An Evidence-based Approach to Phytochemicals and Other Dietary Factors

12 Soy Isoflavones

Isoflavones are polyphenolic compounds that are capable of exerting estrogen-like effects. For this reason, they are classified as phytoestrogens—plant-derived compounds with estrogenic activity.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 release of the sugar molecule from the isoflavone glycoside, leaving an isoflavone aglycone. Soy isoflavone glycosides are called daidzin, genistin, and glycitin; the aglycones are called genistein, daidzein, and glycitein, respectively (Fig. 12.1). Unless otherwise indicated, quantities of isoflavones specified in this article refer to aglycones—not glycosides.

Bioavailability and Metabolism

The biological effects of soy isoflavones are strongly influenced by their metabolism, which is dependent on the activity of bacteria that colonize the human intestine.2 For example, the soy isoflavone daidzein may be metabolized in the intestine to equol (Fig. 12.2), a metabolite that has greater estrogenic activity than daidzein, and to other metabolites that are less estrogenic. Studies that measure urinary equol excretion after soy consumption indicate that only approximately 33% of individuals from Western populations metabolize daidzein to equol.³ Thus, individual differences in the metabolism of isoflavones could have important implications for the biological activities of these phytoestrogens.

Fig. 12.1 Chemical structures of the soy isoflavones, daidzein, genistein, and glycitein, in their aglycone forms.

Fig. 12.2 Chemical structures of 17 β-estradiol, an endogenous estrogen, and equol, a bacterial metabolite of daidzein that has estrogenic activity.

Biological Activities

Estrogenic and Antiestrogenic Activities

Soy isoflavones are known to have weak estrogenic or hormone-like activity. Estrogens are signaling molecules that exert their effects by binding to estrogen receptors within cells. 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 antiestrogenic 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 antiestrogenic effects in humans is currently the focus of considerable scientific research.

Estrogen-Receptor-Independent Activities

Soy isoflavones and their metabolites 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 metabolism, soy isoflavones may alter the biological activity of endogenous estrogens and androgens.^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 significantly lower after 2 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

Disease Prevention

Cardiovascular Disease

Serum Cholesterol

Although controlled clinical trials conducted prior to 1995 suggested that substituting 25–50 g/day of soy protein for animal protein lowered serum low-density lipoprotein (LDL) cholesterol by approximately 13%,15 more recent and better controlled trials indicate that the LDL-cholesterol-lowering effect of soy protein is much more modest. A review in 2000 of 22 randomized controlled trials concluded that substituting 50 g/day of soy protein for animal protein lowered LDL cholesterol by only approximately 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 to have favorable effects on serum lipid profiles.^16,19–21 For more information on soy protein and cholesterol, see Chapter 3.

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.²² To date, results of randomized controlled trials on the effect of soy isoflavones on arterial function have been mixed. However, most placebo-controlled trials found no significant improvement in endothelium-mediated vasodilation when postmenopausal women were supplemented with up to 80 mg/day of soy isoflavones^23–25 or up to 60 g/day of soy protein containing isoflavones.^26–30 Arterial stiffness is another measure of arterial function. Measurements of arterial stiffness assess the distensibility of arteries, and a strong association between arterial stiffness and atherosclerosis has been observed.³¹ In placebo-controlled clinical trials, supplementing the diet of postmenopausal women with 80 mg/day of a soy isoflavone extract for 5 weeks significantly decreased arterial stiffness,³² as did supplementation of men and postmenopausal women at 40 g/day of soy protein, providing 118 mg/day of soy isoflavones for 3 months.²⁹ 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. However, a recent randomized, controlled, crossover trial in hypertensive individuals found that supplementation with soy protein containing 118 mg/day of isoflavones for 6 months did not improve measures of arterial function, including arterial stiffness.³³ More research is needed to determine whether supplementation with soy isoflavones improves arterial function.

Hormone-Associated Cancers

Breast Cancer

The incidence of breast cancer in Asia, where average isoflavone intakes from soy foods range from 25 mg/day to 50 mg/day,34 is lower than breast cancer rates in the Western countries where average isoflavone intakes in non-Asian women are less than 2 mg/day.^35,36 However, many other hereditary and lifestyle factors could contribute to this difference. Epidemiological studies of dietary soy and breast cancer have reported conflicting results. A few studies suggest that a higher soy intake during adolescence may lower risk of developing breast cancer later in life.^37,38 See Chapter 3 for more information about soy consumption and breast cancer risk. At present, there is little evidence that taking soy isoflavone supplements decreases the risk of breast cancer.

Endometrial Cancer

Because the development of endometrial (uterine) cancer is related to prolonged exposure to unopposed estrogens (estrogen not counterbalanced with the hormone progesterone), it has been suggested that high intakes of phytoestrogens with antiestrogenic activity could be protective against endometrial cancer.³⁹ In support of this idea, three retrospective case–control studies found that women with endometrial cancer had lower intakes of soy isoflavones from foods compared with cancer-free control groups.^39–41 However, giving soy protein supplements to postmenopausal women, providing 120 mg/day of isoflavones for 6 months did not prevent endometrial hyperplasia induced by the administration of exogenous estradiol.⁴² Although limited evidence from case–control studies suggests an inverse relationship between consumption of soy foods and endometrial cancer, there is no evidence from intervention trials that taking soy isoflavone supplements decreases the risk of endometrial cancer.

Prostate Cancer

Mortality from prostate cancer is much higher in the United States than in Asian countries, such as Japan and China.43 However, epidemiological studies do not provide consistent evidence that high intakes of soy foods are associated with reduced prostate cancer risk. See Chapter 3 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.⁴⁴ Although soy isoflavone supplementation for up to 1 year did not significantly decrease serum concentration of prostate-specific antigen (PSA) in men without confirmed prostate cancer,^45–47 soy isoflavone supplementation appeared to slow the rising serum PSA concentration associated with prostate tumor growth in two small studies of patients with prostate cancer.^48,49 One small, short-term (<1 month) study in patients with prostate cancer found that men randomized to receive a high-phytoestrogen diet experienced a statistically significant improvement in PSA concentrations compared with men randomized to receive a low-phytoestrogen diet.⁵⁰ A trial of soy milk supplementation (141 mg/day isoflavones) in men with PSA-specific recurrent prostate cancer found that PSA levels increased by an average of 20% over a 12-month period compared with a 56% yearly increase prior to the study.⁵¹ A review published in 2006 found that isoflavone supplementation in prostate cancer patients favorably affected PSA concentrations in four out of eight trials.⁵² Additionally, a recent meta-analysis of eight studies found that consumption of isoflavones was associated with a reduction in risk of prostate cancer, but the association was not statistically significant.⁵³ 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.⁵⁴

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.55 The results of short-term clinical trials (≤6 months) assessing the effects of increased soy intake on biochemical markers of bone formation and bone resorption are inconsistent. Some controlled trials in postmenopausal women have found that increasing intakes of soy foods, soy protein, or soy isoflavones improves markers of bone resorption and formation^56–59 or attenuates bone loss,^59,60 but other trials have found no significant benefit of increasing soy intake.^61–64 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 significantly lower in postmenopausal women given supplements of soy protein containing isoflavones than in those given supplements with equal amounts of milk protein,^62,65 but two longer trials found that BMD loss did not significantly differ between postmenopausal women given supplements with soy protein containing isoflavones and those supplemented with milk protein.^66,67 A 2-year clinical trial found that daily consumption of soy milk containing isoflavones significantly decreased BMD loss in the lumbar spine compared with daily consumption of soy milk without isoflavones,⁶⁸ but three other studies found that BMD loss did not significantly differ between postmenopausal women taking soy protein supplements containing isoflavones and those taking soy protein supplements without or with negligible amounts of isoflavones.^68–70 Loss of bone mineral content at the hip over 1 year was lower in Taiwanese women who took 80 mg/day of isolated soy isoflavones compared with placebo, but the difference was significant only in those women who were at least 4 years past menopause, had lower body weights, or had lower calcium intakes.⁷¹ Another study in Taiwanese women found that those taking 100 mg/day of isolated soy isoflavones for 1 year experienced less bone loss compared with the control group, but women taking 200 mg/day of supplemental isoflavones did not experience any benefit.⁷² Yet, a randomized controlled trial in European post-menopausal women found that supplementation with isoflavone-enriched foods (110 mg/day of isoflavones) for 1 year had no significant effect on BMD.⁷³ A recent placebo-controlled trial in post-menopausal women, aged >60 years, found that neither supplemental soy protein (18 g/day) nor isoflavones (105 mg/day), alone or in combination, significantly affected BMD over a 1-year period.74 To date, results of studies are conflicting, but a recent meta-analysis of nine randomized controlled trials (trial duration: 1–12 months) concluded that soy isoflavones at doses up to 90 mg/day inhibit bone resorption and stimulate bone formation.⁷⁵ Some authors have proposed that the effect of soy isoflavones on bone health may be dependent on whether or not the individual produces the isoflavone metabolite, equol (see the Bioavailability and Metabolism section above).^76–79 This could possibly explain disparate results among clinical trials. Thus, 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. An 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.80 In an Indonesian study of elderly men and women, consumption of tofu was associated with worse memory, while consumption of tempeh was associated with improved memory.⁸¹ In contrast, the results of several small clinical trials in postmenopausal women suggest that increasing soy isoflavone in-take may result in modest improvements in performance on some cognitive tests for up to 6 months. Postmenopausal women given soy extracts, providing 60 mg/day of soy isoflavones for 6–12 weeks, performed better on cognitive tests of picture recall (short-term memory), learning rule reversals (mental flexibility), and a planning task, compared with women given a placebo.^82,83 In a longer trial, postmenopausal women given supplements that provided 110 mg/day of soy isoflavones for 6 months performed better on a test of verbal fluency than women given placebos.⁸⁴ In a crossover trial lasting 6 months, women receiving 60 mg/day of soy isoflavones experienced significant improvements in cognitive performance and overall mood compared with when the women were given a placebo.⁸⁵ However, in larger placebo-controlled trials of postmenopausal women, giving 80 mg/day of isoflavones for 6 months or 99 mg/day of isoflavones for 1 year did not affect performance on a battery of cognitive function tests, including tests for memory, attention, verbal fluency, motor control, and dementia.^67,86 A recent review of eight trials, seven of which were conducted in postmenopausal women, found half reported that soy isoflavone treatment was associated with improvements in cognitive function.⁸⁷

Disease Treatment

Menopausal Symptoms

Hot flushes (flashes) are the primary reason that women seek medical attention for menopausal symptoms.88 Concern over potential adverse effects of hormone replacement therapy^89,90 has led to increased interest in the use of phytoestrogen supplements by women experiencing menopausal symptoms.⁹¹ The effects of increasing soy isoflavone intake on the frequency of hot flushes have been examined in several randomized controlled trials.^92–94 To date, at least four reviews of such trials have been published. A review published in 2002 found that only one out of eight randomized controlled trials of soy foods reported a significant reduction in the frequency of hot flushes, while three out of five controlled trials of soy isoflavone extracts reported a significant reduction in hot flush frequency.⁹⁵ In general, any reductions observed were modest (10%–20%) compared with placebo. A 2004 systematic review that examined 10 randomized controlled trials found that only four trials reported beneficial effects of soy preparations in the treatment of menopausal symptoms like hot flushes.⁹⁴ More recently, another systematic review and meta-analysis of 12 randomized controlled trials found that soy isoflavone supplementation was associated with a small reduction in the number of hot flushes; this analysis found that women with a higher number of daily flushes experienced the greatest benefit from isoflavone therapy.⁹³ One review that analyzed various trials according to the specific isoflavones contained in the supplements found that use of supplements containing primarily genistein reduced symptoms of hot flushes.⁹⁶ Interestingly, a recent study found that only women who produced the isoflavone metabolite, equol (see the Bioavailability and Metabolism section above), which was detected in the urine, experienced improvements in menopausal symptoms like hot flushes following soy isoflavone supplementation.⁹⁷ Breast cancer survivors in particular may experience more frequent and severe hot flushes related to therapies aimed at preventing recurrence of breast cancer.⁹⁸ 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.^99–102 To date, studies on the effect of soy isoflavone consumption on menopausal symptoms have reported mixed results.

Sources

Food Sources

Isoflavones are found in small amounts in several legumes, grains, and vegetables, but soybeans are by far the most concentrated source of isoflavones in the human diet.103,104 Recent surveys suggest that average dietary isoflavone intakes in Japan, China, and other Asian countries range from 25 mg/day to 50 mg/day.³⁴ Dietary isoflavone intakes are considerably lower in Western countries, where studies have found average isoflavone intakes to be as low as 2 mg/day.^35,36 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.¹⁰⁵ Some foods that are rich in soy isoflavones are listed in Table 12.1, along with their isoflavone content.¹⁰⁶ Because the isoflavone content of soy foods can vary considerably between brands and between different lots of the same brand,¹⁰⁵ 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.

Supplements

Soy isoflavone extracts and supplements are available as dietary supplements without a prescription in the United States. 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.107 When isoflavone supplements available in the United States were tested for their isoflavone content by an independent laboratory, the isoflavone content in the product differed by more than 10% from the amount claimed on the label in approximately 50% of the products tested.¹⁰⁸

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 that were commercially available in the United States ranged from 32 mg/L to 47 mg/L (approx. 34 fl oz).109

Safety

For many years, soy isoflavones have been consumed by humans as part of soy-based diets, without any evidence of adverse effects.104 The 75th percentile of dietary isoflavone intake has been reported to be as high as 65 mg/day in some Asian populations.¹¹⁰ 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. One study in older men and women found that 100 mg/day of soy isoflavones for 6 months was well tolerated.¹¹¹ Yet, long-term studies are needed to evaluate the safety of isoflavones.

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.98,112 The effects of high in-takes of soy isoflavones on breast cancer recurrence and survival of breast cancer patients have not been well 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.^113,114 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,¹¹⁵ but it is not known if a similar effect would be seen in humans. A recent prospective study in 5042 female breast cancer survivors in China, who were followed for a median of 3.9 years, found that consumption of isoflavone-rich soy foods was significantly associated with a 29% lower risk of death and a 32% lower risk of cancer recurrence.¹¹⁶ In this study, soy isoflavone consumption was associated with a nonsignificant, 21% reduction in risk of death and a significant, 23% reduction in risk of cancer recurrence.¹¹⁶ Very limited data from clinical trials suggest that increased consumption of soy isoflavones (38–45 mg/day) can have estrogenic effects in human breast tissue.^117,118 However, a study in women with biopsy-confirmed breast cancer found that supplementation with 200 mg/day of soy isoflavones did not increase tumor growth over the next 2–6 weeks before surgery when compared with a control group that did not take soy isoflavones.¹¹⁹ 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.⁹⁸ However, other experts argue that there is not enough evidence to discourage breast cancer survivors from consuming soy foods in moderation,¹¹² and the recent study mentioned above¹¹⁶ indicates that moderate consumption of soy foods (11 g/day of soy protein) may even be beneficial to breast cancer survivors. Due to conflicting results, more research is needed to determine the safety of high soy isoflavone intake in breast cancer survivors.

Soy-Based Infant Formulas

Infant formula made from soy protein isolate has been commercially available since the mid-1960s.¹²⁰ As much as 25% of the infant formula sold in the United States is soy-based formula.¹²¹ 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 growth and development, as well as reproductive and immune function.^109,122 The results of at least six clinical trials comparing infants who were 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.123 A prospective study evaluating growth and development in children fed breast milk, cow's-milk-based formula, or soy-based formula is currently under way at the Arkansas Children's Nutrition Center. Five years into the study, adverse effects of soy formula have not been observed, and no differences in growth and development among the various groups have been noted.¹²⁴ In addition, one retrospective study of 811 men and women aged 20–34 years 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.¹²⁵ The American Academy of Pediatrics recently published a report that reviews the indications and contraindications for the use of soy-based formulas.¹²¹ 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 formula are currently ongoing.^126,127

Thyroid Function

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.^128,129 However, high intakes of soy isoflavones do not appear to increase the risk of hypothyroidism, as long as dietary iodine consumption is adequate.¹³⁰ Since the addition of iodine to soy-based formulas in the 1960s, there have been no further reports of hypothyroidism in infants fed on soy formula.¹³¹ Several clinical trials, mostly in premenopausal and postmenopausal women with sufficient iodine intakes, have not found that increased consumption of soy isoflavones results in clinically significant changes in circulating thyroid hormone levels.^132–136

Pregnancy

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.

Drug Interactions

Because colonic bacteria play an important role in the metabolism of soy isoflavones, antibiotic therapy could decrease their biological activity.137 Some evidence from animal studies suggests that high intakes of soy isoflavones, particularly genistein, can interfere with the antitumor effects of tamoxifen (Nolvadex).¹¹⁵ Until more is known about potential interactions in humans, those taking tamoxifen or other selective estrogen receptor modulators to treat or prevent breast cancer should avoid soy protein supplements or isoflavone extracts (see the Safety for Breast Cancer Survivors section above). High in-takes 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 international normalized ratio (INR; prothrombin time) values upon consuming approximately 16 oz of soy milk daily for 4 weeks.¹³⁸ INR values returned to therapeutic levels 2 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.^131,139 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.¹⁴⁰

Summary

• 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.

• The results of randomized controlled trials suggest that substituting 50 g/day of soy protein for animal protein results in only a modest 3% reduction of low-density lipoprotein cholesterol. Isolated soy isoflavone supplements do not appear to have favorable effects on serum lipid profiles.

• Consumption of soy isoflavones, at doses of <90 mg/day, may inhibit bone resorption and stimulate bone formation.

• 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.

• 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.

• To date, studies on the effect of soy isoflavone consumption on menopausal symptoms have reported mixed results.

• Some health effects of soy isoflavones may be dependent on whether or not the isoflavone metabolite equol is produced.

• 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.

• 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.