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By Mark Messina, PhD, MS
Editor’s Note: This article is “Part Two” in The Soy Connection newsletter series on the topic of soy “Facts vs. Myths.” The series has been produced to help clear up confusion about the health attributes of soyfoods. The first installment of our series (Volume 25, No. 1) looked at fertility, breast cancer, and so-called “male feminization.” The article in this issue reviews research on mineral status, development and cognitive function. In each case, for those who are busy, we first provide the overall conclusion, or “takeaway” message, followed by evidence underlying the concern, and then a summary of the evidence refuting the concern.
Despite being high phytate and oxalate, two compounds that inhibit mineral absorption-- the absorption of calcium (and likely also iron) from soyfoods is only modestly inhibited as a result. Incorporating soyfoods into a healthy diet does not impair mineral status.
Evidence raising concern
The mineral status of those consuming plant-based diets can be compromised as a result of inadequate intake and/or reduced bioavailability.1-3 Soybeans and soyfoods are high in compounds such as phytate4 and oxalate5 and possibly other components6 which can inhibit the absorption of divalent cations such as iron, zinc, and calcium. Vegetarians have lower iron stores because they consume high-phytate diets and do not consume heme iron.1
Evidence refuting concerns
Soyfoods often replace animal foods in the diet so the primary concern with respect to mineral nutriture is their impact on calcium, zinc and iron status. Since relatively little meat is needed to satisfy iron and zinc requirements, the impact of soy is most relevant to vegetarians.7 Vegan and mostly plant-based diets are typically a bit higher in iron, but a bit lower in zinc, and often much lower in calcium than typical Western diets.
Soyfoods are high in phytate which inhibits mineral absorption to varying degrees. Heaney et al.10 showed fractional calcium absorption from high-phytate soybeans was lower (0.310 vs 0.377) than from low-phytate soybeans, but was still remarkably good when compared with calcium absorption from cow’s milk (0.414). More importantly, even though soybeans are also high in oxalate, a potent inhibitor of calcium absorption, calcium absorption from calcium-fortified soymilk11 and calcium-set tofu12 is similar to the absorption of calcium from cow’s milk.
Acute studies show that both soy protein and phytate inhibit the absorption of iron from soy.13 Polyphenols, which are found throughout the plant kingdom, may also have a similar effect.6 However, methodological limitations may have underestimated the actual amount of iron absorbed from soy and possibly other plant foods because much of the iron in soy is in the form of ferritin.18,19 Ferritin appears to be a form of iron insensitive to the effects of dietary compounds that inhibit non-heme iron absorption.
Furthermore, in contrast to prior understanding,14 recent research shows that in response to the chronic consumption of a high-phytate diet, the effect of phytate on mineral absorption is greatly mitigated.15 Therefore, acute studies almost certainly underestimate iron bioavailability from soy. Iron stores of vegetarians are lower than that of non-vegetarians (irrespective of their soy intake) but they are still within the normal range.1
Finally, soyfoods are not particularly good sources of zinc16 and although estimates vary, zinc absorption from soyfoods is approximately 25% lower than from sources of animal protein.17 Because it is difficult to assess zinc status,18 it is often recommended that those consuming plant-based diets take a zinc supplement and/or incorporate zinc-fortified foods into their diet.
Clinical research shows neither soyfood nor isoflavone exposure affect reproductive hormone levels in children, although the data are very limited. A cross-sectional study of U.S. girls shows high soyfood intake does not affect the onset of age of menarche. More research on the effect of soy on development is warranted.
For the past four decades, the age at which puberty occurs among girls—manifested as breast development, appearance of pubic hair, and onset of menarche—has been commencing earlier.19 Corresponding trends have also occurred in boys although probably to a lesser extent. There has also been a rise in the prevalence of precocious puberty (PP), which is defined as the development of pubertal changes, at an age younger than the accepted lower limits for age of onset of puberty, namely, before age 8 years in girls and 9 years in boys.20 According to some experts, the advancement of development has resulted at least in part to exposure to hormonally active environmental agents including dietary constituents.21 Two small Korean case-control studies found that urinary isoflavones in girls with precocious puberty were higher than in children serving as controls.
Evidence refuting concern
Concerns about the impact of soy on development are focused on the potential hormonal effects of isoflavones.24 The impact of soy infant formula (SIF) has received most attention in this regard.25-27 SIF is not discussed here so the reader is referred to the references,28-32 although it is important to point out that after an extensive review, the U.S. National Toxicology Program concluded there was minimal concern about the adverse developmental effects of SIF, although they also acknowledged the need for more research.28
In adults, isoflavone intake even when greatly exceeding typical Japanese intake, does not affect testosterone levels in men,33 or estrogen levels in men34 or women.35Limited clinical research has been conducted in children, but two very small studies found neither soyfood intake nor isoflavone exposure affected reproductive hormone levels in boys or girls. Indirectly, intriguing research indicating that soy consumption during adolescence reduces later risk of developing breast cancer argues against soy causing puberty to occur earlier in life because early puberty is associated with an increased risk of this disease.
