Am. J. Clin. Nutr. 2013, 97, 936–942. [Google Scholar] [CrossRef] [PubMed]
  160. Reverri, E.J.; LaSalle, C.D.; Franke, A.A.; Steinberg, F.M. Soy provides modest benefits on endothelial function without affecting inflammatory biomarkers in adults at cardiometabolic risk. Mol. Nutr. Food Res. 2015, 59, 323–333. [Google Scholar] [CrossRef] [PubMed]
  161. Meyer, B.J.; Larkin, T.A.; Owen, A.J.; Astheimer, L.B.; Tapsell, L.C.; Howe, P.R. Limited lipid-lowering effects of regular consumption of whole soybean foods. Ann. Nutr. Metab. 2004, 48, 67–78. [Google Scholar] [CrossRef] [PubMed]
  162. Buckley, D.I.; Fu, R.; Freeman, M.; Rogers, K.; Helfand, M. C-reactive protein as a risk factor for coronary heart disease: A systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2009, 151, 483–495. [Google Scholar] [CrossRef] [PubMed]
  163. Kaptoge, S.; Di Angelantonio, E.; Lowe, G.; Pepys, M.B.; Thompson, S.G.; Collins, R.; Danesh, J. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: An individual participant meta-analysis. Lancet 2010, 375, 132–140. [Google Scholar] [PubMed]
  164. Dong, J.Y.; Wang, P.; He, K.; Qin, L.Q. Effect of soy isoflavones on circulating C-reactive protein in postmenopausal women: Meta-analysis of randomized controlled trials. Menopause 2011, 18, 1256–1262. [Google Scholar] [CrossRef] [PubMed]
  165. Kani, A.H.; Alavian, S.M.; Esmaillzadeh, A.; Adibi, P.; Azadbakht, L. Effects of a novel therapeutic diet on liver enzymes and coagulating factors in patients with non-alcoholic fatty liver disease: A parallel randomized trial. Nutrition 2014, 30, 814–821. [Google Scholar] [CrossRef] [PubMed]
  166. Sathyapalan, T.; Manuchehri, A.M.; Thatcher, N.J.; Rigby, A.S.; Chapman, T.; Kilpatrick, E.S.; Atkin, S.L. The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: A randomized, double-blind, crossover study. J. Clin. Endocrinol. Metab. 2011, 96, 1442–1449. [Google Scholar] [CrossRef] [PubMed]
  167. Zhang, X.M.; Zhang, Y.B.; Chi, M.H. Soy protein supplementation reduces clinical indices in type 2 diabetes and metabolic syndrome. Yonsei Med. J. 2016, 57, 681–689. [Google Scholar] [CrossRef] [PubMed]
  168. Sathyapalan, T.; Rigby, A.S.; Bhasin, S.; Thatcher, N.J.; Kilpatrick, E.S.; Atkin, S.L. Effect of soy in men with type 2 diabetes mellitus and subclinical hypogonadism—A randomized controlled study. J. Clin. Endocrinol. Metab. 2016. [Google Scholar] [CrossRef] [PubMed]
  169. Tomayko, E.J.; Kistler, B.M.; Fitschen, P.J.; Wilund, K.R. Intradialytic protein supplementation reduces inflammation and improves physical function in maintenance hemodialysis patients. J. Ren. Nutr. 2015, 25, 276–283. [Google Scholar] [CrossRef] [PubMed]
  170. Fanti, P.; Asmis, R.; Stephenson, T.J.; Sawaya, B.P.; Franke, A.A. Positive effect of dietary soy in ESRD patients with systemic inflammation—Correlation between blood levels of the soy isoflavones and the acute-phase reactants. Nephrol. Dial. Transplant. 2006, 21, 2239–2246. [Google Scholar] [CrossRef] [PubMed]
  171. Ruscica, M.; Pavanello, C.; Gandini, S.; Gomaraschi, M.; Vitali, C.; Macchi, C.; Morlotti, B.; Aiello, G.; Bosisio, R.; Calabresi, L.; et al. Effect of soy on metabolic syndrome and cardiovascular risk factors: A randomized controlled trial. Eur. J. Nutr. 2016. [Google Scholar] [CrossRef] [PubMed]
  172. Bakhtiary, A.; Yassin, Z.; Hanachi, P.; Rahmat, A.; Ahmad, Z.; Jalali, F. Effects of soy on metabolic biomarkers of cardiovascular disease in elderly women with metabolic syndrome. Arch. Iran. Med. 2012, 15, 462–468. [Google Scholar] [PubMed]
  173. Mangano, K.M.; Hutchins-Wiese, H.L.; Kenny, A.M.; Walsh, S.J.; Abourizk, R.H.; Bruno, R.S.; Lipcius, R.; Fall, P.; Kleppinger, A.; Kenyon-Pesce, L.; et al. Soy proteins and isoflavones reduce interleukin-6 but not serum lipids in older women: A randomized controlled trial. Nutr. Res. 2013, 33, 1026–1033. [Google Scholar] [CrossRef] [PubMed]
  174. Rebholz, C.M.; Reynolds, K.; Wofford, M.R.; Chen, J.; Kelly, T.N.; Mei, H.; Whelton, P.K.; He, J. Effect of soybean protein on novel cardiovascular disease risk factors: A randomized controlled trial. Eur. J. Clin. Nutr. 2013, 67, 58–63. [Google Scholar] [CrossRef] [PubMed]
  175. Simao, A.N.; Lozovoy, M.A.; Dichi, I. Effect of soy product kinako and fish oil on serum lipids and glucose metabolism in women with metabolic syndrome. Nutrition 2014, 30, 112–115. [Google Scholar] [CrossRef] [PubMed]
  176. Riesco, E.; Choquette, S.; Audet, M.; Lebon, J.; Tessier, D.; Dionne, I.J. Effect of exercise training combined with phytoestrogens on adipokines and C-reactive protein in postmenopausal women: A randomized trial. Metabolism 2012, 61, 273–280. [Google Scholar] [CrossRef] [PubMed]
  177. Hodis, H.N.; Mack, W.J.; Kono, N.; Azen, S.P.; Shoupe, D.; Hwang-Levine, J.; Petitti, D.; Whitfield-Maxwell, L.; Yan, M.; Franke, A.A.; et al. Isoflavone soy protein supplementation and atherosclerosis progression in healthy postmenopausal women: A randomized controlled trial. Stroke 2011, 42, 3168–3175. [Google Scholar] [CrossRef] [PubMed]
  178. Hodis, H.N.; Mack, W.J. A “window of opportunity”: The reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent. Brain Res. 2011, 1379, 244–252. [Google Scholar] [CrossRef] [PubMed]
  179. Liu, Z.M.; Ho, S.C.; Chen, Y.M.; Ho, S.; To, K.; Tomlinson, B.; Woo, J. 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, 709–717. [Google Scholar] [CrossRef] [PubMed]
  180. Mathers, C.D.; Loncar, D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006, 3, e442. [Google Scholar] [CrossRef] [PubMed]
  181. Benfante, R. Studies of cardiovascular disease and cause-specific mortality trends in Japanese-American men living in Hawaii and risk factor comparisons with other Japanese populations in the Pacific region: A review. Hum. Biol. 1992, 64, 791–805. [Google Scholar] [PubMed]
  182. Lou, D.; Li, Y.; Yan, G.; Bu, J.; Wang, H. Soy consumption with risk of coronary heart disease and stroke: A meta-analysis of observational studies. Neuroepidemiology 2016, 46, 242–252. [Google Scholar] [CrossRef] [PubMed]
  183. Sasazuki, S. Case-control study of nonfatal myocardial infarction in relation to selected foods in Japanese men and women. Jpn. Circ. J. 2001, 65, 200–206. [Google Scholar] [CrossRef] [PubMed]
  184. Guo, J.; Li, W.; Wang, Y.; Al, E. Influence of dietary patterns on the risk of acute myocardial infarction in China population: The INTERHEART China study. Chin. Med. J. 2013, 126, 464–470. [Google Scholar] [PubMed]
  185. Ho, S.Y.; Schooling, M.; Hui, L.L.; Al, E. Soy consumption and mortality in Hong Kong: Proxy reported case-control study of all older adult deaths in 1998. Prev. Med. 2006, 43, 20–26. [Google Scholar] [CrossRef] [PubMed]
  186. Zhang, X.; Shu, X.O.; Gao, Y.T.; Yang, G.; Li, Q.; Li, H.; Jin, F.; Zheng, W. Soy food consumption is associated with lower risk of coronary heart disease in Chinese women. J. Nutr. 2003, 133, 2874–2878. [Google Scholar] [PubMed]
  187. Kokubo, Y.; Iso, H.; Ishihara, J.; Okada, K.; Inoue, M.; Tsugane, S. 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, 2553–2562. [Google Scholar] [CrossRef] [PubMed]
  188. Talaei, M.; Koh, W.P.; van Dam, R.M.; Yuan, J.M.; Pan, A. Dietary soy intake is not associated with risk of cardiovascular disease mortality in Singapore Chinese adults. J. Nutr. 2014, 144, 921–928. [Google Scholar] [CrossRef] [PubMed]
  189. Yu, D.; Zhang, X.; Xiang, Y.B.; Yang, G.; Li, H.; Fazio, S.; Linton, M.; Cai, Q.; Zheng, W.; Gao, Y.T.; et al. Association of soy food intake with risk and biomarkers of coronary heart disease in Chinese men. Int. J. Cardiol. 2014, 172, e285–e287. [Google Scholar] [CrossRef] [PubMed]
  190. Fang, J.; Foo, S.H.; Fung, C.; Wylie-Rosett, J.; Alderman, M.H. Stroke risk among Chinese immigrants in New York City. J. Immigr. Minor Health 2006, 8, 387–393. [Google Scholar] [CrossRef] [PubMed]
  191. Okamoto, K.; Horisawa, R. Soy products and risk of an aneurysmal rupture subarachnoid hemorrhage in Japan. Eur. J. Cardiovasc. Prev. Rehabil. 2006, 13, 284–287. [Google Scholar] [CrossRef] [PubMed]
  192. Liang, W.; Lee, A.H.; Binns, C.W.; Huang, R.; Hu, D.; Shao, H. Soy consumption reduces risk of ischemic stroke: A case-control study in southern china. Neuroepidemiology 2009, 33, 111–116. [Google Scholar] [CrossRef] [PubMed]
  193. Nabavi, S.F.; Daglia, M.; Tundis, R.; Loizzo, M.R.; Sobarzo-Sanchez, E.; Orhan, I.E.; Nabavi, S.M. Genistein: A boon for mitigating ischemic stroke. Curr. Top. Med. Chem. 2015, 15, 1714–1721. [Google Scholar] [CrossRef] [PubMed]
  194. Ravnskov, U.; DiNicolantonio, J.J.; Harcombe, Z.; Kummerow, F.A.; Okuyama, H.; Worm, N. The questionable benefits of exchanging saturated fat with polyunsaturated fat. Mayo Clin. Proc. 2014, 89, 451–453. [Google Scholar] [CrossRef] [PubMed]
