SOYFOODS FOR INFANTS, CHILDREN AND ADOLESCENTS
Establishing healthful eating habits early in life is important for two reasons. First, childhood eating habits track into adulthood, and changing adult dietary behavior is difficult [1-5]. Second, evidence suggests that healthful behaviors during childhood and adolescence can affect the risk of developing certain chronic diseases later in life [6-9]. For example, childhood obesity is associated with increased mortality from cardiovascular disease in adulthood, independent of adult weight . Early lifestyle factors are also thought to affect the likelihood of developing breast cancer during adulthood . These observations are important given that 20 percent of U.S. children are obese  and diseases once seen primarily in adults, such as hypertension  and Type 2 diabetes mellitus , are increasingly common in childhood.
Evidence indicates that it isn’t just that chronic diseases begin early in life but that programming during fetal life and infancy, permanently affects risk of developing non-communicable diseases in adult life. Programming refers to permanent changes in the body’s structure, physiology, and metabolism, which influences health throughout life. It is not just limited to the in utero environment, but extends into childhood, where different organs and systems continue to adapt to various cues.
It is also recognized that the beginning stages of chronic diseases, such as coronary heart disease, are already apparent in adolescents [15, 16]. In addition, there is an emerging epidemic of non-alcoholic fatty liver disease (NAFLD) estimated to affect millions of obese children [17, 18]. A recently published autopsy study found that 9.6 percent of the U.S. population, age 2-19 years old, and 38 percent of the obese individuals within this age range have NAFLD . NAFLD can progress to non-alcoholic steatohepatisis, which is characterized by oxidative stress, inflammation, apopotosis and fibrogenesis . Some animal data suggest soy may help to prevent the development of NAFLD [21-24].
Given the importance of early-life dietary behavior, it is essential to understand how the nutritional attributes of soyfoods may impact the health of young people from infancy through the teenage years.
Soy Infant Formula
Although breast milk is the ideal food for infants , about one-third of women are unable to breastfeed or choose not to do so. Of those who choose breastfeeding, most switch to formula feeding at some point in the infant's first year . Commercially-prepared, fortified infant formulas are appropriate to supplement or replace human milk during the first year of life. Various estimates for the prevalence of soy infant formula use exist. One older review noted not surprisingly that cow’s milk formula is the most commonly used product, but that about 13 percent of infants are fed soy infant formula (SF) for some period of time . More recently, a survey of 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, 69 percent consumed cow's milk formula, 12 percent consumed SF, five percent consumed gentle/lactose-reduced formulas, six percent consumed specialty formulas, and 13 percent consumed regular milk products. The percentage of children consuming SF was significantly higher (P < .05) among infants from higher income groups compared with the lower income group .
An allergy to milk protein is among the most common reasons for placing an infant on SF. There is evidence that SF is hypoallergenic relative to cow’s milk formulas . However, because according to some estimates 10-14% of infants who are allergic to cow’s milk formula are also allergic to SF, the American Academy of Pediatrics (AAP) suggests that many infants with documented cow’s milk protein allergy (CMA) should be switched directly to a hydrolyzed protein formula . It should be noted that soybean-specific IgE titers are not an effective predictor of a positive response to the food challenge test .
In contrast to the AAP, an Australian panel of experts concluded that SF is an appropriate alternative for infants over six months old who demonstrate immediate food allergy to cow’s milk and delayed reaction in the form of atopic eczema and other gastrointestinal syndromes . The French Society of Paediatrics holds a similar position but with the caveat that tolerance to soy protein should first be established by clinical challenge . Importantly, UK research found that of the 60 percent of all infants with CMA initially fed SF, only 9 percent remained symptomatic . In contrast, of the 18 percent of patients consuming 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 SF formula may have advantages over hydrolyzed formulas .
Finally, there are the conclusions of a newly published systematic review and meta-analysis, the first of its kind, which included 40 studies that evaluated the prevalence of IgE-mediated soy allergies in infants and children . According to the authors, their findings do not substantiate recommendations to postpone the introduction of SF in infants with IgE-CMA the first six months of life based on the concern for an increased risk of allergy to soy.
Isoflavones in Diets of Infants Fed Soy Formula
An estimated 20 million people in the United States consumed SF during infancy since it first became commercially available in the 1960s . Several cases of goiter were identified in the mid-1960s in infants using SF but this problem was eliminated soon thereafter when iodine was added to the formula [37-39]. Since then, no thyroid problems attributed to SF use have been identified in healthy infants, and research shows that infants fed SF grow and develop normally [27, 40-43].
In addition to iodine, all SF is fortified with iron, methionine, carnitine and taurine, and contains 20 percent more calcium and phosphorous than cow’s milk formulas. However, SF may be contraindicated for infants with congenital hypothyroidism who require synthetic thyroid hormone . This contraindication is because of evidence suggesting soy protein is one of a number of factors that may interfere with the absorption of thyroid medication .
