SOY MYTHS & FACTS

Healthy Family Consumes Soy

 

Introduction

Traditional soyfoods have played an important role in East Asian diets for centuries, and have been consumed by health-conscious individuals in Western countries for decades. More recently, soyfoods have become increasingly popular among mainstream consumers in the West, largely because of research suggesting they offer health benefits independent of the nutrients they provide and because of an increased interest in plant-based diets. Possible benefits include reduced risk of coronary heart disease [1-3], osteoporosis [4-6] and some forms of cancer [7]. Many of the purported benefits of soyfoods are attributed to their uniquely rich isoflavone content. However, isoflavones, which are diphenolic molecules with estrogen-like properties, are also the primary reason that concerns about the potential adverse effects of soyfoods that have been raised.

However, as listed below, several health agencies and academic groups after extensively reviewing the data have concluded that soyfoods do not exert untoward effects:

  • In 1999, as part of the process for approving the soy and coronary heart disease-health claim, the U.S. Food and Drug Administration (FDA) concluded that soyfoods are safe for all except those who are allergenic to soy protein [8]. Most of the concerns being raised today were considered by the FDA.
  • In 2005, the Agency for Healthcare Research and Quality identified only minor problems associated with the intake of large amounts of soy, such as mild gastrointestinal disturbances [9].
  • In 2009, a meta-analysis conducted by Austrian researchers, which was undertaken specifically to address the safety of isoflavone supplements, concluded they have a safe side-effect profile [10].
  • In 2014, Health Canada, which is analogous to the U.S. FDA, approved a health claim for soy protein and coronary heart disease and concluded after reviewing the data that the adverse effects of soy consumption were generally minor and gastrointestinal in nature [11].
  • In 2015, the European Food Safety Authority (EFSA), which is analogous to the U.S. FDA, concluded that the evidence does not suggest there are harmful effects on the three organs considered for their assessment – mammary gland, uterus and thyroid gland [12].

Several specific issues related to soy are discussed below but first, comments about evaluating research are provided.

 

Considerations in Evaluating Soy Research

Most scientists agree that there is a legitimate basis for discussion about potential adverse effects of soy consumption, at least in some individuals and under certain circumstances. It is not surprising that among the approximate 2,000 soy-related scientific papers published annually that some studies, especially in vitro and animal studies, have raised a potential concern.

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However, the relevance of in vitro and animal studies to understanding the effects of soyfoods in humans is questionable. Clearly, in vitro conditions cannot duplicate the complexity of living organisms, human or otherwise. Furthermore, 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. The biological impact of one nutrient or non-nutrient in a food can be affected by the presence of others [13, 14].

Studies in rats and mice 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 [15-22]. Therefore, one may derive at most, only very limited insight about the possible effects of soyfoods in humans based on the results from studies in which rodents are fed isoflavone-rich soy protein or mixed isoflavones as are naturally found in soybeans.

It is also important to recognize that many highly investigated foods and food components have been linked with adverse effects in a small minority of studies including foods that are routinely recommended by nutritionists for their healthful properties. For example, whole grains contain phytate (as do soyfoods), which can decrease mineral absorption [23]. Nevertheless, the nutrition community recommends the intake of whole grains because the overwhelming preponderance of evidence indicates they are nutritionally beneficial [24, 25]. Conclusions about the healthfulness of any food need to be based on the totality of the evidence with careful consideration given to the strengths and weaknesses of study designs.

How Much Soy Protein and Isoflavones do Asians and Americans Consume?

There is confusion about the role soy plays in the diets of Asian populations and about how much soy protein and isoflavones Americans consume. Soy protein is widely used by the U.S. food industry and is found in small amounts in an extensive array of foods. Soy protein is added to foods primarily for its functional purposes, e.g., to improve shelf stability and texture. Consequently, U.S. daily per capita soy protein intake is only 1 to 2 g per day, representing about two percent of total protein intake [26]. Since soy protein intake is low, isoflavone intake is also very low. This is true not only because of the minimal amounts of soy protein consumed but because the protein used by the food industry is typically quite low in isoflavones. According to a recent analysis, which used the USDA isoflavone database and the National Health and Nutrition Examination Survey III 24-hour dietary recall data to estimate intake, adult Americans ingest only 2.35 mg isoflavones daily [27]. There are approximately 25 mg isoflavones in one cup of soymilk.

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Soy consumption among Asian countries markedly differs. Japan is at the higher end of the dietary spectrum whereas Hong Kong is at the lower end. In Japan, the daily intake of soy protein by older individuals is approximately 8 to10 g, which represents about 10 percent of their total protein intake [28]. Chinese soy intake varies markedly among regions. Large studies from Shanghai, a high-soy-consuming area, indicate men consume anywhere from about 9 g to as much as 12 to 13 g of soy protein per day [29], the latter figures represent about 15 percent of total protein intake [30]. Shanghainese women consume about 9 g per day [31]. Individuals in the upper quarter of intake consume about 15 to 20 g soy protein daily. Ten g of soy protein translates to about 1.5 servings since one serving of a traditional soyfood provides about 7 g protein, although some soyfoods can provide considerably more than this amount.

Surprisingly, there is also confusion in the popular media about the type of soy consumed in Asia as it is common to see stated that only fermented soyfoods are used. In actuality, unfermented soyfoods play a bigger role. In Japan, approximately half of the soy consumed comes from unfermented foods, with four foods – tofu, miso, natto and fried tofu – accounting for about 90 percent of all soy consumption [32, 33]. In contrast, in Shanghai, and throughout much of China, most of the soyfoods consumed are unfermented, and soymilk, tofu and processed soy products other than tofu account for about 80 percent of total soy consumption [1].

Finally, soy protein intake can be used to estimate isoflavone intake because in traditional Asian soyfoods, each gram of protein is associated with approximately 3.5 mg isoflavones. However, because the processing used in the making of more refined soy products such as isolated soy protein (ISP) can cause as much as 80 percent of the isoflavone content to be lost, estimating isoflavone intake when a mix of modern soy products and traditional Asian soyfoods is consumed is difficult.

 

Hormonal Balance

Isoflavones bind to and transactivate estrogen receptors and can potentially influence steroid hormone synthesis and metabolism via their effects on enzymes involved in a variety of metabolic pathways [34, 35]. Not surprisingly therefore, there has been investigation of the effects of isoflavone-rich soy products and isoflavone supplements on hormone levels in both men and women. Some of this research was aimed at determining whether decreases in testosterone and estrogen levels might account for the proposed role of soy in reducing risk of hormonally-influenced cancers. However, the clinical data indicate that levels of these hormones are not affected.

