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Soy

Scientific Name(s): Glycine max (L.) Merr.
Common Name(s): Soy, Soy isoflavones, Soya, Soybean

Clinical Overview

Use

Soy is commonly used as a source of fiber, protein, and minerals. A number of meta-analyses are now available; however, evidence is lacking to support a definitive place in therapy for menopausal symptoms, osteoporosis, diabetes, or heart disease. Epidemiologic data suggest an association with a lower incidence of certain cancers with higher intake of dietary soy and benefit in patients with irritable bowel disease has been demonstrated.

Dosing

A large number of clinical trials have been conducted for several conditions (eg, menopause, osteoporosis, breast cancer, cardiovascular diseases, irritable bowel disease) using daily doses of isoflavones from 40 to 120 mg.

Contraindications

Contraindications have not been identified. Women who have current or history of estrogen-dependent tumors (including breast cancer) should consult their physician prior to higher than dietary consumption of soy.

Pregnancy/Lactation

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

Interactions

None well documented.

Adverse Reactions

Soybeans and their products are generally well tolerated. Minor GI disturbances have been reported. The National Toxicology Program (US Department of Health and Human Services) has concluded that there is minimal concern for developmental effects in infants fed soy infant formula.

Toxicology

Evidence exists from animal studies on the adverse effects of the isoflavone genistein on the developing female reproductive tract.

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 in height. The bean pods, stems, and leaves are covered with short, fine hairs and the pods contain up to 4 oval, yellow to brown seeds. Cotyledons ("seed leaf") account for most of a seed's weight and contain nearly all of the oil and protein.1, 2

History

In 2838 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. Soy foods have become increasingly popular among health-conscious individuals since the early 1990s. In 2000, approximately 27% of US consumers reported using soy products at least once a week, nearly double the 1998 figure. As a food source, soy has been used in Asian cultures for thousands of years, with Asian populations consuming 60 to 90 g/day of soy, compared with Western diets that contain approximately one-tenth of that amount. Soybean products are numerous and include milk, flour, curd, sufu, tofu, 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, 3, 4, 5

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.6 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, 3 Soybeans contain isoflavone compounds known as phytoestrogens that are structurally similar to human estrogen and progesterone. The plant's isoflavones include genistein and daidzein, the most abundant, as well as glycitein and equol5 with soy protein preparations varying widely depending on the processing technique.6 Isoflavones remain in soy preparations that are not extracted with alcohol. The dehulling, flaking, and defatting of soybeans produces a relatively pure preparation 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.7

Uses and Pharmacology

Isoflavones, the phytoestrogens in soybean, have weak functional effects similar to those of the female hormone estradiol, including hormonal and nonhormonal actions.5 Hydrolysis of isoflavone glycosides by intestinal glucosidases yields genistein, daidzein, and glycitein, which undergo further metabolism to equol and p-ethyl phenol. This metabolism is highly variable and may depend, for example, on the effect of carbohydrate intake on 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 renal, primarily as glucuronide conjugates.8

Asthma

Adult patients (n = 300) with inadequately controlled asthma who submitted dietary questionnaires that were used to evaluate soy genistein intake underwent baseline pulmonary function evaluation and were followed for a 6-month period for observation of incidence of episodes of poor asthma control (EPAC). Patients were grouped as having minimal, moderate, or high intake of soy genistein. Baseline evaluation of forced expiratory volume in 1 second (FEV1) showed significantly lower mean FEV1 in the minimal soy group compared with the moderate and high intake groups (2.26 L vs 2.53 L and 2.47 L, respectively; P = 0.01). The incidence of EPAC was also significantly higher in the minimal soy intake group compared with moderate and high intake (54% vs 35% vs 40%, respectively; P < 0.001). Between group comparisons were not significantly different for the moderate intake group compared with the high intake group for these outcomes. 101 In contrast, use of soy isoflavone (isoflavones 100 mg/day × 24 weeks) as add-on therapy to daily inhaled corticosteroids and/or a leukotriene modifier in patients older than 12 years (median, 36 years of age) with poorly controlled asthma did not improve lung function (FEV1) or clinical outcomes as evaluated in a randomized, placebo-controlled, double-blind, multicenter trial (N = 386).105

Cancer, breast

Animal data

Isoflavones are selective estrogen receptor modulators, but also possess nonhormonal properties. The weak estrogenic action of soy isoflavones and other phytoestrogens suggest that they could lessen the deleterious effects of more potent endogenous estrogens on breast and endometrial cancer.

