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This is what Oregon State University has found on soy and its actions in the body.
Isoflavones are a class of phytoestrogens—plant-derived compounds with estrogenic activity. Soybeans and soy products are the richest sources of isoflavones in the human diet. (More Information)
The results of recent randomized controlled trials suggest that substituting 50 g/d of soy protein for animal protein results in only a modest 3% reduction of LDL cholesterol. Isolated soy isoflavone supplements do not appear to have favorable effects on serum lipid profiles. (More Information)
Although hip fracture rates are generally lower among Asian populations consuming soy foods than among Western populations, it is not yet clear whether increasing soy isoflavone consumption in Western populations will help prevent osteoporosis. (More Information)
Overall, the results of numerous observational studies do not support the idea that high soy isoflavone intakes in adults are protective against breast cancer. Limited research suggests that higher intakes of soy foods early in life may decrease the risk of breast cancer in adulthood. (More Information)
Although scientists are interested in the potential for soy isoflavones to prevent or inhibit the progression of prostate cancer, evidence from observational studies that soy isoflavones are protective against prostate cancer is limited and inconsistent. (More Information)
Overall, there is little evidence that increasing soy isoflavone intake from food or supplements substantially improves menopausal hot flushes. (More Information)
Although diets rich in soy or soy-containing products appear safe and potentially beneficial, the long-term safety of high doses of soy isoflavone supplements is not yet known. (More Information)
At present, there is no convincing evidence that infants fed soy-based formula are at greater risk for adverse effects than infants fed cow’s milk-based formula. (More Information)
Introduction
Isoflavones are polyphenolic compounds that are capable of exerting estrogen-like effects. For this reason, they are classified as phytoestrogens—compounds with estrogenic activity derived from plants (1). Legumes, particularly soybeans, are the richest sources of isoflavones in the human diet. In soybeans, isoflavones are present as glycosides (bound to a sugar molecule). Fermentation or digestion of soybeans or soy products results in the release of the sugar molecule from the isoflavone glycoside, leaving an isoflavone aglycone. Soy isoflavone glycosides are called genistin, daidzin, and glycitin, while the aglycones are called genistein, daidzein, and glycitein, respectively (chemical structures of isoflavone aglycones). Unless otherwise indicated, quantities of isoflavones specified in this article refer to aglycones—not glycosides.
****bolism and Bioavailability
The biological effects of soy isoflavones are strongly influenced by their ****bolism, which is dependent on the activity of bacteria that colonize the human intestine (2). For example, the soy isoflavone daidzein may be ****bolized to equol, a ****bolite that has greater estrogenic activity than daidzein, and to other ****bolites that are less estrogenic. Studies that measure urinary equol excretion after soy consumption indicate that only about 33% of individuals from Western populations ****bolize daidzein to equol (3). Thus, individual differences in the ****bolism of isoflavones could have important implications for the biological activities of these phytoestrogens.
Biological Activities
Estrogenic and Anti-Estrogenic Activities
Soy isoflavones are known to have weak estrogenic activity. Estrogens are signaling molecules that exert their effects by binding to estrogen receptors within cells (chemical structures of endogenous estrogens). The estrogen-receptor complex interacts with DNA to change the expression of estrogen-responsive genes. Estrogen receptors are present in numerous tissues other than those associated with reproduction, including bone, liver, heart and brain (4). Soy isoflavones and other phytoestrogens can bind to estrogen receptors, mimicking the effects of estrogen in some tissues and antagonizing (blocking) the effects of estrogen in others (5). Scientists are interested in the tissue-selective activities of phytoestrogens because anti-estrogenic effects in reproductive tissue could help reduce the risk of hormone associated cancers (breast, uterine and prostate), while estrogenic effects in other tissues could help maintain bone density and improve blood lipid profiles (cholesterol levels). The extent to which soy isoflavones exert estrogenic and anti-estrogenic effects in humans is currently the focus of considerable scientific research.