According to the conclusions of two meta-analyses, neither soyfoods nor isoflavone supplements show clinically-relevant effects on reproductive hormone levels in men [36, 37] or women [38-40] despite in many studies exposure greatly exceeding typical Japanese intake. One meta-analysis, which included 32 studies and 36 treatment groups, evaluated the effects of soy products on total and free testosterone in men [41]. The other, which included 47 studies, evaluated the effects of soy products on levels of estradiol and other reproductive hormones in pre- and postmenopausal women [42]. In addition, a comprehensive review of the clinical research, found no evidence that isoflavone exposure affects circulating estrogen levels in men [43]. Estrogen is typically thought of a female hormone but men also synthesize estrogen; in fact, estrogen levels in older men are higher than in older women [44, 45].

Fertility

Given the large populations of Asian countries that have historically consumed soy, it is somewhat ironic and almost nonsensical that concerns regarding soy intake and fertility have been raised. On the other hand, in many respects the biological effects of isoflavones first came to the attention of the scientific community in the 1940s because of breeding problems experienced by female sheep in Western Australia grazing on a type of clover rich in isoflavones [46-48]. Also, two decades ago it was established that isoflavone-rich soy, which was part of the standard diet of cheetahs in North American zoos, was a factor in the decline of fertility in these animals [49].

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However, problems in the cheetah are thought to have arisen because felines are poorly able to glucuronidate phenolic compounds, a major step in the bodily elimination of isoflavones – a good example of differences in isoflavone metabolism between animals and humans [50-53]. In the case of sheep, serum levels of equol – a bacterially synthesized metabolite of the soybean isoflavone daidzein – far exceeded anything approaching human levels simply because daily isoflavone intake was estimated to be several grams [54], which dwarfs the 40 mg typically consumed by older Japanese [28].

In women, soyfoods appear to increase the length of the menstrual cycle. However, ovulation is not prevented, but is simply delayed by one day [42]. Interestingly, longer cycles are associated with a decreased breast cancer risk [55]. Furthermore, there is actually some evidence that isoflavones aid fertility. For example, 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 [56].

Also, soy consumption appears to negate the adverse reproductive effects of the endocrine disruptor bisphenol A (BPA). In a study involving 239 women undergoing in vitro fertilization, among those who did not consume soyfoods, urinary BPA levels were inversely related to live birth rates per initiated cycle whereas no such relationship existed among soy-consumers [57]. Although the low isoflavone intake among the soy-consumers (mean intake, 3.4 mg/d) would normally raise doubt about the plausibility of these findings, they do agree with animal data [58, 59].

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 [60]. 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 infertility treatment with 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 birth among couples attending an infertility clinic [61].

More importantly, all three of the clinical studies conducted show that isoflavones have no effect on sperm concentration or quality [62-64]. 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 and allowed the couple to conceive [65].

Soy, Isoflavones and Thyroid Function

The first animal studies investigating the effects of soy intake on thyroid function were published 80 years ago [66-68]. Concerns about the anti-thyroid effects of soy are based primarily on in vitro research [69, 70] and studies in rodents administered isolated isoflavones [71, 72]. 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 [66, 67, 73].

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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 healthy men or women [74]. Studies published since this review are supportive of the conclusion [75-79]. One of these is a 3-year study that included more than 200 postmenopausal women who were given daily supplements that provided either 80 mg or 120 mg isoflavones [80]. Another study which found no effects of isoflavones on thyroid function is especially notable not only because of its 3-year duration but because in addition to measuring thyroid hormones (thyroid stimulating hormone, thyroxine and triiodothyronine) very sensitive indicators of thyroid function – thyroid hormone receptor and retinoid receptor expression from peripheral blood monocytes – were assessed [81]. Not surprisingly, as noted previously, the EFSA concluded that isoflavone supplements don’t affect thyroid function [12].

Although soy has no effect on thyroid function in euthyroid individuals, 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 the medication [82-85]. Soy is not unique in this regard however as many herbs and drugs and fiber and calcium supplements have similar effects [86-94]. 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.

According to a recent position paper from the Pharmacy and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society, it is not necessary to avoid any particular food, or even to take thyroid hormone during the fasting state, but rather, it is important to maintain consistency in medication administration and dietary habits. As long as the medication is taken in a consistent manner and the amount of soyfoods consumed is relatively constant, soyfoods are not an issue [95].

Another thyroid-related question is whether soy may worsen thyroid function in those whose thyroid function is compromised such as subclinical hypothyroid patients and in those whose iodine intake is marginal. Of course, all individuals should be sure to consume adequate iodine. The concern about iodine intake is based on the potential for isoflavones rather than the amino acid tyrosine to be iodinated, thereby inhibiting the synthesis of thyroid hormone [96]. However, clinical research published in 2012 indicates that the iodination of isoflavones is negligible and clinically irrelevant [97].

Only one study has evaluated the effect of soy on subclinical hypothyroid patients. Approximately five percent of the general adult population, and a higher percentage among individuals over the age of 60, have this condition [98]. With time, a certain percentage (~2-6%/year) of these patients, who have normal triiodothyronine and thyroxine levels but elevated levels of thyroid stimulating hormone, will spontaneously progress to overt hypothyroidism [99].

The study in question involved 60 middle-aged, overweight British patients (52 females). They consumed in random order for eight weeks, 30 g ISP containing 2 or 16 mg isoflavones separated by an eight week washout [100]. During the entire 6-month study period, 6 (10%) of the participants consuming the higher-isoflavone-ISP progressed to overt hypothyroidism whereas none did in the low isoflavone group.

These results were unexpected given the relatively small isoflavone intake of the study participants and because the progression of subclinical to overt hypothyroidism among Japanese patients is not elevated [101]; nor does Japan have higher rates of hypothyroidism [102]. Since this study is the only one to be conducted it isn’t possible to reach any firm conclusions about soy and subclinical hypothyroid patients. Furthermore, in response to the higher-isoflavone-ISP, all of the participants in this study, including those who became hypothyroid, experienced marked reductions in systolic and diastolic blood pressure, insulin resistance and inflammation (as assessed by C-reactive protein). Therefore, in theory, isoflavones markedly reduced risk of cardiovascular disease and diabetes in these patients.