Despite its long history of use, SF has become controversial in recent years due to its naturally high isoflavone content [46, 47]. Isoflavones, which are classified as phytoestrogens, exhibit estrogen-like effects under certain experimental conditions . However, isoflavones are very different from the hormone estrogen. The literature is replete with clinical examples demonstrating that isoflavones and estrogen affect a variety of health outcomes differently [49-69]. Furthermore, isolated soy protein, which is the protein source in SF, should not be equated with isoflavones. There is no evidence from clinical studies that SF consumption leads to adverse effects in infants [40, 70-72].
Especially important insight into the health effects SF comes from a unique study underway at the Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences. In this study, breast buds, uterus, ovaries, prostate and testicular volumes were assessed by ultrasonography at four months of age in 40 breast-fed infants, 41 infants fed cow’s milk formula and 39 infants fed SF . In all cases, SF-fed infants were similar to breast-fed or milk formula-fed infants whereas, unexpectedly, milk formula-fed infants had greater mean ovarian volume and greater numbers of ovarian cysts per ovary than did breast-fed infants. At this point the clinical relevance of these findings is unclear. Additional data from this research group continues to show that for a variety of health outcomes, infants fed SF fall well within the normal ranges [73-77].
Long-term data are limited, but in one retrospective study no meaningful differences in a host of biological parameters between adults who had consumed SF or cow’s milk formula as infants were noted . Interestingly, results from a very small and very preliminary study found that girls fed SF as infants were 40-60% less likely to develop breast cancer as adults compared to women who were fed breast milk, cow’s milk formula or a combination of both .
A comprehensive review published in 2004 summarized views on the isoflavone content of SF with this statement: “The evidence from laboratories showing biological activities at doses or tissue concentrations relevant to soy-fed infants is difficult to reconcile with the long record of uneventful use of these formulas” . This sentiment is similar to the current position of the AAP, which was issued in 2008: “… although studied by numerous investigators in various species, there is no conclusive evidence from animal, adult human, or infant populations that dietary soy isoflavones may adversely affect human development, reproduction, or endocrine function” .
An older Puerto Rican epidemiologic study found an association between SF use (along with several other factors) and premature breast development , but no such association was identified in a more recently published Israeli study . Because the types of safety-related research that can be conducted in humans are limited, animal studies are frequently cited in support of potential adverse effects of SF. Results of these studies are of questionable value due to the many physiological differences between animals and humans. Furthermore, many animals, including rodents and monkeys, metabolize isoflavones very differently than humans [83, 84]. For a review of some of the key issues see reference . In 2006, the National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction evaluated the safety of SF. Although their initial conclusions supported the safety of soy formula use, no final report was issued [86, 87].
In 2009, the NTP again took up this issue. The conclusion of the 14-member panel of independent scientists was that there was “minimal concern” (the five levels of concern are negligible concern, minimal concern, some concern, concern and serious concern) about the safety of SF . Two panel members dissented from this consensus opinion, one in favor of “negligible concern” and the other in support of “some concern.” In response to the NTP report, the AAP submitted a formal letter to the NTP, which is part of the public record, in which they stated their position that there is negligible concern about the safety of SF.
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 . Research evaluating the health effects of SF is ongoing [89-93].
Isoflavones in Children's Diets
There is interest in gaining a better understanding of the effects of isoflavones in children although it is recognized that soyfoods have been consumed by young Asians for centuries without any apparent adverse effects. This interest is based on preliminary data indicating that children absorb isoflavones to a greater extent than adults  and that relatively little research involving children has been conducted.
Three clinical studies were designed to determine whether isoflavones or soyfoods exert hormonal effects in children and/or adolescents:
- An Australian study found that isoflavones have no effect on high-density lipoprotein cholesterol (HDLC) levels in teenage boys, which suggests isoflavones don’t exert estrogenic effects . HDLC levels decrease in boys as they enter puberty whereas no such decrease occurs in girls, a difference that may be due to the higher estrogen levels in females. It was therefore hypothesized that isoflavone exposure would raise HDLC levels in boys.
- A small Israeli 12-week cross-over study found isoflavone supplements (0, 16 and 48 mg/d) had no effect on blood reproductive hormone levels in young boys and girls 
- A pilot US study involving 17 girls found that the consumption of approximately one serving of soyfoods daily (average isoflavone intake, ~27 mg) had no effect on urinary sex steroid levels .
The lack of hormonal effects in these clinical trials involving children is consistent with research in adults showing that isoflavone exposure from soyfoods or supplements has no effects on circulating testosterone in men  or estrogen levels in men  or women .
There is increasing interest in understanding the impact of diet on pubertal development because pubertal characteristics are occurring at an earlier age in U.S. girls [101, 102]. Many factors likely contribute to this trend such as increasing adiposity. Epidemiologic studies have found that both total and animal protein intake is associated with earlier menarche and the development of early pubertal characteristics [103, 104]. Xenoestrogen exposure, which includes phytoestrogens such as isoflavones, has been proposed as another factor. For this reason, there is interest in determining whether soy intake affects pubertal development.