  195. Ramsden, C.E.; Zamora, D.; Majchrzak-Hong, S.; Faurot, K.R.; Broste, S.K.; Frantz, R.P.; Davis, J.M.; Ringel, A.; Suchindran, C.M.; Hibbeln, J.R. Re-evaluation of the traditional diet-heart hypothesis: Analysis of recovered data from Minnesota Coronary Experiment (1968–1973). BMJ 2016, 353. [Google Scholar] [CrossRef]
  196. Panel on Dietetic Products, Nutrition and Allergies. Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. EFSA J. 2010, 8, 1461. [Google Scholar]
  197. Eckel, R.H.; Jakicic, J.M.; Ard, J.D.; de Jesus, J.M.; Houston Miller, N.; Hubbard, V.S.; Lee, I.M.; Lichtenstein, A.H.; Loria, C.M.; Millen, B.E.; et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014, 63, 2960–2984. [Google Scholar] [CrossRef] [PubMed]
  198. Li, Y.; Hruby, A.; Bernstein, A.M.; Ley, S.H.; Wang, D.D.; Chiuve, S.E.; Sampson, L.; Rexrode, K.M.; Rimm, E.B.; Willett, W.C.; et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: A prospective cohort study. J. Am. Coll. Cardiol. 2015, 66, 1538–1548. [Google Scholar] [CrossRef] [PubMed]
  199. Harris, W.S.; Mozaffarian, D.; Rimm, E.; Kris-Etherton, P.; Rudel, L.L.; Appel, L.J.; Engler, M.M.; Engler, M.B.; Sacks, F. Omega-6 fatty acids and risk for cardiovascular disease: A science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation 2009, 119, 902–907. [Google Scholar] [PubMed]
  200. Johnson, G.H.; Fritsche, K. Effect of dietary linoleic acid on markers of inflammation in healthy persons: A systematic review of randomized controlled trials. J. Acad. Nutr. Diet. 2012, 112, 1029–1041. [Google Scholar] [CrossRef] [PubMed]
  201. Rett, B.S.; Whelan, J. Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: A systematic review. Nutr. Metab. 2011, 8, 36. [Google Scholar] [CrossRef] [PubMed]
  202. Harris, W.S.; Shearer, G.C. Omega-6 fatty acids and cardiovascular disease: Friend, not foe? Circulation 2014, 130, 1562–1564. [Google Scholar] [CrossRef] [PubMed]
  203. Ramsden, C.E.; Hibbeln, J.R.; Majchrzak, S.F.; Davis, J.M. n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: A meta-analysis of randomised controlled trials. Br. J. Nutr. 2010, 104, 1586–1600. [Google Scholar] [CrossRef] [PubMed]
  204. Finkelstein, J.S.; Brockwell, S.E.; Mehta, V.; Greendale, G.A.; Sowers, M.R.; Ettinger, B.; Lo, J.C.; Johnston, J.M.; Cauley, J.A.; Danielson, M.E.; et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J. Clin. Endocrinol. Metab. 2008, 93, 861–868. [Google Scholar] [CrossRef] [PubMed]
  205. Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.; Howard, B.V.; Johnson, K.C.; et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288, 321–333. [Google Scholar] [PubMed]
  206. Brandi, M.L.; Gennari, C. Ipriflavone: New insights into its mechanisms of action on bone remodeling. Calcif. Tissue Int. 1993, 52, 151–152. [Google Scholar] [CrossRef] [PubMed]
  207. Zhang, X.; Shu, X.O.; Li, H.; Yang, G.; Li, Q.; Gao, Y.T.; Zheng, W. Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch. Intern. Med. 2005, 165, 1890–1895. [Google Scholar] [CrossRef] [PubMed]
  208. Koh, W.P.; Wu, A.H.; Wang, R.; Ang, L.W.; Heng, D.; Yuan, J.M.; Yu, M.C. Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am. J. Epidemiol. 2009, 170, 901–909. [Google Scholar] [CrossRef] [PubMed]
  209. Matthews, V.L.; Knutsen, S.F.; Beeson, W.L.; Fraser, G.E. Soy milk and dairy consumption is independently associated with ultrasound attenuation of the heel bone among postmenopausal women: The Adventist Health Study-2. Nutr. Res. 2011, 31, 766–775. [Google Scholar] [CrossRef] [PubMed]
  210. Ma, D.F.; Qin, L.Q.; Wang, P.Y.; Katoh, R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women: Meta-analysis of randomized controlled trials. Clin. Nutr. 2008, 27, 57–64. [Google Scholar] [CrossRef] [PubMed]
  211. Ma, D.F.; Qin, L.Q.; Wang, P.Y.; Katoh, R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: Meta-analysis of randomized controlled trials. Eur. J. Clin. Nutr. 2008, 62, 155–161. [Google Scholar] [CrossRef] [PubMed]
  212. Taku, K.; Melby, M.K.; Takebayashi, J.; Mizuno, S.; Ishimi, Y.; Omori, T.; Watanabe, S. Effect of soy isoflavone extract supplements on bone mineral density in menopausal women: Meta-analysis of randomized controlled trials. Asia Pac. J. Clin. Nutr. 2010, 19, 33–42. [Google Scholar] [PubMed]
  213. Marini, H.; Bitto, A.; Altavilla, D.; Burnett, B.P.; Polito, F.; Di Stefano, V.; Minutoli, L.; Atteritano, M.; Levy, R.M.; D’Anna, R.; et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: A follow-up study. J. Clin. Endocrinol. Metab. 2008, 93, 4787–4796. [Google Scholar] [CrossRef] [PubMed]
  214. Alekel, D.L.; Van Loan, M.D.; Koehler, K.J.; Hanson, L.N.; Stewart, J.W.; Hanson, K.B.; Kurzer, M.S.; Peterson, C.T. The soy isoflavones for reducing bone loss (SIRBL) study: A 3-year randomized controlled trial in postmenopausal women. Am. J. Clin. Nutr. 2010, 91, 218–230. [Google Scholar] [CrossRef] [PubMed]
  215. Levis, S.; Strickman-Stein, N.; Ganjei-Azar, P.; Xu, P.; Doerge, D.R.; Krischer, J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch. Intern. Med. 2011, 171, 1363–1369. [Google Scholar] [CrossRef] [PubMed]
  216. Tai, T.Y.; Tsai, K.S.; Tu, S.T.; Wu, J.S.; Chang, C.I.; Chen, C.L.; Shaw, N.S.; Peng, H.Y.; Wang, S.Y.; Wu, C.H. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: A 2-year randomized double-blind placebo-controlled study. Osteoporos. Int. 2012, 23, 1571–1580. [Google Scholar] [CrossRef] [PubMed]
  217. Pawlowski, J.W.; Martin, B.R.; McCabe, G.P.; McCabe, L.; Jackson, G.S.; Peacock, M.; Barnes, S.; Weaver, C.M. 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, 695–703. [Google Scholar] [CrossRef] [PubMed]
  218. Adachi, J.D.; Rizzoli, R.; Boonen, S.; Li, Z.; Meredith, M.P.; Chesnut, C.H., III. Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: A meta-analysis of individual patient data. Aging Clin. Exp. Res. 2005, 17, 150–156. [Google Scholar] [CrossRef] [PubMed]
  219. Pisani, P.; Parkin, D.M.; Bray, F.; Ferlay, J. Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer 1999, 83, 18–29. [Google Scholar] [CrossRef]
  220. Zhang, J.; Dhakal, I.B.; Zhao, Z.; Li, L. Trends in mortality from cancers of the breast, colon, prostate, esophagus, and stomach in East Asia: Role of nutrition transition. Eur. J. Cancer Prev. 2012, 21, 480–489. [Google Scholar] [CrossRef] [PubMed]
  221. Chen, M.; Rao, Y.; Zheng, Y.; Wei, S.; Li, Y.; Guo, T.; Yin, P. Association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women: A meta-analysis of epidemiological studies. PLoS ONE 2014, 9, e89288. [Google Scholar] [CrossRef] [PubMed]
  222. Lamartiniere, C.A.; Moore, J.; Holland, M.; Barnes, S. Neonatal genistein chemoprevents mammary cancer. Proc. Soc. Exp. Biol. Med. 1995, 208, 120–123. [Google Scholar] [CrossRef] [PubMed]
  223. Lamartiniere, C.A.; Moore, J.B.; Brown, N.M.; Thompson, R.; Hardin, M.J.; Barnes, S. Genistein suppresses mammary cancer in rats. Carcinogenesis 1995, 16, 2833–2840. [Google Scholar] [CrossRef] [PubMed]
  224. Lamartiniere, C.A.; Zhao, Y.X.; Fritz, W.A. Genistein: Mammary cancer chemoprevention, in vivo mechanisms of action, potential for toxicity and bioavailability in rats. J. Women’s Cancer 2000, 2, 11–19. [Google Scholar]
  225. Korde, L.A.; Wu, A.H.; Fears, T.; Nomura, A.M.; West, D.W.; Kolonel, L.N.; Pike, M.C.; Hoover, R.N.; Ziegler, R.G. Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol. Biomark. Prev. 2009, 18, 1050–1059. [Google Scholar] [CrossRef] [PubMed]
  226. Wu, A.H.; Wan, P.; Hankin, J.; Tseng, C.C.; Yu, M.C.; Pike, M.C. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 2002, 23, 1491–1496. [Google Scholar] [CrossRef] [PubMed]
  227. Shu, X.O.; Jin, F.; Dai, Q.; Wen, W.; Potter, J.D.; Kushi, L.H.; Ruan, Z.; Gao, Y.T.; Zheng, W. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol. Biomark. Prev. 2001, 10, 483–488. [Google Scholar]
  228. Lee, S.A.; Shu, X.O.; Li, H.; Yang, G.; Cai, H.; Wen, W.; Ji, B.T.; Gao, J.; Gao, Y.T.; Zheng, W. Adolescent and adult soy food intake and breast cancer risk: Results from the Shanghai Women’s Health Study. Am. J. Clin. Nutr. 2009, 89, 1920–1926. [Google Scholar] [CrossRef] [PubMed]
  229. Hooper, L.; Madhavan, G.; Tice, J.A.; Leinster, S.J.; 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, 745–760. [Google Scholar] [CrossRef] [PubMed]
  230. Wu, A.H.; Spicer, D.; Garcia, A.; Tseng, C.C.; Hovanessian-Larsen, L.; Sheth, P.; Martin, S.E.; Hawes, D.; Russell, C.; MacDonald, H.; et al. Double-blind randomized 12-month soy intervention had no effects on breast MRI fibroglandular tissue density or mammographic density. Cancer Prev. Res. 2015, 8, 942–951. [Google Scholar] [CrossRef] [PubMed]