Soyfoods and Breast Cancer Risk

The estrogen-like effects of isoflavones form the theoretical basis for concern that soyfoods are contraindicated for women with an increased risk of developing breast cancer and for women with estrogen-sensitive breast cancer [103-107]. However, the evidence that estrogen therapy increases risk of developing breast cancer is unimpressive. This point is reinforced by the results of the Women’s Health Initiative Trial, which involved over 10,000 women, half of whom received a placebo and the other half conjugated equine estrogens (CEE). Over a 13-year period (average duration of use, 7.2 years), women in the CEE were significantly less likely to develop invasive breast cancer than were women in the placebo group (p=0.02) [108].

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Nevertheless, in one mouse model, isoflavones stimulate the growth of existing estrogen-responsive mammary tumors [109, 110]. However, not all rodent models show that soy or isoflavones stimulate the growth of existing mammary tumors [111-113] and even in the rodent model that does, minimally processed soyfoods do not have this effect [114]. Furthermore, slightly tweaking this model causes a complete loss of the ability of isoflavones to stimulate tumor growth [112]. And, as has been already mentioned, because rodents metabolize isoflavones differently than humans, the value of rodent studies for understanding effects in humans is in doubt [15-20]. More importantly, the human data indicate that isoflavones, regardless of the source, do not exert harmful effects on breast tissue.

Although no clinical trials evaluating the effects of soy or isoflavones on breast cancer recurrence have been conducted, many studies have investigated effects on markers of breast cancer risk including mammographic density [115, 116] and in vivo breast cell proliferation [38, 117-121]. The latter studies require taking biopsies at study enrollment and termination. These studies show isoflavone exposure, even at doses much higher than typical Japanese intake, do not adversely affect breast tissue. In contrast to the lack of effects of isoflavones, estrogen plus progestin therapy, which increases breast cancer risk [122], increases breast cell proliferation four to ten-fold within just 12 weeks [123, 124].

Furthermore, the prospective epidemiologic data show that post-diagnosis soy intake improves prognosis. To this point, a meta-analysis of five prospective studies, two from the United States and three from China, involving over 11,000 women with breast cancer, found soy consumption after a diagnosis of breast cancer was associated with reductions in both breast cancer recurrence (hazard ratio, 0.85; 95% confidence interval: 0.77, 0.93) and mortality (hazard ratio, 0.79; 95% confidence interval: 0.72, 0.87). Importantly, soy consumption is similarly beneficial in Asian and non-Asian women. Also, in contrast to studies in mice, the epidemiologic data suggest that soy consumption may actually enhance the efficacy of chemotherapeutic agents used to treat breast cancer [125, 126].

Given the above data, it is not surprising that after a multi-year comprehensive review, the EFSA concluded that isoflavone supplements do not increase breast cancer risk when taken by postmenopausal women [12]. Both the American Cancer Society [127] and the American Institute for Cancer Research [128] have concluded that soyfoods can be safely consumed by breast cancer patients. And the World Cancer Research Fund International concluded there is a possible link between consuming soyfoods and improved breast cancer prognosis [129].

Effects of Soy on Mineral Status

Soyfoods are frequently used in place of animal foods, many of which are good sources of iron, zinc and, in the case of dairy foods, calcium. Relatively little red meat is needed to meet daily iron and zinc requirements, so questions about the effects of soy on the status of these two minerals pertains mostly to those eating a predominately plant-based diet [130].

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As noted previously, soybeans, like other legumes and whole grains, are high in phytate [131], which reduces the absorption of some minerals, including zinc and iron [132]. Zinc absorption from soyfoods is only modestly lower than that from other sources. However, because soybeans contain relatively little zinc, unfortified soyfoods are not particularly good sources of this mineral [133-136]. Zinc status is difficult to assess [137, 138] and those consuming a plant-based diet are advised to identify good plant sources of zinc in their diet or to take a zinc supplement [139-143].

In contrast to zinc, soyfoods are relatively high in iron [144]. Until fairly recently, it was believed that the iron in essentially all plant foods, including soyfoods, was poorly absorbed. However, relatively new research utilizing improved methodology indicates that iron absorption from soy may be much higher than previously thought because most of the iron in soy is in the form of ferritin. Although there is debate about the bioavailability of ferritin iron, two important clinical studies in which participants were fed either soyfoods or soybean ferritin show it to be highly bioavailable [145, 146].

In support of these observations are the results from a study designed specifically to examine the effect of soyfoods on mineral status. In this study, young premenopausal women consumed either two or three servings of soyfoods daily or non-soyfoods matched for type of food—such as hamburgers in place of soy burgers or cow’s milk in place of soymilk. Results showed there were no statistically significant effects of soy on urinary and serum zinc, serum hemoglobin and iron, or transferrin saturation [79].

Finally, a study published in 2015 shows that in contrast to older understanding [147] there appears to be adaptation to the inhibitory effects of phytate on iron absorption [148]. For this study, 32 nonanemic premenopausal women with suboptimal iron stores were randomly assigned to high or low-phytate diet for eight weeks. The serum iron response over four hours after a test meal containing 350 mg of phytate was measured at baseline and postintervention. The serum iron response to the test meal increased in the high-phytate group at post intervention, resulting in a 41percent increase in the area under the curve. However, no effect was observed in the low-phytate group.

In addition to phytate, soybeans are also high in oxalate, another compound that binds calcium and reduces its absorption [149]. Oxalate is one reason that even though spinach is high in calcium it is not a good source of this mineral. Despite the presence of both phytate and oxalate, calcium absorption from soybeans is surprisingly good [150]. This is also true for calcium-set tofu [151] and calcium-fortified soymilk [152, 153]. In fact, the absorption of calcium from these foods is comparable to the absorption of calcium from cow’s milk.

Bioavailability of calcium from calcium-fortified products, such as soymilk, depends to some extent on the type of supplemental calcium used [151]. When calcium carbonate is used as the fortificant in soymilk, absorption is similar to that seen with cow’s milk [152]. In contrast, calcium absorption from soymilk fortified with tricalcium phosphate is about 25 percent lower than from cow’s milk [154]. However, because of the high amounts of tricalcium phosphate added, the amount of calcium available to the body from both types of calcium-fortified soymilk is similar to that from cow’s milk [152].

Finally, there have been questions about the solubility of calcium in soymilk. Some research indicates that, even with vigorous shaking, the calcium in soymilk comes out of the solution [155]. While some sedimentation may occur in certain soymilks, this sediment is re-suspended with mild shaking for the majority of soymilk purchased in the United States.

