Health Care Professional Information

Scientific Name
Glycine max
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Common Name

Soybean, soya, tofu, miso, tempeh

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Clinical Summary

Soy is derived from the seed of Glycine max. Soybeans are rich in protein and other essential nutrients and are widely consumed as food. Soy also contains significant amounts of isoflavones — genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone), and glycitein (4',7-dihydroxy-6-methoxyisoflavone) (1). They are marketed as dietary supplements to treat hot flashes, high cholesterol, and for cancer prevention. Isoflavones are thought to exhibit both selective estrogen receptor modulator activity and non-hormonal effects. Studies on the effect of soy for menopausal symptoms are inconclusive (2) (3) (4) (5) (6) (7) (8) (9). While some studies indicate that soy may slow bone density loss, (10) (11) others report no effects on bone mineral density in postmenopausal women (12) (13). Soy was shown to reduce low-density-lipoprotein (LDL)(14) in postmenopausal women (15) and blood pressure in hypertensive postmenopausal women (16), suggesting a benefit for cardiovascular health (17). Genistein also reduced fasting blood glucose and insulin levels as well as improving insulin resistance (18). Soy intake also reduced proteinuria in type 2 diabetic patients with nephropathy (19). However, conflicting data suggest no such protective effects of soy consumption against diabetes (20).

Soy may reduce risk of prostate (21) (22) (23), lung (24) (80), and endometrial (25) (26) cancers, but can increase the risk of bladder cancer (27) and endometrial hyperplasia (28). It was also shown to prevent breast cancer (29) (30) but conflicting data suggest that soy supplementation may have adverse effects (31) (32). A study done in mice suggests that consumption of soy products may increase metastasis (33). Genistein, the most estrogenic soy isoflavone (34), demonstrates antiproliferative effects in multiple cell lines, including breast cancer (ER-positive and negative) (35), prostate cancer (androgen-dependent and independent) (36), nasopharyngeal carcinoma (37), neuroblastoma, sarcoma, and retinoblastoma cells (36). Animal studies also show that genistein antagonizes the effects of tamoxifen (38) (39) and promotes tumor progression in advanced prostate cancer (40). Conflicting data show a decrease in serum PSA levels in prostate cancer patients (41). Further research is needed to evaluate the role of genistein in cancer prevention.

Soy consumption reduced mortality and recurrence in breast cancer patients, regardless of tamoxifen use (42). It also prolongs survival among women with lung cancer (81). Supplementation with soy isoflavones may reduce the adverse effects associated with chemotherapy (43) and radiotherapy (44), but when used together with vitamin E and selenium, did not prevent prostate cancer progression (45).

Patients should consult their physicians about the use of soy supplements.

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Food Sources

Raw soybeans, low-fat soy flour, roasted soybeans, dry-roasted soy beans, soy milk, tofu, and soy protein isolate. There are no isoflavones in soy sauce or soy oil.

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Purported Uses
  • Cancer prevention
  • Cardiovascular disease
  • High cholesterol
  • Menopausal symptoms
  • Osteoporosis
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Constituents
  • Isoflavones: Genistein, daidzein, glycitein
  • Glucosides
  • Phospholipids: Phosphatidylcholine, lecithin, linoleic acid, oleic acid
  • Protein
  • Carbohydrate
    (1) (46)
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Mechanism of Action

Animal studies suggest that genistein and daidzein have an ability to prevent or reduce bone loss in a manner similar to synthetic estrogen due to increased beta versus alpha estrogen receptor (ER) binding (10). Both isoflavones may modulate bone remodeling through ERs by regulating target gene expression (50). Soy may also contribute to maintaining bone density by causing less calcium to be excreted in the urine (35).

Proposed mechanisms of soy’s cholesterol-lowering effect include phytoestrogen-induced hyperthyroid state and increased excretion of bile acids, which may enhance removal of LDL. Isoflavones may inhibit oxidation of LDL and may alter hepatic metabolism with enhanced removal of LDL and VLDL by hepatocytes (17). Serum lipids may also be regulated through modified transcription factor and downstream gene expression and by promoting antioxidant enzyme activity (51).

The phytochemicals in soybeans also exhibit anticarcinogenic activity, for which many mechanisms have been proposed. Genistein affects microRNA expression—targeted translation inhibitors for multiple proteins implicated in the regulation of various pathobiological processes in cancer (52). In addition, genistein demonstrated an anti-minichromosome maintenance (MCM) effect, a gene family frequently upregulated in various cancers and considered a promising anticancer drug target (53).

In breast cancer, genistein acts as an agonist to estrogen receptor (ER)-alpha in ER-alpha-predominant breast cancer cells, but likely acts as an antiestrogen in cells with ER-beta alone, suggesting therapeutic potential for premenopausal women with ER-alpha-negative/ER-beta-positive tumors (54). However, in an in vitro breast model, genistein also induced estrogen-dependent MCF-7 tumor cell growth and increased breast cancer-associated aromatase expression and activity, suggesting that soy-based supplements may affect the efficacy of aromatase inhibitors used in breast cancer treatment (55). Genistein is also known to negate the inhibitory effect of tamoxifen on MCF-7 tumor growth and increase expression of estrogen-responsive genes (38). Alternatively, soy isoflavones may reduce breast cancer risk by decreasing endogenous ovarian steroid levels (56). Studies suggest that some benefits ascribed to dietary isoflavones may depend on early life exposure, thereby impacting gene expression at an epigenetic level. (47) (48) (49)