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 and recommended that the impact of isoflavones on breast tissue should be evaluated at the cellular level in high-risk women.9

Clinical data

Reviews of cohort and case-control studies evaluating the risk of breast cancer incidence and a meta-analysis of prospective studies on the risk of breast cancer recurrence are available.10, 11, 92 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. Summary relative risk (RR) for the association of soy isoflavone consumption and incidence of breast cancer were 0.89 (95% confidence interval [CI], 0.79 to 0.99) in 1 meta-analysis of 14 prospective studies; however, when the data were evaluated by ethnicity, a protective effect was only found for Asian populations.11 Data for risk of breast cancer recurrence from 4 studies yielded similar results (summary RR = 0.84 [95% CI, 0.7 to 0.99]. Another modifier may be menopausal status because no association was evident in premenopausal women. No dose-response relationship was revealed.11 Another meta-analysis found that soy does not appear to interfere with tamoxifen and anastrazole.92

However, it should be noted that data also exist of increased breast cancer risk and it is possible that isoflavones in soy may actually stimulate breast tumor growth through their estrogenic activity.10, 12, 13 There was a modest increase in breast tissue density among premenopausal women but not in postmenopausal women in a meta-analysis of 8 clinical trials of isoflavone supplementation. The clinical importance of this finding is unclear.14 A 12-month, randomized, controlled study found no significant difference in breast density in postmenoapusal women who received a daily supplement containing 60 mg of soy isoflavones compared with the control group.93

A 2014 meta-analysis of epidemiological studies reporting associations between soy and breast cancer performed subanalyses of data based on menopausal status (pre- or post-), region of study (Asian or Western), soy intake (soy isoflavone, soy protein, soy food), and study design (cohort, nested case-control, case-control). Statistically significant inverse associations between soy consumption and risk of breast cancer were identified for (1) premenopausal Asian women but not those from Western nations with soy bean/soy products showing a stronger association and (2) postmenopausal women consuming highest soy isoflavone intakes with a stronger association in Asian women than Western.104

Cancer, prostate

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

Animal data

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.16 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.18

Clinical data

Meta-analyses of observational studies of soy consumption and risk of prostate cancer have been published.18, 19 An inverse association has been observed for soy consumption and risk of prostate cancer (RR/odds ratio [OR] = 0.7 [95% CI, 0.63 to 0.89].18 Available data suggest benefits may be limited to nonfermented soy products and Asian populations.18, 19 Randomized clinical trials have been conducted. In a pilot study, soy isoflavones reduced adverse urinary, intestinal, and sexual effects of radiation in men with prostate cancer.20 A 12-week study of 20 g daily soy protein supplementation (isoflavone 160 mg) found no effect on any of the outcomes measured (cognition, sleep quality, vasomotor symptoms, or quality of life).21 Another trial showed no effect on prostate-specific antigen levels after 6 months of genistein 450 mg and daidzein 300 mg despite an increase in serum isoflavone levels.22 Data from a preliminary study in 86 men with localized prostate cancer suggests gene expression in prostate tissue may be altered by intake of soy isoflavones (80 mg/day; 51 mg/day aglucon units), but serum biomarkers were not significantly affected.90 A randomized, placebo-controlled trial evaluating the benefit of soy protein supplement 20 g/day for prevention of recurrence in men who underwent radical prostatectomy for prostate cancer was stopped early when interim analysis showed no benefit (hazard ratio [HR] 0.96 [95% CI, 0.53 to 1.72; log-rank P = 0.89]).94

