Code of Federal Regulations. Health claims: Soy protein and risk of coronary heart disease. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee.
FDA Statement. Statement from Susan Mayne, Ph. October 30, Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev. Quantitative efficacy of soy isoflavones on menopausal hot flashes. British journal of clinical pharmacology. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials.
Annals of internal medicine. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. Meta-analysis of soy intake and breast cancer risk. Journal of the National Cancer Institute. Diet and breast cancer: a review of the prospective observational studies. Linos E, Willett WC. Diet and breast cancer risk reduction.
Journal of the National Comprehensive Cancer Network. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Annals of Pharmacotherapy. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent MCF-7 tumors in a dose-dependent manner. Cancer research. Nutrition and cancer. The clinical importance of the metabolite equol—a clue to the effectiveness of soy and its isoflavones.
The Journal of nutrition. Metabolism of dietary soy isoflavones to equol by human intestinal microflora—implications for health. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Experimental biology and medicine. Lampe JW. Emerging Research on Equol and Cancer—3.
The American journal of clinical nutrition. The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status.
International journal of cancer. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast cancer research and treatment. BJU international. Soy consumption and the risk of prostate cancer: An updated systematic review and meta-analysis.
Does phytoestrogen supplementation improve cognition in humans? A systematic review. Annals of the New York Academy of Sciences.
Daidzein and its Effects on Brain. Current medicinal chemistry. Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women. In a recent six-month placebo -controlled intervention study in postmenopausal equol-producing women with prehypertension, supplementation with whole soy — but not daidzein — improved lipid profiles and lowered the concentrations of CRP Current evidence suggests that whole soy components other than isoflavones may have favorable effects on cardiometabolic risk factors.
The preservation of normal arterial function plays an important role in cardiovascular disease prevention. The ability of all types of blood vessels, including arteries, to dilate in response to nitric oxide NO produced by the endothelial cells that line their inner surface is compromised in people at high risk for cardiovascular disease In the presence of cardiovascular risk factors e.
Measures of brachial flow-mediated dilation FMD , a surrogate marker of endothelial function, have been found to be inversely associated with risk of future cardiovascular events A more inclusive meta-analysis of 17 trials in either healthy individuals or in individuals with hyperlipidemia showed an increase of FMD with the intake of isolated isoflavones but not of isoflavones-containing soy protein Arterial stiffness or impaired arterial distensibility, another marker of vascular damage and an indicator of cardiovascular disease risk, is generally assessed using measures of aortic pulse-wave velocity PWV Some, but not all, placebo-controlled clinical trials have suggested that supplementation with isoflavone-containing soy protein or isoflavone extracts might significantly decrease arterial stiffness A recent randomized, double-blind , placebo-controlled study found that carotid-femoral PWV could be significantly reduced 24 hours after a single oral intake of 80 mg of soy isoflavones but only in participants able to produce equol 3.
Long-term interventions are needed to evaluate the clinical relevance of such a result. Finally, whether whole soy or isoflavones reduce the burden of subclinical atherosclerosis 99 , and lower blood pressure in individuals at high CVD risk requires further examination.
Scientific research on the effect of soy isoflavones on cognitive function has been recently reviewed by Soni et al. An observational study — the Honolulu-Asia Asian Study — that examined the relationship between soy intake and cognitive function found that Hawaiian men who reported consuming tofu non-fermented soy product at least twice weekly during midlife were more likely to have poor cognitive test scores 20 to 25 years later than those who reported consuming tofu less than twice a week In an Indonesian study of elderly men and women, consumption of tofu was associated with worse memory, while consumption of tempeh fermented soy was associated with improved memory In the multicenter, prospective , SWAN phytoestrogen ancillary study, the highest versus lowest tertile of isoflavone intakes was found to be associated with better scores in the processing speed test but worse scores in the verbal memory test in late perimenopausal and postmenopausal Asian women The results of several randomized controlled trials have been mixed.
In a review of 12 trials, only half reported an improvement in cognitive function with soy isoflavone supplementation There has been little investigation regarding the potential effects of soy isoflavones in individuals with cognitive impairments Concern over potential adverse effects of hormone replacement therapy , has led to an increased interest in the use of phytoestrogen supplements in the management of menopausal symptoms To date, the effects of increasing soy isoflavone intake on the frequency and severity of menopausal symptoms have been examined in over 60 randomized controlled trials of small sample size The results of these trials have been mixed, as reflected by the conclusions of several systematic reviews and meta-analyses published in the last decade , This result was consistent with previous analyses reporting alleviation of hot flashes in higher- rather than lower-genistein supplementation trials , , Nevertheless, in a meta-analysis by Taku et al.
