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Abstract

Traditional soyfoods have been consumed for centuries throughout much of East Asia and, recently, these foods have also become popular in the West. Soyfoods and specific soybean components, such as the protein and isoflavones, have attracted attention for their possible health benefits. Isoflavones are classified as phytoestrogens and have been postulated to be natural alternatives to hormone therapy for menopausal women. To provide guidance on optimal soy intake, this article evaluates Asian soy consumption and both clinical and Asian epidemiologic studies that examined the relationship between soy intake and a variety of health outcomes. On the basis of these data and the standard principles of dietary practice the author suggests that optimal soy protein and isoflavone intakes are 15–20 g/day and 50–90 mg/day, respectively. In addition, an intake of 25 g/day soy protein can be specifically used as the recommendation for cholesterol reduction.

Keywords

China coronary heart disease hot flashes isoflavones Japan osteoporosis protein recommended intake soyfoods

Traditional soyfoods such as tofu and miso have been consumed for centuries throughout much of East Asia. More recently, these foods have become popular in many Western countries. This popularity can be attributed primarily to consumer awareness of research suggesting that soyfoods exert health benefits in a variety of areas, independent of their nutrient content. Soy protein and isoflavones are the two soybean components that have been the focus of most research. Isoflavones are of particular interest to postmenopausal women and have been posited to be natural alternatives to conventional hormone therapy [1 –3]. These soybean constituents have been shown in many studies, but not all, to alleviate hot flashes [4] and inhibit bone resorption [5].

Health professionals and organizations offer guidance on desirable intake goals for food groups and even individual foods. Recommendations exist, for example, for fruits and vegetables, dairy products and whole grains, but no such recommendation exists for soyfoods. In awarding the soy protein and coronary heart disease (CHD) health claim in 1999, the US FDA established 25 g/day soy protein as the threshold intake for cholesterol reduction; however, this threshold has limited value as a guide for incorporating soy into the diet for general nutritional and health purposes and for proposed benefits unrelated to cholesterol reduction [6]. Furthermore, the claim provides no guidance regarding isoflavone intake.

Therefore, the purpose of this perspective is to provide guidance on soy intake based on three considerations: Asian soy consumption, clinical and Asian epidemiologic studies that have examined the relationship between soy intake and a variety of health outcomes, and standard principles of dietary practice. Soy intake will be expressed in terms of both soy protein and isoflavones. A perspective will also be provided on the compatibility of consuming 25 g/day soy protein with both Asian soy intake and with public health recommendations regarding variety and moderation in dietary choices. Finally, arguments for and against the use of isoflavone supplements are provided.

Isoflavone & protein content of soyfoods

The soybean is unique among commonly consumed foods in that it is a rich source of isoflavones [7]. The three soybean isoflavone aglycones are genistein, daidzein and glycitein (Figure 1). In soybeans and most soyfoods, there is slightly more genistein than daidzein and relatively little glycitein (≤10%) (Figure 2) [8,9]. The aglycone form of isoflavones is the biologically active form [10] and the form in which isoflavone absorption occurs [11,12]; but, in the soybean and nonfermented soyfoods isoflavones are naturally present primarily as glycosides [8,13]. However, although not all data are in agreement [14] – as a result of the in vivo hydrolysis that occurs during digestion [12] – evidence indicates that total isoflavone absorption is not affected by the form in which isoflavones are present in foods [15,16]. Throughout this paper, isoflavone values refer to the aglycone weight, as has been the recommended convention [17].

Figure 1.

Soybean isoflavone aglycones.

Figure 2.

Relative isoflavone profile in soyfoods and supplements made by two different processes.

Finally, although there is considerable variability in the isoflavone concentration among different soybean varieties [18,19], as a general rule, each gram of soy protein in the soybean and traditional soyfoods is associated with approximately 3.5 mg isoflavones [20]. Traditional soyfoods provide from as few as 6 to as many as 20 g protein per serving (Asian serving sizes tend to be smaller than in the West).

Cellular actions of isoflavones

Isoflavones are diphenolic compounds that have a chemical structure similar to that of the hormone estrogen (Figure 1) so it is not surprising that they bind to estrogen receptors (ERs) – something first demonstrated four decades ago [21], and exert estrogen-like effects under certain experimental conditions [22]. However, it has been shown that isoflavones bind with much greater affinity to ERβ (identified in 1996 [23]) than ERα and so it is fair to say that, until recently, their potency was underestimated [24]. In any event, because plasma isoflavone levels in subjects consuming 50–100 mg/day isoflavones can reach the low μM concentrations, which is approximately 1000-fold higher than plasma estrogen levels, it is obvious that these soybean constituents hold the potential to exert physiological effects [25]. Importantly, the identification of ERβ not only requires a new perspective on potency but has led to isoflavones being classified by some as selective ER modulators (SERMs) [1 –3]. SERMs such as tamoxifen and raloxifene exert tissue selective effects, functioning as estrogen agonists in some tissues but having either no effects or anti-estrogenic effects in others [26].

Despite their estrogen-like actions, it is worth noting that much of the initial interest in isoflavones was because genistein was shown to be a specific inhibitor of tyrosine protein kinases, enzymes frequently overexpressed in cancer cells [27]. Even aside from the kinase effects, there is considerable interest in the role that ER-independent mechanisms play in the ability of genistein to influence cellular processes and, in particular, to inhibit carcinogenesis [28,29].

Asian soy intake

Per capita, soy intake differs markedly among East Asian countries and, within some countries such as China, there is considerable regional variation in dietary habits and soy consumption [30,31]. Disappearance data from the Food and Agricultural Organization of the United Nations provides a good reference for comparing soy intake among nations. As shown in Table 1 , on an absolute basis (g/day), per capita soy protein intake ranges from a high of 9.6 (North Korea) to a low of 2.0 g/day (Thailand), whereas on a percentage calorie basis the range is from 15.3 (North Korea) to 2.3% (Hong Kong) [20]. Because considerable intake data exist for China (specifically Shanghai) and Japan, and a large number of Chinese (specifically Shanghai) and Japanese epidemiologic studies examining the relationship between soy intake and a variety of health outcomes have been conducted, intake data based on individual food frequency questionnaires (FFQs) is discussed below for only these two countries.

Table 1.

Estimated soy protein from the Food and Agricultural Organization of the United Nations for the year 2002*.

Country	Protein intake
	g/day	% kcal
North Korea	9.6	15.3
Japan	8.7	9.5
Indonesia	8.2	12.8
South Korea	4.9	5.5
China	2.7	3.3
Hong Kong	2.3	2.3
Thailand	2.0	3.5

Data for Hong Kong for the year 1998.