Cancer, other

Animal data

Inhibition of early cancer markers in human epithelial cells has been demonstrated by genistein.23 Another report found genistein to slow growth of implanted tumors in mice and in vitro.24 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.25

Clinical data

Meta-analyses of endometrial, ovarian, gastric, and colorectal cancer have been published. A protective effect was reported for high soy intake over low intake in a meta-analysis of 7 case-control and cohort studies in endometrial and ovarian cancer (OR = 0.61 [95% CI 0.53 to 0.72].16, 26 Reduced risk of ovarian cancer was also demonstrated in a case-control study (n = 1,000) conducted in Chinese women who consumed at least 120 g/day of soy foods compared with 61 g/day with a similar significant inverse relationship noted between isoflavone intakes and ovarian cancer risk (P < 0.001).102 However, there was no association between risk of ovarian cancer and soy phytoestrogen consumption in the Women's Lifestyle and Health Cohort study.27

Among Japanese and Korean populations, a meta-analysis showed a significant increase in risk of gastric cancer, with high intake of fermented soy products (OR = 1.22 [95% CI, 1.02 to 1.44]) and a significant decrease in risk of gastric cancer with high intake of nonfermented products (OR = 0.64 [95% CI, 0.54 to 0.77]).28 A meta-analysis of studies evaluating the protective effect of soy against colorectal cancer established no association, except when a subgroup analysis was conducted by gender, revealing a decreased risk in women.29 A group of investigators evaluated the relationship between soy intake and lung cancer in a cohort (n = 74,942) of 40 to 70 year old women during 9.1 years of followup. There were 370 lung cancer cases, and 340 of these were in women who had never smoked. Soy consumption was documented during patient interviews, and the highest quintile of soy intake had a significantly lower incidence of lung cancer compared with the lowest quintile of soy intake (HR, 0.63 [95% CI, 0.44 to 0.90]). When the investigators pooled their results with those of other studies (7 case-control, 4 cohort studies including the current one, n = 231,494), the summary relative risk was 0.83 (95% CI, 0.72 to 0.96).95

Cardiovascular disease

Animal data

Soy isoflavones exhibit strong biological properties in animal studies, causing arterial vasodilation, the lowering of serum cholesterol, and the inhibition of atherosclerosis in postmenopausal monkeys.30, 31 However, beneficial effects observed in animal models have not translated well to studies in humans. The widespread availability of clinical trial data now make data from animal studies largely irrelevant.7

Clinical data

Soy protein has gained considerable attention for its potential role in improving risk factors for cardiovascular disease.7 However, based on a review of the evidence, the American Heart Association7 and an expert panel from the American College of Cardiology32 found that the evidence for clinical benefit of soy in reducing the risk of cardiovascular disease is uncertain and cannot be routinely recommended. Delineation of the efficacy of isoflavone content in soy preparations or the relevance of baseline lipid profiles have not been established with any certainty, nor has a dose-response relationship been determined.7, 32

Several meta-analyses of clinical trials conducted up to 2009 have been published. Findings are generally consistent with regard to small decreases in low-density lipoprotein cholesterol (LDL-C). However, influences on total cholesterol, triglycerides, and high-density lipoprotein cholesterol, as well as on lipoprotein(a) and blood pressure are inconsistent.7, 33, 34, 35, 36, 37 Clinical trials conducted subsequent to the meta-analyses likewise have found equivocal results.38, 39, 40, 41

A meta-analysis examining the effect of soy isoflavones on blood pressure pooled data from 11 studies (n = 1,173; duration range 4 to 12 weeks) found clinically modest and statistically nonsignificant reductions of 2.5 mm Hg (95% CIs, 5.35 to 0.34 mm Hg; P = 0.08) for systolic blood pressure, and 1.5 mm Hg (95% CIs, 3.09 to 0.17 mm Hg; P = 0.08) for diastolic blood pressure.96