In contrast to the two aforementioned Korean studies, 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.40 Another U.S. study found isoflavone exposure was associated with delayed breast development, although this cross-sectional study was quite small in size.41 Nevertheless, this finding agrees with the results of a German longitudinal study.42 Finally, in a British study, gestational urinary levels of genistein and daidzein, two main isoflavones in soybeans, were unrelated to menarche age in the offspring.43 However, these U.S. and European studies are of very questionable value for understanding the health effects of soy because soy intake among the participants is so low.44
An exception to this generalization is a U.S. cross-sectional study involving 327 Seventh-day Adventist (SDA) girls aged 12 to 18.45 SDAs are a high-soy-consuming population. To this point, the mean number of servings of soyfoods among the adolescent girls was 12.9 per week and 21.1% of the girls consumed soyfoods ≥4x/day. The mean age of menarche among the girls was 12.5 years. The intake of total soyfoods and three specific soyfoods was unrelated to age of menarche.45
Clinical evidence suggests that in postmenopausal women, isoflavone exposure may improve some aspects of cognitive function, such as memory. In contrast, epidemiologic research evaluating the relationship between soy intake and cognitive function has produced mixed and conflicting results. Decisions about incorporating soy into the diet should not be based on its possible effects on cognition.
Isoflavones have the potential to affect cognition via their interaction with estrogen receptors.46 A Hawaiian prospective study found that mid-life tofu intake was associated with poor cognitive test performance and low brain weight.47 Likewise, among elderly Indonesians, intake of tofu (but not tempeh) was associated with worse memory among elderly Indonesians.48 In Shanghai, tofu intake was associated with worse cognitive performance.49
The aforementioned Hawaiian study, initiated in 1965, was not designed to evaluate cognitive function, but rather coronary heart disease.47 The dietary questionnaire included only 26 questions, which pales in comparison to questionnaires commonly used today that include >100 questions. The questionnaire was designed primarily to differentiate between Western and Japanese dietary patterns, not so much to gather information about specific foods. Furthermore, the questions used to evaluate tofu intake changed throughout the course of the follow up period so an arbitrary classification had to be created to evaluate the relationship between tofu and cognition.
In the case of the Indonesia study,48 follow up research by the authors failed to confirm the tofu finding; in fact, among those individuals with an average age of 67, results showed significantly positive associations between weekly tofu and tempeh consumption and better immediate recall.50 Also, in the initial study, tempeh intake was associated with better memory. The authors speculated that the opposing findings between tofu and tempeh were because the latter contains higher levels of folate. However, not only is the relationship between folate and cognition unclear,51but the possible slightly higher folate content of tempeh in comparison to tofu almost certainly is not sufficient to affect cognition.52 Thus, the results of this study are internally inconsistent. Overall, epidemiologic research that has evaluated the impact of soy intake on cognition has produced very mixed findings.
Furthermore, the clinical data suggest that isoflavone exposure may improve cognition.56 More specifically, a meta-analysis of 10 placebo-controlled randomized clinical trials involving 1,024 postmenopausal women found that soy isoflavones favorably affected summary cognitive function and visual memory in postmenopausal women.56 A second meta-analysis also found isoflavones improved memory (episodic) and possibly also global cognition.57 However, the data are inconsistent. Notable in this regard is a 3-year trial involving over 300 postmenopausal women which failed to show that isoflavone-rich soy protein affected global cognition.58 More recently, a six-month study found that 100 mg/d isoflavones did not improve cognition in older men and women with Alzheimer’s disease.59
Overall, given the inconsistency of the data, it is not surprising that the authors of a recently published comprehensive review concluded that “… the evidence to date is not sufficient to make any recommendations about the association between dietary intake of soy isoflavones and cognition in older adults.”
1. Haider LM, Schwingshackl L, Hoffmann G, Ekmekcioglu C. The effect of vegetarian diets on iron status in adults: A systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2016:0.
2. Weaver CM, Proulx WR, Heaney R. Choices for achieving adequate dietary calcium with a vegetarian diet. Am J Clin Nutr. 1999;70:543S-8S.
3. Foster M, Samman S. Vegetarian diets across the lifecycle: impact on zinc intake and status. Adv Food Nutr Res. 2015;74:93-131.
4. Harland BF, Smikle-Williams S, Oberleas D. High performance liquid chromatography analysis of phytate (IP6) in selected foods. J Food Comp Anal. 2004;17:227-33.