In a recent review of Asian soy consumption that included five Japanese studies [32 –36] that assessed soy protein consumption, intake in adult women ranged from a low of 6.0 [35] to a high of 10.5 g/day [34], whereas the range in males was 8.0 [36] to 11.3 g/day [34]. Soyfoods contributed from 6.5 [35] to 12.8% [34] of total protein intake. In a large study published after this review that included 3956 females (average age: 18.1 years), mean soy protein intake was only 4.6 g/day [37]. In agreement, a study of over 1000 pregnant Japanese women found mean soy protein intake to be quite low – approximately 4.5 g/day [38]. However, it should be noted that the low soy intake in these two studies is probably because of the very young age of the participants since soy intake has declined precipitously among younger people [20].

With regards to Shanghai, in a report from the Shanghai Women's Health Study (SWHS), a large cohort that included nearly 46,000 women, the mean ± standard deviation (SD) soy protein intake was 8.8 ± 6.3 g/day; in an earlier publication from this cohort, soy protein was found to account for 12.8% of total protein intake [39]. In the Shanghai Men's Health Study (SMHS), which included 54,219 middle-aged men (mean age ± SD: 55.0 ± 9.9 years), mean ± SD soy protein intake was 12.5 ± 7.94 g/day among the entire cohort based on FFQs and 13.6 ± 6.8 g in a small subset of these men who also filled out 24-h dietary records [40].

Estimates of isoflavone intake referred to previously, based on the isoflavone (mg):protein (g) ratio in traditional soyfoods are generally consistent with intakes actually reported. For example, in the SMHS, mean ± SD isoflavone intakes based on the FFQ and 24-h dietary records were 36.2 ± 24.4 and 39.0 ± 25.9 mg/day, respectively [40]. Furthermore, in the SWHS, mean daily isoflavone ± SD intake was 40.8 ± 28.7 mg [41]. These results are consistent with those from another study of approximately 1500 Chinese women that found a mean ± SD isoflavone intake of 40.9 ± 39.5 mg/day [42].

For Japan, estimates of female isoflavone intake are quite variable; for example, three small studies reported mean intakes of only 26–30 mg/day [32,35,43]; however, the women in these studies were relatively young whereas three other studies reported mean intakes of approximately 37 [44], 47 [45] and 54 mg/day [46]. One survey that included 12 regions in Japan found an average intake of only approximately 23 mg for both men and women, but the total protein intake reported was much lower than in other surveys, suggesting there may have been some under-reporting of food intake [47]. In contrast to this low intake, a survey of nearly 1000 males in Nagoya reported a median isoflavone intake of 31.7 mg (25th and 75th percentiles; 16.2 and 51.4 mg/day, respectively) [48]. Finally, a national survey of Japanese households reported a mean ± SD isoflavone intake of 28.7 ± 4.1 mg/day [49] and intake of approximately 35 mg/day was estimated using the market-basket method [50].

With regards to the upper range of soy intake, two studies from Shanghai are especially worth noting. In one study that involved over 3000 women, the soy protein intake cutoff for the 90th percentile was 19.9 g/day or less [42] and, in the other, the SWHS, the 95th percentile soy protein intake was 19.7 g/day [39]. Approximately 2% of the women in this cohort consumed approximately 146 mg/day isoflavones and at least 25 g/day soy protein [41]. In addition, approximately 10% of the women consumed between 15.1 and 24.9 g/day soy protein [41].

In Japan, a study involving over 3000 subjects found mean fourth-quartile soy protein intakes for men and women to be 13.0 and 11.0 g/day, respectively [39]. The authors of this study suggested that their FFQ may have underestimated soy intake by as much as 30%. Higher values were reported in a Japanese study involving 30,000 subjects, which found that mean third tertile soy protein intakes for men and women were 17.4 and 15.9 g/day, respectively [Chisato Nagata, March 9, 2004, Pers. Comm.]. Furthermore, in the Japan Public Health Center-based prospective study, which included 43,509 Japanese men aged 45–74 years, mean ± SD genistein and daidzein intakes among subjects in the fourth quartile were 49.1 ± 30.9 and 29.9 ± 17.8 mg/day, respectively [51]. Finally, in agreement with this study are the results from a relatively small case–control study (n = 400 men), in which the fourth quartile isoflavone intake cutoff was 89.9 mg/day or greater (50 controls and 23 cases fell into this category) [52].

Regarding the types of soyfoods used in East Asian countries, it is known, for example, that soymilk is widely consumed in Shanghai but is relatively uncommon in Japan. Wakai et al. found that among the Japanese subjects in their study, four soyfoods (tofu, miso, natto and fried tofu) accounted for approximately 90% of total isoflavone intake [48]. Similarly, Somekawa et al. found that soybean curd, fermented soybeans and soybean paste provided 88% of the total isoflavone intake of Japanese women [46]. Among Chinese women, Zhang et al. reported that soymilk, tofu and processed soy products other than tofu accounted for 81% of total soy protein intake [39]. Finally, although fermented (e.g., miso and natto) foods were the first soyfoods to be consumed in Asia, historical records referring to nonfermented soyfoods (e.g., tofu) date back more than 2500 years in China and 800 years in Japan [William Shurtleff, Soyinfo Center, Lafayette, CA, USA, March 17, 2008, Pers. Comm.] and today, in both Japan and China, nonfermented soyfoods provide approximately half of the total isoflavone intake [39,46,48,53 –55].

Review of health effects

Clinical studies

Subjects in clinical studies that have evaluated the effects of various soy protein and isoflavone-containing products on different health outcomes have generally been exposed to between 50 and 100 mg/day isoflavones [56,57]. These studies have produced inconsistent findings and almost no direct dose–response data are available. Nevertheless, it is possible to arrive at an approximate isoflavone intake that is likely to produce benefit, if in fact isoflavones are efficacious, by considering three health effects or outcomes:

Improvement in bone mineral density (BMD)

Alleviation of hot flashes

Improvement in arterial function assessed by either arterial systematic compliance or endothelium-dependent flow-mediated dilation

Bone mineral density

The first clinical study to examine the effects of isoflavone-rich soy protein on BMD was published in 1998 [58]. Since that time, 22 trials of at least 3 months duration have assessed the effect of an isoflavone-containing product on BMD in postmenopausal women [57,59]. These data are suggestive of benefit, but most trials were relatively small in size and short in duration; few included more than 50 subjects per group or were conducted for more than 1 year [57,59]. Nevertheless, a recent meta-analysis that included ten trials and 608 subjects concluded that isoflavones improve spinal postmenopausal BMD and that the optimal isoflavone exposure is greater than or equal to 90 mg/day [60].