A combination product containing extractives of red yeast rice, bitter gourd, chlorella, soy protein, and licorice was evaluated in a 12-week randomized, double-blind, placebo-controlled trial (n = 96) in patients with metabolic syndrome. Total cholesterol (5.4 ± 0.8 to 4.4 ± 0.6 mmol/L [208.8 ± 30.9 mg/dL to 170.1 ± 23.2 mg/dL], P < 0.001) and LDL-C (3.4 ± 0.7 to 2.7 ± 0.5 mmol/L [131.5 ± 27.1 mg/dL to 104.4 ± 19.3 mg/dL], P < 0.001) were significantly reduced after treatment with plant extractives, and the reductions were significantly greater than with placebo (−1.0 ± 0.6 vs 0.0 ± 0.6mmol/L [−38.7 ± 23.2 mg/dL vs 0 ± 23.2 mg/dL], P < 0.001; −0.7 ± 0.6 vs 0 ± 0.6 mmol/L [−27.1 ± 23.2 mg/dL vs 0 ± 23.2 mg/dL] P < 0.001). The reduction in the fasting triglycerides level was significantly greater with plant-extractive than placebo (−0.5 ± 0.8 vs −0.2 ± 1 mmol/L [−44.3 ± 70.9 mg/dL vs 17.7 ± 88.6 mg/dL], P = 0.039). There was also a significantly greater reduction in the proportion of subjects with hypertensive criteria in the plant-extractive group than in the placebo group (−15.4% vs −11.4%, P = 0.040).97

Diabetes

Animal data

Encouraging data from rats fed a high soy-isoflavone diet that revealed improved insulin secretion and better glycemic control have led to studies in humans.42, 43 The widespread availability of clinical trial data has made data from animal studies largely irrelevant.

Clinical data

As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the American Diabetes Association Standards of Care (2014) recommend an increase in foods containing alpha-linolenic acid based on beneficial effects observed on lipoprotein profiles, heart disease prevention, and overall positive health in patients with diabetes (moderate-quality evidence).102 Meta-analyses have been conducted on the effects of soy isoflavone supplementation, genistein, and high soy-isoflavone diets on markers of diabetes. A meta-analysis of 10 trials in non-Asian perimenopausal and postmenopausal women found no effect of soy isoflavones on fasting blood glucose.42 Another analysis, which included Asian populations, also found no changes in measures of glycemic control in general, but suggested in a subgroup analysis that whole soy foods might be favorable for reducing fasting glucose parameters.43 Among Chinese postmenopausal women with early diabetes a mild, positive effect on body weight and body mass index was reported in a randomized trial with soy protein with isoflavones over 6 months.44 Decreased abdominal fat and overall fat was observed in a randomized clinical trial among white and black postmenopausal obese women with soy supplementation. No effect on glucose metabolism was found.45 A 2013 meta-analysis evaluated benefits of soy isoflavones for body weight and glucose metabolism in non-Asian postmenopausal women. The authors found 9 studies (n = 528) on body weight reduction, with a weighted mean difference (WMD) of −0.515 (95% CI, −0.895 to −0.134; P = 0.008). Glucose reduction (12 studies, n = 98) failed to reach statistical significance (WMD = −0.143 [95% CI, −0.294 to 0.009; P = 0.065]), but fasting insulin levels were significantly lower (WMD = −0.918 [95% CI, −1.7 to −0.137; P = 0.021]).99 A meta-analysis published in 2016 of 17 randomized controlled trials (N=1,529) reported the effects of soy isoflavones on glucose metabolism in menopausal women. Mixtures of isoflavones as well as genistein alone were administered in doses of 40 to 161 mg/day for 30 to 36 months among studies conducted I Europe, the Americas, and Asia. Definitive conclusions could not be made with regards to effects on fasting blood glucose, fasting insulin, or insulin sensitivity due to high heterogeneity among studies. However, studies using genistein alone (N=673) had low heterogeneity and showed a statistically significant improvement in fasting blood glucose (P<0.00001) and insulin levels (P<0.00001). Pooled estimates of treatment effects according to subgroups again showed that treatment with genistein alone had minimal heterogeneity. Additionally, subgroup analysis with low heterogeneity that showed a beneficial effect was administration of low doses (less than 70 mg) compared to higher doses. The majority of studies were of high quality, with 6 ranked as relatively low quality.109