5. Chai W, Liebman M. Oxalate content of legumes, nuts, and grain-based flours. J Food Comp Anal. 2005;18:723-29.
6. Petry N, Egli I, Zeder C, Walczyk T, Hurrell R. Polyphenols and phytic acid contribute to the low iron bioavailability from common beans in young women. J Nutr. 2010;140:1977-82.
7. Johnson JM, Walker PM. Zinc and iron utilization in young women consuming a beef-based diet. J Am Diet Assoc. 1992;92:1474-8.
8. Davey GK, Spencer EA, Appleby PN, Allen NE, Knox KH, Key TJ. EPIC-Oxford: lifestyle characteristics and nutrient intakes in a cohort of 33 883 meat-eaters and 31 546 non meat-eaters in the UK. Public health nutrition. 2003;6:259-69.
9. Rizzo NS, Jaceldo-Siegl K, Sabate J, Fraser GE. Nutrient profiles of vegetarian and nonvegetarian dietary patterns. Journal of the Academy of Nutrition and Dietetics. 2013;113:1610-9.
10. Heaney RP, Weaver CM, Fitzsimmons ML. Soybean phytate content: effect on calcium absorption. Am J Clin Nutr. 1991;53:745-7.
11. Zhao Y, Martin BR, Weaver CM. Calcium bioavailability of calcium carbonate fortified soymilk is equivalent to cow's milk in young women. J Nutr. 2005;135:2379-82.
12. Weaver CM, Heaney RP, Connor L, Martin BR, Smith DL, Nielsen E. Bioavailability of calcium from tofu vs. milk in premenopausal women. J Food Sci. 2002;68:3144-7.
13. Reddy MB, Hurrell RF, Juillerat MA, Cook JD. The influence of different protein sources on phytate inhibition of nonheme-iron absorption in humans. Am J Clin Nutr. 1996;63:203-7.
14. Brune M, Rossander L, Hallberg L. Iron absorption: no intestinal adaptation to a high-phytate diet. Am J Clin Nutr. 1989;49:542-5.
15. Armah SM, Boy E, Chen D, Candal P, Reddy MB. Regular consumption of a high-phytate diet reduces the inhibitory effect of phytate on nonheme-iron absorption in women with suboptimal iron stores. J Nutr. 2015;145:1735-9.
16. Davidsson L, Almgren A, Sandstrom B, Juillerat M, Hurrell RF. Zinc absorption in adult humans: the effect of protein sources added to liquid test meals. Br J Nutr. 1996;75:607-13.
17. Hurrell RF. Influence of vegetable protein sources on trace element and mineral bioavailability. J Nutr. 2003;133:2973S-7S.
18. Hunt JR. Moving toward a plant-based diet: are iron and zinc at risk? Nutr Rev. 2002;60:127-34.
19. McDowell MA, Brody DJ, Hughes JP. Has age at menarche changed? Results from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. J Adolesc Health. 2007;40:227-31.
20. Berberoglu M. Precocious puberty and normal variant puberty: definition, etiology, diagnosis and current management. Journal of clinical research in pediatric endocrinology. 2009;1:164-74.
21. Schoeters G, Den Hond E, Dhooge W, van Larebeke N, Leijs M. Endocrine disruptors and abnormalities of pubertal development. Basic Clin Pharmacol Toxicol. 2008;102:168-75.
22. Kim J, Kim S, Huh K, Kim Y, Joung H, Park M. High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls. Clin Endocrinol (Oxf). 2011;75:831-5.
23. Yum T, Lee S, Kim Y. Association between precocious puberty and some endocrine disruptors in human plasma. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2013;48:912-7.
24. Ozen S, Darcan S. Effects of environmental endocrine disruptors on pubertal development. Journal of clinical research in pediatric endocrinology. 2011;3:1-6.
25. Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol. 2010;31:400-19.
26. Adgent MA, Daniels JL, Edwards LJ, Siega-Riz AM, Rogan WJ. Early-life soy exposure and gender-role play behavior in children. Environ Health Perspect. 2011;119:1811-6.
27. Adgent MA, Daniels JL, Rogan WJ, et al. Early-life soy exposure and age at menarche. Paediatr Perinat Epidemiol. 2012;26:163-75.
28. McCarver G, Bhatia J, Chambers C, et al. NTP-CERHR expert panel report on the developmental toxicity of soy infant formula. Birth Defects Res B Dev Reprod Toxicol. 2011;92:421-68.
29. Andres A, Cleves MA, Bellando JB, Pivik RT, Casey PH, Badger TM. Developmental status of 1-year-old infants fed breast milk, cow's milk formula, or soy formula. Pediatrics. 2012;129:1134-40.
30. Andres A, Moore MB, Linam LE, Casey PH, Cleves MA, Badger TM. Compared with feeding infants breast milk or cow-milk formula, soy formula feeding does not affect subsequent reproductive organ size at 5 years of age. J Nutr. 2015.