This conclusion is consistent with the results of a 6-month study that directly compared the efficacy of isolated soy protein (ISP; by definition is ≥90% protein) that provided 56 or 90 mg/day isoflavones [58]. It is also consistent with the findings from a trial that was the longest (2 years) and largest (>300 subjects) in this subject area published to date [61]. Among the Italian postmenopausal osteopenic women in this study, those taking 54 mg/day genistein experienced an approximately 6% increase in spinal and hip BMD, whereas women in the placebo group lost approximately the same amount of BMD at both sites (Figure 3). This amount of genistein would be present in approximately 100 mg total isoflavones. By contrast, a recently published large, 1-year European, placebo-controlled trial failed to observe skeletal benefits in response to 110 mg/day isoflavones [62]. However, in contrast to the Italian study [61], in the European study even women in the placebo group lost relatively little bone [62]. Although speculative, it may be that the effects of isoflavones are most apparent in women undergoing very pronounced bone loss.

Figure 3.

Changes in lumbar spinal and femoral neck bone mineral density in postmenopausal osteopenic Italian women from the placebo and genistein (54 mg/day) groups.

Hot flash alleviation

The first study to examine the effects of an isoflavone-rich soy product on hot flashes was published in 1995 [63]. Since then, approximately 50 trials of isoflavone-containing products (including those derived from red clover) have been published. A few reviews of these data have concluded that isoflavones alleviate menopause-related hot flashes [4,64,65], although because of the inconsistent data, most have not confirmed this [66 –68]. However, reviews that have failed to do so have generally not distinguished among the different isoflavone preparations used in the clinical studies. Evidence suggests this may be an important oversight. Williamson-Hughes et al. found that mixed isoflavone preparations containing 15 mg or more of genistein and approximately 50 mg total isoflavones were efficacious, whereas those providing similar amounts of total isoflavones but lower amounts of genistein were not [4]. The two primary commercially available supplements contain rather different isoflavone profiles; one mimics the profile in the soybean, being high in genistein and low in glycitein, whereas, in the other, the relative concentrations of these isoflavones is reversed (Figure 2) [18,69].

Several recently published studies provide good examples of hot flash alleviation in response to isoflavones. For example, Nahas et al. found that in a 10-month study, hot flash frequency was reduced by 31 and 62% in post-menopausal Brazilian women receiving a placebo and approximately 60 mg/day isoflavones, respectively [70]. Furthermore, in a large 1-year Italian study, relative to the placebo, hot flash frequency decreased by 50% in women receiving 54 mg/day genistein [71]. Somewhat lower amounts of isoflavones have also been found to be efficacious, although most trials have used 50 mg/day or more. For example, in a 12-week Swedish study, Cheng et al. [72] reported that the severity of night sweats and hot flashes was significantly reduced in response to only approximately 36 mg/day isoflavones [73].

Systemic arterial compliance & endothelial function

In 1997, research by Nestel et al. was the first to demonstrate an improvement in arterial health in response to the ingestion of isoflavones [74]. Specifically, they found that in peri- and post-menopausal women, 40–80 mg/day isoflavones improved systemic arterial compliance (SAC) by 26% (p < 0.001), which is similar to the effect of estrogen. In agreement, SAC was also significantly improved (p = 0.04) in 80 healthy subjects, including 46 men and 34 women aged 45–75 years, who received 80 mg/day isoflavones enriched with either biochanin A (a precursor of genistein) or formononetin (a precursor of daidzein) [75]. SAC involves the ability of the aorta to distend during the elevated blood pressure associated with systolic ejection and recoil during the resting diastolic phase of the cardiac cycle. Progressive atherosclerotic arterial disease leads to a gradual stiffening of the arterial walls and impaired cardiac functioning [76]. In contrast to these favorable results, however, several studies in which subjects were exposed to similar amounts of isoflavones from either extracts [77] or soy protein [78,79] failed to lead to improvements in SAC.

Another commonly used measure of arterial health is endothelial function; in fact, endothelial function has been referred to as a global indicator of CHD risk [80]. Endothelial cells in the intima layer of blood vessels play a central role in inhibiting the development of atherosclerosis and its thrombotic consequences. In the year 2000, Walker et al. found that in both men and pre- and post-menopausal women, genistein, but not daidzein, when infused into the brachial artery, produced a dose-dependent increase in forearm blood flow [81]. Two years later, Squadrito et al. [82,83] reported that at both 6 [83] and 12 months [82] endothelium-dependent flow-mediated dilation of the brachial artery was significantly improved in response to 54 mg/day genistein; genistein levels were directly correlated with plasma levels of nitric oxide end products [82,83]. Statistically significant improvements in postmenopausal endothelial function were also noted in studies by Colacurci et al. [84] and Cupisti et al. [85]. A supplement providing approximately 60 mg/day isoflavones and commercially available soyfoods providing 25 g soy protein and approximately 50 mg isoflavones were the intervention products in the former and latter studies. However, as in the case of SAC, it is not possible to reach definitive conclusions about the effects of isoflavones on endothelial function as a result of inconsistent data [79,86,87].

Epidemiologic studies

Epidemiologic investigations involving soyfoods have involved a wide array of health outcomes and diseases. However, for purposes of developing guidance on soy intake only, CHD and osteoporosis will be considered since clinical data exist for both, allowing comparisons to be made between the two types of data. The epidemiologic research has involved both Asian and non-Asian subjects, but only the former will be discussed because it is unlikely that the low soy intakes common to non-Asians are sufficient to exert biological effects [88]. It is possible that benefits associated with soy exposure in epidemiologic studies derive, at least partially, from lifelong exposure, if childhood and/or adolescent soy intake tracks into adulthood. In fact, there are intriguing data indicating that early soy intake is associated with protection against breast cancer later in life [89 –92]. However, evidence suggests that this is not the case for skeletal benefits, improvements in arterial health and, obviously, for the relief of menopausal symptoms. These conditions are thought to be favorably affected by isoflavones as a result of the lower estrogen environment that exists in postmenopausal women. By contrast, the cholesterol-lowering effects of soy protein are operative at younger ages and the earlier the age at which this reduction occurs, the greater the protection – in theory – against CHD [93,94].

Coronary heart disease

Results suggest that soy exerts lipid-independent coronary benefits; intake of soyfoods and/or isoflavones has been shown to be inversely related to coronary events in several studies with risk reductions ranging from 32 to 86%, which is far greater than could be expected from the modest reduction in blood cholesterol associated with soy protein [39,49,95,96]. The report from the SWHS by Zhang et al. is especially worth noting because of the study size – approximately 65,000 postmenopausal women – and the magnitude of the risk reduction [39]. This study found an inverse association between nonfatal myocardial infarction and soy intake; the relative risk (RR) and 95% confidence interval (CI) was 0.14 and 0.04–0.48, respectively, when comparing the fourth with the first soy protein intake quartile (p for trend = 0.001). The mean fourth quartile soy protein intake was approximately 16 g/day.