Allergies

Soy protein can cause allergic reactions in sensitive individuals, as is the case for essentially all food proteins. Soy protein is one of the eight foods responsible for approximately 90 percent of all food-induced allergic reactions in the United States [156]. However, these foods are not equally allergenic and allergy to soy protein is relatively rare [157]. A nationally representative telephone survey found that an estimated one in 2,500 adults reported having a doctor-diagnosed allergy to soy protein [158]. This survey found that cow’s milk allergy (CMA) is about 40 times more common than soy allergy. The prevalence of soy allergy is higher in children than adults, as children are more likely to have food allergies in general. However, by age 10, an estimated 70 percent of children will outgrow their soy allergies [159]. Consequently, it is estimated that by that age, only approximately one out of 1,000 children are allergic to soy. It should be noted that soybean-specific IgE titers are not an effective predictor of a positive response to the food challenge test [160].

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According to the American Academy of Pediatrics (AAP), extensively hydrolyzed protein formula should be considered as the first alternative for infants with documented CMA (especially for IgE-mediated reactions), because 10 to 14 percent of these infants will also have a soy protein allergy [161]. However, recently conducted British research found that of the 60 percent of all infants with CMA who were initially treated with soy, only nine percent of patients remained symptomatic [162]. In contrast, of the 18 percent of patients treated with extensively hydrolyzed formula, 29 percent remained symptomatic. The results from a small retrospective study from Portugal, which evaluated children with persistent CMA, also suggest that soy formula may have advantages over hydrolyzed formulas [163].

Finally, in 2013, the first systematic review and meta-analysis of studies evaluating the prevalence of IgE-mediated soy allergies in infants and children was published [164]. The analysis, which included 40 studies, found that the prevalence of soy allergies ranged from 0 to 0.5 percent for the general population, 0.4 to 3.1 percent for the referred population (those referred to an allergy clinic for evaluation of food-related problems or other allergy issues), and 0 to 12.9 percent for allergic (atopic) children. The authors concluded concern about soy allergy is no reason to postpone the use of soy infant formula in IgE-mediated CMA infants.

Soy Infant Formula

Soy infant formula (SF) has been in use for more than 50 years. A nationally representative sample of 1,864 infants, 0 to 12 months old, from the National Health and Nutrition Examination Survey, 2003-2010, found that among the 81 percent of infants who were fed formula or regular milk, 12.9 percent consumed soy formula [165]. An estimated 20 million infants have used SF over the past 40 years.

SF produces normal growth and development; nevertheless, SF use has become controversial because of its high isoflavone content. In 2009, the U.S. National Toxicology Program (NTP) concluded there was minimal concern about the safety of SF [166]. In response to this conclusion, the AAP submitted a letter to the NTP, which is now part of the public record, stating that, in their view, there was negligible concern about the safety of SF. The five levels of concern are negligible, minimal, some, concern and serious concern.

Over the next few years, considerable insight to the health effects of SF will be gained as a result of research underway at the Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences. At this center, the health status of infants fed breast milk, cow’s milk formula and SF is being compared. Thus far, findings indicate that all health parameters assessed in infants fed SF are well within the normal range [167-171]. Nevertheless, continued research in this area is warranted.

Finally, the first systematic review and meta-analysis focused on the safety of SF concluded that SF intake in normal full-term infants – even during the most rapid phase of growth – is associated with normal anthropometric growth, adequate protein status, bone mineralization and normal immune development [172].

 

Soyfood Processing

Tofu and miso are commonly consumed soyfoods in Asia whereas in the United States, many people choose more processed forms of soy such as meat analogs and energy bars [28]. Numerous human studies demonstrate that processed soy products provide very high-quality protein [173, 174].

Depending on processing methods, the isoflavone content of these foods can be markedly reduced [175]. The isoflavone content of a large number of soy-containing foods can be found in an online database created by Iowa State University and the United States Department of Agriculture at: http://www.ars.usda.gov/services/docs.htm?docid=6382

Many traditional soyfoods such as miso, tempeh and natto undergo fermentation. While mineral absorption may be very slightly improved with fermentation and may give rise to other potentially beneficial compounds, there is little evidence that these foods are superior to unfermented ones. In fact, several epidemiologic studies show protective effects against different cancers of non-fermented but not fermented soyfoods [176, 177]. Non-fermented soyfoods have been consumed in Japan [178] and China [179] for at least 500 years and 1,000 years, respectively. In Japan, where many unfermented foods are popular, at least half of the total soy consumed comes from foods that are not fermented [32, 33]. And in China, most of the soy is consumed in non-fermented form [1].

Summary and Conclusions

When evaluating the safety of soyfoods, it is imperative to consider the totality of the scientific research and to place appropriate weight on studies according to their experimental design. The research overall indicates that soyfoods can be safely incorporated into the diets of essentially all healthy individuals with the exception of those allergic to soy protein. Nevertheless, because all foods have the potential to cause undesirable effects in some individuals, people with specific health concerns should consult their healthcare provider regarding unique nutritional needs.

References

  1. Zhang, X., et al., Soy food consumption is associated with lower risk of coronary heart disease in Chinese women. J Nutr, 2003. 133(9): p. 2874-8.
  2. Kokubo, Y., et al., Association of dietary intake of soy, beans, and isoflavones with risk of cerebral and myocardial infarctions in Japanese populations: the Japan Public Health Center-based (JPHC) study cohort I. Circulation, 2007. 116(22): p. 2553-62.
  3. Messina, M. and B. Lane, Soy protein, soybean isoflavones, and coronary heart disease risk: Where do we stand? Future Lipidology, 2007. 2: p. 55-74.
  4. Ma, D.F., et al., Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. Eur J Clin Nutr, 2007.
  5. Marini, H., et al., Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med, 2007. 146(12): p. 839-47.