31. Messina M, Badger TM. Health effects of isoflavones misrepresented. Food Chem. 2017;225:289-92.
32. Vandenplas Y, Castrellon PG, Rivas R, et al. Safety of soya-based infant formulas in children. Br J Nutr. 2014;111:1340-60.
33. Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ. Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis. Fertil Steril. 2010;94:997-1007.
34. Messina M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril. 2010;93:2095-104.
35. Hooper L, Ryder JJ, Kurzer MS, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update. 2009;15:423-40.
36. Zung A, Shachar S, Zadik Z, Kerem Z. Soy-derived isoflavones treatment in children with hypercholesterolemia: a pilot study. J Pediatr Endocrinol Metab. 2010;23:133-41.
37. Maskarinec G, Morimoto Y, Novotny R, Nordt FJ, Stanczyk FZ, Franke AA. Urinary sex steroid excretion levels during a soy intervention among young girls: a pilot study. Nutr Cancer. 2005;52:22-8.
38. Messina M, Hilakivi-Clarke L. Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr Cancer. 2009;61:792-8.
39. Messina M, Wu AH. Perspectives on the soy-breast cancer relation. Am J Clin Nutr. 2009;89:1673S-9S.
40. Wolff MS, Teitelbaum SL, McGovern K, et al. Environmental phenols and pubertal development in girls. Environ Int. 2015;84:174-80.
41. Wolff MS, Britton JA, Boguski L, et al. Environmental exposures and puberty in inner-city girls. Environ Res. 2008;107:393-400.
42. Cheng G, Remer T, Prinz-Langenohl R, Blaszkewicz M, Degen GH, Buyken AE. Relation of isoflavones and fiber intake in childhood to the timing of puberty. Am J Clin Nutr. 2010;92:556-64.
43. Marks KJ, Hartman TJ, Taylor EV, Rybak ME, Northstone K, Marcus M. Exposure to phytoestrogens in utero and age at menarche in a contemporary British cohort. Environ Res. 2017;155:287-93.
44. Messina M. Western soy intake is too low to produce health effects. Am J Clin Nutr. 2004;80:528-9.
45. Segovia-Siapco G, Pribis P, Messina M, Oda K, Sabate J. Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption. Nutrition journal. 2014;13:54.
46. Luine VN. Estradiol and cognitive function: past, present and future. Horm Behav. 2014;66:602-18.
47. White LR, Petrovitch H, Ross GW, et al. Brain aging and midlife tofu consumption. J Am Coll Nutr. 2000;19:242-55.
48. Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord. 2008;26:50-7.
49. Xu X, Xiao S, Rahardjo TB, Hogervorst E. Tofu intake is associated with poor cognitive performance among community-dwelling elderly in China. J Alzheimers Dis. 2015;43:669-75.
50. Hogervorst E, Mursjid F, Priandini D, et al. Borobudur revisited: soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res. 2011;1379:206-12.
51. Krause D, Roupas P. Effect of Vitamin Intake on Cognitive Decline in Older Adults: Evaluation of the Evidence. The journal of nutrition, health & aging. 2015;19:745-53.
52. Ma F, Wu T, Zhao J, et al. Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI. Scientific reports. 2016;6:37486.
53. Woo J, Lynn H, Lau WY, et al. Nutrient intake and psychological health in an elderly Chinese population. Int J Geriatr Psychiatry. 2006;21:1036-43.
54. Huang MH, Luetters C, Buckwalter GJ, et al. Dietary genistein intake and cognitive performance in a multiethnic cohort of midlife women. Menopause. 2006;13:621-30.
55. Ozawa M, Ninomiya T, Ohara T, et al. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr. 2013;97:1076-82.
56. Cheng PF, Chen JJ, Zhou XY, et al. Do soy isoflavones improve cognitive function in postmenopausal women? A meta-analysis. Menopause. 2015;22:198-206.
57. Lehert P, Villaseca P, Hogervorst E, Maki PM, Henderson VW. Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis. Climacteric : the journal of the International Menopause Society. 2015;18:678-89.
58. St John JA, Henderson VW, Hodis HN, et al. Associations between urine excretion of isoflavonoids and cognition in postmenopausal women in the Women's Isoflavone Soy Health clinical trial. J Am Geriatr Soc. 2014;62:629-35.
59. Gleason CE, Fischer BL, Dowling NM, et al. Cognitive effects of soy isoflavones in patients with Alzheimer's disease. J Alzheimers Dis. 2015;47:1009-19.
Mark Messina, PhD, MS, is the co-owner of Nutrition Matters, Inc., a nutrition consulting company, and is an adjunct professor at Loma Linda University. His research focuses on the health effects of soyfoods and soybean components. He is chairman of The Soy Connection Editorial Board and executive director of the Soy Nutrition Institute.
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