In agreement are the results from the Japan Public Health Center-based study cohort, a prospective investigation involving 40,462 Japanese participants who were 40–59 years old and without cardiovascular disease or cancer at baseline [96]. Over the 12-year follow-up period, isoflavone intake was associated with a reduction in risk of both cerebral and myocardial infarction; the multivariable hazard ratios for the highest versus the lowest quintiles of isoflavone intake in women were 0.35 (0.21–0.59) for cerebral infarction and 0.37 (0.14–0.98) for myocardial infarction. The mean (±95% CI) isoflavone intakes (mg/day) in the fifth quintiles for men and women were 45.2 (39.6, 87.4) and 41.3 (37.7, 73.1), respectively [96]. Estimates of soy protein intake were not provided but based on the ratio previously discussed, mean intake in the fifth quintiles for men and women would be approximately 13 and 12 g/day, respectively.

Osteoporosis

Although Asian spinal fracture rates and BMD are similar to that of Caucasians [97 –104], epidemiologic studies generally show that among Asian women, soy intake is positively associated with BMD [59,105]. Interestingly, the isoflavone intakes associated with higher BMD in these studies are lower than the doses associated with benefits in the clinical studies.

Importantly, in the only prospective study to include fractures as an end point, among Chinese postmenopausal women, after adjustment for age, major risk factors of osteoporosis, socioeconomic status and other dietary factors, the RRs (95% CIs) of fracture were 1.00, 0.72 (0.62–0.83), 0.69 (0.59–0.80), 0.64 (0.55–0.76) and 0.63 (0.53–0.76) across quintiles of soy protein intake (p < 0.001 for trend) [106]. During the 4.5-year follow-up period, among the more than 24,000 women in this cohort, there were nearly 1800 fractures. The soy protein intake cutoff for the fifth quintile was approximately 18 g/day. Protection was most evident in early postmenopausal women (50–60 years of age), whose risk was reduced by approximately 50%. Among older women (>60 years), risk was reduced by only 20%.

Perspective on the US FDA soy protein health claim

As noted, the FDA established 25 g/day soy protein as the threshold intake for cholesterol reduction [6]. This threshold was established, not because data indicated that fewer than 25 g/day were ineffective, but rather because few studies used less than this amount. In fact, the lack of a dose–response relationship between 25 and 50 g/day [107 –109] and the findings from a few clinical studies showing that fewer than 25 g/day soy protein lowers cholesterol [109,110], raise the possibility that the established threshold intake may be too high.

In any event, it is clear that 25 g/day soy protein exceeds the soy protein intake of at least 90% of the Japanese and Shanghai populations, although it is also fair to conclude that this intake level is still within the dietary range, albeit at the very upper end. This is especially true if some allowance is made for the larger body type of Caucasians compared with Asians. In total, 25 g soy protein from traditional soyfoods provides as much as 100 mg isoflavones, whereas the same amount of protein from processed forms of soy may provide as little as 15 mg isoflavones as processing can result in significant isoflavone loss [111]. Since both processed and unprocessed forms of soy are consumed in Western countries, the isoflavone intake from the consumption of 25 g/day soy protein is more consistent with current Asian isoflavone than soy protein intake.

According to the National Health and Nutrition Examination Survey III, US adult men and women consume approximately 65 and 97 g/day total protein, respectively, and two-thirds of that comes from animal sources [112]. Substituting 25 g soy protein for other sources of protein would result in a diet in which soy protein comprises approximately 26 and 38% of total protein for men and women, respectively. By comparison, dairy products provide approximately 14% and meat, fish and poultry provide approximately 29% of the total protein intake [112]. However, the three servings of dairy recommended by the dairy industry [113] and several health organizations, including the American Dietetic Association [301], would provide approximately 25 g protein. Substituting 25 g soy protein for animal protein in the diet would cause the US dietary ratio of animal to plant protein to be reversed from 2:1 to 1:2, the lower ratio being much closer to the dietary ratio that existed near the turn of the 20th Century and that is arguably more in line with current health recommendations [114].

By contrast, since diet variety is considered a desirable goal, obtaining large amounts of a single nutrient from one source may be subject to criticism [115]. However, the 25 g/day intake is a therapeutic recommendation specific for cholesterol reduction rather than a general intake recommendation. Furthermore, in reality, few individuals are likely to make a 1:1 substitution of soy protein for nonsoy protein, especially since many soyfoods (e.g., miso, edemame, energy bars and soynuts) are not necessarily intended to replace protein-rich foods. It is, therefore, likely that greater incorporation of soyfoods into the diet will lead to an overall increase in protein intake. As a result, the percentage of total protein contributed specifically by soy would decrease.

Such an increase in total protein would not appear problematic since the US Institute of Medicine (IOM) has concluded that to meet the body's daily nutritional needs while minimizing risk for chronic disease, adults should consume from 10–35% of their calories from protein [116]. Currently, approximately 15% of the US caloric intake comes from protein [112]. Therefore, dietary protein could be increased quite markedly and still fall well within the range recommended by the IOM. In fact, recent data suggest the current recommended dietary allowance (RDA) for protein is actually too low [117], and there is increasing evidence that consuming protein in excess of the RDA may be advantageous for weight loss [118], reduction for risk of osteoporosis [119], preventing sarcopenia in the elderly [120], possibly for lowering blood pressure [121] and for those engaged in vigorous physical activity [122]. Concerns about the impact of higher protein intakes on renal function are generally thought applicable only to those with existing, or at very high risk of developing, renal disease [123].

Safety considerations

In the process of awarding the soy protein and CHD health claim, the FDA addressed concerns that soyfood intake might lead to adverse effects in a subset of individuals [6]. Despite their conclusion that such claims were without merit, questions about the safety of soyfood consumption, and especially isoflavone supplement use, persist. This is not surprising considering the enormous amount of soy-related research conducted during the last 10 years and that, in theory, essentially all foods may cause some untoward effects in certain individuals. For example, cow's milk causes allergic reactions [124] and gastrointestinal disturbances [125], and has been linked in some studies with colorectal cancer [126], prostate cancer [127] and diabetes [128], but nevertheless, is generally viewed by nutritionists as healthy food.