Estrogen Receptor-Independent Activities
Soy isoflavones and their ****bolites also have biological activities that are unrelated to their interactions with estrogen receptors (6). By inhibiting the synthesis and activity of certain enzymes involved in estrogen ****bolism, soy isoflavones may alter the biological activity of endogenous estrogens and testosterones (7-9). Soy isoflavones have also been found to inhibit tyrosine kinases (10), enzymes that play critical roles in the signaling pathways that stimulate cell proliferation. Additionally, isoflavones can act as antioxidants in vitro (11), but the extent to which they contribute to the antioxidant status of humans is not yet clear. Plasma F2-isoprostanes, biomarkers of lipid peroxidation in vivo, were lower after two weeks of daily consumption of soy protein containing 56 mg of isoflavones than after consumption of soy protein providing only 2 mg of isoflavones (12). However, daily supplementation with 50-100 mg of isolated soy isoflavones did not significantly alter plasma or urinary F2-isoprostane levels (13, 14).Prevention
Cardiovascular Disease
Serum Cholesterol
Although controlled clinical trials conducted prior to 1995 suggested that substituting 25-50 g/d of soy protein for animal protein lowered serum LDL cholesterol by about 13% (15), more recent and better controlled trials indicate that the LDL cholesterol-lowering effect of soy protein is much more modest. A recent review of 22 randomized controlled trials concluded that substituting 50 g/d of soy protein for animal protein lowered LDL cholesterol by only about 3% (16). There is limited evidence that soy protein containing isoflavones is more effective than soy protein without isoflavones in lowering LDL cholesterol (17,18), but the consumption of soy isoflavones alone (as supplements or extracts) does not appear have favorable effects on serum lipid profiles (19,20). For more information on soy protein and cholesterol, see the article on Legumes.
Effects on Arterial Function
The preservation of normal arterial function plays an important role in cardiovascular disease prevention. The ability of arteries to dilate in response to nitric oxide produced by the endothelial cells that line their inner surface (endothelium-mediated vasodilation) is compromised in people at high risk for cardiovascular disease (21). However, most placebo-controlled trials found no significant improvement in endothelium-mediated vasodilation when postmenopausal women were supplemented with up to 80 mg/d of soy isoflavones (22-24) or up to 60 g/d of soy protein containing isoflavones (25-28). Measures of arterial stiffness assess the distensibility of arteries, and a strong association between arterial stiffness and atherosclerosis has been observed (29). In placebo-controlled clinical trials, supplementation of postmenopausal women with 80 mg/d of a soy isoflavone extract for 5 weeks significantly decreased arterial stiffness (23), as did supplementation of men and postmenopausal women with 40 g/d of soy protein providing 118 mg/d of soy isoflavones for 3 months (28). Although most studies have not found supplementation with soy protein or isoflavones to improve endothelium-mediated vasodilation, preliminary research suggests that soy isoflavone supplementation may decrease arterial stiffness.
Hormone-associated Cancers
Breast Cancer
Breast cancer rates in Asia, where average isoflavone intakes from soy foods range from 11-47 mg/d (30), are lower than breast cancer rates in the Western countries where average isoflavone intakes in non-Asian women may be less than 2 mg/d (31, 32). However, many other hereditary and lifestyle factors could contribute to this difference in breast cancer rates. Most epidemiological studies have not found that women with higher soy intakes are at lower risk of breast cancer, with the possible exception of women who had higher soy intakes during adolescence (33). At present, there is no evidence that taking soy isoflavone supplements decreases breast cancer risk. See the article on Legumes for more information about soy consumption and breast cancer risk.
Endometrial Cancer
Because the development of endometrial (uterine) cancer is related to prolonged exposure to unopposed estrogens, it has been suggested that high intakes of phytoestrogens with anti-estrogenic activity in uterine tissue could be protective against endometrial cancer (34). In support of this idea, two retrospective case-control studies found that women with endometrial cancer had lower intakes of soy isoflavones from foods compared to cancer-free control groups (34, 35). However, supplementation of postmenopausal women with soy protein providing 120 mg/d of isoflavones for 6 months did not prevent endometrial hyperplasia induced by the administration of exogenous estradiol (36). Although limited evidence from case-control studies suggests that higher dietary intakes of soy foods may be associated with lower endometrial cancer risk, there is no evidence that taking soy isoflavone supplements decreases endometrial cancer risk.