  231. Hargreaves, D.F.; Potten, C.S.; Harding, C.; Shaw, L.E.; Morton, M.S.; Roberts, S.A.; Howell, A.; Bundred, N.J. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J. Clin. Endocrinol. Metab. 1999, 84, 4017–4024. [Google Scholar] [CrossRef] [PubMed]
  232. Sartippour, M.R.; Rao, J.Y.; Apple, S.; Wu, D.; Henning, S.; Wang, H.; Elashoff, R.; Rubio, R.; Heber, D.; Brooks, M.N. A pilot clinical study of short-term isoflavone supplements in breast cancer patients. Nutr. Cancer 2004, 49, 59–65. [Google Scholar] [CrossRef] [PubMed]
  233. Palomares, M.R.; Hopper, L.; Goldstein, L.; Lehman, C.D.; Storer, B.E.; Gralow, J.R. Effect of soy isoflavones on breast proliferation in postmenopausal breast cancer survivors. Breast Cancer Res. Treat. 2004, 88, 4002. [Google Scholar]
  234. Cheng, G.; Wilczek, B.; Warner, M.; Gustafsson, J.A.; Landgren, B.M. Isoflavone treatment for acute menopausal symptoms. Menopause 2007, 14, 468–473. [Google Scholar] [CrossRef] [PubMed]
  235. Khan, S.A.; Chatterton, R.T.; Michel, N.; Bryk, M.; Lee, O.; Ivancic, D.; Heinz, R.; Zalles, C.M.; Helenowski, I.B.; Jovanovic, B.D.; et al. Soy isoflavone supplementation for breast cancer risk reduction: A randomized phase II trial. Cancer Prev. Res. 2012, 5, 309–319. [Google Scholar] [CrossRef] [PubMed]
  236. Shike, M.; Doane, A.S.; Russo, L.; Cabal, R.; Reis-Filo, J.; Gerald, W.; Cody, H.; Khanin, R.; Bromberg, J.; Norton, L. The effects of soy supplementation on gene expression in breast cancer: A randomized placebo-controlled study. J. Natl. Cancer Inst. 2014, 106. [Google Scholar] [CrossRef] [PubMed]
  237. Potischman, N.; Linet, M.S. Invited commentary: Are dietary intakes and other exposures in childhood and adolescence important for adult cancers? Am. J. Epidemiol. 2013, 178, 184–189. [Google Scholar] [CrossRef] [PubMed]
  238. Baglia, M.L.; Zheng, W.; Li, H.; Yang, G.; Gao, J.; Gao, Y.T.; Shu, X.O. The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status. Int. J. Cancer 2016, 139, 742–748. [Google Scholar] [CrossRef] [PubMed]
  239. Messina, M. Western soy intake is too low to produce health effects. Am. J. Clin. Nutr. 2004, 80, 528–529. [Google Scholar] [PubMed]
  240. Travis, R.C.; Allen, N.E.; Appleby, P.N.; Spencer, E.A.; Roddam, A.W.; Key, T.J. A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women. Int. J. Cancer. 2008, 122, 705–710. [Google Scholar] [CrossRef] [PubMed]
  241. Messina, M.; Wu, A.H. Perspectives on the soy-breast cancer relation. Am. J. Clin. Nutr. 2009, 89, 1673S–1679S. [Google Scholar] [CrossRef] [PubMed]
  242. Russo, J.; Mailo, D.; Hu, Y.F.; Balogh, G.; Sheriff, F.; Russo, I.H. Breast differentiation and its implication in cancer prevention. Clin. Cancer Res. 2005, 11, 931s–936s. [Google Scholar] [PubMed]
  243. Brown, N.M.; Belles, C.A.; Lindley, S.L.; Zimmer-Nechemias, L.D.; Zhao, X.; Witte, D.P.; Kim, M.O.; Setchell, K.D. The chemopreventive action of equol enantiomers in a chemically induced animal model of breast cancer. Carcinogenesis 2010, 31, 886–893. [Google Scholar] [CrossRef] [PubMed]
  244. De Assis, S.; Warri, A.; Benitez, C.; Helferich, W.; Hilakivi-Clarke, L. Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression. Cancer Prev. Res. 2011, 4, 1436–1448. [Google Scholar] [CrossRef] [PubMed]
  245. Rahal, O.M.; Simmen, R.C. Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling. Endocrinology 2011, 152, 3409–3421. [Google Scholar] [CrossRef] [PubMed]
  246. Mishra, P.; Kar, A.; Kale, R.K. Prepubertal daidzein exposure enhances mammary gland differentiation and regulates the expression of estrogen receptor-alpha and apoptotic proteins. ISRN Oncol. 2011, 2011, 896826. [Google Scholar] [CrossRef] [PubMed]
  247. Manson, J.E.; Chlebowski, R.T.; Stefanick, M.L.; Aragaki, A.K.; Rossouw, J.E.; Prentice, R.L.; Anderson, G.; Howard, B.V.; Thomson, C.A.; LaCroix, A.Z.; et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013, 310, 1353–1368. [Google Scholar] [CrossRef] [PubMed]
  248. Ju, Y.H.; Allred, C.D.; Allred, K.F.; Karko, K.L.; Doerge, D.R.; Helferich, W.G. 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, 2957–2962. [Google Scholar] [PubMed]
  249. Allred, C.D.; Ju, Y.H.; Allred, K.F.; Chang, J.; Helferich, W.G. Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. Carcinogenesis 2001, 22, 1667–1673. [Google Scholar] [CrossRef] [PubMed]
  250. Kang, X.; Jin, S.; Zhang, Q. Antitumor and antiangiogenic activity of soy phytoestrogen on 7,12-dimethylbenz[alpha]anthracene-induced mammary tumors following ovariectomy in Sprague-Dawley rats. J. Food Sci. 2009, 74, H237–H242. [Google Scholar] [CrossRef] [PubMed]
  251. Onoda, A.; Ueno, T.; Uchiyama, S.; Hayashi, S.; Kato, K.; Wake, N. Effects of S-equol and natural S-equol supplement (SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice. Food Chem. Toxicol. 2011, 49, 2279–2284. [Google Scholar] [CrossRef] [PubMed]
  252. Mishra, R.; Bhadauria, S.; Murthy, P.K.; Murthy, P.S. Glycine soya diet synergistically enhances the suppressive effect of tamoxifen and inhibits tamoxifen-promoted hepatocarcinogenesis in 7,12-dimethylbenz[alpha]anthracene-induced rat mammary tumor model. Food Chem. Toxicol. 2011, 49, 434–440. [Google Scholar] [CrossRef] [PubMed]
  253. Allred, C.D.; Allred, K.F.; Ju, Y.H.; Goeppinger, T.S.; Doerge, D.R.; Helferich, W.G. Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 2004, 25, 1649–1657. [Google Scholar] [CrossRef] [PubMed]
  254. Hooper, L.; Ryder, J.J.; Kurzer, M.S.; Lampe, J.W.; Messina, M.J.; Phipps, W.R.; Cassidy, A. 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, 423–440. [Google Scholar] [CrossRef] [PubMed]
  255. Guha, N.; Kwan, M.L.; Quesenberry, C.P., Jr.; Weltzien, E.K.; Castillo, A.L.; Caan, B.J. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: The Life After Cancer Epidemiology study. Breast Cancer Res. Treat. 2009, 118, 395–405. [Google Scholar] [CrossRef] [PubMed]
  256. Caan, B.J.; Natarajan, L.; Parker, B.; Gold, E.B.; Thomson, C.; Newman, V.; Rock, C.L.; Pu, M.; Al-Delaimy, W.; Pierce, J.P. Soy food consumption and breast cancer prognosis. Cancer Epidemiol. Biomark. Prev. 2011, 20, 854–858. [Google Scholar] [CrossRef] [PubMed]
  257. Shu, X.O.; Zheng, Y.; Cai, H.; Gu, K.; Chen, Z.; Zheng, W.; Lu, W. Soy food intake and breast cancer survival. JAMA 2009, 302, 2437–2443. [Google Scholar] [CrossRef] [PubMed]
  258. Kang, X.; Zhang, Q.; Wang, S.; Huang, X.; Jin, S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ 2010, 182, 1857–1862. [Google Scholar] [CrossRef] [PubMed]
  259. Zhang, Y.F.; Kang, H.B.; Li, B.L.; Zhang, R.M. Positive effects of soy isoflavone food on survival of breast cancer patients in China. Asian Pac. J. Cancer Prev. 2012, 13, 479–482. [Google Scholar] [CrossRef] [PubMed]
  260. Chi, F.; Wu, R.; Zeng, Y.C.; Xing, R.; Liu, Y.; Xu, Z.G. Post-diagnosis soy food intake and breast cancer survival: A meta-analysis of cohort studies. Asian Pac. J. Cancer Prev. 2013, 14, 2407–2412. [Google Scholar] [CrossRef] [PubMed]
  261. Nechuta, S.J.; Caan, B.J.; Chen, W.Y.; Lu, W.; Chen, Z.; Kwan, M.L.; Flatt, S.W.; Zheng, Y.; Zheng, W.; Pierce, J.P.; 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, 123–132. [Google Scholar] [CrossRef] [PubMed]
  262. Du, M.; Yang, X.; Hartman, J.A.; Cooke, P.S.; Doerge, D.R.; Ju, Y.H.; Helferich, W.G. Low-dose dietary genistein negates the therapeutic effect of tamoxifen in athymic nude mice. Carcinogenesis 2012, 33, 895–901. [Google Scholar] [CrossRef] [PubMed]
  263. Ju, Y.H.; Doerge, D.R.; Allred, K.F.; Allred, C.D.; Helferich, W.G. 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, 2474–2477. [Google Scholar] [PubMed]
  264. Ju, Y.H.; Doerge, D.R.; Woodling, K.A.; Hartman, J.A.; Kwak, J.; Helferich, W.G. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis 2008, 29, 2162–2168. [Google Scholar] [CrossRef] [PubMed]
  265. Rock, C.L.; Doyle, C.; Demark-Wahnefried, W.; Meyerhardt, J.; Courneya, K.S.; Schwartz, A.L.; Bandera, E.V.; Hamilton, K.K.; Grant, B.; McCullough, M.; et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J. Clin. 2012, 62, 242–274. [Google Scholar] [CrossRef] [PubMed]
  266. American Institute for Cancer Research. Soy is Safe for Breast Cancer Survivors. 2012. Available online: (accessed on 5 Feburary 2013).
  267. Eakin, A.; Kelsberg, G.; Safranek, S. Clinical inquiry: Does high dietary soy intake affect a woman’s risk of primary or recurrent breast cancer? J. Fam. Pract. 2015, 64, 660–662. [Google Scholar]
  268. World Cancer Research Fund International. Continuous Update Project Report: Diet, Nutrition, Physical Activity, and Breast Cancer Survivors. 2014. Available online: (accessed on 10 December 2014).