Soy protein, like milk and many other food proteins, can cause allergic reactions. In fact, it is classified as one of the eight foods thought to be responsible for 90% of the food allergies in the USA [129]. However, these eight foods are not equally allergenic and the number of adults with doctor-diagnosed soy protein allergies is quite small [130]. The phytate (inositol hexaphosphate) in soybeans, as in the case for whole grains, inhibits mineral absorption, although there is no evidence that typical dietary soyfood intake leads to mineral imbalances [131]. There are also reports of minor gastrointestinal disturbances in response to the consumption of large amounts of soy protein [56] and isoflavones [61]. A particularly controversial issue involving soy is the use of soy infant formula. This issue is unrelated to the current perspective but it is worth noting that over the past four decades, there are estimates that in excess of 20 million infants have used soy formula and that the evidence indicates that in these infants growth and development are normal [132]. Most concerns about soyfoods, and certainly extracts, pertain to isoflavones and, specifically, to their estrogen-like effects. In fact, on the basis of animal studies, isoflavones are sometimes classified as endocrine disruptors [133,134], although as noted previously, they are also classified as SERMs [1 –3]. Concerns about isoflavones include increased breast and endometrial cancer risk, hormonal imbalance and impaired thyroid and cognitive function. These concerns are briefly addressed below.

Cognitive function

An analysis of the Honolulu-Asia Aging Study (HAAS), a prospective cohort study that began in 1965 (which is an offshoot of the Honolulu Heart Program) reported in the year 2000 that among 3734 men aged 71–93 years, poor cognitive test performance, enlargement of ventricles and low brain weight were each significantly and independently associated with higher mid-life tofu consumption [135]. Furthermore, a similar association of mid-life tofu intake with poor latelife cognitive test scores was also observed among wives of cohort members, using the husband's intake as proxy for the wife's consumption. These findings were unexpected because at that time estrogen therapy (and, therefore, perhaps also isoflavones) was thought to exert cognitive benefits [136]. However, the HAAS had several weaknesses, for example, the intake of only 26 foods was assessed and the intake questions pertaining to tofu differed from one time point to the next. Furthermore, in contrast to the results of the HAAS, a cross-sectional study, which included 3999 men and women aged 65 years and older from Hong Kong, found that isoflavone intake was unrelated to cognitive function as assessed by the cognitive part of the community screening instrument for dementia [137]. Equally important, the clinical studies that have examined the impact of isoflavone-rich products actually suggest that, at least in younger postmenopausal women, isoflavones favorably affect several aspects of cognitive function [138].

Thyroid function

The possibility that soy adversely affects thyroid function is a frequent topic of discussion among some health-conscious consumers. Understanding this relationship is important because as many as 10% of postmenopausal women – the group for whom soyfoods are of particular interest – are hypothyroid [139]. Furthermore, many postmenopausal women believe themselves to be hypothyroid even though they are not. Isoflavones in vitro [140,141] and in rats [142] inhibit the activity of thyroid peroxidase although, despite being very sensitive to goitrogenic influences [143], rat thyroid function remains normal with exposure to isoflavones [142]. More importantly, a review of 14 clinical trials concluded that there is little evidence that soyfoods or isoflavones adversely affect thyroid function in healthy men or women [144]. Research published after this review are consistent with this conclusion [145 –147].

Preliminary results from research currently underway also indicate that soy has no adverse effects on thyroid function in subjects with subclinical hypothyroidism [Stephen L Atkin, the University of Hull, Pers. Comm.]. This condition occurs in a fairly large number of older people, and is defined as having normal levels of thyroxine and triiodothyronine but elevated levels of thyroid stimulating hormone [148]. Finally, by inhibiting absorption, soyfoods may in fact increase the amount of thyroid medication needed by hypothyroid patients [149 –152] but this is also true of many foods, herbs and drugs, including fiber supplements [153 –161]. It is not necessary for thyroid patients (with the exception of infants with congenital hypothyroidism) [152] to avoid soyfoods because medication dosages can easily be adjusted to compensate for any theoretical effects of soy.

Effects on hormone levels & endometrial tissue

At least 40 clinical studies have examined the impact of soy or isoflavones on circulating reproductive hormone levels. However, although studies have shown both increases [162] and decreases [163] in estrogen, the vast majority demonstrate no effects; although, overall, there may be a slight increase in circulating estrogen levels in postmenopausal women and a slight decrease in levels of follicle-stimulating hormone and luteinizing hormone in premenopausal women [72,164,165]. Importantly, even in studies demonstrating effects on hormone levels, all values remain well within the normal range. In vitro isoflavones have been shown to influence enzymes involved in steroid metabolism, including aromatase [166], 17β-hydroxysteroid dehydrogenases, steroid sulfatases and sulfotransferases [167], but these effects have generally been observed only at concentrations beyond that which is likely to be achievable in vivo.

The endometrium is a classical hormone-dependent tissue and most of the endometrial adenocarcinomas are hormone-dependent tumors. Evidence overwhelmingly indicates that the hormone estrogen plays a role in the etiology of endometrial cancer [168]. Estrogen stimulates the proliferation of endometrial tissue and ‘ever users’ of unopposed estrogen therapy are approximately twice as likely to develop endometrial cancer as ‘never users’ [169,170]. As such, it is unsurprising that there has been considerable clinical investigation of the effects of isoflavones, from both supplements and soyfoods, on endometrial tissue.

Although a few case reports describing endometrial abnormalities in women consuming high amounts of soyfoods have been published [171,172], with one exception, the clinical studies – which number more than 15 – show that, in contrast to the hormone estrogen, isoflavone exposure neither increases cell proliferation nor endometrial thickness. The exception is a 5-year study by Unfer et al., which found a small but statistically significant increase in the number of women who developed simple endometrial hyperplasia (a reversible condition) in response to isoflavone supplements [173]. The size and duration of this study are worth noting but the findings need to be placed within the context of the literature overall. Furthermore, the study by Unfer et al. [173] had several weaknesses as highlighted by Foth and Nawroth [174] in a letter to the editor and then acknowledged by an expert panel convened at the request of the US NIH [302].

Breast cancer

The estrogen-like effects of isoflavones and, especially, genistein have raised concern that soyfoods may increase the risk of breast cancer in high-risk women and/or stimulate the growth of existing estrogen-sensitive breast tumors. Support for this concern comes primarily from research utilizing ovariectomized athymic-nude mice implanted with MCF-7 cells, an estrogen-sensitive breast cancer cell line. In this model, exposure to a variety of genistein-containing products stimulates tumor growth [175 –179]. An interesting finding from this model is products that underwent a higher degree of processing, despite containing similar amounts of genistein, stimulate tumor growth more than less processed products [179]. In fact, soyflour does not stimulate tumor growth, although it does not allow for complete tumor regression as occurs in response to the soy-free diet. Whether these processing effects are relevant to humans is unknown but there is certainly considerable reason for doubt. In humans, isoflavone pharmacokinetics appear to be similar in response to the consumption of soyfoods and isoflavone supplements [180] and, with the exception of cholesterol reduction, the limited number of direct comparisons has shown similar effects of supplements and soyfoods on health outcomes [181].