Two small Korean epidemiologic studies found that urinary isoflavones in children with precocious puberty were higher than in children serving as controls [105, 106]. Age of menarche (AOM) has been declining (i.e., occurring at a young age) in Korea but an analysis found that in addition to diet/nutrition, maternal menarcheal age, body mass index and maternal age at birth were variables that appear to influence AOM in Korean girls . It is important to note the AOM is generally declining throughout the world including in countries where soyfoods are not consumed.
In contrast to the Korean studies [105, 106], a prospective study involving 1,239 U.S. girls aged 6-8 who were followed for seven years found no relationship between pubertal development and urinary isoflavone excretion . In fact, another U.S. study found isoflavone exposure was associated with delayed breast development, although this study was small and utilized a cross-sectional design . Nevertheless, this finding agrees with the results of a German longitudinal study . However, epidemiologic studies conducted outside of Asia involving the general population are of questionable utility for understanding the health effects of soy consumption because isoflavone intake is so low (<2 mg/d).
One U.S. cross-sectional study that does provide meaningful insight into whether soy intake impacts pubertal development involved Seventh-day Adventist (SDA) girls (N=327; age range 12 to 18; mean age, 15) . Approximately 40 percent of SDAs are vegetarians so their soy consumption is much higher than the general U.S. population. The authors of this study assumed that current soy intake reflected past intake. There is research to support this assumption. A study involving a diverse population of children ages 9–18 years, in which dietary intake patterns were assessed 5 years apart, found intake to be stable over time .
The mean number of servings of soyfoods among the adolescent girls was 12.9 per week and 21.1 percent of the girls consumed soyfoods ≥4x/week. These findings confirm the higher soy intake among SDA compared with the general population. The results showed that the consumption of total soyfoods and the intake of three specific soyfoods was not significantly associated with AOM or with the odds for early- or late-AOM .
One adverse effect associated with earlier puberty in girls is an increased risk of developing breast cancer later in life. While the effect of soy on puberty has been studied to only a very limited extent, there is an impressive body of research, consisting of both epidemiologic [113-116] and animal [117-119] data, indicating that soy intake when young reduces breast cancer risk later in life. This evidence is consistent with mounting data that early life events greatly impact breast cancer risk . The first 20 years of life appear to be particularly important . In fact, a recent commentary concluded that there is growing evidence linking childhood and adolescent lifestyle and environmental exposures with subsequent risk of a range of cancers arising in adulthood .
Research has shown that when rats are given genistein, the primary isoflavone in soybeans, for just a few weeks early in life and then put on a typical laboratory diet, they develop 50 percent fewer chemically-induced mammary tumors than rats not given this isoflavone . Isoflavone exposure causes mammary cells to be transformed in a way that makes them permanently less likely to develop into cancer cells later in life . The effect of isoflavones may be similar in some ways to that of early pregnancy, which is protective against breast cancer . Several mechanisms for the hypothesized protective effects of isoflavones have been proposed including increases in cell differentiation [120, 124], BRCA1 gene expression  and estrogen receptor-β expression .
The epidemiologic data suggest that quite modest amounts (perhaps just one serving daily) of soy during the early years are likely sufficient to reduce breast cancer risk [113-116]. The period of exposure to soy that is theoretically most protective against breast cancer is unclear. Although most studies focused on the teenage years [113-115], the results of a small study by Korde et al.  suggest soy consumption during childhood may be most protective.
Effects of Soy Protein on Cholesterol Levels in Children
As with adults, clinical research in children shows that soy protein favorably affects lipid levels [127-131]. In the most recent study, when soy protein (average intake 0.5 g/kg body weight) was incorporated into the diets of children and adolescents (mean age 8.8 years; range 4-18 years) with familial and polygenic hypercholesterolemia, low-density lipoprotein cholesterol decreased by 6.4 percent beyond the 11 percent decrease that occurred in response to the adoption of a standard low-saturated fat diet during the three-month run-in period . Therefore, soy protein used in combination with other dietary therapies can help to reduce cholesterol levels to target goals . Soy protein may also serve as an adjunct to therapy in children taking medication for lowering cholesterol, thereby reducing the required medication dose, which may help to minimize or eliminate side effects .
Soy Protein Quality
Soyfoods provide high-quality protein and are generally low in saturated fat . Soy protein can meet the protein needs of growing children. In 2000, the U.S. Department of Agriculture removed limits on the amount of soy protein that can be used in the National School Lunch Program .
Providing healthful sources of protein without excessive saturated fat content is important for children. Higher-protein diets are associated with greater satiety and weight loss . Also, recent evidence in young boys shows that consumption of protein above the recommended dietary allowance enhances the favorable impact of physical activity on bone mineral density . Additionally, evidence indicates that the protein requirements of children may be 50 percent higher than the current recommended dietary allowance .
Many protein-rich foods in children’s diets are high in saturated fat. Substituting soyfoods for more traditional sources of protein generally improves overall diet quality. Even substituting soy protein for part of the beef or pork protein in a recipe can lead to a decrease in the fat, saturated fat and calorie content for the total entree, as long as portion size stays the same [139, 140]. Similarly, combining cheese, eggs or meat with tofu leads to improved nutritional quality of entrees .