Prostate Cancer
Mortality from prostate cancer is much higher in the US than in Asian countries, such as Japan and China (37). However, epidemiological studies do not provide consistent evidence that high intakes of soy foods are associated with reduced prostate cancer risk. See the article on Legumes for more information about soy foods and prostate cancer risk. The results of cell culture and animal studies suggest a potential role for soy isoflavones in limiting the progression of prostate cancer. Although soy isoflavone supplementation for up to one year did not significantly decrease serum prostate specific antigen (PSA) concentrations in men without confirmed prostate cancer (38-40), soy isoflavone supplementation appeared to slow rising serum PSA concentrations associated with prostate tumor growth in two small studies of prostate cancer patients (41, 42). Although such preliminary findings are encouraging, the results of larger randomized controlled trials, which are currently ongoing, are needed to determine whether soy isoflavone supplementation can play a role in the prevention or treatment of prostate cancer.
Osteoporosis
Although hip fracture rates are generally lower among Asian populations consuming soy foods than among Western populations, it is not yet clear whether increasing soy isoflavone consumption in Western populations helps to prevent osteoporosis (43). The results of short-term clinical trials (6 months or less) assessing the effects of increased soy intake on biochemical markers of bone formation and bone resorption are inconsistent. While some controlled trials in postmenopausal women found that increasing intakes of soy foods, soy protein or soy isoflavones improved markers of bone resorption and formation (44-47), others found no improvement (48-50). Randomized controlled trials of longer duration are required to determine whether increased soy intake can actually prevent losses in bone mineral density (BMD) or osteoporotic fracture. Two controlled clinical trials found that BMD losses over 6 months were lower in postmenopausal women supplemented with soy protein containing isoflavones than in those supplemented with equal amounts of milk protein (49, 51), but two longer trials found that BMD loss did not differ between postmenopausal women supplemented with soy protein containing isoflavones and those supplemented with milk protein (52, 53). A 2-year clinical trial found that daily consumption of soy milk containing isoflavones decreased BMD loss in the lumbar spine compared to daily consumption of soymilk without isoflavones (54), but two others studies found that BMD loss did not differ between postmenopausal women taking soy protein supplements containing isoflavones and those taking soy protein supplements without isoflavones (55, 56). Loss of bone mineral content at the hip over one year was lower in Taiwanese women who took 80 mg/d of isolated soy isoflavones compared to placebo, but the difference was significant only in those women who were at least 4 years past menopause, had lower body weights or lower calcium intakes (57). While there is some evidence that isoflavone-rich diets have bone-sparing effects, it is not known whether increasing soy isoflavone intake appreciably decreases the risk of osteoporosis or osteoporotic fracture.
Cognitive Decline
Scientific research on the effect of soy isoflavones on cognitive function is limited. The only published observational study that examined the relationship between soy intake and cognitive function found that Hawaiian men who reported consuming tofu at least twice weekly during midlife were more likely to have poor cognitive test scores 20-25 years later than those who reported consuming tofu less than twice a week (58). In contrast, the results of several small clinical trials in postmenopausal women suggest that increasing soy isoflavone intake may result in modest improvements in performance on some cognitive tests for up to six months. Postmenopausal women given soy extracts providing 60 mg/d of soy isoflavones for 6-12 weeks performed better than women given a placebo on cognitive tests of picture recall (short-term memory), learning rule reversals (mental flexibility) and a planning task (59, 60). In a longer trial, postmenopausal women given supplements that provided 110 mg/d of soy isoflavones for six months performed better than women given placebos on a test of verbal fluency (61). However, in the largest placebo-controlled trial in postmenopausal women to date, daily intake of soy protein providing 99 mg of isoflavones for one year did not affect performance on a battery of cognitive function tests, including tests for memory, attention, verbal fluency and dementia (53).