More importantly, in contrast to the stimulatory effects observed in the ovariectomized athymic mouse, the human data suggest isoflavones pose no risk. Four clinical studies have taken breast biopsies before and after exposure to isoflavones; in three studies the intervention product was an isoflavone supplement [72,182,183] and in one study, the intervention product was soy protein [184]. One of the four studies involved healthy women [72], two examined breast cancer patients [182,183] and the last involved women undergoing breast biopsy or definitive surgery for breast cancer [184]. Breast cell proliferation was assessed in each study and was found to not increase in any of the studies. Studies also indicate that isoflavones from either soy or red clover do not affect breast tissue density [185 –189]. These findings are consistent with the limited epidemiologic data demonstrating that soy intake does not adversely affect the survival of breast cancer patients [190,191] and contrast with the effects of combined hormone therapy, which increases breast cell proliferation [192], breast tissue density [193] and breast cancer risk [194]. The American Cancer Society has concluded that breast cancer patients can safely consume up to three servings of soyfoods daily, although they also recommend against the use of more concentrated powders and supplements [195].

Estimates of efficacious intakes: epidemiologic versus clinical studies

Results from the clinical studies suggest efficacious doses of isoflavones are 50 or 60 mg/day for the alleviation of hot flashes [4,196], and perhaps over 90 mg/day [60] for improvements in arterial and bone health, although the optimal dose for the former is less clear. By contrast, the epidemiologic data suggest lower intakes are efficacious for reducing risk of CHD and osteoporosis. For example, in the previously cited study by Zhang et al., fracture risk was reduced by a third in those women in the fifth isoflavone intake quintile despite the fact that the cutoff was only 60 mg/day or more [106]; furthermore, most of the reduction occurred in the second quintile even though isoflavone intake in this group ranged from only 21.2 to 32.4 mg/day. There was also a 75% reduction in ischemic cardiovascular disease risk, associated with a mean isoflavone intake of 41 mg/day among postmenopausal women in the Japanese prospective study by Kokubo et al. [96]. In the SWHS, the 86% reduction in the risk of nonfatal myocardial infarction was associated with a mean soy protein intake of approximately 16 g/day, which would provide only approximately 55 mg of isoflavones [39]. Parenthetically, several epidemiologic studies have also found blood cholesterol levels to be inversely related to soy intake at levels much below the amounts typically used in clinical studies [36,197,198].

It is certainly possible that the benefits observed in these epidemiologic studies are not causally related to soy protein or isoflavone intake. Although these studies typically control for a large number of potentially confounding variables, soyfood intake might simply be a marker for a healthy lifestyle. However, this possibility appears unlikely because among older Asians, soy is consumed as part of a traditional diet and not because of any newly proposed health benefits. Thus, older soy consumers and nonconsumers are much more similar in terms of overall lifestyle in Japan and China than would be the case in the West, where the former tend to be more health conscious [199].

An alternative explanation for the discrepancy between the efficacious doses noted in the clinical and epidemiologic studies is that Asians are more sensitive to soy protein and isoflavones than non-Asians, possibly as a result of differences in metabolism. It is known, for example, that there is a higher percentage of equol (a bacterially derived metabolite of daidzein) producers among Japanese in comparison to Westerners [200]. Equol has been proposed to be an especially beneficial isoflavonoid [201]. It may also be that, as already briefly discussed, the epidemiologic studies are reflecting the effects of long-term or even lifelong consumption and that because the clinical studies are relatively short-term, they underestimate the potency of soy. Finally, as noted at the onset, it is the traditional soyfoods that are consumed by the Asians in epidemiologic studies, whereas in the clinical studies, generally either ISPs or isoflavone supplements are used. Conceivably, these latter products are missing ingredients that contribute to the efficacy of soyfoods. This is an attractive although quite speculative hypothesis and one that is inconsistent with the few clinical studies that have directly compared the health effects of traditional soyfoods with more processed soy products [181,202]. Furthermore, most of the proposed benefits are specifically attributed to isoflavones and the available evidence suggests, as already noted, that the consumption of traditional soyfoods leads to similar isoflavone pharmacokinetics as does the use of more processed products [180].

Arguments for & against the use of supplements

While public health recommendations focus on the importance of obtaining nutrients from foods, there are instances wherein supplements are considered acceptable and even desirable. For example, because of the difficulty of meeting calcium requirements, postmenopausal women are often advised to use calcium supplements. However, the use of isoflavone supplements is a contentious issue.

Certainly, if the desired amounts of a dietary component can be obtained relatively easily from food, there is little justification for the use of supplements. However, this is not the case for isoflavones among Western populations. Not only are soyfoods not a traditional part of Western diets, but the amount of soy theoretically required to provide the quantity of isoflavones needed to derive the proposed benefits represents a significant dietary challenge, even for the highly motivated. Relatively few non-Asians are likely to chronically consume sufficient soyfoods – approximately four servings daily – to obtain the 90 mg isoflavones tentatively identified as the optimal amount required for skeletal benefits [203]. Thus, supplements may have a role in providing isoflavones. Arguments for and against their use are briefly discussed below and summarized in Table 2.

Table 2.

Arguments for and against the use of soybean isoflavone supplements.

Against	For
The soybean contains many biologically active constituents that are not found in supplements	Evidence indicates isoflavones are responsible for most of the proposed benefits of soyfoods
Discourage soyfood use and overall dietary change	Encourage dietary change and soyfood use by providing a more consumer-acceptable approach to obtaining isoflavones that includes a combination of foods and supplements
May lead to excessive isoflavone intake	Most supplements provide only the amount of isoflavones found in about one serving of a traditional soyfood
Lack of safety data and historical precedent for use	Isoflavone source is unlikely to influence biological outcome
Poor quality control – the amount of active ingredient listed on the product label often differs from the actual product content	Many supplement providers participate in quality-assurance programs

Objection 1: isoflavone supplements are not as beneficial as soyfoods

Clinical trials using single nutrients often fail to produce results that support either epidemiologic observations about the benefits of consuming foods rich in those nutrients or preliminary laboratory work using these nutrients in isolation [204,205]. Whether this simply represents a failure of epidemiology [206] or an overly simplistic understanding of the diet–chronic disease relationship is unclear, but certainly these discrepancies highlight the need for a cautious approach towards the use of supplements.