In addition, the meta-analysis of nine trials women showed a Moreover, the observation that longer trials showed a greater efficacy of soy isoflavones was confirmed in a recent model-based meta-analysis by Li et al. Several relatively small intervention studies have examined the potential of equol to relieve these symptoms reviewed in A recent study in Chinese postmenopausal and equol-producing women showed no benefits of daily supplementation with soy flour 40 g or daidzein 63 mg for six months on the frequency or severity of menopausal symptoms Nevertheless, because this study lacked an inert placebo control group, the results should be viewed with caution.
At present, supplements containing sufficient amounts of genistein may help alleviate vasomotor symptoms in women transitioning through menopause , Isoflavones are found in small amounts in a number of legumes , grains, and vegetables, but soybeans are by far the most concentrated source of isoflavones in the human diet , Dietary isoflavone intakes are considerably lower in Western countries.
Compared to other European countries, the isoflavone intake was slightly higher in the British general population 2. Traditional Asian foods made from soybeans include tofu, tempeh, miso, and natto. Edamame refers to varieties of soybeans that are harvested and eaten in their green phase. Soy products that are gaining popularity in Western countries include soy-based meat substitutes, soy milk, soy cheese, and soy yogurt. The isoflavone content of a soy protein isolate depends on the method used to isolate it.
Soy protein isolates prepared by an ethanol wash process generally lose most of their associated isoflavones, while those prepared by aqueous wash processes tend to retain them Some foods that are rich in soy isoflavones are listed in Table 1 , along with their isoflavone content. Because the isoflavone content of soy foods can vary considerably among brands and among different lots of the same brand , these values should be viewed only as a guide.
Given the potential health implications of diets rich in soy isoflavones, accurate and consistent labeling of the soy isoflavone content of soy foods is needed. Of note, foods of animal origin also contain low levels of isoflavones and other phytoestrogens , derived from animal feeds and pastures Soy isoflavone extracts and supplements are available as dietary supplements without a prescription in the US.
These products are not standardized, and the amounts of soy isoflavones they provide may vary considerably. Moreover, quality control may be an issue with some of these products Soy protein-based infant formulas are made from soy protein isolate and contain significant amounts of soy isoflavones Table 2.
Soy isoflavones have been consumed by humans as part of soy-based diets for many years without any evidence of adverse effects Although diets rich in soy or soy-containing products appear safe and potentially beneficial, the long-term safety of very high supplemental doses of soy isoflavones is not yet known. Yet, longer-term studies are needed to evaluate the safety of isoflavones. The safety of high intakes of soy isoflavones and other phytoestrogens for breast cancer survivors is an area of concern among scientists and clinicians.
A few large prospective cohort studies have examined the association between soy isoflavone intake and breast cancer recurrence and survival. In the Shanghai Breast Cancer Survival Study that followed 5, female breast cancer survivors for a median of 3. A subgroup analysis showed that the inverse association between soy isoflavone intake and recurrence was significant only among women taking the anticancer drug, tamoxifen.
No inverse association was reported between soy isoflavone intake and the risks of all-cause and breast cancer-specific mortality Nevertheless, there is not enough evidence to discourage breast cancer survivors from consuming soy foods in moderation , Infant formula made from soy protein isolate has been commercially available since the mids Soy protein-based formulas are especially indicated for infants with galactosemia and hereditary lactase deficiency, but they have no proven value in the prevention or management of infantile colic and fussiness Since infants fed soy-based formulas are exposed to relatively high levels of isoflavones , which they can absorb and metabolize , concern has been raised regarding potential long-term effects on anthropometric growth, bone health, as well as reproductive, endocrine , and immune functions , In addition to the AAP review , a recent systematic review and meta-analysis of data published between and found no clinical concerns regarding nutritional adequacy, sexual development, thyroid disease, immune function, and neurodevelopment in infants fed soy protein-fed formulas In addition, the results of three observational studies suggested no adverse effects of soy protein-based formula on the neurodevelopment of children Two of these observational studies of low-to-moderate quality also reported associations between soy protein-based formula intake and marginal adverse events, including early menarche , and increased duration of menstrual bleeding Finally, no adverse health effects have been associated with the presence of phytates and aluminum in soy protein-based formulas fed to full-term infants reviewed in Nonetheless, if current evidence shows a safety profile for use of soy protein-based formulas in term infants, they are not designed or recommended for preterm infants Also, recent preliminary findings suggesting potential links between consumption of soy protein-based formulas and adverse effects in autistic children deserve further investigation , Exposure to isoflavones including at levels above typical Asian dietary intakes has not been shown to affect either the concentrations of estrogen and testosterone, or the quality of sperm and semen , Thorough reviews of the literature found no basis for concern but emphasized the need for long-term, large scale comprehensive human studies , In cell culture and animal studies, soy isoflavones have been found to inhibit the activity of thyroid peroxidase, an enzyme required for thyroid hormone synthesis , However, high intakes of soy isoflavones do not appear to increase the risk of hypothyroidism as long as dietary iodine consumption is adequate Since the addition of iodine to soy-based formulas in the s, there have been no further reports of hypothyroidism in soy formula-fed infants Several clinical trials , mostly in women with sufficient iodine intakes, have not found increased consumption of soy isoflavones to result in clinically significant changes in circulating thyroid hormone concentrations To date, studies have not examined the effect of an isoflavone-rich diet on fetal development or pregnancy outcomes in humans, and the safety of isoflavone supplements during pregnancy has not been established.