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  • Koh, W.P., et al., Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am J Epidemiol, 2009. 170(7): p. 901-9.
  • Shu, X.O., et al., Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev, 2001. 10(5): p. 483-8.
  • Food Labeling: Health Claims; Soy Protein and Coronary Heart Disease, in Federal Register: (Volume 64, Number 206)]1999. p. 57699-57733.
  • Balk, E., et al., Effects of soy on health outcomes. Evidence report/technology assessment No. 126 (prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022.) AHRQ Publication No. 05-E024-2., July 2005: Rockville, MD Agency for Healthcare Research and Quality.
  • Tempfer, C.B., et al., Side effects of phytoestrogens: a meta-analysis of randomized trials. Am J Med, 2009. 122(10): p. 939-46 e9.
  • Benkhedda, K.B., B, et al., 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. 4:22 | doi: 10.5772/59411.
  • EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), 2015. Scientific opinion on the risk assessment for peri- and post-menopausal women taking food supplements containing isolated isoflavones. EFSA J, 2015. 13(10): p. 4246 (342 pp).
  • Rozen, P., et al., Calcium supplements interact significantly with long-term diet while suppressing rectal epithelial proliferation of adenoma patients. Cancer, 2001. 91(4): p. 833-40.
  • Bolca, S., et al., Cosupplementation of isoflavones, prenylflavonoids, and lignans alters human exposure to phytoestrogen-derived 17beta-estradiol equivalents. J Nutr, 2009. 139(12): p. 2293-300.
  • Wisniewski, A.B., et al., Exposure to genistein during gestation and lactation demasculinizes the reproductive system in rats. J Urol, 2003. 169(4): p. 1582-6.
  • Fielden, M.R., et al., 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(4): p. 447-54.
  • Ojeda, S.R., et al., Recent advances in the endocrinology of puberty. Endocr Rev, 1980. 1(3): p. 228-57.
  • Robinson, J.D., et al., Amniotic fluid androgens and estrogens in midgestation. J Clin Endocrinol Metab, 1977. 45(4): p. 755-61.
  • Gu, L., et al., Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr, 2006. 136(5): p. 1215-21.
  • Setchell, K.D., et al., Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr, 2011. 94(5): p. 1284-94.
  • Jiang, H., et al., A robust analytical method for measurement of phytoestrogens and related metabolites in serum with liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci, 2016. 1012-1013: p. 106-112.
  • Islam, M.A., et al., Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. Toxicol In Vitro, 2015. 29(4): p. 706-15.
  • Larsson, M., et al., Improved zinc and iron absorption from breakfast meals containing malted oats with reduced phytate content. Br J Nutr, 1996. 76(5): p. 677-88.
  • Harris, K.A. and P.M. Kris-Etherton, Effects of whole grains on coronary heart disease risk. Curr Atheroscler Rep, 2010. 12(6): p. 368-76.
  • Slavin, J., Whole grains and human health. Nutr Res Rev, 2004. 17(1): p. 99-110.
  • Smit, E., et al., Estimates of animal and plant protein intake in US adults: results from the Third National Health and Nutrition Examination Survey, 1988-1991. J Am Diet Assoc, 1999. 99(7): p. 813-20.
  • Bai, W., C. Wang, and C. Ren, Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr, 2014. 65(1): p. 9-20.
  • Messina, M., C. Nagata, and A.H. Wu, Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer, 2006. 55(1): p. 1-12.
  • Lee, S.A., et al., Assessment of dietary isoflavone intake among middle-aged Chinese men. J Nutr, 2007. 137(4): p. 1011-1016.
  • Villegas, R., et al., Validity and reproducibility of the food-frequency questionnaire used in the Shanghai men's health study. Br J Nutr, 2007. 97(5): p. 993-1000.
  • Yang, G., et al., Longitudinal study of soy food intake and blood pressure among middle-aged and elderly Chinese women. Am J Clin Nutr, 2005. 81(5): p. 1012-7.
  • Wakai, K., et al., Dietary intake and sources of isoflavones among Japanese. Nutr Cancer, 1999. 33(2): p. 139-45.
  • Somekawa, Y., et al., Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet Gynecol, 2001. 97(1): p. 109-115.
  • Rice, S., H.D. Mason, and S.A. Whitehead, Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells. J Steroid Biochem Mol Biol, 2006. 101(4-5): p. 216-25.
  • Lacey, M., et al., Dose-response effects of phytoestrogens on the activity and expression of 3beta-hydroxysteroid dehydrogenase and aromatase in human granulosa-luteal cells. J Steroid Biochem Mol Biol, 2005. 96(3-4): p. 279-86.
  • Dillingham, B.L., et al., Soy protein isolates of varying isoflavone content exert minor effects on serum reproductive hormones in healthy young men. J Nutr, 2005. 135(3): p. 584-91.
  • Hamilton-Reeves, J.M., et al., Isoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-{beta} expression or serum hormonal profiles in men at high risk of prostate cancer. J Nutr, 2007. 137(7): p. 1769-1775.
  • Cheng, G., et al., Isoflavone treatment for acute menopausal symptoms. Menopause, 2007. 14(3 Pt 1): p. 468-73.
  • Brown, B.D., et al., Types of dietary fat and soy minimally affect hormones and biomarkers associated with breast cancer risk in premenopausal women. Nutr Cancer, 2002. 43(1): p. 22-30.
  • Duncan, A.M., et al., Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab, 1999. 84(10): p. 3479-84.
  • Hamilton-Reeves, J.M., et al., Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis. Fertil Steril, 2010. 94(3): p. 997-1007.
  • Hooper, L., et al., Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update, 2009. 15(4): p. 423-40.
  • Messina, M., Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril, 2010. 93(7): p. 2095-104.
  • Greendale, G.A., S. Edelstein, and E. Barrett-Connor, Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res, 1997. 12(11): p. 1833-43.
  • Simpson, E.R., Sources of estrogen and their importance. J Steroid Biochem Mol Biol, 2003. 86(3-5): p. 225-30.
  • Bennetts, H.W., E.J. Underwood, and F.L. Shier, A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust J Agric Res, 1946. 22: p. 131-138.
  • Bradbury, R.B. and D.R. White, Estrogen and related substances in plants, in Vitamins and Hormones, R.S. Harris, G.F. Marrian, and K.V. Thimann, Editors. 1954, Academic Press: New York. p. 207-230.