Like all plants foods, the soybean contains many biologically active components. Furthermore, there are benefits of soy consumption that supplements can not provide, such as cholesterol reduction attributed to the protein [207]. Similarly, the hypotensive effect of soy noted in some studies [208,209] is more likely to be caused by peptides than by isoflavones [210]. However, the preponderance of evidence suggests isoflavones are responsible for most of the proposed benefits of soy, including the inhibition of bone resorption [5,61,203], alleviation of hot flashes [4,70,71], improvement in arterial health [83] and reduction in the risk of breast [89] and prostate cancer [211]. Not only does this contention make biological sense, but clinical trials provide direct support. Thus, lack of efficacy per se, at least in regard to specific health outcomes, would not appear to be a justifiable argument against the use of isoflavone supplements.

Objection 2: supplements discourage dietary change

Overall, when traditional soyfoods replace more common sources of protein in Western diets, dietary quality is often improved; for example, saturated fat and cholesterol intake are decreased and folate and potassium intake are increased. Thus, there is the potential for both direct and indirect benefits from incorporating soyfoods into the diet. However, this is not the case for all substitutions; for example, in instances when soynuts replace nuts or soy breakfast cereals replace oat or whole grain cereals. Despite this, the consumption of these soyfoods is still encouraged. Thus, the lack of improvement in dietary content alone is not a justifiable argument against supplements.

Furthermore, an argument can be made that supplements actually encourage, rather than discourage, soy consumption. If, as the data suggest, at least two and perhaps as many as four servings of soyfoods are needed daily to derive health benefits, many individuals may not feel up to the challenge and opt to consume no soy at all. However, by providing consumers with an approach that includes the use of supplements as a secondary means of obtaining isoflavones when soyfood intake alone is inadequate, attitudes towards soyfood consumption may actually be improved. This type of approach is often recommended for meeting the needs of problem nutrients, such as calcium. This having been said, emphasis should always be placed on foods as the first and primary means of obtaining isoflavones.

Objection 3: supplements lead to excessive isoflavone intake

In theory, the convenience of supplements makes it possible to consume isoflavones in amounts that exceed typical Asian intake more easily than does soyfood use alone. By contrast, analyses show that most supplements provide no more than 30 mg (the amount in approximately one serving of a traditional soyfood) per pill or tablet [212,213]. Therefore, at least four pills/tablets would be required to exceed intakes compatible with Asian soyfood consumption. More importantly, the possibility that a few individuals may overindulge does not justify admonishing the use of all supplements, isoflavone-based or otherwise. Instead, supplement users should be educated as to what is considered a healthy intake. Although there are exceptions, manufacturers of supplements typically recommended a total daily isoflavone intake of approximately 50 mg.

Objection 4: lack of safety data & historical precedent for use

Unlike traditional soyfoods, there is no history of use for isoflavone supplements. Although historical precedent in and of itself does not demonstrate safety, it does provides some level of comfort or assurance in this regard [214]. However, for those areas for which concerns about isoflavones have been raised, some of the more notable findings and observations actually come from studies involving foods and not supplements [135,171,184,215]. In fact, there are issues related to soyfoods – such as the inhibitory effects of phytic acid on mineral absorption and allergic reactions to soy protein – that do not apply to isoflavone supplements. Furthermore, if isoflavone exposure does lead to adverse effects, it appears likely, given relatively similar pharmacokinetics, that isoflavone source (supplements or foods) would be of little importance [180]. As already cited, there is one example in the literature wherein increased processing led to a more undesirable biological effect in rodents [179]; but, as discussed in the section on breast cancer, evidence in humans is not supportive of this finding.

Objection 5: quality-control issues

Several surveys have identified large discrepancies between the amount of active ingredient in supplements and the amount listed on the product label. In the case of isoflavones, one survey found that of the 31 isoflavone supplements analyzed, 15 were within 20% of the stated amount, nine were within 20–40% and six differed by between 50 and 90% [212]. In nearly all cases of significant discrepancies, the supplements contained less, not more, isoflavones than the stated amount. It is worth noting that while the discrepancy between actual amount and product label amount is a legitimate criticism, there is a large variation in the isoflavone content of different batches of the same brand of soy product, and among different brands of the same type of soy product, which in most cases will be unknown to the user [216]. In any event, there are independent quality assurance programs that are used by supplement manufacturers that can provide the consumer with a degree of confidence about their purchase.

Conclusion

The public looks to health professionals for advice on appropriate intakes for food groups and individual foods. There is particular need for intake advice about soyfoods because they are not part of traditional Western diets and their proposed health benefits have generated considerable attention. Postmenopausal women, in particular, have embraced soy as a result of research suggesting soyfoods and soybean isoflavones are useful for addressing many of the diseases and conditions associated with the menopausal years. This perspective has attempted to arrive at a soy intake recommendation based on three considerations: Asian soy intake, clinical and epidemiologic studies assessing the health consequences of soy consumption and general principles of dietary practice. On this basis, it is argued that optimal soy protein and isoflavone intakes are 15–20 g/day and 50–90 mg/day, respectively. Higher soy protein intakes of 25 g/day can be used as the recommendation specifically for cholesterol reduction. Achieving the recommended intake represents a significant dietary challenge for most non-Asians. However, the availability of soy products made from traditional ingredients with characteristics of Western-style foods has made achieving this goal more feasible.

Future perspective

The inconsistent results of clinical studies involving soyfoods and isoflavones prevent making definitive conclusions about their proposed health effects in many areas. Several factors are likely to contribute to this inconsistency including small study sample size, variation among studies in subject baseline characteristics and differences in the chemical composition of intervention products. By considering these different design elements, future research will probably be able to provide more insight into which types of products are most efficacious for specific populations. This insight will allow health professionals to better advise the public about the amounts and types of soy products that hold potential for providing health benefits independent of their nutrient content.

Executive summary

Introduction

Isoflavone and protein content of soyfoods:

– In traditional soyfoods, such as tofu and miso, each gram of protein is associated with approximately 3.5 mg isoflavones expressed as the aglycone weight.

– In the soybean, the two primary isoflavones are genistein and daidzein; there is relatively little of the third isoflavone, glycitein.

Cellular actions of isoflavones:

– Isoflavones have a similar chemical structure to the hormone estrogen, bind to both estrogen receptors (ERs) although preferentially to ERβ, and exert some estrogen-like effects.

– The relative binding affinity of isoflavones is less than that of the hormone estrogen, but in people consuming soyfoods or using soy supplements, circulating isoflavone concentrations are as much as 1000-fold higher than estrogen.