  269. Bray, F.; Ren, J.S.; Masuyer, E.; Ferlay, J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int. J. Cancer 2013, 132, 1133–1145. [Google Scholar] [CrossRef] [PubMed]
  270. Haas, G.P.; Delongchamps, N.; Brawley, O.W.; Wang, C.Y.; de la Roza, G. The worldwide epidemiology of prostate cancer: Perspectives from autopsy studies. Can. J. Urol. 2008, 15, 3866–3871. [Google Scholar] [PubMed]
  271. Yan, L.; Spitznagel, E.L. Soy consumption and prostate cancer risk in men: A revisit of a meta-analysis. Am. J. Clin. Nutr. 2009, 89, 1155–1163. [Google Scholar] [CrossRef] [PubMed]
  272. Hwang, Y.W.; Kim, S.Y.; Jee, S.H.; Kim, Y.N.; Nam, C.M. Soy food consumption and risk of prostate cancer: A meta-analysis of observational studies. Nutr. Cancer 2009, 61, 598–606. [Google Scholar] [CrossRef] [PubMed]
  273. He, J.; Wang, S.; Zhou, M.; Yu, W.; Zhang, Y.; He, X. Phytoestrogens and risk of prostate cancer: A meta-analysis of observational studies. World J. Surg. Oncol. 2015, 13, 231. [Google Scholar] [CrossRef] [PubMed]
  274. Zhang, Q.; Feng, H.; Qluwakemi, B.; Wang, J.; Yao, S.; Cheng, G.; Xu, H.; Qiu, H.; Zhu, L.; Yuan, M. Phytoestrogens and risk of prostate cancer: An updated meta-analysis of epidemiologic studies. Int. J. Food Sci. Nutr. 2016, 1–15. [Google Scholar] [CrossRef] [PubMed]
  275. Pendleton, J.M.; Tan, W.W.; Anai, S.; Chang, M.; Hou, W.; Shiverick, K.T.; Rosser, C.J. Phase II Trial of Isoflavone in prostate specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer 2008, 8, 132. [Google Scholar] [CrossRef] [PubMed]
  276. Messina, M.; Kucuk, O.; Lampe, J.W. An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J. AOAC Int. 2006, 89, 1121–1134. [Google Scholar] [PubMed]
  277. 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, 198–207. [Google Scholar] [CrossRef] [PubMed]
  278. Ide, H.; Tokiwa, S.; Sakamaki, K.; Nishio, K.; Isotani, S.; Muto, S.; Hama, T.; Masuda, H.; Horie, S. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 2010, 70, 1127–1133. [Google Scholar] [CrossRef] [PubMed]
  279. Bosland, M.C.; Kato, I.; Zeleniuch-Jacquotte, A.; Schmoll, J.; Enk Rueter, E.; Melamed, J.; Kong, M.X.; Macias, V.; Kajdacsy-Balla, A.; Lumey, L.H.; et al. Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: A randomized trial. JAMA 2013, 310, 170–178. [Google Scholar] [CrossRef] [PubMed]
  280. Fleshner, N.E.; Kapusta, L.; Donnelly, B.; Tanguay, S.; Chin, J.; Hersey, K.; Farley, A.; Jansz, K.; Siemens, D.R.; Trpkov, K.; et al. Progression from high-grade prostatic intraepithelial neoplasia to cancer: A randomized trial of combination vitamin-E, soy, and selenium. J. Clin. Oncol. 2011, 29, 2386–2390. [Google Scholar] [CrossRef] [PubMed]
  281. Kristal, A.R.; Darke, A.K.; Morris, J.S.; Tangen, C.M.; Goodman, P.J.; Thompson, I.M.; Meyskens, F.L., Jr.; Goodman, G.E.; Minasian, L.M.; Parnes, H.L.; et al. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J. Natl. Cancer Inst. 2014, 106, djt456. [Google Scholar] [CrossRef] [PubMed]
  282. Key, T.J.; Appleby, P.N.; Travis, R.C.; Albanes, D.; Alberg, A.J.; Barricarte, A.; Black, A.; Boeing, H.; Bueno-de-Mesquita, H.B.; Chan, J.M.; et al. Carotenoids, retinol, tocopherols, and prostate cancer risk: Pooled analysis of 15 studies. Am. J. Clin. Nutr. 2015, 102, 1142–1157. [Google Scholar] [CrossRef] [PubMed]
  283. Hamilton-Reeves, J.M.; Vazquez, G.; Duval, S.J.; Phipps, W.R.; Kurzer, M.S.; Messina, M.J. Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: Results of a meta-analysis. Fertil Steril. 2010, 94, 997–1007. [Google Scholar] [CrossRef] [PubMed]
  284. Xu, L.; Ding, Y.; Catalona, W.J.; Yang, X.J.; Anderson, W.F.; Jovanovic, B.; Wellman, K.; Killmer, J.; Huang, X.; Scheidt, K.A.; et al. MEK4 function, genistein treatment, and invasion of human prostate cancer cells. J. Natl. Cancer Inst. 2009, 101, 1141–1155. [Google Scholar] [CrossRef] [PubMed]
  285. Jin, Y.; Qu, S.; Tesikova, M.; Wang, L.; Kristian, A.; Maelandsmo, G.M.; Kong, H.; Zhang, T.; Jeronimo, C.; Teixeira, M.R.; et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc. Natl. Acad. Sci. USA 2013, 110, E2572–E2581. [Google Scholar] [CrossRef] [PubMed]
  286. Bektic, J.; Berger, A.P.; Pfeil, K.; Dobler, G.; Bartsch, G.; Klocker, H. Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor beta. Eur. Urol. 2004, 45, 245–251. [Google Scholar] [CrossRef] [PubMed]
  287. Zhang, W.; Makela, S.; Andersson, L.C.; Salmi, S.; Saji, S.; Webster, J.I.; Jensen, E.V.; Nilsson, S.; Warner, M.; Gustafsson, J.A. A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc. Natl. Acad. Sci. USA 2001, 98, 6330–6335. [Google Scholar]
  288. Imamov, O.; Morani, A.; Shim, G.J.; Omoto, Y.; Warner, M.; Gustafsson, J.A. Estrogen receptor-beta regulates epithelial cell differentiation in the mouse ventral prostate. Proc. Natl. Acad. Sci. USA 2004, 101, 9375–9380. [Google Scholar] [CrossRef] [PubMed]
  289. McPherson, S.J.; Hussain, S.; Balanathan, P.; Hedwards, S.L.; Niranjan, B.; Grant, M.; Chandrasiri, U.P.; Toivanen, R.; Wang, Y.; Taylor, R.A.; et al. Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. Proc. Natl. Acad. Sci. USA 2010, 107, 3123–3128. [Google Scholar] [CrossRef] [PubMed]
  290. Coresh, J.; Selvin, E.; Stevens, L.A.; Manzi, J.; Kusek, J.W.; Eggers, P.; Van Lente, F.; Levey, A.S. Prevalence of chronic kidney disease in the United States. JAMA 2007, 298, 2038–2047. [Google Scholar] [CrossRef] [PubMed]
  291. Anderson, J.W. Beneficial effects of soy protein consumption for renal function. Asia Pac. J. Clin. Nutr. 2008, 17, 324–328. [Google Scholar] [PubMed]
  292. Azadbakht, L.; Esmaillzadeh, A. Soy-protein consumption and kidney-related biomarkers among type 2 diabetics: A crossover, randomized clinical trial. J. Ren. Nutr. 2009, 19, 479–486. [Google Scholar] [CrossRef] [PubMed]
  293. Anderson, J.W.; Blake, J.E.; Turner, J.; Smith, B.M. Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Am. J. Clin. Nutr. 1998, 68, 1347S–1353S. [Google Scholar] [PubMed]
  294. Zhou, J.; Yuan, W.-J. Effects of soy protein containing isoflavones in patients with chronic kidney disease: A systematic review and meta-analysis. Clin. Nutr. 2015, 35, 117–124. [Google Scholar]
  295. Fourtounas, C. Phosphorus metabolism in chronic kidney disease. Hippokratia 2011, 15, 50–52. [Google Scholar] [PubMed]
  296. McGraw, N.J.; Krul, E.S.; Grunz-Borgmann, E.; Parrish, A.R. Soy-based renoprotection. World J. Nephrol. 2016, 5, 233–257. [Google Scholar] [CrossRef] [PubMed]
  297. Kronenberg, F. Hot flashes: Epidemiology and physiology. Ann. N. Y. Acad. Sci. 1990, 592, 52–86. [Google Scholar] [CrossRef] [PubMed]
  298. Berg, G.; Gottwall, T.; Hammar, M.; Lindgren, R.; Gottgall, T. Climacteric symptoms among women aged 60–62 in Linkoping, Sweden, in 1986. Maturitas 1988, 10, 193–199. [Google Scholar] [CrossRef]
  299. Rodstrom, K.; Bengtsson, C.; Lissner, L.; Milsom, I.; Sundh, V.; Bjorkelund, C. A longitudinal study of the treatment of hot flushes: The population study of women in Gothenburg during a quarter of a century. Menopause 2002, 9, 156–161. [Google Scholar] [CrossRef] [PubMed]
  300. Avis, N.E.; Crawford, S.L.; Greendale, G.; Bromberger, J.T.; Everson-Rose, S.A.; Gold, E.B.; Hess, R.; Joffe, H.; Kravitz, H.M.; Tepper, P.G.; et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern. Med. 2015, 175, 531–539. [Google Scholar] [CrossRef] [PubMed]
  301. Adlercreutz, H.; Hamalainen, E.; Gorbach, S.; Goldin, B. Dietary phyto-oestrogens and the menopause in Japan. Lancet 1992, 339, 1233. [Google Scholar] [CrossRef]
  302. Murkies, A.L.; Lombard, C.; Strauss, B.J.; Wilcox, G.; Burger, H.G.; Morton, M.S. Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat. Maturitas 1995, 21, 189–195. [Google Scholar] [CrossRef]
  303. Lethaby, A.; Brown, J.; Marjoribanks, J.; Kronenberg, F.; Roberts, H.; Eden, J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst. Rev. 2007, 17, CD001395. [Google Scholar]
  304. Lethaby, A.; Marjoribanks, J.; Kronenberg, F.; Roberts, H.; Eden, J.; Brown, J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst. Rev. 2013, 12, CD001395. [Google Scholar]
  305. Taku, K.; Melby, M.K.; Kronenberg, F.; Kurzer, M.S.; 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, 776–790. [Google Scholar] [CrossRef] [PubMed]
  306. Williamson-Hughes, P.S.; Flickinger, B.D.; Messina, M.J.; Empie, M.W. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: A critical review of published studies. Menopause 2006, 13, 831–839. [Google Scholar] [CrossRef] [PubMed]
  307. LeBlanc, E.S.; Janowsky, J.; Chan, B.K.; Nelson, H.D. Hormone replacement therapy and cognition: Systematic review and meta-analysis. JAMA 2001, 285, 1489–1499. [Google Scholar] [CrossRef] [PubMed]