  • Lundh, T.J.-O., H.L. Petterson, and K.A. Martinsson, Comparative levels of free and conjugated plant estrogens in blood plasma of sheep and cattle fed estrogenic silage. J Agric Food Chem, 1990. 38: p. 1530-1534.
  • Setchell, K.D., et al., Dietary estrogens--a probable cause of infertility and liver disease in captive cheetahs. Gastroenterology, 1987. 93(2): p. 225-33.
  • Setchell, K.D., N.M. Brown, and E. Lydeking-Olsen, The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr, 2002. 132(12): p. 3577-84.
  • Rowland, I., et al., Bioavailability of phyto-oestrogens. Br J Nutr, 2003. 89 Suppl 1: p. S45-58.
  • Rowland, I.R., et al., Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer, 2000. 36(1): p. 27-32.
  • Redmon, J.M., et al., Soy isoflavone metabolism in cats compared with other species: urinary metabolite concentrations and glucuronidation by liver microsomes. Xenobiotica, 2015: p. 1-10.
  • Urpi-Sarda, M., et al., Tissue distribution of isoflavones in ewes after consumption of red clover silage. Arch Biochem Biophys, 2008. 476(2): p. 205-10.
  • Kurzer, M.S., Hormonal effects of soy in premenopausal women and men. J Nutr, 2002. 132(3): p. 570S-3S.
  • Vanegas, J.C., et al., Soy food intake and treatment outcomes of women undergoing assisted reproductive technology. Fertil Steril, 2015. 103(3): p. 749-55 e2.
  • Chavarro, J.E., et al., Soy intake modifies the relation between urinary bisphenol A concentrations and pregnancy outcomes among women undergoing assisted reproduction. J Clin Endocrinol Metab, 2016: p. jc20153473.
  • Muhlhauser, A., et al., Bisphenol A effects on the growing mouse oocyte are influenced by diet. Biol Reprod, 2009. 80(5): p. 1066-71.
  • Dolinoy, D.C., D. Huang, and R.L. Jirtle, Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A, 2007. 104(32): p. 13056-61.
  • Chavarro, J.E., et al., Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod, 2008. 23(11): p. 2584-90.
  • Minguez-Alarcon, L., et al., Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center. Andrology, 2015. 3(4): p. 702-8.
  • Mitchell, J.H., et al., Effect of a phytoestrogen food supplement on reproductive health in normal males. Clin Sci (Lond), 2001. 100(6): p. 613-8.
  • Messina, M., S. Watanabe, and K.D. Setchell, Report on the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment. J Nutr, 2009. 139(4): p. 796S-802S.
  • Beaton, L.K., et al., Soy protein isolates of varying isoflavone content do not adversely affect semen quality in healthy young men. Fertil Steril, 2010. 94(5): p. 1717-22.
  • Casini, M.L., S. Gerli, and V. Unfer, 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(7): p. 399-401.
  • Van Wyk, J.J., et al., The effects of a soybean product on thyroid function in humans. Pediatrics, 1959. 24: p. 752-760.
  • Shepard, T.H., et al., Soybean goiter. New Engl J Med, 1960. 262: p. 1099-1103.
  • Hydovitz, J.D., Occurrence of goiter in an infant on a soy diet. New England J Medicine, 1960. 262: p. 351-353.
  • Divi, R.L. and D.R. Doerge, Inhibition of thyroid peroxidase by dietary flavonoids. Chem Res Toxicol, 1996. 9(1): p. 16-23.
  • Divi, R.L., H.C. Chang, and D.R. Doerge, Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol, 1997. 54(10): p. 1087-96.
  • Chang, H.C. and D.R. Doerge, Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicol Appl Pharmacol, 2000. 168(3): p. 244-52.
  • Chang, H.C., et al., Mass spectrometric determination of genistein tissue distribution in diet-exposed Sprague-Dawley rats. J Nutr, 2000. 130(8): p. 1963-70.
  • Pinchera, A., et al., Thyroid refractiveness in an athyreotic cretin fed soybean formula. N Engl J Med, 1965. 273: p. 83-87.
  • Messina, M. and G. Redmond, Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid, 2006. 16(3): p. 249-58.
  • Ryan-Borchers, T., et al., Effects of dietary and supplemental forms of isoflavones on thyroid function in healthy postmenopausal women. Topics Clinical Nutr, 2008. 23: p. 13-22.
  • Romualdi, D., et al., Is there a role for soy isoflavones in the therapeutic approach to polycystic ovary syndrome? Results from a pilot study. Fertil Steril, 2008. 90(5): p. 1826-33.
  • Nahas, E.A., et al., Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas, 2007. 58(3): p. 249-58.
  • Khaodhiar, L., et al., Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause, 2008. 15(1): p. 125-32.
  • Zhou, Y., et al., The effect of soy food intake on mineral status in premenopausal women. J Womens Health (Larchmt), 2011. 20(5): p. 771-80.
  • Alekel, D.L., et al., 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(2): p. 185-97.
  • Bitto, A., 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(6): p. 3067-72.
  • Doerge, D.R. and D.M. Sheehan, Goitrogenic and estrogenic activity of soy isoflavones. Environ Health Perspect, 2002. 110 Suppl 3: p. 349-53.
  • Fitzpatrick, M., Soy formulas and the effects of isoflavones on the thyroid. N Z Med J, 2000. 113(1103): p. 24-6.
  • Bell, D.S. and F. Ovalle, Use of soy protein supplement and resultant need for increased dose of levothyroxine. Endocr Pract, 2001. 7(3): p. 193-4.
  • Conrad, S.C., H. Chiu, and B.L. Silverman, Soy formula complicates management of congenital hypothyroidism. Arch Dis Child, 2004. 89(1): p. 37-40.
  • Liel, Y., I. Harman-Boehm, and S. Shany, 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(2): p. 857-9.
  • Chiu, A.C. and S.I. Sherman, Effects of pharmacological fiber supplements on levothyroxine absorption. Thyroid, 1998. 8(8): p. 667-71.
  • Shakir, K.M., et al., Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J, 1997. 90(6): p. 637-9.
  • Liel, Y., A.D. Sperber, and S. Shany, Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. Am J Med, 1994. 97(4): p. 363-5.
  • Sperber, A.D. and Y. Liel, Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med, 1992. 152(1): p. 183-4.
  • Sherman, S.I., E.T. Tielens, and P.W. Ladenson, Sucralfate causes malabsorption of L-thyroxine. Am J Med, 1994. 96(6): p. 531-5.
  • Siraj, E.S., M.K. Gupta, and S.S. Reddy, Raloxifene causing malabsorption of levothyroxine. Arch Intern Med, 2003. 163(11): p. 1367-70.