The addition of soy-soluble polysaccharides to glucose solutions or liquid and gelled dairy products was associated with minimal effects on postprandial blood glucose or insulin levels in healthy males in a randomized, double-blind, crossover, postprandial study (n = 12). Although glucose area under the curve and GI values were significantly lower with flaxseed gum- (2.5 g) and soy-soluble polysaccharide-fortified (2.25 g) products than the glucose reference, the significant inverse correlation to product viscosity (which was greatest with flaxseed gum) pointed to this as the more relevant factor. Fortification of food products, especially dairy, with 1% low-viscosity soluble fibers does not appear to be a useful means of attenuating postprandial blood glucose or insulin response.91 A small (n = 25) randomized, crossover trial in type 2 diabetic nephropathy patients evaluated 4 week courses of soy milk versus cow’s milk for impact on indicators of inflammation, coagulation, and oxidative stress. The only significant difference seen with soy milk was a reduction in D-dimer (−3.77 vs +16.13%; P < 0.05). After controlling for confounders, no significant difference was seen for tumor necrosis factor-alpha, interleukin-6, high-sensitivity C-reactive protein, or malondialdehyde levels.98

Food allergy/intolerance in infants

Animal data

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

Clinical data

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 (eg, soy) are substituted for cow's milk.46 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) or food intolerance. Many infants with food intolerance become tolerant over time, with the risk of persistent intolerance increasing with evidence of atopy.47

GI effects

In 1 report, the use of fiber-supplemented soy formula reduced the duration of diarrhea in 44 infants.67 Soy also has been investigated in studies for the treatment of infantile colic68 and recurrent abdominal pain in childhood.69 However, there is no evidence to suggest soy has any beneficial effect in these conditions. In contrast, a 2 × 2 factorial randomized, placebo-controlled study conducted in 100 adult women with irritable bowel syndrome (IBS) observed significant improvements in symptom severity scores (P=0.001) in women who received soy isoflavones for 6 weeks compared to those who did not. Additionally, severity of abdominal pain (P=0.018), duration of abdominal pain (P=0.001), satisfaction of bowel habits (P=0.011), and life disruption (P<0.001) were all significantly improved with soy compared to placebo, with some data suggesting a synergistic effect with coadministration of vitamin D as seen in total IBS scores and satisfaction of bowel habits. The soy isoflavone supplements contained diadzein 10 mg, genstein 8.5 mg, and glycerin 1.5 mg and were taken twice daily; vitamin D was taken once biweekly and contained 50,000 units of cholecalciferol.108

Menopausal symptoms

Because of their weak estrogenic activity, soy isoflavones have been hypothesized to improve several estrogen-dependent conditions, including perimenopausal vasomotor symptoms (eg, 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.48

Animal data

The widespread availability of clinical trial data has made data from animal studies largely irrelevant.

Clinical data

Reviews and meta-analyses of clinical trials evaluating the efficacy of soy products and phytoestrogens in managing the symptoms of menopause are available and include a Cochrane meta-analysis.48, 49, 50 Problems of heterogeneity of included study populations, treatment regimens, and outcomes measures exist, as well as of trial methodology. A placebo effect is acknowledged, making adequate blinding and randomization vital to the results in these studies.48