  308. O’Brien, J.; Jackson, J.W.; Grodstein, F.; Blacker, D.; Weuve, J. Postmenopausal hormone therapy is not associated with risk of all-cause dementia and Alzheimer’s disease. Epidemiol. Rev. 2014, 36, 83–103. [Google Scholar] [CrossRef] [PubMed]
  309. Marjoribanks, J.; Farquhar, C.; Roberts, H.; Lethaby, A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst. Rev. 2012, 7, CD004143. [Google Scholar]
  310. Fox, M.; Berzuini, C.; Knapp, L.A. Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer’s risk in a cohort of British women. Psychoneuroendocrinology 2013, 38, 2973–2982. [Google Scholar] [CrossRef] [PubMed]
  311. White, L.R.; Petrovitch, H.; Ross, G.W.; Masaki, K.; Hardman, J.; Nelson, J.; Davis, D.; Markesbery, W. Brain aging and midlife tofu consumption. J. Am. Coll. Nutr. 2000, 19, 242–255. [Google Scholar] [CrossRef] [PubMed]
  312. Hogervorst, E.; Sadjimim, T.; Yesufu, A.; Kreager, P.; Rahardjo, T.B. High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement. Geriatr. Cogn. Disord. 2008, 26, 50–57. [Google Scholar] [CrossRef] [PubMed]
  313. Hogervorst, E.; Mursjid, F.; Priandini, D.; Setyawan, H.; Ismael, R.I.; Bandelow, S.; Rahardjo, T.B. Borobudur revisited: Soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res. 2011, 1379, 206–212. [Google Scholar] [CrossRef] [PubMed]
  314. Woo, J.; Lynn, H.; Lau, W.Y.; Leung, J.; Lau, E.; Wong, S.Y.; Kwok, T. Nutrient intake and psychological health in an elderly Chinese population. Int. J. Geriatr. Psychiatr. 2006, 21, 1036–1043. [Google Scholar] [CrossRef] [PubMed]
  315. Xu, X.; Xiao, S.; Rahardjo, T.B.; Hogervorst, E. Tofu intake is associated with poor cognitive performance among community-dwelling elderly in China. J. Alzheimers Dis. 2015, 43, 669–675. [Google Scholar] [PubMed]
  316. Huang, M.H.; Luetters, C.; Buckwalter, G.J.; Seeman, T.E.; Gold, E.B.; Sternfeld, B.; Greendale, G.A. Dietary genistein intake and cognitive performance in a multiethnic cohort of midlife women. Menopause 2006, 13, 621–630. [Google Scholar] [CrossRef] [PubMed]
  317. Ozawa, M.; Ninomiya, T.; Ohara, T.; Doi, Y.; Uchida, K.; Shirota, T.; Yonemoto, K.; Kitazono, T.; Kiyohara, Y. Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study. Am. J. Clin. Nutr. 2013, 97, 1076–1082. [Google Scholar] [CrossRef] [PubMed]
  318. Cheng, P.F.; Chen, J.J.; Zhou, X.Y.; Ren, Y.F.; Huang, W.; Zhou, J.J.; Xie, P. Do soy isoflavones improve cognitive function in postmenopausal women? A meta-analysis. Menopause 2015, 22, 198–206. [Google Scholar] [CrossRef] [PubMed]
  319. St John, J.A.; Henderson, V.W.; Hodis, H.N.; Kono, N.; McCleary, C.A.; Franke, A.A.; Mack, W.J. Associations between urine excretion of isoflavonoids and cognition in postmenopausal women in the Women’s Isoflavone Soy Health clinical trial. J. Am. Geriatr. Soc. 2014, 62, 629–635. [Google Scholar] [CrossRef] [PubMed]
  320. Gleason, C.E.; Fischer, B.L.; Dowling, N.M.; Setchell, K.D.; Atwood, C.S.; Carlsson, C.M.; Asthana, S. Cognitive effects of soy isoflavones in patients with Alzheimer’s disease. J. Alzheimer’s Dis. 2015, 47, 1009–1019. [Google Scholar] [CrossRef] [PubMed]
  321. Soni, M.; Rahardjo, T.B.; Soekardi, R.; Sulistyowati, Y.; Lestariningsih; Yesufu-Udechuku, A.; Irsan, A.; Hogervorst, E. Phytoestrogens and cognitive function: A review. Maturitas 2014, 77, 209–220. [Google Scholar] [CrossRef] [PubMed]
  322. Spijker, J.; Graaf, R.; Bijl, R.V.; Beekman, A.T.; Ormel, J.; Nolen, W.A. Functional disability and depression in the general population. Results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Acta Psychiatr. Scand. 2004, 110, 208–214. [Google Scholar] [CrossRef] [PubMed]
  323. Ustun, T.B.; Ayuso-Mateos, J.L.; Chatterji, S.; Mathers, C.; Murray, C.J. Global burden of depressive disorders in the year 2000. Br. J. Psychiatry 2004, 184, 386–392. [Google Scholar] [CrossRef] [PubMed]
  324. Van de Velde, S.; Bracke, P.; Levecque, K. Gender differences in depression in 23 European countries. Cross-national variation in the gender gap in depression. Soc. Sci. Med. 2010, 71, 305–313. [Google Scholar] [CrossRef] [PubMed]
  325. Bromberger, J.T.; Kravitz, H.M.; Chang, Y.F.; Cyranowski, J.M.; Brown, C.; Matthews, K.A. Major depression during and after the menopausal transition: Study of Women’s Health Across the Nation (SWAN). Psychol. Med. 2011, 41, 1879–1888. [Google Scholar] [CrossRef] [PubMed]
  326. Freeman, E.W.; Sammel, M.D.; Lin, H.; Nelson, D.B. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch. Gen. Psychiatr. 2006, 63, 375–382. [Google Scholar] [CrossRef] [PubMed]
  327. Cohen, L.S.; Soares, C.N.; Vitonis, A.F.; Otto, M.W.; Harlow, B.L. Risk for new onset of depression during the menopausal transition: The Harvard study of moods and cycles. Arch. Gen. Psychiatr. 2006, 63, 385–390. [Google Scholar] [CrossRef] [PubMed]
  328. Sarris, J.; Logan, A.C.; Akbaraly, T.N.; Amminger, G.P.; Balanza-Martinez, V.; Freeman, M.P.; Hibbeln, J.; Matsuoka, Y.; Mischoulon, D.; Mizoue, T.; et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatr. 2015, 2, 271–274. [Google Scholar] [CrossRef]
  329. Messina, M.; Gleason, C. Evaluation of the potential antidepressant effects of soybean isoflavones. Menopause 2016, 23, 1348–1360. [Google Scholar] [CrossRef] [PubMed]
  330. Atteritano, M.; Mazzaferro, S.; Bitto, A.; Cannata, M.L.; D’Anna, R.; Squadrito, F.; Macri, I.; Frisina, A.; Frisina, N.; Bagnato, G. Genistein effects on quality of life and depression symptoms in osteopenic postmenopausal women: A 2-year randomized, double-blind, controlled study. Osteoporos. Int. 2014, 25, 1123–1129. [Google Scholar] [CrossRef] [PubMed]
  331. Hirose, A.; Terauchi, M.; Akiyoshi, M.; Owa, Y.; Kato, K.; Kubota, T. Low-dose isoflavone aglycone alleviates psychological symptoms of menopause in Japanese women: A randomized, double-blind, placebo-controlled study. Arch. Gynecol. Obstet. 2016, 293, 609–615. [Google Scholar] [CrossRef] [PubMed]
  332. Estrella, R.E.; Landa, A.I.; Lafuente, J.V.; Gargiulo, P.A. Effects of antidepressants and soybean association in depressive menopausal women. Acta Pol. Pharm. 2014, 71, 323–327. [Google Scholar] [PubMed]
  333. Thornton, M.J.; Taylor, A.H.; Mulligan, K.; Al-Azzawi, F.; Lyon, C.C.; O’Driscoll, J.; Messenger, A.G. The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit. J. Investig. Dermatol. Symp. Proc. 2003, 8, 100–103. [Google Scholar] [CrossRef] [PubMed]
  334. Thornton, M.J.; Taylor, A.H.; Mulligan, K.; Al-Azzawi, F.; Lyon, C.C.; O’Driscoll, J.; Messenger, A.G. Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin. Exp. Dermatol. 2003, 12, 181–190. [Google Scholar] [CrossRef] [PubMed]
  335. Hall, G.; Phillips, T.J. Estrogen and skin: The effects of estrogen, menopause, and hormone replacement therapy on the skin. J. Am. Acad. Dermatol. 2005, 53, 555–568. [Google Scholar] [CrossRef] [PubMed]
  336. Hall, G.K.; Phillips, T.J. Skin and hormone therapy. Clin. Obstet. Gynecol. 2004, 47, 437–449. [Google Scholar] [CrossRef] [PubMed]
  337. Schmidt, J.B.; Binder, M.; Macheiner, W.; Kainz, C.; Gitsch, G.; Bieglmayer, C. Treatment of skin ageing symptoms in perimenopausal females with estrogen compounds. A pilot study. Maturitas 1994, 20, 25–30. [Google Scholar] [CrossRef]
  338. Sator, P.G.; Schmidt, J.B.; Rabe, T.; Zouboulis, C.C. Skin aging and sex hormones in women—Clinical perspectives for intervention by hormone replacement therapy. Exp. Dermatol. 2004, 13, 36–40. [Google Scholar] [CrossRef] [PubMed]
  339. Pierard, G.E.; Letawe, C.; Dowlati, A.; Pierard-Franchimont, C. Effect of hormone replacement therapy for menopause on the mechanical properties of skin. J. Am. Geriatr. Soc. 1995, 43, 662–665. [Google Scholar] [CrossRef] [PubMed]
  340. Pierard-Franchimont, C.; Letawe, C.; Goffin, V.; Pierard, G.E. Skin water-holding capacity and transdermal estrogen therapy for menopause: A pilot study. Maturitas 1995, 22, 151–154. [Google Scholar] [CrossRef]
  341. Snell, R.S.; Turner, R. Skin pigmentation in relation to the menstrual cycle. J. Investig. Dermatol. 1966, 47, 147–155. [Google Scholar] [CrossRef] [PubMed]
  342. Harvell, J.; Hussona-Saeed, I.; Maibach, H.I. Changes in transepidermal water loss and cutaneous blood flow during the menstrual cycle. Contact Dermat. 1992, 27, 294–301. [Google Scholar] [CrossRef]
  343. Thornton, M.J. Oestrogen functions in skin and skin appendages. Expert Opin. Ther. Targets 2005, 9, 617–629. [Google Scholar] [CrossRef] [PubMed]
  344. Draelos, Z.D.; Blair, R.; Tabor, A. Oral soy supplementation and dermatology. Cosmet. Dermatol. 2007, 20, 202–204. [Google Scholar]