Fermented soy foods contain highly variable amounts of the biologically active amine, tyramine, which is catabolized in the body by monoamine oxidase enzyme MAO and excreted in the urine. The ingestion of very high amount of tyramine may saturate the detoxification system and lead to clinical symptoms of intoxication. Because individuals taking MAO inhibitors MAOIs; phenelzine, tranylcypromine are at greater risk of adverse effects, they should avoid consuming fermented soy products , Because colonic bacteria play an important role in the metabolism of soy isoflavones, antibiotic therapy could decrease their biological activity Some evidence from animal studies suggested that high intakes of soy isoflavones, particularly genistein, could interfere with the antitumor effects of tamoxifen Nolvadex Yet, a recent pooled analysis of three prospective cohort studies found that the risk of recurrence in breast cancer survivors was reduced to a greater extent with soy isoflavone intake in tamoxifen users than in nonusers see Safety for breast cancer survivors Nonetheless, until more is known about potential interactions in humans, those taking tamoxifen or other selective estrogen receptor modulators SERMs to treat or prevent breast cancer should be cautious and seek medical advice regarding the use of soy protein supplements or isoflavone extracts High intakes of soy protein may interfere with the efficacy of the anticoagulant medication warfarin.
INR values returned to therapeutic levels two weeks after discontinuing soy milk. The amount of levothyroxine required for adequate thyroid hormone replacement has been found to increase in infants with congenital hypothyroidism fed soy formula , Taking levothyroxine at the same time as a soy protein supplement also increased the levothyroxine dose required for adequate thyroid hormone replacement in an adult with hypothyroidism Regular consumption of a diet high in soy — rather than supplementation with isoflavone extracts or isoflavone containing isolated soy protein — may help lower fasting glucose concentrations It is unknown whether individuals taking antidiabetic agents might be at risk of hypoglycemia if they follow a soy-based meal replacement plan rather than a diet plan recommended by the American Diabetes Association Originally written in by: Jane Higdon, Ph.
Updated in January by: Jane Higdon, Ph. Updated in December by: Victoria J. Drake, Ph. Updated in August by: Barbara Delage, Ph. Reviewed in October by: Alison M. Duncan, Ph. Lampe JW. Isoflavonoid and lignan phytoestrogens as dietary biomarkers. J Nutr. Absorption, distribution, metabolism, and excretion of isoflavonoids after soy intake. Arch Biochem Biophys. Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial.
Am J Clin Nutr. Setchell KD, Clerici C. Equol: history, chemistry, and formation. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora.
Method of defining equol-producer status and its frequency among vegetarians. National Cancer Institute. January Wang LQ. Mammalian phytoestrogens: enterodiol and enterolactone. Isoflavonoids and chronic disease: mechanisms of action. The role of soy phytoestrogens in prostate cancer.
Curr Opin Urol. Molecular basis of the inhibition of human aromatase estrogen synthetase by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Environ Health Perspect.
Acute and chronic effects of genistein, tyrphostin and lavendustin A on steroid synthesis in luteinized human granulosa cells. Hum Reprod. The soy isoflavone genistein induces estrogen synthesis in an extragonadal pathway.
Mol Cell Endocrinol. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res.