In general, soyfoods help children meet the Dietary Guidelines [139, 140]. Short-term studies show that soyfoods support the normal growth and development of children  and improve growth when substituted for legumes in the diets of malnourished preschoolers [143, 144]. Also, according to a recent clinical trial involving Australian children 18 to 114 months old, soymilk may help to alleviate chronic functional constipation (CFC), which is defined as having one bowel motion every three to 15 days . CFC occurs commonly in children and among those children attending a consultation with a pediatrician, the prevalence may be as high as 36 percent.
Collectively, the evidence shows soyfoods can play an important part in a healthful and varied diet.
Soy Protein and Allergies
Essentially all food proteins have the potential to cause allergic reactions in some individuals. Although soy protein is one of the eight food proteins responsible for approximately 90 percent of all allergic reactions, these eight foods are not equally allergenic. The number of adults allergic to soy is quite small . In fact, a recent survey found that cow’s milk allergy was 40-fold more common than allergy to soy protein .
The relative number of children allergic to soy protein is almost certainly higher than the number of adults because children are much more sensitive to dietary proteins in general . Nevertheless, according to a new systematic review, even among infants and children, the prevalence of soy allergies among the general population ranges from 0 to only 0.5 percent .
Most children are thought to outgrow their soy allergies early on in life , although the pace at which this occurs is a matter of some recent discussion . One study reported that more than 80 percent of infants outgrew their soy allergy by two years of age  although a more recent study found that 70 percent of children outgrow their soy allergies by age 10 . The higher the baseline soy-specific serum IgE levels, the longer it takes for this to occur. Data suggest that by age 10, only about one out of every 1000 children are allergic to soy protein.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is being diagnosed with increased frequency in both children and adults and which is related to allergies. Clinical symptoms in children range from food aversion and malnutrition in infants and toddlers, to vomiting in preschoolers and abdominal pain in preteenagers. The immune-mediated esophageal inflammation is triggered by a food antigen in most children and adults.
A 6-food elimination diet (SFED) excluding cow’s milk, soy, wheat, egg, peanuts/tree nuts, and seafood has been shown to induce remission in a majority of children with EoE. However, in a recent study, it was shown that of 36 of 46 children (mean age, 7.6 years) who were initially successfully treated with SFED :
- 25 reacted to cow’s milk (74%)
- 8 to wheat (26%)
- 4 to eggs (17%)
- 3 to soy (10%)
Acceptance of Soyfoods in Children's Diets
Research shows that soyfoods are generally well-accepted by children [141, 153, 154]. For example, among preschool children, three to six years old, who attended a Head Start program, soy-enhanced lunches were as readily consumed as those made with more traditional ingredients, as evidenced by the amounts eaten .
Negative beliefs about soy’s palatability persist among some populations. When non-vegetarian study participants were told that a product contained soy, they were more likely to rate it as "grainy, chalky, dry, and unappealing" even though the product did not actually contain any soy ingredients . Foods containing soy are also generally thought by U.S. consumers to be more “healthy tasting” . Ratings reflect the amount of soy consumed by a given individual.
Summary and Conclusions
Establishing good eating habits early in life is important. Childhood dietary intake may impact adult chronic disease risk and influence eating habits in adulthood. Soyfoods provide important options for improving the diets of young people, and research shows that these foods are accepted and enjoyed by children.
Therefore, soyfoods can be viewed as healthful additions to the diets of children and adolescents. Other than relatively rare soy protein allergy, there is no clinical evidence that soyfoods exert any adverse effects. To the contrary, there is evidence suggesting that exposure to soy during childhood and adolescence reduces breast cancer risk later in life.
- Mikkila, V., et al., Consistent dietary patterns identified from childhood to adulthood: the cardiovascular risk in Young Finns Study. Br J Nutr, 2005. 93(6): p. 923-31.
- Mennella, J.A., C.E. Griffin, and G.K. Beauchamp, Flavor programming during infancy. Pediatrics, 2004. 113(4): p. 840-5.
- Mennella, J.A. and G.K. Beauchamp, Flavor experiences during formula feeding are related to preferences during childhood. Early Hum Dev, 2002. 68(2): p. 71-82.
- Birch, L.L., Development of food acceptance patterns in the first years of life. Proc Nutr Soc, 1998. 57(4): p. 617-24.
- Anonymous, Guidelines for school health programs to promote lifelong healthy eating. Centers for Disease Control and Prevention. MMWR Recomm Rep, 1996. 45(RR-9): p. 1-41.
- Adair, L.S. and A.M. Prentice, A critical evaluation of the fetal origins hypothesis and its implications for developing countries. J Nutr, 2004. 134(1): p. 191-3.
- McCormack, V.A., et al., Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort. Bmj, 2003. 326(7383): p. 248.
- Robinson, R., The fetal origins of adult disease. Bmj, 2001. 322(7283): p. 375-6.