  345. Izumi, T.; Makoto, S.; Obata, A.; Masayuki, A.; Yamaguchi, H.; Matsuyama, A. Oral intake of soy isoflavone aglycone improves the aged skin of adult women. J. Nutr. Sci. Vitaminol. 2007, 53, 57–62. [Google Scholar] [CrossRef] [PubMed]
  346. Jenkins, G.; Wainwright, L.J.; Holland, R.; Barrett, K.E.; Casey, J. Wrinkle reduction in post-menopausal women consuming a novel oral supplement: A double-blind placebo-controlled randomised study. Int. J. Cosmet. Sci. 2013, 36, 22–31. [Google Scholar] [CrossRef] [PubMed]
  347. Mikkila, V.; Rasanen, L.; Raitakari, O.T.; Pietinen, P.; Viikari, J. Consistent dietary patterns identified from childhood to adulthood: The cardiovascular risk in Young Finns Study. Br. J. Nutr. 2005, 93, 923–931. [Google Scholar] [CrossRef] [PubMed]
  348. Mennella, J.A.; Griffin, C.E.; Beauchamp, G.K. Flavor programming during infancy. Pediatrics 2004, 113, 840–845. [Google Scholar] [CrossRef] [PubMed]
  349. Mennella, J.A.; Beauchamp, G.K. Flavor experiences during formula feeding are related to preferences during childhood. Early Hum. Dev. 2002, 68, 71–82. [Google Scholar] [CrossRef]
  350. Birch, L.L. Development of food acceptance patterns in the first years of life. Proc. Nutr. Soc. 1998, 57, 617–624. [Google Scholar] [CrossRef] [PubMed]
  351. Anonymous. Guidelines for school health programs to promote lifelong healthy eating. Centers for Disease Control and Prevention. MMWR Recomm. Rep. 1996, 45, 1–41. [Google Scholar]
  352. Adair, L.S.; Prentice, A.M. A critical evaluation of the fetal origins hypothesis and its implications for developing countries. J. Nutr. 2004, 134, 191–193. [Google Scholar] [PubMed]
  353. McCormack, V.A.; dos Santos Silva, I.; De Stavola, B.L.; Mohsen, R.; Leon, D.A.; Lithell, H.O. Fetal growth and subsequent risk of breast cancer: Results from long term follow up of Swedish cohort. BMJ 2003, 326, 248. [Google Scholar] [CrossRef] [PubMed]
  354. Robinson, R. The fetal origins of adult disease. BMJ 2001, 322, 375–376. [Google Scholar] [CrossRef] [PubMed]
  355. Van der Pols, J.C.; Gunnell, D.; Williams, G.M.; Holly, J.M.; Bain, C.; Martin, R.M. Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort. Heart 2009, 95, 1600–1606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  356. Laurin, D.; Jacques, H.; Moorjani, S.; Steinke, F.H.; Gagne, C.; Brun, D.; Lupien, P.J. Effects of a soy-protein beverage on plasma lipoproteins in children with familial hypercholesterolemia. Am. J. Clin. Nutr. 1991, 54, 98–103. [Google Scholar] [PubMed]
  357. Widhalm, K.; Brazda, G.; Schneider, B.; Kohl, S. Effect of soy protein diet versus standard low fat, low cholesterol diet on lipid and lipoprotein levels in children with familial or polygenic hypercholesterolemia. J. Pediatr. 1993, 123, 30–34. [Google Scholar] [CrossRef]
  358. Gaddi, A.; Descovich, G.C.; Noseda, G.; Fragiacomo, C.; Nicolini, A.; Montanari, G.; Vanetti, G.; Sirtori, M.; Gatti, E.; Sirtori, C.R. Hypercholesterolaemia treated by soybean protein diet. Arch. Dis. Child. 1987, 62, 274–278. [Google Scholar] [CrossRef] [PubMed]
  359. Blumenschein, S.; Torres, E.; Kushmaul, E.; Crawford, J.; Fixler, D. Effect of oat bran/soy protein in hypercholesterolemic children. Ann. N. Y. Acad. Sci. 1991, 623, 413–415. [Google Scholar] [CrossRef] [PubMed]
  360. Weghuber, D.; Widhalm, K. Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet. Br. J. Nutr. 2008, 99, 281–286. [Google Scholar] [CrossRef] [PubMed]
  361. Dwyer, T.; Hynes, K.L.; Fryer, J.L.; Blizzard, C.L.; Dalais, F.S. The lack of effect of isoflavones on high-density lipoprotein cholesterol concentrations in adolescent boys: A 6-week randomised trial. Public Health Nutr. 2008, 11, 955–962. [Google Scholar] [CrossRef] [PubMed]
  362. Zung, A.; Shachar, S.; Zadik, Z.; Kerem, Z. Soy-derived isoflavones treatment in children with hypercholesterolemia: A pilot study. J. Pediatr. Endocrinol. Metab. 2010, 23, 133–141. [Google Scholar] [CrossRef] [PubMed]
  363. Maskarinec, G.; Morimoto, Y.; Novotny, R.; Nordt, F.J.; Stanczyk, F.Z.; Franke, A.A. Urinary sex steroid excretion levels during a soy intervention among young girls: A pilot study. Nutr. Cancer 2005, 52, 22–28. [Google Scholar] [CrossRef] [PubMed]
  364. Euling, S.Y.; Herman-Giddens, M.E.; Lee, P.A.; Selevan, S.G.; Juul, A.; Sorensen, T.I.; Dunkel, L.; Himes, J.H.; Teilmann, G.; Swan, S.H. Examination of US puberty-timing data from 1940 to 1994 for secular trends: Panel findings. Pediatrics 2008, 121, S172–S191. [Google Scholar] [CrossRef] [PubMed]
  365. Biro, F.M.; Galvez, M.P.; Greenspan, L.C.; Succop, P.A.; Vangeepuram, N.; Pinney, S.M.; Teitelbaum, S.; Windham, G.C.; Kushi, L.H.; Wolff, M.S. Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics 2010, 126, e583–e590. [Google Scholar] [CrossRef] [PubMed]
  366. Gunther, A.L.; Karaolis-Danckert, N.; Kroke, A.; Remer, T.; Buyken, A.E. Dietary protein intake throughout childhood is associated with the timing of puberty. J. Nutr. 2010, 140, 565–571. [Google Scholar] [CrossRef] [PubMed]
  367. Rogers, I.S.; Northstone, K.; Dunger, D.B.; Cooper, A.R.; Ness, A.R.; Emmett, P.M. Diet throughout childhood and age at menarche in a contemporary cohort of British girls. Public Health Nutr. 2010, 13, 2052–2063. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  368. Kim, J.; Kim, S.; Huh, K.; Kim, Y.; Joung, H.; Park, M. High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls. Clin. Endocrinol. 2011, 75, 831–835. [Google Scholar] [CrossRef] [PubMed]
  369. Yum, T.; Lee, S.; Kim, Y. Association between precocious puberty and some endocrine disruptors in human plasma. J. Environ. Sci. Health A Tox Hazard Subst. Environ. Eng. 2013, 48, 912–917. [Google Scholar] [CrossRef] [PubMed]
  370. Segovia-Siapco, G.; Pribis, P.; Messina, M.; Oda, K.; Sabate, J. Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption. Nutr. J. 2014, 13, 54. [Google Scholar] [CrossRef] [PubMed]
  371. Bennetts, H.W.; Underwood, E.J.; Shier, F.L. A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust. J. Agric. Res. 1946, 22, 131–138. [Google Scholar] [CrossRef]
  372. Bradbury, R.B.; White, D.R. Estrogen and Related Substances in Plants. In Vitamins and Hormones; Harris, R.S., Marrian, G.F., Thimann, K.V., Eds.; Academic Press: New York, NY, USA, 1954; pp. 207–230. [Google Scholar]
  373. Lundh, T.J.-O.; Petterson, H.L.; Martinsson, K.A. Comparative levels of free and conjugated plant estrogens in blood plasma of sheep and cattle fed estrogenic silage. J. Agric. Food Chem. 1990, 38, 1530–1534. [Google Scholar] [CrossRef]
  374. Setchell, K.D.; Gosselin, S.J.; Welsh, M.B.; Johnston, J.O.; Balistreri, W.F.; Kramer, L.W.; Dresser, B.L.; Tarr, M.J. Dietary estrogens—A probable cause of infertility and liver disease in captive cheetahs. Gastroenterology 1987, 93, 225–233. [Google Scholar] [CrossRef]
  375. Urpi-Sarda, M.; Morand, C.; Besson, C.; Kraft, G.; Viala, D.; Scalbert, A.; Besle, J.M.; Manach, C. Tissue distribution of isoflavones in ewes after consumption of red clover silage. Arch. Biochem. Biophys. 2008, 476, 205–210. [Google Scholar] [CrossRef] [PubMed]
  376. Rowland, I.R.; Wiseman, H.; Sanders, T.A.; Adlercreutz, H.; Bowey, E.A. Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equol production by the gut microflora. Nutr. Cancer 2000, 36, 27–32. [Google Scholar] [CrossRef] [PubMed]
  377. Redmon, J.M.; Shrestha, B.; Cerundolo, R.; Court, M.H. Soy isoflavone metabolism in cats compared with other species: Urinary metabolite concentrations and glucuronidation by liver microsomes. Xenobiotica 2016, 46, 406–415. [Google Scholar] [CrossRef] [PubMed]
  378. Kurzer, M.S. Hormonal effects of soy in premenopausal women and men. J. Nutr. 2002, 132, 570S–573S. [Google Scholar] [PubMed]
  379. Vanegas, J.C.; Afeiche, M.C.; Gaskins, A.J.; Minguez-Alarcon, L.; Williams, P.L.; Wright, D.L.; Toth, T.L.; Hauser, R.; Chavarro, J.E. Soy food intake and treatment outcomes of women undergoing assisted reproductive technology. Fertil. Steril. 2015, 103, 749–755. [Google Scholar] [CrossRef] [PubMed]
  380. Chavarro, J.E.; Minguez-Alarcon, L.; Chiu, Y.H.; Gaskins, A.J.; Souter, I.; Williams, P.L.; Calafat, A.M.; Hauser, R. Soy intake modifies the relation between urinary bisphenol A concentrations and pegnancy outcomes among women undergoing assisted reproduction. J. Clin. Endocrinol. Metab. 2016, 101, 1082–1090. [Google Scholar] [CrossRef] [PubMed]
  381. Muhlhauser, A.; Susiarjo, M.; Rubio, C.; Griswold, J.; Gorence, G.; Hassold, T.; Hunt, P.A. Bisphenol A effects on the growing mouse oocyte are influenced by diet. Biol. Reprod. 2009, 80, 1066–1071. [Google Scholar] [CrossRef] [PubMed]
  382. Dolinoy, D.C.; Huang, D.; Jirtle, R.L. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl. Acad. Sci. USA 2007, 104, 13056–13061. [Google Scholar] [CrossRef] [PubMed]