Isoflavone phytoestrogens consumed in soy decrease F 2 -isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Isoflavonoids do not inhibit in vivo lipid peroxidation in subjects with high-normal blood pressure. Effect of soy isoflavone supplementation on markers of oxidative stress in men and women. Cancer Lett. Global cancer statistics, CA Cancer J Clin. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. Messina M, Hilakivi-Clarke L.
Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Epidemiology of soy exposures and breast cancer risk. Br J Cancer. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies.
Breast Cancer Res Treat. A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women. Int J Cancer. Childhood soy intake and breast cancer risk in Asian American women.
Cancer Epidemiol Biomarkers Prev. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Adolescent dietary phytoestrogen intake and breast cancer risk Canada.
Cancer Causes Control. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies. Adv Exp Med Biol. 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. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Double-blind randomized month soy intervention had no effects on breast MRI fibroglandular tissue density or mammographic density. Cancer Prev Res Phila. The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.
Endometrial thickness and risk of breast and endometrial carcinomas in the prostate, lung, colorectal and ovarian cancer screening trial.
Soy intake is associated with lower endometrial cancer risk: a systematic review and meta-analysis of observational studies. Medicine Baltimore. Legume, soy, tofu, and isoflavone intake and endometrial cancer risk in postmenopausal women in the multiethnic cohort study. J Natl Cancer Inst. It is important to recognize that most epidemiologic studies that have examined the relationship between soy intake and health outcomes have involved Asian populations and therefore evaluated the intake of traditional soy foods, such as tofu or soy milk, that are derived from whole or dehulled soybeans.
In contrast, few animal or human intervention studies have involved whole soy foods. Instead, soy concentrates, soy isolates, isolated isoflavone mixtures, supplements, or pure genistein are generally used. Some studies have evaluated full-fat or defatted soy flours or textured soy protein usually mixtures of soy concentrates and soy flour. Thus, a major distinction usually occurs between the population-based association studies of soy food intake and health outcomes and most experimental research that is based on use of isolated fractions of the soybean.
The dozens of products used for research differ markedly in both macro protein, fat, and carbohydrates and micro isoflavones, saponins, phytic acid, phytosterols, vitamins, and minerals constituents 2.
Table 1 shows the substantial compositional differences in macronutrient content among soy flours, concentrates, and isolates. Research articles often use terms such as soy, soy protein, or even soy supplements without specifying what is meant or has been used in a study. Unfortunately, researchers often neglect to provide sufficient details in the methods sections of papers to allow others to understand, interpret, or repeat their work.
Percentage composition of soy protein products moisture-free basis 1. Modified from Endres 2. Chemical composition of soy concentrates or isolates is affected by processing techniques, including both solubilization method and temperature. Both water and alcohol ethanol washing are used to concentrate the proteins by removing sugars and oligosaccharides from soy.
Water, and to some degree ethanol, will also remove some of the low-molecular-weight peptides those below that contain high amounts of sulfur amino acids. Alcohol washing also removes most of the isoflavones and other lipid-soluble phytochemicals such as saponins from the product 3 , 4. Table 2 lists the total and individual isoflavone contents of selective soy foods 5. Estimated isoflavone contents of selected soy protein products 1, 2. Modified from Jackson and Gilani 5. Recent research indicates alcohol washing may substantially alter the protein matrix and structure.
For example, Gianazza et al. Gianazza et al. Researchers often compare ethanol-washed with nonethanol-washed soy protein and then assume that any differences seen in health outcomes are due to the isoflavone component when saponins, other alcohol soluble material, and the protein and peptide composition could conceivably contribute or be responsible for the observations.
The composition of specific standardized soy foods varies substantially. Setchell and Cole 8 recently evaluated the variations in isoflavone levels in soy foods and soy protein isolates. They found a 2—3-fold variation in total isoflavones in soy protein isolates over 3 y and fivefold differences in isoflavone levels in different commercial soy milks.
Figure 1 shows the variations in total isoflavones in soy milks 8. The differences among products are due in part to the variety of soybeans, differences in growing and storage conditions, and differential food processing techniques. Clearly, it is important for the scientific community to accurately understand the chemical composition of study products.
Total isoflavone content of 85 samples from 40 different brands of commercial soy milks grouped according to milk type. Bars represent means of 4 or more replicate analyses. The insoluble okara is removed from whole bean soy milks during processing whereas the entire bean soy milks contain the okara.
Modified from Setchell and Cole 8. Another major source of confusion is the nomenclature used for isoflavones. The soybean contains 6 major and 6 minor forms of isoflavones.
In contrast the hypocotyl, or germ, contains high concentrations of glycitin and some glycitein, moderate amounts of daidzin, and relatively small amounts of genistin. Many commercial soy isoflavone supplements are made from the soy germ.