Findings from the included studies provide conflicting data. Subgroup analyses in 1 meta-analysis suggest weak evidence to support the use of soy concentrates (genistein or daidzein) or soy extracts, but not dietary supplementation with soy, in the management of menopausal vasomotor symptoms,51 while the Cochrane meta-analysis found no evidence for effect.48 Another analysis evaluated the effect of soy protein and isoflavones on circulating hormones in pre- and postmenopausal women. No effect on hormones (estradiol, estrone, sex hormone–binding protein, follicle-stimulating hormone [FHS] and luteinizing hormone [LH]) was reported in postmenopausal populations, and only a modest effect was found on FSH and LH in premenopausal women.52 A small randomized clinical trial published subsequent to the meta-analyses evaluated the effect of dietary soy, hormone replacement therapy, and placebo on menopausal symptoms and revealed a reduction in the severity of hot flashes, bone/joint pain, and vaginal dryness for soy and hormone therapy.53 The outcomes of the 2-year SPARE (Soy Phytoestrogens As Replacement Estrogen) study evaluating the effect of soy isoflavones as replacement estrogen in menopausal women are awaited.54 No significant benefit on cognitive function in postmenopausal women was found in a 2.5-year, randomized, placebo-controlled trial (n = 313) that used a soy dose selected to mimic soy intake in a typical Asian diet.100

Guidelines have been published discussing soy and the treatment of menopausal symptoms. The American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of menopause (2011) notes that though soy may have some estrogen agonist properties, long-term safety issues, particularly in patients with breast cancer, remain of concern for high-dose therapy. A healthful diet that incorporates some soy protein seems reasonable.85 The Society of Obstetricians and Gynaecologists of Canada revised clinical practice guidelines on managing menopause (2014) recommend that complementary and alternative medicine that has demonstrated efficacy for mild menopausal symptoms, including products containing isoflavones sourced from soy, may be offered by health care providers (Level I-B).86 The Endocrine Society clinical practice guidelines for the treatment of symptoms of the menopause (2015) recommend counseling patients on the lack of consistent evidence for benefit of complementary medicine therapies, including soy isoflavones, as an alternative nonhormonal therapy for vasomotor symptoms (weak recommendation; low quality evidence).106

Metabolic function

Soy isoflavones were found to have significant favorable effects on the metabolic status of women with polycystic ovary syndrome (PCOS) in a double-blind, randomized, placebo-controlled trial (n=70). Patients completed food and activity diaries at baseline and every 3 weeks. After 12 weeks, both placebo (undefined) and soy isoflavone (50 mg/day equivalent to 500 mL/day soy milk) groups exhibited significant improvements from baseline in measures of insulin resistance, beta-cell function, insulin sensitivity, triglycerides, very low-density lipoprotein (VLDL), and malondialdehyde. Those in the soy group also had significant improvements in glutathione levels. The differences observed in the soy group were significantly greater than placebo for all of these measures (P<0.001 to P=0.02) as well as for nitric oxide (P=0.02). Soy isoflavone supplementation was well tolerated with no report of side effects.107

Osteoarthritis

Avocado/soybean unsaponifiables consist of one-third avocado oil and two-thirds soybean oil. Preclinical studies showed this combination to have some antiosteoarthritis activity, possibly via effects on interleukin-1 and collagen synthesis. A meta-analysis of 4 clinical trials (664 patients; knee and hip osteoarthritis) suggests greater improvement in pain scores and functional indices, especially for osteoarthritis of the knee.70 However results of avocado/soybean unsaponifiables relating to structure-modifying properties are yet to be confirmed by radiographic evidence through independent trials.70, 71, 72

Osteoporosis

Animal data

The effect of soy protein with and without isoflavones has been studied in a number of animal models with conflicting results.55, 56, 57, 58 The widespread availability of clinical trial data now make data from animal studies largely irrelevant.

Clinical data

Several meta-analyses have been conducted on clinical trials evaluating the efficacy of soy preparations in protecting against decreases in bone mineral density (BMD), and include trials up to 2008.59, 60, 61, 62, 63 Heterogeneity is present among the included trials and the influence of ethnicity, basal BMD, and duration of intervention have not been determined. Data from the meta-analyses are conflicting, with some reporting small improvements in bone density59, 60, 63 and others reporting no effect.61, 62 Data from long-term clinical trials have been published subsequent to the meta-analyses, finding no treatment effect after 3 years of supplementation (SIRBL [Soy Isoflavones for Reducing Bone Loss] study)64 an increase in whole BMD after 2 years but no influence at common spine and hip fracture sites65 and no effect after 3 years on biomarkers in general in healthy postmenopausal women.66 Studies evaluating reductions in fracture rates in women with osteoporosis are lacking.