- van der Pols, J.C., et al., Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort. Heart, 2009. 95(19): p. 1600-6.
- Must, A., et al., Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med, 1992. 327(19): p. 1350-5.
- Russo, J., et al., Pathways of carcinogenesis and prevention in the human breast. Eur J Cancer, 2002. 38 Suppl 6: p. S31-2.
- Ogden, C.L., et al., Prevalence of high body mass index in U.S. children and adolescents, 2007-2008. JAMA, 2010. 303(3): p. 242-9.
- Sorof, J.M., Prevalence and consequence of systolic hypertension in children. Am J Hypertens, 2002. 15(2 Pt 2): p. 57S-60S.
- Lipton, R.B., Incidence of diabetes in children and youth--tracking a moving target. Jama, 2007. 297(24): p. 2760-2.
- Berenson, G.S., et al., Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med, 1998. 338(23): p. 1650-6.
- Daniels, S.R. and F.R. Greer, Lipid screening and cardiovascular health in childhood. Pediatrics, 2008. 122(1): p. 198-208.
- Nobili, V. and C. Day, Childhood NAFLD: a ticking time-bomb? Gut, 2009. 58(11): p. 1442.
- Roberts, E.A., Non-alcoholic fatty liver disease (NAFLD) in children. Front Biosci, 2005. 10: p. 2306-18.
- Schwimmer, J.B., et al., Prevalence of fatty liver in children and adolescents. Pediatrics, 2006. 118(4): p. 1388-93.
- Hashimoto, E. and K. Tokushige, Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol, 2011. 46 Suppl 1: p. 63-9.
- Kim, M.H., K.S. Kang, and Y.S. Lee, The inhibitory effect of genistein on hepatic steatosis is linked to visceral adipocyte metabolism in mice with diet-induced non-alcoholic fatty liver disease. Br J Nutr, 2010. 104(9): p. 1333-42.
- Qiu, L.X. and T. Chen, Novel insights into the mechanisms whereby isoflavones protect against fatty liver disease. World J Gastroenterol, 2015. 21(4): p. 1099-107.
- Hakkak, R., et al., Short- and long-term soy diet versus casein protects liver steatosis independent of the arginine content. J Med Food, 2015. 18(11): p. 1274-80.
- Wojcik, J.L., et al., Protein source in a high-protein diet modulates reductions in insulin resistance and hepatic steatosis in fa/fa Zucker rats. Obesity (Silver Spring), 2016. 24(1): p. 123-31.
- Breastfeeding and the use of human milk. American Academy of Pediatrics. Work Group on Breastfeeding. Pediatrics, 1997. 100(6): p. 1035-9.
- Ahluwalia, I.B., et al., Who is breast-feeding? Recent trends from the pregnancy risk assessment and monitoring system. J Pediatr, 2003. 142(5): p. 486-91.
- Merritt, R.J. and B.H. Jenks, Safety of soy-based infant formulas containing isoflavones: the clinical evidence. J Nutr, 2004. 134(5): p. 1220S-1224S.
- Rossen, L.M., A.E. Simon, and K.A. Herrick, Types of infant formulas consumed in the United States. Clin Pediatr (Phila), 2015.
- Osborn, D.A. and J. Sinn, Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev, 2006(4): p. CD003741.
- Bhatia, J. and F. Greer, Use of soy protein-based formulas in infant feeding. Pediatrics, 2008. 121(5): p. 1062-8.
- 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.
- Kemp, A.S., et al., Guidelines for the use of infant formulas to treat cows milk protein allergy: an Australian consensus panel opinion. Med J Aust, 2008. 188(2): p. 109-112.
- Dupont, C., et al., Dietary treatment of cows' milk protein allergy in childhood: a commentary by the Committee on Nutrition of the French Society of Paediatrics. Br J Nutr, 2011: p. 1-14.
- 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.
- Chien, M.Y., T.Y. Huang, and Y.T. Wu, Prevalence of sarcopenia estimated using a bioelectrical impedance analysis prediction equation in community-dwelling elderly people in Taiwan. J Am Geriatr Soc, 2008. 56(9): p. 1710-5.
- 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.
- Pinchera, A., et al., Thyroid refractiveness in an athyreotic cretin fed soybean formula. N Engl J Med, 1965. 273: p. 83-87.
- Klein, K.O., Isoflavones, soy-based infant formulas, and relevance to endocrine function. Nutr Rev, 1998. 56(7): p. 193-204.
- Lasekan, J.B., et al., Growth of newborn, term infants fed soy formulas for 1 year. Clin Pediatr (Phila), 1999. 38(10): p. 563-71.
- American Academy of Pediatrics. Committee on Nutrition. Soy protein-based formulas: recommendations for use in infant feeding. Pediatrics, 1998. 101(1 Pt 1): p. 148-53.
- American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics, 2000. 106(2 Pt 1): p. 346-9.
- 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.
- 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.
- Barrett, J.R., Soy and children's health: a formula for trouble. Environ Health Perspect, 2002. 110(6): p. A294-6.