  • Rosenberg, R., Malabsorption of thyroid hormone with cholestyramine administration. Conn Med, 1994. 58(2): p. 109.
  • Harmon, S.M. and C.F. Seifert, Levothyroxine-cholestyramine interaction reemphasized. Ann Intern Med, 1991. 115(8): p. 658-9.
  • Zeitler, P. and P. Solberg, Food and levothyroxine administration in infants and children. J Pediatr, 2010. 157(1): p. 13-14.
  • Doerge, D. and H. Chang, Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo. J Chromatogr B Analyt Technol Biomed Life Sci, 2002. 777(1-2): p. 269-279.
  • Sosvorova, L., et al., The presence of monoiodinated derivates of daidzein and genistein in human urine and its effect on thyroid gland function. Food Chem Toxicol, 2012. 50(8): p. 2774-9.
  • Villar, H.C., et al., Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev, 2007(3): p. CD003419.
  • Aoki, Y., et al., Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid, 2007. 17(12): p. 1211-23.
  • Sathyapalan, T., et al., 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(5): p. 1442-9.
  • Imaizumi, M., et al., Risk for progression to overt hypothyroidism in an elderly Japanese population with subclinical hypothyroidism. Thyroid, 2011. 21(11): p. 1177-82.
  • Kasagi, K., et al., 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(9): p. 937-44.
  • Bouker, K.B. and L. Hilakivi-Clarke, Genistein: Does it Prevent or Promote Breast Cancer? Environ Health Perspect, 2000. 108(8): p. 701-708.
  • Messina, M.J. and C.L. Loprinzi, Soy for breast cancer survivors: a critical review of the literature. J Nutr, 2001. 131(11): p. 3095S-108S.
  • Affenito, S.G. and J. Kerstetter, Position of the American Dietetic Association and Dietitians of Canada: women's health and nutrition. J Am Diet Assoc, 1999. 99(6): p. 738-51.
  • American College of Obstetricians and Gynecologists, Use of botanicals for management of menopausal symptoms. ACOG Practice Bulletin, 2001. 28(June): p. 1-11.
  • American Cancer Society Workshop on Nutrition and Physical Activity for Cancer Survivors, Nutrition during and after cancer treatment: a guide for informed choices by cancer survivors. CA Cancer J Clin, 2001. 51: p. 153-187.
  • Manson, J.E., 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(13): p. 1353-68.
  • Ju, Y.H., et al., Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. Journal of Nutrition, 2001. 131(11): p. 2957-62.
  • Allred, C.D., et al., Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. Carcinogenesis, 2001. 22(10): p. 1667-73.
  • Kang, X., S. Jin, and Q. Zhang, 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(7): p. H237-42.
  • Onoda, A., et al., 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(9): p. 2279-84.
  • Mishra, R., et al., 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(2): p. 434-40.
  • Allred, C.D., et al., Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis, 2004. 25(9): p. 1649-57.
  • Hooper, L., et al., Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update, 2010. 16(6): p. 745-60.
  • Wu, A.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 (Phila), 2015. 8(10): p. 942-51.
  • Hargreaves, D.F., et al., Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab, 1999. 84(11): p. 4017-24.
  • Sartippour, M.R., et al., A pilot clinical study of short-term isoflavone supplements in breast cancer patients. Nutr Cancer, 2004. 49(1): p. 59-65.
  • Palomares, M.R., et al., Effect of soy isoflavones on breast proliferation in postmenopausal breast cancer survivors. Breast Cancer Res Treatment, 2004. 88 (Suppl 1): p. 4002 (Abstract).
  • Khan, S.A., et al., Soy isoflavone supplementation for breast cancer risk reduction: A randomized phase II trial. Cancer Prev Res (Phila), 2012. 5(2): p. 309-19.
  • Shike, M., et al., The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study. J Natl Cancer Inst, 2014. 106(9).
  • Writing Group for the Women's Health Initiative Investigators, Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA, 2002. 288(3): p. 321-33.
  • Boyd, N.F., et al., Mammographic density as a marker of susceptibility to breast cancer: a hypothesis. IARC Sci Publ, 2001. 154: p. 163-9.
  • Boyd, N.F., et al., Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 2006. 15(5): p. 961-6.
  • Kang, X., et al., Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ, 2010. 182(17): p. 1857-62.
  • Nechuta, S.J., et al., Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr, 2012. 96(1): p. 123-32.
  • Rock, C.L., et al., Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin, 2012. 62(4): p. 242-74.
  • American Institute for Cancer Research, Soy is safe for breast cancer survivors. http://www.aicr.org/cancer-research-update/november_21_2012/cru-soy-safe.html (accessed Feburary 5, 2013), 2012.
  • World Cancer Research Fund International. Continuous Update Project Report: Diet, Nutrition, Physical Activity, and Breast Cancer Survivors. 2014. Available at: www.wcrf.org/sites/default/files/Breast-Cancer-Survivors-2014-Report.pdf.
  • Johnson, J.M. and P.M. Walker, Zinc and iron utilization in young women consuming a beef-based diet. J Am Diet Assoc, 1992. 92(12): p. 1474-8.
  • Thompson, D.B. and J.W.J. Erdman, Phytic acid determination in soybeans. J Food Sci, 1982. 47: p. 513-517.
  • Urbano, G., et al., The role of phytic acid in legumes: antinutrient or beneficial function? J Physiol Biochem, 2000. 56(3): p. 283-94.
  • Sandstrom, B. and A. Cederblad, Zinc absorption from composite meals. II. Influence of the main protein source. Am J Clin Nutr, 1980. 33(8): p. 1778-83.
  • Sandstrom, B., B. Kivisto, and A. Cederblad, Absorption of zinc from soy protein meals in humans. J Nutr, 1987. 117(2): p. 321-7.
  • Davidsson, L., et al., Zinc absorption in adult humans: the effect of protein sources added to liquid test meals. Br J Nutr, 1996. 75(4): p. 607-13.
  • Lonnerdal, B., et al., The effect of individual components of soy formula and cows' milk formula on zinc bioavailability. Am J Clin Nutr, 1984. 40(5): p. 1064-70.
  • de Portela, M.L. and A.R. Weisstaub, Basal urinary zinc/creatinine ratio as an indicator of dietary zinc intake in healthy adult women. J Am Coll Nutr, 2000. 19(3): p. 413-7.