  383. Chavarro, J.E.; Toth, T.L.; Sadio, S.M.; Hauser, R. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum. Reprod. 2008, 23, 2584–2590. [Google Scholar] [CrossRef] [PubMed]
  384. Minguez-Alarcon, L.; Afeiche, M.C.; Chiu, Y.H.; Vanegas, J.C.; Williams, P.L.; Tanrikut, C.; Toth, T.L.; Hauser, R.; Chavarro, J.E. Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center. Andrology 2015, 3, 702–708. [Google Scholar] [CrossRef] [PubMed]
  385. Mitchell, J.H.; Cawood, E.; Kinniburgh, D.; Provan, A.; Collins, A.R.; Irvine, D.S. Effect of a phytoestrogen food supplement on reproductive health in normal males. Clin. Sci. 2001, 100, 613–618. [Google Scholar] [CrossRef] [PubMed]
  386. Messina, M.; Watanabe, S.; Setchell, K.D. Report on the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment. J. Nutr. 2009, 139, 796S–802S. [Google Scholar] [CrossRef] [PubMed]
  387. Beaton, L.K.; McVeigh, B.L.; Dillingham, B.L.; Lampe, J.W.; Duncan, A.M. Soy protein isolates of varying isoflavone content do not adversely affect semen quality in healthy young men. Fertil. Steril. 2010, 94, 1717–1722. [Google Scholar] [CrossRef] [PubMed]
  388. Casini, M.L.; Gerli, S.; Unfer, V. An infertile couple suffering from oligospermia by partial sperm maturation arrest: can phytoestrogens play a therapeutic role? A case report study. Gynecol. Endocrinol. 2006, 22, 399–401. [Google Scholar] [CrossRef] [PubMed]
  389. Martinez, J.; Lewi, J.E. An unusual case of gynecomastia associated with soy product consumption. Endocr. Pract. 2008, 14, 415–418. [Google Scholar] [CrossRef] [PubMed]
  390. Siepmann, T.; Roofeh, J.; Kiefer, F.W.; Edelson, D.G. Hypogonadism and erectile dysfunction associated with soy product consumption. Nutrition 2011, 27, 859–862. [Google Scholar] [CrossRef] [PubMed]
  391. Messina, M. Soybean isoflavone exposure does not have feminizing effects on men: A critical examination of the clinical evidence. Fertil. Steril. 2010, 93, 2095–2104. [Google Scholar] [CrossRef] [PubMed]
  392. Deibert, P.; Solleder, F.; Konig, D.; Vitolins, M.Z.; Dickhuth, H.H.; Gollhofer, A.; Berg, A. Soy protein based supplementation supports metabolic effects of resistance training in previously untrained middle aged males. Aging Male 2011, 14, 273–279. [Google Scholar] [CrossRef] [PubMed]
  393. Miyanaga, N.; Akaza, H.; Hinotsu, S.; Fujioka, T.; Naito, S.; Namiki, M.; Takahashi, S.; Hirao, Y.; Horie, S.; Tsukamoto, T.; 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, 125–130. [Google Scholar] [CrossRef] [PubMed]
  394. Reidy, P.T.; Borack, M.S.; Markofski, M.M.; Dickinson, J.M.; Deer, R.R.; Husaini, S.H.; Walker, D.K.; Igbinigie, S.; Robertson, S.M.; Cope, M.B.; et al. Protein supplementation has minimal effects on muscle adaptations during resistance exercise training in young men: A double-blind randomized clinical trial. J. Nutr. 2016, 146, 1660–1669. [Google Scholar] [CrossRef] [PubMed]
  395. Divi, R.L.; Doerge, D.R. Inhibition of thyroid peroxidase by dietary flavonoids. Chem. Res. Toxicol. 1996, 9, 16–23. [Google Scholar] [CrossRef] [PubMed]
  396. Divi, R.L.; Chang, H.C.; Doerge, D.R. Anti-thyroid isoflavones from soybean: Isolation, characterization, and mechanisms of action. Biochem. Pharmacol. 1997, 54, 1087–1096. [Google Scholar] [CrossRef]
  397. Chang, H.C.; Doerge, D.R. Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicol. Appl. Pharmacol. 2000, 168, 244–252. [Google Scholar] [CrossRef] [PubMed]
  398. Chang, H.C.; Churchwell, M.I.; Delclos, K.B.; Newbold, R.R.; Doerge, D.R. Mass spectrometric determination of genistein tissue distribution in diet-exposed Sprague-Dawley rats. J. Nutr. 2000, 130, 1963–1970. [Google Scholar] [PubMed]
  399. Van Wyk, J.J.; Arnold, M.B.; Wynn, J.; Pepper, F. The effects of a soybean product on thyroid function in humans. Pediatrics 1959, 24, 752–760. [Google Scholar] [PubMed]
  400. Shepard, T.H.; Gordon, E.P.; Kirschvink, J.F.; McLean, C.M. Soybean goiter. N. Engl. J. Med. 1960, 262, 1099–1103. [Google Scholar] [CrossRef]
  401. Pinchera, A.; MacGillivray, H.; Crawford, J.D.; Freeman, A.G. Thyroid refractiveness in an athyreotic cretin fed soybean formula. N. Engl. J. Med. 1965, 273, 83–87. [Google Scholar] [CrossRef] [PubMed]
  402. 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, 249–258. [Google Scholar] [CrossRef] [PubMed]
  403. Ryan-Borchers, T.; Boon, C.; Park, J.S.; McGuire, M.; Fournier, L.; Beerman, K. Effects of dietary and supplemental forms of isoflavones on thyroid function in healthy postmenopausal women. Top. Clin. Nutr. 2008, 23, 13–22. [Google Scholar] [CrossRef]
  404. Romualdi, D.; Costantini, B.; Campagna, G.; Lanzone, A.; Guido, M. Is there a role for soy isoflavones in the therapeutic approach to polycystic ovary syndrome? Results from a pilot study. Fertil Steril. 2008, 90, 1826–1833. [Google Scholar] [CrossRef] [PubMed]
  405. Nahas, E.A.; Nahas-Neto, J.; Orsatti, F.L.; Carvalho, E.P.; Oliveira, M.L.; Dias, R. Efficacy and safety of a soy isoflavone extract in postmenopausal women: A randomized, double-blind, and placebo-controlled study. Maturitas 2007, 58, 249–258. [Google Scholar] [CrossRef] [PubMed]
  406. Khaodhiar, L.; Ricciotti, H.A.; Li, L.; Pan, W.; Schickel, M.; Zhou, J.; Blackburn, G.L. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause 2008, 15, 125–132. [Google Scholar] [CrossRef] [PubMed]
  407. Zhou, Y.; Alekel, D.L.; Dixon, P.M.; Messina, M.; Reddy, M.B. The effect of soy food intake on mineral status in premenopausal women. J. Womens Health 2011, 20, 771–780. [Google Scholar] [CrossRef] [PubMed]
  408. Alekel, D.L.; Genschel, U.; Koehler, K.J.; Hofmann, H.; Van Loan, M.D.; Beer, B.S.; Hanson, L.N.; Peterson, C.T.; Kurzer, M.S. Soy Isoflavones for Reducing Bone Loss study: Effects of a 3-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women. Menopause 2015, 22, 185–197. [Google Scholar] [CrossRef] [PubMed]
  409. Bitto, A.; Polito, F.; Atteritano, M.; Altavilla, D.; Mazzaferro, S.; Marini, H.; Adamo, E.B.; D’Anna, R.; Granese, R.; Corrado, F.; et al. Genistein aglycone does not affect thyroid function: Results from a three-year, randomized, double-blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 2010, 95, 3067–3072. [Google Scholar] [CrossRef] [PubMed]
  410. Doerge, D.R.; Sheehan, D.M. Goitrogenic and estrogenic activity of soy isoflavones. Environ. Health Perspect. 2002, 110, 349–353. [Google Scholar] [CrossRef] [PubMed]
  411. Fitzpatrick, M. Soy formulas and the effects of isoflavones on the thyroid. N. Z. Med. J. 2000, 113, 24–26. [Google Scholar] [PubMed]
  412. Bell, D.S.; Ovalle, F. Use of soy protein supplement and resultant need for increased dose of levothyroxine. Endocr. Pract. 2001, 7, 193–194. [Google Scholar] [CrossRef] [PubMed]
  413. Conrad, S.C.; Chiu, H.; Silverman, B.L. Soy formula complicates management of congenital hypothyroidism. Arch. Dis. Child. 2004, 89, 37–40. [Google Scholar] [CrossRef] [PubMed]
  414. Liel, Y.; Harman-Boehm, I.; Shany, S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. J. Clin. Endocrinol. Metab. 1996, 81, 857–859. [Google Scholar] [PubMed]
  415. Chiu, A.C.; Sherman, S.I. Effects of pharmacological fiber supplements on levothyroxine absorption. Thyroid 1998, 8, 667–671. [Google Scholar] [CrossRef] [PubMed]
  416. Shakir, K.M.; Chute, J.P.; Aprill, B.S.; Lazarus, A.A. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med. J. 1997, 90, 637–639. [Google Scholar] [CrossRef] [PubMed]
  417. Liel, Y.; Sperber, A.D.; Shany, S. Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. Am. J. Med. 1994, 97, 363–365. [Google Scholar] [CrossRef]
  418. Sperber, A.D.; Liel, Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch. Intern. Med. 1992, 152, 183–184. [Google Scholar] [CrossRef] [PubMed]
  419. Sherman, S.I.; Tielens, E.T.; Ladenson, P.W. Sucralfate causes malabsorption of l-thyroxine. Am. J. Med. 1994, 96, 531–535. [Google Scholar] [CrossRef]
  420. Siraj, E.S.; Gupta, M.K.; Reddy, S.S. Raloxifene causing malabsorption of levothyroxine. Arch. Intern. Med. 2003, 163, 1367–1370. [Google Scholar] [CrossRef] [PubMed]
  421. Rosenberg, R. Malabsorption of thyroid hormone with cholestyramine administration. Conn. Med. 1994, 58, 109. [Google Scholar] [PubMed]
  422. Harmon, S.M.; Seifert, C.F. Levothyroxine-cholestyramine interaction reemphasized. Ann. Intern. Med. 1991, 115, 658–659. [Google Scholar] [CrossRef] [PubMed]
  423. Zeitler, P.; Solberg, P. Food and levothyroxine administration in infants and children. J. Pediatr. 2010, 157, 13–14. [Google Scholar] [CrossRef] [PubMed]