Those soy isoflavone supplements do not contain the same isoflavone profile as that obtained from the consumption of soy foods that are produced primarily from the whole or the dehulled soybean. This difference leads to markedly different plasma isoflavone profiles Other soy isoflavone products derived from whole soy or recovered from the ethanol wash during the preparation of soy concentrates and isolates also contain various profiles and amounts of isoflavones and other constituents.
Modified from Gugger 9. On a dry weight basis hypocotyl, cotyledon, and seed coat are represented by 2. Considerable confusion exists about how the isoflavone content of a product is expressed. As previously noted, isoflavones are naturally present in the soybean primarily as glycosides.
However, as a result of processing, and especially fermentation, some of the glycosides in soy foods are converted to aglycones. Researchers often express the isoflavone content of the product fed to subjects without indicating whether the stated amount refers to the aglycone or glycoside value. Thus, mg isoflavones may represents anywhere from 60 to mg active isoflavones depending on the type of soy product.
Simply indicating the form of the isoflavones in a product is not sufficient. Ideally, all values should be expressed as the aglycone equivalent. Of course, as noted by Murphy et al. In addition, summing of isoflavone intakes may not be useful because the biological activities of daidzein and genistein are quite different and the activities of other isoflavones are not well characterized.
Even scientists specializing in soy nutrition find it difficult to synthesize the findings from the hundreds of papers published yearly on soy foods, soy isoflavones, and genistein. These publications range from epidemiologic investigations to human intervention trials, animal studies, and cell culture work. Although several epidemiologic studies involving Western populations have noted positive associations between soy intake and favorable health outcome, some questions remain about the plausibility of there being a soy-related biological basis for the reported results because of the very limited soy intakes noted in these studies.
As is always the case with epidemiologic studies, there is the issue of uncontrolled confounding variables. Because soy foods, which are generally perceived as healthful, are not a traditional part of Western diets, higher soy consumption may reflect an overall healthful lifestyle that is not so easily identified or controlled for Similarly, in Asian countries, soy intake may be more a marker of a traditional diet and lifestyle low fat, low red meat, more green tea, more exercise, etc.
Precise quantification is difficult because small amounts of soy protein containing variable amounts of isoflavones are added to literally hundreds of commonly consumed processed foods. Although the goals of these trials are important, we should be mindful that provision of high amounts of soy protein and isoflavones exceeds habitual intakes in soy-consuming populations.
On a kilogram body weight basis, isoflavone intake is 4—8 times greater in infants exclusively fed soy infant formulas when compared with intake of adults.
Not unexpectedly, the concentration of isoflavones in blood and tissues of infants is 10 times greater than in adults with comparable daily intakes of soy products, especially because infants are continually consuming isoflavones throughout the day Despite these very high levels with their potential for biological effects, it is worth noting that soy infant formula has been generally shown to be nutritionally safe and adequate for normal growth and development. Moreover, acute species differences in colonic metabolism and biotransformation of isoflavones may influence response to an intervention Although experiments in animals are usually designed to show a difference between diet groups, interpretation or translation of those results to humans should be done with the knowledge that these effects may not occur at the lower intake levels typically found in Western or perhaps even in Asian cultures.
Studies that use the addition of genistein either by injection or diet provide valuable information about its pharmacological actions, but caution is needed when extrapolating findings to humans consuming soy protein foods, especially because genistein is rarely present in substantial amounts in most human diets.
Specialized animal models are frequently used to study specific health aspects of food components. There are a variety of cancer, diabetes, and coronary heart disease models, usually involving rodents rats and mice bred especially to express these diseases. Because no individual animal model is totally comparable with humans with regard to disease progression or metabolism, researchers should consider the strengths and weaknesses of an animal model system when relating the results to humans.
This is especially important when investigating the effects of in utero and prepubescent soy exposure. The microflora in the intestinal tract of rodents and monkeys are more efficient than microflora in humans in producing the isoflavone metabolite equol; in fact, rodents and monkeys are referred as to as equol machines Because equol has been suggested to be a particularly potent biologically active isoflavone 22 , outcomes of studies with rats and mice may not predict the effect of soy isoflavone consumption by humans.
Perhaps the source of the most confusion and conflicting results is the use of supraphysiological levels of genistein or isoflavone mixtures in cell culture studies. Cell culture studies often use isoflavone concentrations of 10— times higher than physiological levels and provide isoflavones without other soy components.
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