- Barrett, J.R., The science of soy: what do we really know? Environ Health Perspect, 2006. 114(6): p. A352-8.
- Setchell, K.D., et al., Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet, 1997. 350(9070): p. 23-7.
- Ho, J.Y., et al., Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Hum Reprod, 2006. 21(10): p. 2715-20.
- Lakoski, S.G., B. Brosnihan, and D.M. Herrington, Hormone therapy, C-reactive protein, and progression of atherosclerosis: data from the Estrogen Replacement on Progression of Coronary Artery Atherosclerosis (ERA) trial. Am Heart J, 2005. 150(5): p. 907-11.
- Helgason, S., et al., A comparative longitudinal study on sex hormone binding globulin capacity during estrogen replacement therapy. Acta Obstet Gynecol Scand, 1982. 61(2): p. 97-100.
- Serin, I.S., et al., Long-term effects of continuous oral and transdermal estrogen replacement therapy on sex hormone binding globulin and free testosterone levels. Eur J Obstet Gynecol Reprod Biol, 2001. 99(2): p. 222-5.
- Reid, I.R., et al., A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women. Arch Intern Med, 2004. 164(8): p. 871-9.
- Shulman, L.P., Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. Am J Cardiol, 2002. 89(12A): p. 47E-54E; discussion 54E-55E.
- Marqusee, E., et al., The effect of droloxifene and estrogen on thyroid function in postmenopausal women. J Clin Endocrinol Metab, 2000. 85(11): p. 4407-10.
- Abech, D.D., et al., Effects of estrogen replacement therapy on pituitary size, prolactin and thyroid-stimulating hormone concentrations in menopausal women. Gynecol Endocrinol, 2005. 21(4): p. 223-6.
- Davies, G.C., et al., Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause, 1999. 6(3): p. 188-95.
- Meuwissen, J.H. and H. van Langen, Monitoring endometrial thickness during estrogen replacement therapy with vaginosonography. Radiology, 1992. 183(1): p. 284.
- Kaari, C., et al., Randomized clinical trial comparing conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas, 2006. 53(1): p. 49-58.
- Yildiz, M.F., et al., Effects of raloxifene, hormone therapy, and soy isoflavone on serum high-sensitive C-reactive protein in postmenopausal women. Int J Gynaecol Obstet, 2005. 90(2): p. 128-33.
- D'Anna, R., et al., The effect of the phytoestrogen genistein and hormone replacement therapy on homocysteine and C-reactive protein level in postmenopausal women. Acta Obstet Gynecol Scand, 2005. 84(5): p. 474-7.
- Garrido, A., et al., Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas, 2006. 54(3): p. 270-6.
- Hall, W.L., et al., Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production. Am J Clin Nutr, 2006. 83(3): p. 592-600.
- Katz, D.L., et al., Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric, 2007. 10(6): p. 500-7.
- Cheng, G., et al., Isoflavone treatment for acute menopausal symptoms. Menopause, 2007. 14(3 Pt 1): p. 468-73.
- Bruce, B., M. Messina, and G.A. Spiller, Isoflavone supplements do not affect thyroid function in iodine-replete postmenopausal women. J Med Food, 2003. 6(4): p. 309-16.
- 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.
- Sammartino, A., et al., Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol, 2003. 17(1): p. 45-9.
- 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.
- Setchell, K.D., Assessing risks and benefits of genistein and soy. Environ Health Perspect, 2006. 114(6): p. A332-3.
- Munro, I.C., et al., Soy isoflavones: a safety review. Nutr Rev, 2003. 61(1): p. 1-33.
- Vandenplas, Y., et al., Safety of soya-based infant formulas in children. Br J Nutr, 2014. 111(8): p. 1340-60.
- 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.
- 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.
- 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.
- Strom, B.L., et al., Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA, 2001. 286(7): p. 807-14.
- Boucher, B.A., et al., Soy formula and breast cancer risk. Epidemiology, 2008. 19(1): p. 165-166.
- Chen, A. and W.J. Rogan, Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants. Annu Rev Nutr, 2004. 24: p. 33-54.
- Freni-Titulaer, L.W., et al., Premature thelarche in Puerto Rico. A search for environmental factors. Am J Dis Child, 1986. 140(12): p. 1263-7.
- de Vries, L., et al., Premature thelarche: age at presentation affects clinical course but not clinical characteristics or risk to progress to precocious puberty. J Pediatr, 2010. 156(3): p. 466-71.
- Gu, L., et al., Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr, 2006. 136(5): p. 1215-21.
- Soukup, S.T., et al., Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: a cross-species and sex comparison. Arch Toxicol, 2016.
- Badger, T.M., et al., The health implications of soy infant formula. Am J Clin Nutr, 2009. 89(5): p. 1668S-1672S.
- Rozman, K.K., et al., NTP-CERHR expert panel report on the reproductive and developmental toxicity of genistein. Birth Defects Res B Dev Reprod Toxicol, 2006. 77(6): p. 485-638.