Treatment
Menopausal Symptoms
Hot flushes (flashes) are the primary reason that women seek medical attention for menopausal symptoms (62). Concern over potential adverse effects of hormone replacement therapy (63) has led to increased interest in the use of phytoestrogen supplements by women experiencing menopausal symptoms. The effects of increasing soy isoflavone intake on the frequency of hot flushes have been examined in a number of randomized controlled trials (64). Out of 8 randomized controlled trials of soy foods, only one found a significant reduction in the frequency of hot flushes, while 3 out of 5 controlled trials of soy isoflavone extracts reported a significant reduction in hot flush frequency (65). In general, any reductions observed were modest (10-20%) compared to placebo. Breast cancer survivors in particular may experience more frequent and severe hot flushes related to therapies aimed at preventing breast cancer recurrence (66). However, none of the randomized controlled trials in breast cancer survivors found that soy isoflavone supplementation was significantly more effective than a placebo in decreasing the frequency or severity of hot flushes (67-70). Overall, there is little evidence that increasing soy isoflavone intake from food or supplements substantially improves menopausal hot flushes (65).
Sources
Food Sources
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 (30, 71). Recent surveys suggest that average dietary isoflavone intakes in Japan, China and other Asian countries range from 11-47 mg/d (72, 73). Dietary isoflavone intakes are considerably lower in Western countries, where studies have found average isoflavone intakes to be as low as 2 mg/d (32, 74). 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 (75). Some foods that are rich in soy isoflavones are listed in the table below along with their isoflavone content (76). Because the isoflavone content of soy foods can vary considerably between brands and between different lots of the same brand (75), 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. More information on the isoflavone content of foods is available from the USDA nutrient data laboratory.
Total Isoflavone, Daidzein and Genistein Aglycone Content of Selected Foods
Food Serving Total Isoflavones (mg) Daidzein (mg) Genistein (mg)
Soy protein concentrate, aqueous washed 3.5 oz 102 43 56
Soy protein concentrate, alcohol washed 3.5 oz 12 7 5
Miso ½ cup 59 22 34
Soybeans, boiled ½ cup 47 23 24
Tempeh 3 ounces 37 15 21
Soybeans, dry roasted 1 ounce 37 15 19
Soy milk 1 cup 30 12 17
Tofu yogurt ½ cup 21 7 12
Tofu 3 ounces 20 8 12
Soybeans, green, boiled (Edamame) ½ cup 12 6 6
Meatless (soy) hot dog 1 hot dog 11 3 6
Meatless (soy) sausage 3 links 3 0.6 2
Soy cheese, mozzarella 1 oz 2 0.3 1
Supplements
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. When isoflavone supplements available in the US were tested for their isoflavone content by independent laboratories, the isoflavone content in the product differed by more than 10% from the amount claimed on the label in 30-50% of the products tested (77, 78).
Infant Formulas
Soy-based infant formulas are made from soy protein isolate and contain significant amounts of soy isoflavones. In 1997, the total isoflavone content of soy-based infant formulas, commercially available in the US, ranged from 32-47 mg/liter (~ 34 fluid ounces) (79).
Total Isoflavone, Daidzein and Genistein Aglycone Content of Selected Soy-based Infant Formulas
Soy-based Formula Serving Total isoflavones (mg) Daidzein (mg) Genistein (mg)
Mead Johnson Prosobee, ready to feed
8 fl oz 9.4 4.1 5.3
Ross Isomil, ready to feed 8 fl oz 10.2 4.7 5.5
Wyeth-Ayerst Nursoy, ready to feed 8 fl oz 6.4 1.8 3.9
Safety
Soy isoflavones have been consumed by humans as part of soy-based diets for many years without any evidence of adverse effects (30). The 75th percentile of dietary isoflavone intake has been reported to be as high as 65 mg/d in some Asian populations (80). 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.