  • Hunt, J.R., Moving toward a plant-based diet: are iron and zinc at risk? Nutr Rev, 2002. 60(5 Pt 1): p. 127-34.
  • Messina, V., V. Melina, and A.R. Mangels, A new food guide for North American vegetarians. Can J Diet Pract Res, 2003. 64(2): p. 82-6.
  • Messina, V., V. Melina, and A.R. Mangels, A new food guide for North American vegetarians. J Am Diet Assoc, 2003. 103(6): p. 771-5.
  • Mangels, A.R. and V. Messina, Considerations in planning vegan diets: infants. J Am Diet Assoc, 2001. 101(6): p. 670-7.
  • Messina, V. and A.R. Mangels, Considerations in planning vegan diets: children. J Am Diet Assoc, 2001. 101(6): p. 661-9.
  • Messina, V.K. and K.I. Burke, Position of the American Dietetic Association: vegetarian diets. J Am Diet Assoc, 1997. 97(11): p. 1317-21.
  • Karr-Lilienthal, L.K., et al., Chemical composition and protein quality comparisons of soybeans and soybean meals from five leading soybean-producing countries. J Agric Food Chem, 2004. 52(20): p. 6193-9.
  • Murray-Kolb, L.E., et al., Women with low iron stores absorb iron from soybeans. Am J Clin Nutr, 2003. 77(1): p. 180-4.
  • Lonnerdal, B., et al., Iron absorption from soybean ferritin in nonanemic women. Am J Clin Nutr, 2006. 83(1): p. 103-7.
  • Brune, M., L. Rossander, and L. Hallberg, Iron absorption: no intestinal adaptation to a high-phytate diet. Am J Clin Nutr, 1989. 49(3): p. 542-5.
  • Armah, S.M., et al., 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(8): p. 1735-9.
  • Sandberg, A.S., Bioavailability of minerals in legumes. Br J Nutr, 2002. 88 Suppl 3: p. S281-5.
  • Heaney, R.P., C.M. Weaver, and M.L. Fitzsimmons, Soybean phytate content: effect on calcium absorption. Am J Clin Nutr, 1991. 53(3): p. 745-7.
  • Weaver, C.M., et al., Bioavailability of calcium from tofu vs. milk in premenopausal women. J Food Sci, 2002. 68: p. 3144-3147.
  • Zhao, Y., B.R. Martin, and C.M. Weaver, Calcium bioavailability of calcium carbonate fortified soymilk is equivalent to cow's milk in young women. J Nutr, 2005. 135(10): p. 2379-82.
  • Tang, A.L., et al., 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(2): p. 243-9.
  • Heaney, R.P., et al., Bioavailability of the calcium in fortified soy imitation milk, with some observations on method. Am J Clin Nutr, 2000. 71(5): p. 1166-9.
  • Heaney, R.P. and K. Rafferty, The settling problem in calcium-fortified soybean drinks. J Am Diet Assoc, 2006. 106(11): p. 1753; author reply 1755.
  • Food and Drug Administration (FDA). Food Allergen Labeling and Consumer Protection (FALCP) Act of 2004, h.w.c.f.g.a.a.p., http:// www.cfsan.fda.gov/~acrobat/alrgact.pdf.
  • Food and Drug Administration (FDA), Food Allergen Labeling and Consumer Protection (FALCP) Act of 2004. http://www.cfsan.fda.gov/~acrobat/alrgact.pdf,. 2004.
  • Vierk, K.A., et al., Prevalence of self-reported food allergy in American adults and use of food labels. J Allergy Clin Immunol, 2007. 119(6): p. 1504-10.
  • Savage, J.H., et al., The natural history of soy allergy. J Allergy Clin Immunol, 2010. 125(3): p. 683-686.
  • Sato, M., et al., Oral challenge tests for soybean allergies in Japan: A summary of 142 cases. Allergol Int, 2016. 65(1): p. 68-73.
  • Bhatia, J. and F. Greer, Use of soy protein-based formulas in infant feeding. Pediatrics, 2008. 121(5): p. 1062-8.
  • Sladkevicius, E., et al., Resource implications and budget impact of managing cow milk allergy in the UK. J Med Econ, 2010. 13(1): p. 119-28.
  • Dias, A., A. Santos, and J.A. Pinheiro, Persistence of cow's milk allergy beyond two years of age. Allergol Immunopathol (Madr), 2010. 38(1): p. 8-12.
  • Katz, Y., et al., A comprehensive review of sensitization and allergy to soy-based products. Clin Rev Allergy Immunol, 2014. 46(3): p. 272-81.
  • Rossen, L.M., A.E. Simon, and K.A. Herrick, Types of infant formulas consumed in the United States. Clin Pediatr (Phila), 2015.
  • McCarver, G., et al., NTP-CERHR expert panel report on the developmental toxicity of soy infant formula. Birth Defects Res B Dev Reprod Toxicol, 2011. 92(5): p. 421-68.
  • Li, J., et al., Cortical responses to speech sounds in 3- and 6-month-old infants fed breast milk, milk formula, or soy formula. Dev Neuropsychol, 2010. 35(6): p. 762-84.
  • Pivik, R.T., A. Andres, and T.M. Badger, Diet and gender influences on processing and discrimination of speech sounds in 3- and 6-month-old infants: a developmental ERP study. Dev Sci, 2011. 14(4): p. 700-12.
  • Gilchrist, J.M., et al., Ultrasonographic patterns of reproductive organs in infants fed soy formula: comparisons to infants fed breast milk and milk formula. J Pediatr, 2010. 156(2): p. 215-20.
  • Pivik, R.T., et al., Infant diet, gender and the development of vagal tone stability during the first two years of life. Int J Psychophysiol, 2015. 96(2): p. 104-14.
  • Andres, A., et al., Developmental status of 1-year-old infants fed breast milk, cow's milk formula, or soy formula. Pediatrics, 2012. 129(6): p. 1134-40.
  • Vandenplas, Y., et al., Safety of soya-based infant formulas in children. Br J Nutr, 2014. 111(8): p. 1340-60.
  • Rand, W.M., P.L. Pellett, and V.R. Young, Meta-analysis of nitrogen balance studies for estimating protein requirements in healthy adults. Am J Clin Nutr, 2003. 77(1): p. 109-27.
  • Hughes, G.J., et al., Protein digestibility-corrected amino acid scores (PDCAAS) for soy protein isolates and concentrate: Criteria for evaluation. J Agric Food Chem, 2011. 59(23): p. 12707-12.
  • Murphy, P.A., et al., Isoflavones in retail and institutional soy foods. J Agric Food Chem, 1999. 47(7): p. 2697-704.
  • Yang, W.S., et al., Soy intake is associated with lower lung cancer risk: results from a meta-analysis of epidemiologic studies. Am J Clin Nutr, 2011. 94(6): p. 1575-83.
  • Kim, J., et al., Fermented and non-fermented soy food consumption and gastric cancer in Japanese and Korean populations: a meta-analysis of observational studies. Cancer Sci, 2011. 102(1): p. 231-44.
  • Shurtleff, W., Database search of tofu and Japan before 1900, 2003, The Soyfoods Center: LaFayette.
  • Shurtleff, W., Database search of tofu and China before 1900, 2003, The Soyfoods Center: Lafayette.