– Isoflavones are often classified as selective ER modulators but also have ER-independent actions in cells, although the physiological relevance of these effects is unclear.

Asian soy intake:

– In Japan and Chinese cities such as Shanghai, mean daily soy protein and isoflavone intakes are approximately 8–12 g and 25–40 mg, respectively.

– In Japan, approximately half of the isoflavone intake comes from fermented (e.g., miso and natto) soyfoods and half comes from nonfermented soyfoods (e.g., tofu) whereas in Shanghai most soy is consumed in nonfermented forms.

Review of health effects

Clinical studies:

– Introduction: clinical studies that have examined the effects of soyfoods and isoflavone supplements on changes in bone mineral density (BMD), arterial health and the alleviation of hot flashes, have produced encouraging although somewhat inconsistent results. In these studies, subjects were generally exposed to between 50 and 100 mg/day isoflavones.

– BMD: more than 20 clinical studies have examined the effects of soyfoods or isoflavone supplements on BMD. Despite the mixed results, a recently published meta-analysis concluded that isoflavones inhibit postmenopausal spinal bone loss and that the optimal dose is >90 mg/day.

– Hot flash alleviation: results from the approximately 50 studies that have evaluated the effects of isoflavone-containing products on the alleviation of hot flashes in postmenopausal women have produced mixed results. Evidence indicates that at least some of the inconsistent clinical data stem from the variable genistein content of the intervention products; those products higher in this isoflavone are more consistently efficacious.

Systemic arterial compliance and endothelial function:

– Systemic arterial compliance involves the ability of the aorta to distend during the elevated blood pressure associated with systolic ejection and recoil during the resting diastolic phase of the cardiac cycle.

– Endothelial cells in the intima layer of blood vessels play a central role in inhibiting the development of atherosclerosis and its thrombotic consequences.

– Several clinical studies have found that in response to between 50 and 100 mg/day, isoflavones improved systemic arterial compliance and endothelium-dependent flow-mediated dilation of the brachial artery.

Epidemiologic studies:

– Introduction: Asian epidemiologic investigations involving soyfoods have involved a wide array of health outcomes and diseases. Epidemiologic studies involving Western subjects probably provide little insight into the health effects of soy, since intake is almost certainly too low to exert biological effects.

– Coronary heart disease: results from several case-control and prospective studies suggest that soyfoods exert lipid-independent coronary benefits as evidenced by the lower levels of coronary heart disease and myocardial infarction associated with soy intake beyond that which could be attributed to the cholesterol-lowering effects of soy protein.

– Osteoporosis: soy intake among Asians is generally associated with greater BMD. The one prospective study to include fractures as an end point found that relative risk was reduced by approximately a third when comparing Chinese postmenopausal women in the fifth with those in the first soy protein intake quintile.

Perspective on the US FDA soy protein health claim

The US FDA established 25 g/day soy protein as the threshold intake for cholesterol reduction.

Substituting 25 g soy protein for other sources of protein in the US diet would result in a diet in which soy protein comprises approximately 26 and 38% of total protein intake for men and women, respectively.

Since most individuals when incorporating soyfoods into the diet are unlikely to make a 1:1 substitution of soy protein for nonsoy protein, the overall protein intake would probably increase.

The protein content of the diet as a result of greater soyfood consumption would not exceed the guidelines issued by the US Institute of Medicine.

Safety considerations

Questions about the safety of soyfoods and especially isoflavone supplements have been raised despite the FDA conclusions at the time the soy protein and coronary heart disease health claim was approved that these claims were without merit.

Most issues related to safety are based on the estrogen-like effects of isoflavones.

For women, the major concern is the possibility, as shown in athymic ovariectomized mice, that isoflavones could stimulate the growth of existing estrogen-sensitive tumors.

Clinical studies show that isoflavone-containing products do not stimulate breast cell proliferation or increase breast tissue density and are, therefore, supportive of safety.

Estimates of efficacious intakes: epidemiologic versus clinical studies

In general, isoflavone doses shown to be efficacious in clinical studies are higher than the intake associated with health benefits in epidemiologic studies.

One explanation for this discrepancy, although speculative, is that the more processed forms of soy, which are generally used in the clinical studies, are less efficacious than the traditional soyfoods as consumed by Asians outside the clinical setting.

A second explanation is that the benefits identified in epidemiologic studies reflect lifelong or long-term soy consumption.

Arguments for & against the use of supplements

In general, nutritionists recommend that nutrients and other dietary constituents be obtained from foods rather than supplements; however, this is not easily accomplished in the case of isoflavones.

Although soyfoods should be the first and primary means of obtaining isoflavones, for specific health outcomes isoflavone supplements appear to represent a useful approach.

Conclusion

Based on Asian soy intake, clinical and epidemiologic studies assessing the health consequences of soy consumption and general principles of dietary practice, the optimal soy protein and isoflavone intakes appear to be from 15 to 20 g/day and 50 to 90 mg/day, respectively.

Footnotes

The author regularly consults for companies and organizations involved in the soyfood industry, including those that manufacture and/or sell soyfoods and/or soy supplements. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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51.

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52.

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53.

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54.

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55.

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56.

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57.

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58.

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59.

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62.

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63.

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64.

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66.

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67.

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68.

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69.

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71.

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74.

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75.

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76.

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77.

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78.

A 12-week intervention study that not only found isoflavone supplements reduced the severity of hot flashes and, based on breast biopsies, also found that isoflavones did not affect cell proliferation and other markers of estrogenicity.

79.

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80.

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81.

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82.

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83.

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84.

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85.

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86.

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87.

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88.

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89.

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90.

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91.

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93.

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94.

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96.

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97.

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98.

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99.

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102.

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116.

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117.

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126.

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Investigating the Optimal Soy Protein and Isoflavone Intakes for Women: A Perspective

Abstract

Keywords

Isoflavone & protein content of soyfoods

Cellular actions of isoflavones

Asian soy intake

Review of health effects

Clinical studies

Bone mineral density

Hot flash alleviation

Systemic arterial compliance & endothelial function

Epidemiologic studies

Coronary heart disease

Osteoporosis

Perspective on the US FDA soy protein health claim

Safety considerations

Cognitive function

Thyroid function

Effects on hormone levels & endometrial tissue

Breast cancer

Estimates of efficacious intakes: epidemiologic versus clinical studies

Arguments for & against the use of supplements

Objection 1: isoflavone supplements are not as beneficial as soyfoods

Objection 2: supplements discourage dietary change

Objection 3: supplements lead to excessive isoflavone intake

Objection 4: lack of safety data & historical precedent for use

Objection 5: quality-control issues

Conclusion

Future perspective

Footnotes

References