Guidelines have been published concerning the use of soy in osteoporosis. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin (2012) states that studies of soy isoflavone supplements have produced mixed results regarding effects on bone mineral density and that there are no prospective studies on the effect of soy isoflavones on fracture rate. No recommendations regarding the use of soy are offered.87 The North American Menopause Society position statement on osteoporosis (2010) states that the data regarding dietary isoflavones (soy) in the prevention or treatment of postmenopausal osteoporosis, are relatively weak. Benefits, in terms of bone density and turnover, are minor at best. No recommendations regarding the use of soy are offered.88

Polycystic ovary syndrome

The effect of soy isoflavones on the metabolic status of women with polycystic ovary syndrome (PCOS) was investigated in a double-blind, randomized, placebo-controlled trial (n=70). Patients completed food and activity diaries at baseline and every 3 weeks. After 12 weeks, both placebo (undefined) and soy isoflavone (50 mg/day equivalent to 500 mL/day soy milk) groups exhibited significant improvements from baseline in measures of insulin resistance, beta-cell function, insulin sensitivity, total testosterone, sex hormone-binding globulin, free androgen index, triglycerides, VLDL, and malondialdehyde. Those in the soy group also had significant improvements in glutathione levels and hirsutism. The differences observed in the soy group were significantly greater than placebo for all of these measures (P<0.001 to P=0.02) as well as for nitric oxide (P=0.02). Soy isoflavone supplementation was well tolerated with no report of side effects.107

Dosing

One gram of soy protein in traditional soy foods contains approximately isoflavones 3.5 mg (aglycone weight).73

A large number of clinical trials have been conducted for several conditions (eg, menopause, osteoporosis, breast cancer, cardiovascular diseases) using daily doses of isoflavones from 40 to 120 mg.11, 33, 36, 37, 48, 59, 60, 61, 62, 63, 93 An avocado/soybean unsaponifiable fraction has been studied in osteoarthritis at 300 to 600 mg daily.70, 71, 72 Doses of soy protein in clinical trials in conditions including prostate cancer prevention and menopause used 20 to 25 g/day, and a study in diabetic nephropathy used 240 mL of soy milk.94, 98, 100

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Generally recognized as safe (GRAS) when used as food. Avoid dosages above those found in food.

Interactions

Estrogen Derivatives: Herbs (Estrogenic Properties) may enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy.85, 110

Adverse Reactions

Soybeans and their products are generally well tolerated. A 2-year trial of 80 and 120 mg daily soy isoflavones reported no effect on all measured laboratory indices except a minimal increase in blood urea nitrogen at the 2-year mark.75

The effects of phytoestrogens in soy-based infant formulas and in commercial soy preparations have been of concern.76, 77 However, a meta-analysis of 15 clinical studies showed no effect on testosterone or sex hormone-binding globulin levels73 and semen quality in healthy men was unaffected by 2 months of high-dose isoflavones in another clinical trial.78

A randomized clinical trial evaluated the effect of soy phytoestrogens in subclinical hypothyroidism over 8 weeks. Six participants in the study, receiving higher-dose phytoestrogen (16 mg daily), developed overt hypothyroidism, while secondary outcomes for the study populations were positive for decreased blood pressure and insulin resistance.79 Soy formula-fed infants may be at risk of thyroid dysfunction, although case-reports are lacking, and the National Toxicology Program (US Department of Health and Human Services) has concluded that there is minimal concern for developmental effects in infants fed soy infant formula.80, 81

Allergy, including asthma and anaphylaxis, has been reported. Although soybeans and peanuts, as well as other beans, are phylogenetically and antigenetically similar, there are insufficient data to recommend soy avoidance in peanut-allergic patients.82, 83, 84

Toxicology

Evidence exists from animal studies on the adverse effects of genistein on the developing female reproductive tract, including decreased age at vaginal opening; abnormal estrous cyclicity; decreased fertility, implants, and litter size; and histopathology of the female reproductive tract.81

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