  424. Doerge, D.; Chang, H. Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2002, 777, 269–279. [Google Scholar] [CrossRef]
  425. Sosvorova, L.; Miksatkova, P.; Bicikova, M.; Kanova, N.; Lapcik, O. The presence of monoiodinated derivates of daidzein and genistein in human urine and its effect on thyroid gland function. Food Chem. Toxicol. 2012, 50, 2774–2779. [Google Scholar] [CrossRef] [PubMed]
  426. Imaizumi, M.; Sera, N.; Ueki, I.; Horie, I.; Ando, T.; Usa, T.; Ichimaru, S.; Nakashima, E.; Hida, A.; Soda, M.; et al. Risk for progression to overt hypothyroidism in an elderly Japanese population with subclinical hypothyroidism. Thyroid 2011, 21, 1177–1182. [Google Scholar] [CrossRef] [PubMed]
  427. Kasagi, K.; Takahashi, N.; Inoue, G.; Honda, T.; Kawachi, Y.; Izumi, Y. Thyroid function in Japanese adults as assessed by a general health checkup system in relation with thyroid-related antibodies and other clinical parameters. Thyroid 2009, 19, 937–944. [Google Scholar] [CrossRef] [PubMed]
  428. Pisani, P.; Bray, F.; Parkin, D.M. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int. J. Cancer 2002, 97, 72–81. [Google Scholar] [CrossRef] [PubMed]
  429. Parkin, D.M.; Pisani, P.; Ferlay, J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int. J. Cancer 1999, 80, 827–841. [Google Scholar] [CrossRef]
  430. Weiderpass, E.; Adami, H.O.; Baron, J.A.; Magnusson, C.; Bergstrom, R.; Lindgren, A.; Correia, N.; Persson, I. Risk of endometrial cancer following estrogen replacement with and without progestins. J. Natl. Cancer Inst. 1999, 91, 1131–1137. [Google Scholar] [CrossRef] [PubMed]
  431. North American Menopause Society. Role of progestogen in hormone therapy for postmenopausal women: Position statement of The North American Menopause Society. Menopause 2003, 10, 113–132. [Google Scholar]
  432. Grady, D.; Gebretsadik, T.; Kerlikowske, K.; Ernster, V.; Petitti, D. Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstet. Gynecol. 1995, 85, 304–313. [Google Scholar] [CrossRef]
  433. Liu, J.; Yuan, F.; Gao, J.; Shan, B.; Ren, Y.; Wang, H.; Gao, Y. Oral isoflavone supplementation on endometrial thickness: A meta-analysis of randomized placebo-controlled trials. Oncotarget 2016, 7, 17369–17379. [Google Scholar] [CrossRef] [PubMed]
  434. Zhang, G.Q.; Chen, J.L.; 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 2015, 94, e2281. [Google Scholar] [CrossRef] [PubMed]
  435. Bitto, A.; Granese, R.; Triolo, O.; Villari, D.; Maisano, D.; Giordano, D.; Altavilla, D.; Marini, H.; Adamo, E.B.; Nicotina, P.A.; et al. Genistein aglycone: A new therapeutic approach to reduce endometrial hyperplasia. Phytomedicine 2010, 17, 844–850. [Google Scholar] [CrossRef] [PubMed]
  436. Vierk, K.A.; Koehler, K.M.; Fein, S.B.; Street, D.A. Prevalence of self-reported food allergy in American adults and use of food labels. J. Allergy Clin. Immunol. 2007, 119, 1504–1510. [Google Scholar] [CrossRef] [PubMed]
  437. Gupta, R.S.; Springston, E.E.; Warrier, M.R.; Smith, B.; Kumar, R.; Pongracic, J.; Holl, J.L. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011, 128, e9–e17. [Google Scholar] [CrossRef] [PubMed]
  438. Katz, Y.; Gutierrez-Castrellon, P.; Gonzalez, M.G.; Rivas, R.; Lee, B.W.; Alarcon, P. A comprehensive review of sensitization and allergy to soy-based products. Clin. Rev. Allergy Immunol. 2014, 46, 272–281. [Google Scholar] [CrossRef] [PubMed]
  439. Jenkins, D.J.; Kendall, C.W.; Faulkner, D.; Vidgen, E.; Trautwein, E.A.; Parker, T.L.; Marchie, A.; Koumbridis, G.; Lapsley, K.G.; Josse, R.G.; et al. A dietary portfolio approach to cholesterol reduction: Combined effects of plant sterols, vegetable proteins, and viscous fibers in hypercholesterolemia. Metabolism 2002, 51, 1596–1604. [Google Scholar] [CrossRef] [PubMed]
Table 1. Nutrient composition of boiled soybeans and selected legumes per cup (source, reference [11]).
Table 1. Nutrient composition of boiled soybeans and selected legumes per cup (source, reference [11]).
Legume/USDA Nutrient Database NumberkcalMacronutrients % kcal/g per CupFiber (g)Minerals (mg) per CupVitamins (Amounts per Cup) 1
ProteinFatCHO 2CaIronZincPKMgDFE 3B2B6B3Thiaminα-Toc 4K
Pinto beans/1604324525.2/15.44.1/1.173.2/44.815.4793.571.68251746862940.1060.3920.5440.3301.616.0
Navy beans/1603825523.5/15.04.0/1.174.4/47.419.11264.301.87262708962550.1200.2511.1810.4310.021.1
Kidney beans/1602822527.3/15.43.5/0.971.8/40.411.3623.931.77244717742300.1030.2121.0230.2830.0514.9
Black beans/1601522726.9/15.23.7/0.971.9/40.815.0463.611.932416111202560.1010.1190.8690.4201.505.7
Adzuki beans/1600229423.5/17.30.7/0.277.5/57.016.8644.604.0738612241202780.1470.2211.6490.264NRNR
Great Northern/1602520928.2/14.73.4/0.871.4/37.312.41203.771.56292692881810.1040.2071.2050.280NRNR
Lima beans/1637221627.1/14.73.0/0.772.7/39.313.2324.491.79209955811560.1030.3030.7910.303NR3.8
1 Units are mg for vitamins B2, B6, B3, thiamin and vitamin E; µg for folate and vitamin K; 2 CHO, carbohydrate; 3 DFE, dietary folate equivalents; 4 α-Toc, α-tocopherol.
Table 2. Fatty acid composition of soybean oil by seed coat color (grams per 100 g of oil).
Table 2. Fatty acid composition of soybean oil by seed coat color (grams per 100 g of oil).
Type of FatSoybeans 1Black (n = 5) 2Brown (n = 4) 2Green (n = 2) 2Yellow (n = 7) 2
Total saturated15.614.9814.67–15.1810.2810.10–10.4913.7613.03–13.7611.767.08–22.68
Palmitic (% of saturated)73.411.3911.21–11.646.065.86–6.1910.289.58–10.977.763.54–10.61
Stearic (% of saturated)24.73.593.03––4.363.483.45–3.514.003.48–6.08
Monounsaturated (oleic)23.819.6517.13–22.9941.1541.01–41.4824.8023.51–26.0829.3521.71–36.03
Total polyunsaturated60.762.7158.66–66.0346.1145.93–46.4758.7556.83–60.9655.5544.95–61.84
Linoleic (% of PUFA 3)88.253.1250.63–55.1442.8842.63–43.1350.7148.88–52.5350.1848.31–53.99
α-Linolenic (% of PUFA)11.89.597.99–10.783.233.10–3.318.057.76–8.335.373.37–9.07
1 Source, reference [11]; 2 Source: reference [44]; 3 PUFA, Polyunsaturated fatty acids.
Table 3. Meta-analysis of clinical studies evaluating the effects of soy protein on lipid levels.
Table 3. Meta-analysis of clinical studies evaluating the effects of soy protein on lipid levels.
Author/(Reference)Year PublishedNumber of Trialsn 1Change from Baseline
LDL-C 2HDL-C 3Triglyceride
Tokede [126]201522 4 −5.88 mg/dL+1.42 mg/dL−7.12 mg/dL
13 5 −7.62 mg/dL+1.15 mg/dL−7.48 mg/dL
Benkhedda [118]2014593731−4.0%+0.03 mmol/l−0.06 mmol/L
Yang [127]20117 6158−0.30 mmol/L+0.05 mmol/l−0.22 mmol/L
Anderson [125]201120 71946−5.5%+3.2%−10.7%
Jenkins [122]201022757−4.2%NR 8NR 8
Harland [124]2008102913−6.0%+4.6%−5.3%
Hooper [128]2008392747−0.19 mmol/L0.02 mmol/LNR 8
Reynolds [129]2006361387−4.0%+0.77 mg/dl−6.26 mg/dL
Zhan [123]2005331749−5.3%+3.0%−7.3%
Weggemans [130]200321959−4.0%+3.0%NR 8
1 Refers to participants for LDL-cholesterol measurements; 2 LDL-C, LDL-cholesterol; 3 HDL-C, high-density-lipoprotein cholesterol; 4 Trials intervening with soy protein containing isoflavones; 5 Trials intervening with soy protein without isoflavones; 6 All participants had type 2 diabetes; 7 Refers to parallel studies only; 8 NR, not reported.
Table 4. Experimental details of prospective epidemiologic studies included evaluating the impact of post-diagnosis soy intake on breast cancer recurrence and survival 1.
Table 4. Experimental details of prospective epidemiologic studies included evaluating the impact of post-diagnosis soy intake on breast cancer recurrence and survival 1.
Author/(Reference)LocationnFollow up (Year)DeathsRecurrences
Zhang [259]China6164.379NA 2
Caan [256]United States30887.3271448
Kang [258]China5245.1154185
Shu [257]China50423.9444534
Guha [255]United States19546.3NA 2282
1 Adapted from reference [260]; 2 NA, not applicable.
Table 5. Effects of isoflavones on the decrease in hot flash frequency according to the genistein content of the supplement 1.
Table 5. Effects of isoflavones on the decrease in hot flash frequency according to the genistein content of the supplement 1.
Genistein Dose (mg/Day)Number of TrialsnFixed Effects ModelRandom Effects Model
Percent95% CIp ValuePercent95% CIp Value
≤18.87596−12.47−17.34, −7.60<0.00001Same as Fixed Effects Model
>18.86600−26.50−33.11, −19.90<0.00001−29.13−43.09, −15.17<0.0001
Test for Subgroup Differencep = 0.0008p = 0.03
1 Source: reference [305].

Share and Cite

MDPI and ACS Style

Messina, M. Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature. Nutrients 2016, 8, 754.

AMA Style

Messina M. Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature. Nutrients. 2016; 8(12):754.

Chicago/Turabian Style

Messina, Mark. 2016. "Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature" Nutrients 8, no. 12: 754.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop