Soy

Scientific Name(s): Glycine max (L.) Merr. Family: Fabaceae (beans)

Common Name(s): Soy , soybean , soya

Clinical Overview

Uses of Soy

Soy is commonly used as a source of fiber, protein, and minerals. Clinical trial information indicates that isoflavone compounds in soybeans may improve bone mineral density in osteoporosis as well as treating minor GI problems. In other studies, soy exerted a small effect on total cholesterol and low-density lipoprotein (LDL) cholesterol.

Soy Dosing

Standardized soy isoflavone products are available under the names Phyto Soya and Abacor . A large number of clinical trials have been conducted for conditions such as menopause, osteoporosis, breast cancer, and diabetes using daily doses of isoflavones from 40 to 120 mg. However, efficacy in these disease states has not been confirmed. An avocado-soy unsaponafiable fraction has been studied in osteoarthritis at 300 to 600 mg daily.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Generally recognized as safe when used as food. Avoid dosages above those found in food because safety and efficacy are unproven.

Soy Interactions

None well documented.

Soy Adverse Reactions

Overall tolerance to soybeans is good to excellent for most patients. Although there are no strong studies, the effects of phytoestrogens found in soy-based infant formulas on CNS and psychomotor developmental processes of newborns are a concern.

Toxicology

Toxicity and allergy have been reported.

Botany

Legumes such as soy are able to fix free nitrogen from the air into a useable form for growth via the bacterium Rhizobium japonicum , which is associated with the roots. Soybean is an annual plant that grows 0.3 to 1.5 m tall. The bean pods, stems, and leaves are covered with short, fine hairs. The pods contain up to 4 oval, yellow to brown seeds. The cotyledons account for most of a seed's weight and contain nearly all of the oil and protein. 1

History

In 2,838 BC, Chinese emperor Shung Nang described soybeans as China's most important crop. The plant was introduced to Japan, Europe, and eventually to the United States by the early 1800s. The United States now produces 49% of the world's soybeans. 1 , 2 , 3 Soy foods have become increasingly popular among health-conscious individuals since the early 1990s. In 2000, approximately 27% of United States consumers reported using soy products at least once a week, nearly double the 1998 figure. 4

Chemistry

Soybeans are high in nutritional value and contain up to 35% oil, 24% carbohydrate, and 50% protein. 1 Isolation of certain proteins and the determination methods used often characterize soybeans and their products. 5 Fatty acids in beans include linoleic (55%), palmitic (9%), and stearic (6%) acids. Soybeans are rich in minerals and trace elements, including calcium, iron potassium, amino acids, and vitamins, and are a good fiber source. 1 , 2 Soybeans contain isoflavone compounds with phytoestrogen structures somewhat similar to natural estrogens. The plant's isoflavones include genistein and daidzein, the most abundant, as well as glycitein and equol. 4 Their abundance in soy protein preparations varies widely and depends upon the processing technique employed. 5 Isoflavones remain in soy preparations that are not extracted with alcohol. Dehulling, flaking, and defatting soybeans produces a relatively pure preparation of the protein that is low in isoflavones. Isoflavone concentrations range from approximately 2 mg/g of protein in textured soy protein, soy flour, and soy granules to 0.6 to 1 mg/g protein in isolated soy protein. 6

Soy Uses and Pharmacology

Dietary phytoestrogens have been studied extensively for their proposed roles in cancer prevention, as well as for treatment of menopausal symptoms, osteoporosis, cardiovascular disease, and GI disorders. Isoflavones, the phytoestrogens in soybean, are broadly similar to the main female hormone estradiol and have similar but weak functional effects, including hormonal and nonhormonal actions. 4 Hydrolysis of isoflavone glycosides by intestinal glucosidases yields genistein, daidzein, and glycitein. These compounds undergo further metabolism to equol and p-ethyl phenol. This metabolism is highly variable and may depend, for example, on carbohydrate intake altering intestinal fermentation. Isoflavones are secreted into bile via the enterohepatic circulation. Plasma half-life of genistein and daidzein is approximately 8 hours, with peak concentration achieved in 6 to 8 hours in adults. Elimination is in urine, primarily as glucuronide conjugates. 7

In some studies, soybeans appear to exert modest anticancer activity. 8 Inhibition of early cancer markers in human epithelial cells has been demonstrated by genistein. 9 Another report found genistein to retard growth of implanted tumors in mice and in vitro. 10 These anticancer effects of genistein may be related to its ability to reduce expression of stress response-related genes. Induction of stress proteins in tumor cells protects them against cell death, so inhibition of this stress response by the isoflavone is beneficial. 11

Isoflavones are selective estrogen receptor modulators but also possess nonhormonal properties.

The weak estrogenic action of soy isoflavones and other phytoestrogens suggested that they could lessen the deleterious effects of more potent endogenous estrogens on breast and endometrial cancer. This suggestion is consistent with the low incidence of breast and endometrial cancer in Asian countries. 5 However, epidemiological studies of the association between intake of soy foods and isoflavones and the incidence of breast cancer have been mixed, with some studies showing protective association and some showing no association at all. 12

In 1990 and 2005, The National Cancer Institute held workshops following reports of decreased chemically-induced rat mammary cancer after the addition of soy protein to a typical diet. 13

In 1991, a case controlled study reported a 50% reduction in premenopausal breast cancer risk associated with soy consumption. 4 However, there are conflicting data as other investigators have reported that isoflavones in soy may actually stimulate breast tumor growth through their estrogenic activity. 14 Studies of 1-year duration indicated that isoflavone supplements do not affect breast tissue density in premenopausal women but may decrease density in postmenopausal women. These effects are in opposition to those of hormone replacement therapy (HRT). Overall, the data are not persuasive that adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of breast cancer patients. Nonetheless, if breast cancer patients enjoy soy products, it seems reasonable for them to continue to use them. 4 Several organizations, including the American Cancer Society, American Diabetes Association, and American College of Obstetricians and Gynecologists, have commented positively on the consumption of soy in breast cancer patients. However, none of these statements are the result of a comprehensive evaluation of the relevant literature.

Because uterine endometrial cancer is also an estrogen-dependent cancer, the same concepts with regard to soy isoflavones and breast cancer are applicable, although data are much less extensive. Soy food or isoflavone intake was associated with low risk for endometrial cancer in case control studies. 15

Soy isoflavones have estrogenic, antiandrogenic, and other activities that could prevent prostate cancer or slow its progression. 16 Prostate cancer incidence appears to decrease with increased isoflavone intake. 15

Rats fed soy-protein diets showed a reduced incidence of prostate tumors compared with rats fed casein. Tumor latency was increased only in the rats fed a diet containing isoflavone-rich, isolated soy protein. 15 In prostate cancer cells, genistein reduced the synthesis of prostate-specific antigen, a marker of prostate cancer development and progression. 17 Genistein inhibits the growth of androgen-dependent and androgen-independent prostate cancer cells in vitro in a dose-dependent manner. 15

Some epidemiological studies have shown an inverse association between soy foods, serum phytoestrogen levels, and prostate cancer. 15 However, these findings are inconsistent. Asian men who consume low-fat, soy-based diets have a lower incidence of prostate cancer than European or North American men. Isoflavones have been reported in prostatic fluid and in the metabolic data on these men. 18

Research reveals no animal data for food allergy/intolerance in infants.

Allergy to cow's milk affects approximately 2.5% of children. The allergy is characterized by a specific immunoglobulin E (IgE) response. In clinical practice, alternate protein sources from vegetables, such as soy, are substituted for cow's milk. 19 Food intolerance does not imply a specific mechanism but is a reproducible adverse reaction to a specific food. Cow-milk protein intolerance is most common in infants. It has been suggested that exposure to cow's milk early in life may predispose an infant to increased risk of allergy and intolerance. There is insufficient evidence to suggest that substitution with soy milk can prevent the development of atopy (hereditary hypersensitivity) 20 or food intolerance. 21 Many infants with food intolerance become tolerant over time, with the risk of persisting intolerance increased with evidence of atopy. 20

Because of their weak estrogenic activity, soy isoflavones have been hypothesized to improve several estrogen-dependent conditions, including perimenopausal vasomotor symptoms (hot flashes) and postmenopausal bone loss. Interest in the use of soy and its derivatives for the treatment of menopausal symptoms has been encouraged by observations of a lower prevalence of menopausal complaints, especially hot flashes, among women in Asian countries where soy is an important component of the traditional diet. 5

Research reveals no animal data regarding the use of soy for menopausal symptoms.

Women of menopausal age who suffer from symptoms of decreased estrogen production may benefit from HRT, a combination of estrogen and progesterone. However, a 5-year study has shown that HRT increases the risk of heart disease and breast cancer. 22 Soy products may offer a favorable alternative to conventional HRT. Hot flashes and postmenopausal symptoms, including bone mineral loss, may be reduced by a daily intake of 45 g of soy flour. 2 Hot flashes were decreased 45% in one report of postmenopausal women given soy powder, compared with 30% reduction with placebo powder. 7

In a review of 11 clinical trials of soy protein or isoflavones for treating hot flashes, only 3 of 8 studies with treatment lasting longer than 6 weeks found modest improvement in hot flashes; however, most benefits disappeared after 6 weeks. 23 Longer studies showed no benefit of isoflavones at 24 weeks 24 or 2 years. 25 Reduction of hot flashes by 40% to 60% occurred in the placebo or control group in these studies, similar to the reduction in the soy group. In contrast, estrogen replacement produced marked reductions in hot flashes, compared with placebo. 23 Further, a review of 10 studies comparing soy food, beverage, or powder supplementation with placebo failed to show a beneficial effect of soy on menopausal symptoms. 26 Other studies comparing soy-derived isoflavones in doses of 50 to 150 mg/day produced conflicting results. The quality of these studies make drawing conclusions difficult. 26 However, the available evidence suggests no superiority over placebo for the relief of menopausal symptoms, frequency, or severity.

A review of 3 studies evaluating soy products for the treatment of menopausal symptoms in breast cancer found no evidence to support their use. Incidence of hot flashes did not differ among groups in any studies. 26

The effect of soy protein with and without isoflavones has been studied in a number of animal models with conflicting results. Osteoprotective activity was demonstrated in an ovariectomized rat model. 27 Another study demonstrated preservation of bone-mass density that did not translate into improvement in biomechanical strength. 28 In sexually mature Sprague-Dawley rats, no obvious effects on bone mass or architecture were seen. 29 A long-term study in postmenopausal monkeys showed that soy isoflavones did not slow bone loss, whereas estrogen replacement increased bone mineral content and density as expected. 30

Evidence for an estrogenic, bone-preserving effect of isoflavones has been provided in a number of studies. However, clinical trials have had insufficient duration and population size to be conclusive. A Japanese study evaluating daily intakes of isoflavones in 478 postmenopausal women displayed evidence of increased bone mineral density. However, another trial demonstrated no effect. 16 Thus, evidence in this area is weak, especially when taking into account that no studies have examined reduction in fracture rates in osteoporotic women.

Research reveals no animal data regarding the use of soy for OA.

Current treatments for OA generally consist of pain relief. Avocado/soybean unsaponifiables (ASU) consist of one-third avocado oil and two-thirds soybean oil. Preclinical studies showed this combination to have some anti-OA activity, possibly via effects on interleukin-1 and collagen synthesis. In one study, patients with OA (N = 164) of the knee or hip were entered into a randomized controlled trial with a 6-month treatment period and a 2-month posttreatment follow-up. Patients were given ASU or placebo. Greater improvement in pain scores and functional indices was noted for the active treatment group. The study suggests that ASU when prescribed before nonsteroidal anti-inflammatory agents may slow the symptomatic activity of OA. However, because no radiographs were performed in the trial, the effects of ASU relating to structure-modifying properties are inconclusive. 31

Atherosclerosis begins in adolescence as fatty streak lipid deposits in the arterial wall. High concentrations of total plasma cholesterol and LDL cholesterol accelerate atherogenesis in the teenage years and lead to cardiovascular disease. Phytosterols are in the forefront of research on the development of food products that lower plasma cholesterol concentrations.

Soy isoflavones have strong biological properties in animals, 32 causing arterial vasodilation, lowering serum cholesterol, and inhibiting atherosclerosis in postmenopausal monkeys. 33

Soy protein has gained considerable attention for its potential role in improving risk factors for cardiovascular disease. 5

In October 1999, the US Food and Drug Administration approved labeling for foods containing soy as protective against coronary heart disease. Soybean phytosterols lowered total and LDL cholesterol in a randomized, controlled trial of men with elevated LDL cholesterol. 34 Increased consumption of soy in Asian populations is associated with decreased rates of cardiovascular disease. 35 A vegetarian diet consisting of soy-based products was given to 32 coronary heart disease patients who discontinued their conventional hyperlipidemic medications. The diet resulted in normalization of serum lipids, with the best results associated with the group who maintained this diet for the longest period of time. 36

In 1995, a meta-analysis of 38 controlled studies 37 concluded that substituting soy protein for animal protein lowered total cholesterol, LDL cholesterol, and triglycerides without affecting high-density lipoprotein (HDL) cholesterol. These effects were greater in subjects with higher baseline cholesterol levels. Daily soy protein consumption resulted in a 9.3% decrease in total serum cholesterol, a 12.9% decrease in LDL cholesterol, and a 10.5% decrease in triglycerides. This cholesterol lowering effect was additive to the effect seen with a low-fat/low-cholesterol diet. The average amount of soy protein consumed to achieve these results was 47 g/day. 37

Overall dietary replacement of animal protein with soy protein may have a favorable, yet variable, effect on serum lipid values in men and women. The addition of soy protein to the diet may be useful for patients requiring only modest reductions in cholesterol.

The precise mechanism by which soy improves the blood lipid profile is unknown. One possible mechanism is altered hepatic metabolism with enhanced removal of LDL and very low density lipoprotein cholesterol by hepatocytes. 38

The biological properties of soy isoflavones in animals led to the assumption that only soy products high in isoflavones produced favorable results. Consequently, in a review by the American Heart Association (AHA) in 2006, studies were grouped according to whether isoflavones were present or not.

In 22 randomized trials, isolated soy protein with isoflavones was compared with casein or milk protein, wheat protein, or mixed animal proteins. The range of soy protein was 23 to 135 g/day; the range for isoflavones was 40 to 318 mg. LDL or non-HDL cholesterol concentrations decreased in most studies and were statistically significant in 8 trials, with an overall effect of approximately 0.3% (weighted average). 5

A meta-analysis 39 that included 10 studies published from 1995 through 2002 found a similar percentage reduction (4%) in LDL cholesterol with no dose effect.

Studies with 50 g of soy protein showed a drop in LDL cholesterol concentrations similar to studies using a smaller amount of soy. 5 No effects were evident for HDL cholesterol or triglycerides in most of the studies; the weighted average effects were very small: 1.5% for HDL cholesterol and -5% for triglycerides.

In 7 trials, soy protein washed with alcohol to remove isoflavones was compared with casein, milk protein, or various animal protein. Two of the studies showed small decreases in LDL cholesterol; however, other well-controlled studies did not find effects of soy protein on LDL cholesterol. Changes in HDL cholesterol and triglycerides occurred in 1 out of 7 trials. No dose effect was evident. A meta-analysis concluded that isoflavones do not affect blood lipid concentration. 39

The effect of soy protein or isoflavones on LDL cholesterol does not appear to be modulated by the saturated fat and cholesterol content of the diet. 5

In a meta-analysis, 37 the degree of LDL cholesterol reduction was related to initial cholesterol levels: subjects with severe hypercholesterolemia more than 335 mg/dL (8.66 mmol/L) had reductions of 19.6%; 259 to 333 mg/dL (6.7 to 8.61 mmol/L) had reductions of 7.4%; 200 to 255 mg/dL (5.2 to 6.6 mmol/L) had reductions of 4.4%; and less than 200 mg/dL had reductions of 3.3%. However, in a 2006 review, 5 a larger percentage reduction in LDL cholesterol in hypercholesterolemia was not evident in 22 trials. In studies of isoflavones, no relation was evident between initial cholesterol and cholesterol reduction.

The AHA now states that the direct cardiovascular health benefit of soy protein or isoflavone supplements is minimal. A very large amount of soy protein, more than half the daily protein intake, may lower LDL cholesterol by a few percentage points when it replaces dairy protein or a mixture of animal proteins. No benefit is evident on HDL cholesterol, triglycerides, lipoprotein (a) or blood pressure. 5

Several studies have tested the effect of soy protein with isoflavones on blood pressure. Blood pressure was reduced in only 1 of 6 studies. The weighted average change in systolic blood pressure was −1 mm Hg. Soy isoflavones showed no effect on blood pressure. 5

Beneficial effects on large bowel function were found in rats given a mixture of soybean and cereals versus a standard diet. Soybean fiber can prevent constipation, reducing the incidence of bowel diseases. 2

In one report, the use of fiber-supplemented soy formula reduced the duration of diarrhea in 44 infants. 40 Soy also has been investigated in studies for the treatment of infantile colic 41 and recurrent abdominal pain in childhood. 42 However, there is no evidence to suggest soy has any beneficial effect in these conditions.

Soy is an important food source and has been used in Asian cultures for thousands of years. These cultures consume 60 to 90 g/day of soy, compared with Western diets that contain about one tenth of that amount. 3 Soybean products are numerous and include milk, flour, curd, sufu, tofu (cheese-like cake high in protein and calcium), tempeh (Indonesian ingredient), miso (fermented soybean paste), sprouts, soy sauce, soybean oil, textured soy proteins (in meat extenders), soy protein drinks, and livestock feeds. Because of its low cost, good nutritional value, and versatility, soy protein is used as part of food programs in less developed countries. 1

Dosage

Standardized soy isoflavone products are available under the names Phyto Soya and Abacor . A large number of clinical trials have been conducted for conditions such as menopause, osteoporosis, breast cancer, and diabetes using daily doses of isoflavones from 40 to 120 mg. An avocado-soy unsaponafiable fraction has been studied in osteoarthritis at 300 to 600 mg daily. 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55

Pregnancy/Lactation

Generally recognized as safe when used as food. Avoid dosages above those found in food because safety and efficacy are unproven.

Interactions

A subtherapeutic international normalized ratio (INR) was reported in a 70-year-old man stabilized on warfarin after he started drinking soy milk. 56 The INR returned to the therapeutic range when he stopped drinking soy milk.

Adverse Reactions

Overall tolerance to soybeans is good to excellent for most patients.

The effects of phytoestrogens in soy-based infant formulas are of concern and could have clinical consequences. 57 , 58 In one report, daily exposure of infants to the isoflavones in soy-based formula was found to be 13,000 to 22,000 times higher than plasma estradiol concentrations in early life, 59 whereas the contribution of isoflavones from breast milk and cow milk are negligible. Additionally, goitrogenic effects of soy have been reported since the 1930s. A study by Japanese researchers concluded that intake of soy 30 g/day could cause enlargement of the thyroid and suppress thyroid function. It has been proposed that soy formula-fed infants are at risk of thyroid dysfunction. Alteration of thyroid levels during the neonatal period may lead to disorders of the CNS and abnormal psychomotor development. In 1998, the United States Environmental Protection Agency examined priorities for research into the phytoestrogen content of soy formulas. 60

Inhalation of soy dust caused an asthma epidemic in 26 patients exposed to unloading of the product. This incident was confined only to Barcelona, Spain. Skin prick tests confirmed exposure to soy in all cases. Specific immunoglobulins, such as IgE, are associated with this type of soybean asthma. 61

Soybeans and peanuts, as well as other beans, are phylogenetically and antigenetically similar. Exposure to both is widespread, and they are common cause of food allergy. Positive tests for IgE antibody to these foods are often found in individuals who are clinically reactive to one or the other. However, there is not enough data to recommend soy avoidance in peanut allergic patients. 62

Treating soybeans with the appropriate proteases reduces their allergenicity. 63 Reports also are available that describe how fatal allergic reactions from soy can be prevented. 64 Cases of late onset anaphylaxis to fermented soy beans have been reported. 65

Toxicology

Tolerance to soy preparations in one study (N = 164) was reported to be good to excellent for most patients. 31 However, both toxicity and allergy have been reported.

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