- Rozman, K.K., et al., NTP-CERHR expert panel report on the reproductive and developmental toxicity of soy formula. Birth Defects Res B Dev Reprod Toxicol, 2006. 77(4): p. 280-397.
- 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.
- Adgent, M.A., et al., Early-life soy exposure and gender-role play behavior in children. Environ Health Perspect, 2011. 119(12): p. 1811-6.
- Adgent, M.A., et al., Early-life soy exposure and age at menarche. Paediatr Perinat Epidemiol, 2012. 26(2): p. 163-75.
- Westmark, C.J., Soy infant formula may be associated with autistic behaviors. Autism Open Access, 2013. 3.
- Westmark, C.J., Soy infant formula and seizures in children with autism: a retrospective study. PLoS One, 2014. 9(3): p. e80488.
- Westmark, C.J., P.R. Westmark, and J.S. Malter, Soy-based diet exacerbates seizures in mouse models of neurological disease. J Alzheimers Dis, 2013. 33(3): p. 797-805.
- Halm, B.M., L.A. Ashburn, and A.A. Franke, Isoflavones from soya foods are more bioavailable in children than adults. Br J Nutr, 2007. 98(5): p. 998-1005.
- Dwyer, T., et al., The lack of effect of isoflavones on high-density lipoprotein cholesterol concentrations in adolescent boys: a 6-week randomised trial. Public Health Nutr, 2008. 11(9): p. 955-62.
- Zung, A., et al., Soy-derived isoflavones treatment in children with hypercholesterolemia: a pilot study. J Pediatr Endocrinol Metab, 2010. 23(1-2): p. 133-41.
- Maskarinec, G., et al., Urinary sex steroid excretion levels during a soy intervention among young girls: a pilot study. Nutr Cancer, 2005. 52(1): p. 22-8.
- 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.
- 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.
- 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.
- Euling, S.Y., et al., Examination of U.S. puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics, 2008. 121 Suppl 3: p. S172-91.
- Biro, F.M., et al., Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics, 2010. 126(3): p. e583-90.
- Rogers, I.S., et al., Diet throughout childhood and age at menarche in a contemporary cohort of British girls. Public Health Nutr, 2010: p. 1-12.
- Gunther, A.L., et al., Dietary protein intake throughout childhood is associated with the timing of puberty. J Nutr, 2010. 140(3): p. 565-71.
- Kim, J., et al., High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls. Clin Endocrinol (Oxf), 2011. 75(6): p. 831-5.
- Yum, T., S. Lee, and Y. Kim, Association between precocious puberty and some endocrine disruptors in human plasma. J Environ Sci Health A Tox Hazard Subst Environ Eng, 2013. 48(8): p. 912-7.
- Cho, G.J., et al., Age at menarche in a Korean population: secular trends and influencing factors. Eur J Pediatr, 2010. 169(1): p. 89-94.
- Wolff, M.S., et al., Environmental phenols and pubertal development in girls. Environ Int, 2015. 84: p. 174-80.
- Wolff, M.S., et al., Environmental exposures and puberty in inner-city girls. Environ Res, 2008. 107(3): p. 393-400.
- Cheng, G., et al., Relation of isoflavones and fiber intake in childhood to the timing of puberty. Am J Clin Nutr, 2010. 92(3): p. 556-64.
- Segovia-Siapco, G., et al., Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption. Nutr J, 2014. 13(1): p. 54.
- Cutler, G.J., et al., Major patterns of dietary intake in adolescents and their stability over time. J Nutr, 2009. 139(2): p. 323-8.
- 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.
- Lee, S.A., et al., Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women's Health Study. Am J Clin Nutr, 2009. 89(6): p. 1920-6.
- Wu, A.H., et al., Dietary patterns and breast cancer risk in Asian American women. Am J Clin Nutr, 2009. 89(4): p. 1145-54.
- Korde, L.A., et al., Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol Biomarkers Prev, 2009. 18(4): p. 1050-9.
- Lamartiniere, C.A., Y.X. Zhao, and W.A. Fritz, Genistein: mammary cancer chemoprevention, in vivo mechanisms of action, potential for toxicity and bioavailability in rats. J Women's Cancer, 2000. 2: p. 11-19.
- Peng, J.H., et al., Prepubertal octylphenol exposure up-regulate BRCA1 expression, down-regulate ERalpha expression and reduce rat mammary tumorigenesis. Cancer Epidemiol, 2009. 33(1): p. 51-5.
- Mishra, P., A. Kar, and R.K. Kale, Prepubertal daidzein exposure enhances mammary gland differentiation and regulates the expression of estrogen receptor-alpha and apoptotic proteins. ISRN Oncol, 2011. 2011: p. 896826.
- Russo, J., et al., Breast differentiation and its implication in cancer prevention. Clin Cancer Res, 2005. 11(2 Pt 2): p. 931s-6s.
- Shimizu, H., et al., Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer, 1991. 63(6): p. 963-6.