Adverse Effects
Safety for Breast Cancer Survivors
The safety of high intakes of soy isoflavones and other phytoestrogens for breast cancer survivors is an area of considerable debate among scientists and clinicians (66, 81). The effects of high intakes of soy isoflavones on breast cancer survival and breast cancer recurrence in humans have not been studied. The results of cell culture and animal studies are conflicting, but some have found that soy isoflavones can stimulate the growth of estrogen receptor positive (ER+) breast cancer cells (82, 83). The effects of high intakes of soy isoflavones in breast cancer survivors who are taking tamoxifen (an anti-estrogenic drug) have not been studied, but high intakes of the soy isoflavone, genistein, interfered with the ability of tamoxifen to inhibit the growth of ER+ breast cancer cells implanted in mice (84). Very limited data from clinical trials suggests that increased consumption of soy isoflavones (38-45 mg/d) can have estrogenic effects in human breast tissue (85, 86). However, a recent study in women with biopsy-confirmed breast cancer found that supplementation with 200 mg/d of soy isoflavones did not increase tumor growth over the next 2-6 weeks before surgery when compared to a control group that did not take soy isoflavones (87). Given the available data, some experts think that women with a history of breast cancer, particularly ER+ breast cancer, should not increase their consumption of phytoestrogens, including soy isoflavones (66). However, other experts argue that there is not enough evidence to discourage breast cancer survivors from consuming soy foods in moderation (81).
Soy-based Infant Formulas
Infant formula made from soy protein isolate has been commercially available since the mid 1960s (88). As much as 25% of the infant formula sold in the US is soy-based formula. Since infants fed soy-based formulas are exposed to relatively high levels of isoflavones, which they can absorb and ****bolize, concern has been raised regarding potential long-term effects on growth, development, and reproductive and immune function (79, 89). The results of at least 6 clinical trials comparing infants fed soy-based formula with infants fed cow’s milk-based formula indicate that soy-based formula supports normal growth and development in the first year of life (90). Limited data are available on the long-term effects of feeding infants soy-based formula. One retrospective study of 811 men and women at 20-34 years of age found no differences in height, weight, time of puberty, general health or pregnancy outcomes between those fed soy-based formula as infants and those fed cow’s milk-based formula, although women fed soy-based formula reported significantly greater use of asthma or allergy drugs than women fed cow’s milk formula (91). At present, there is no convincing evidence that infants fed soy-based formula are at greater risk for adverse effects than infants fed cow’s milk-based formula. However, long-term studies on the growth and development of infants fed soy-based formulas are currently ongoing (92).
Thyroid Function
Soy isoflavones have been found to inhibit the activity of thyroid peroxidase, an enzyme required for thyroid hormone synthesis in cell culture and animal studies (93, 94). 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 1960s, there have been no further reports of hypothyroidism developing in soy formula-fed infants (95). Several clinical trials in premenopausal and postmenopausal women with sufficient iodine intakes have not found high intakes of soy isoflavones to result in clinically significant changes in circulating thyroid hormone levels (96-99).
Pregnancy
Although there is no evidence that diets rich in soy isoflavones have adverse effects on fetal development or pregnancy outcomes in humans, the safety of isoflavone supplements during pregnancy has not been established.
Drug interactions
Because colonic bacteria play an important role in the ****bolism of soy isoflavones, antibiotic therapy could decrease their biological activity (100). Some evidence from animal studies suggests that high intakes of soy isoflavones, particularly genistein, can interfere with the antitumor effects of tamoxifen (Nolvadex) (84). 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 avoid soy protein supplements or isoflavone extracts (see Safety for Breast Cancer Survivors). High intakes of soy protein may interfere with the efficacy of the anticoagulant medication warfarin. There is one case report of an individual on warfarin who developed subtherapeutic INR (prothrombin time) values upon consuming ~16 ounces of soy milk daily for four weeks (101). 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 (95, 102). 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 (103).
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