- Potischman, N. and M.S. Linet, Invited commentary: are dietary intakes and other exposures in childhood and adolescence important for adult cancers? Am J Epidemiol, 2013. 178(2): p. 184-9.
- Messina, M. and L. Hilakivi-Clarke, Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr Cancer, 2009. 61(6): p. 792-798.
- Brown, N.M., et al., The chemopreventive action of equol enantiomers in a chemically induced animal model of breast cancer. Carcinogenesis, 2010. 31(5): p. 886-93.
- de Assis, S., et al., Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression. Cancer Prev Res (Phila), 2011. 4(9): p. 1436-48.
- Rahal, O.M. and R.C. Simmen, Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling. Endocrinology, 2011. 152(9): p. 3409-21.
- Laurin, D., et al., Effects of a soy-protein beverage on plasma lipoproteins in children with familial hypercholesterolemia. Am J Clin Nutr, 1991. 54(1): p. 98-103.
- Widhalm, K., et al., Effect of soy protein diet versus standard low fat, low cholesterol diet on lipid and lipoprotein levels in children with familial or polygenic hypercholesterolemia. J Pediatr, 1993. 123(1): p. 30-4.
- Gaddi, A., et al., Hypercholesterolaemia treated by soybean protein diet. Arch Dis Child, 1987. 62(3): p. 274-8.
- Blumenschein, S., et al., Effect of oat bran/soy protein in hypercholesterolemic children. Ann N Y Acad Sci, 1991. 623: p. 413-5.
- Weghuber, D. and K. Widhalm, Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet. Br J Nutr, 2008. 99(2): p. 281-6.
- Jenkins, D.J., et al., Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. Jama, 2003. 290(4): p. 502-10.
- Shanes, J.G., A review of the rationale for additional therapeutic interventions to attain lower LDL-C when statin therapy is not enough. Curr Atheroscler Rep, 2012. 14(1): p. 33-40.
- 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.
- U.S. Department of Agriculture, Modification of the Vegetable Protein Products Requirements for the National School Lunch Program, School Breakfast Program, Summer Food Service Program and Child and Adult Care Food Program. Federal Register, 2000. 7 CFR Parts 210, 215, 220, 225 and 226: p. 12429-12442.
- Astrup, A., The satiating power of protein--a key to obesity prevention? Am J Clin Nutr, 2005. 82(1): p. 1-2.
- Chevalley, T., et al., High-Protein Intake Enhances the Positive Impact of Physical Activity on BMC in Prepubertal Boys. J Bone Miner Res, 2008. 23(1): p. 131-42.
- Elango, R., et al., Protein requirement of healthy school-age children determined by the indicator amino acid oxidation method. Am J Clin Nutr, 2011. 94(6): p. 1545-52.
- Thomas, J.M. and S.F. Lutz, Soy protein lowers fat and saturated fat in school lunch beef and pork entrees. J Am Diet Assoc, 2001. 101(4): p. 461-3.
- McMindes, M.K., Applications of isolated soy protein in low-fat meal products. Food Technology, 1991. 45: p. 61-4.
- Ashraf, H.R., C. Schoeppel, and J.A. Nelson, Use of tofu in preschool meals. J Am Diet Assoc, 1990. 90(8): p. 1114-6.
- Egana, J.I., et al., Protein quality comparison of a new isolated soy protein and milk in chilean preschool children. Nutr Res, 1983. 3: p. 195-202.
- Kay, T., et al., Use of soya bean to improve the protein content of the diet in West Africa and thus prevent kwashiorkor. J Trop Pediatr Environ Child Health, 1975. 21(1-B): p. 45-8.
- Mathew, A. and D.S. Raut, Effect of soyamilk on the growth of malnourished children admitted to hospital wards. Ind J Nutr Dietet, 1981. 18: p. 260-267.
- Crowley, E.T., et al., Does milk cause constipation? A crossover dietary trial. Nutrients, 2013. 5(1): p. 253-66.
- 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.
- Cordle, C.T., Soy protein allergy: incidence and relative severity. J Nutr, 2004. 134(5): p. 1213S-9S.
- 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.
- Skripak, J.M., et al., The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol, 2007. 120(5): p. 1172-7.
- Aaronov, D., et al., Natural history of food allergy in infants and children in Israel. Ann Allergy Asthma Immunol, 2008. 101(6): p. 637-40.
- Savage, J.H., et al., The natural history of soy allergy. J Allergy Clin Immunol, 2010. 125(3): p. 683-686.
- Kagalwalla, A.F., et al., Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. J Pediatr Gastroenterol Nutr, 2011. 53(2): p. 145-9.
- Endres, J., et al., Soy-enhanced lunch acceptance by preschoolers. J Am Diet Assoc, 2003. 103(3): p. 346-51.
- Reilly, J.K., et al., Acceptability of soymilk as a calcium-rich beverage in elementary school children. J Am Diet Assoc, 2006. 106(4): p. 590-3.
- Wansink, B. and R. Westgren, Profiling taste-motivated segments. Appetite, 2003. 41(3): p. 323-7.