In prostate cancer, soy protein extracts appear to influence the progression of established tumors rather than inhibit etiologic factors. Furthermore, soy protein consumption reduces androgen receptor expression in prostate tumors (57). Other proposed prevention mechanisms include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis (22). Growth inhibition appears to be independent of genistein’s estrogenic effects. In human prostate cancer cell lines, both genistein and daidzein affect microRNA regulation (58) and induce decreased methylation of gene promoters including BRCA1(59). In tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant prostate cancer cells, soy isoflavones enhance TRAIL-mediated apoptosis by engaging apoptotic pathways and regulating NF-κB activity (60) (61). However, in a patient-derived prostate cancer xenograft model, increased proliferation and metastasis in genistein-treated groups were linked to enhanced activities of tyrosine kinases, the epidermal growth factor receptor, and its downstream Src (40). Both genistein and daidzein also act as radiosensitizers for prostate cancer in vitro and in vivo, but pure genistein increased lymph node metastasis, whereas the combination of genistein, daidzein, and glycitein did not. Daidzein may protect against genistein-induced metastasis, and its ability to inhibit cell growth and potentiate radiation appears to be androgen-receptor-independent (62). In addition, soy isoflavones radiosensitized human A549 NSCLC cells, and decreased hemorrhages, inflammation, and fibrosis caused by radiation suggesting protection of normal lung tissue (63). The combination of genistein, daidzein, and glycitein also mediated growth-suppressive effects via ER-beta in DLD-1 human colon adenocarcinoma cells (64). 7,3’,4’-trihydroxyisoflavone (THIF), a daidzein metabolite, targets Cot and MKK4 to inhibit UVB-induced skin cancer (65) and cyclin-dependent kinases and phosphatidylinositol 3-kinase to inhibit EGF-induced proliferation and transformation in JB6 P+ mouse epidermal cells (66).

The intestinally derived isoflavone metabolite R-equol, but not S-equol, was also found to be potently chemopreventive (67). However, neonatal and prepubertal exposure to equol showed no long-term chemoprevention against DMBA-induced mammary tumors even though an equol-exposure ‘imprinting’ effect resulted in a decrease in immature terminal end structures and an increase in mature lobules (68).

The soy peptide lunasin exhibits chemopreventive properties via gene expression upregulation (69) and cell adhesion (70), apoptosis (71), and anti-inflammatory activity (72).

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Pharmacokinetics

Pre-absorption: Prior to absorption, isoflavones undergo extensive metabolism in the intestinal tract. Genistein is formed from biochanin A, and daidzein from formonentin. Genistein, daidzein, and glycitein may be metabolized further to specific metabolites such as equol, O-desmethylangolensis, dihydrogenistein, and p-ethylphenol. Many variables can affect this metabolism. An analysis of phytoestrogen supplements and extracts demonstrated notable differences in isoflavone content as compared with manufacturer claims (73). Qualitative and quantitative differences in plasma concentrations of isoflavones were observed based on the type of supplement used. Such variations in pharmacokinetics and metabolism should be taken into consideration when conducting clinical studies.

Metabolism/Excretion: Following absorption, isoflavones undergo enterohepatic circulation, are secreted into bile, and are eliminated via the kidneys primarily as glucuronide conjugates. However, a portion of isoflavones in the portal blood can escape first-pass liver uptake, entering peripheral circulation. The plasma half-life of genistein and daidzein is approximately 8 hours. In adults, peak concentrations occur in 6 to 8 hours (74).

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Contraindications
  • Soy is contraindicated in patients who are hypersensitive to soy products.
  • UGT (Uridine 5'-diphospho-glucuronosyltransferase) substrates: Soy modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them (75).
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Adverse Reactions
  • Flatulence, allergic reactions.
Case Reports
A 60-year-old man developed gynecomastia following consumption of soy milk over a period of six months. His symptoms resolved after discontinuing soy use (76).

Three women experienced abnormal uterine bleeding with endometrial pathology after high intake of soy products. Their symptoms improved following withdrawal of soy use (77).

A 19-year-old type diabetic but otherwise healthy man experienced sudden onset of loss of libido and erectile dysfunction following consumption of large amounts of soy-based products in a vegan-style diet. His symptoms improved one year after discontinuing the vegan diet (78).

A 55-year-old woman died from massive pulmonary edema following consumption of a large quantity of Japanese soy sauce, shoyu (79).
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Herb-Drug Interactions

Tamoxifen: Animal studies suggest that genistein, a soy isoflavone, may antagonize the effects of tamoxifen on estrogen-dependent breast cancer (MCF-7) (38) (39).

Aromatase Inhibitors: Genistein also induced MCF-7 tumor cell growth and increased breast cancer-associated aromatase expression and activity in an in vitro breast model, suggesting that soy-based supplements may affect the efficacy of aromatase inhibitors used in breast cancer treatment (55).

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Literature Summary and Critique

Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA 2009;302(22):2437-43.
This is a large, population-based cohort study of 5042 female breast cancer survivors conducted in China. Information about cancer diagnosis, treatment, lifestyle changes, and disease progression was collected at 6 months after diagnosis with three follow-up points at 18, 36, and 60 months post diagnosis. The main outcome measures were total mortality and breast cancer recurrence. Researchers observed an inverse association between consumption of soy foods and mortality and recurrence. Further, this association was seen in women with both estrogen receptor-positive or negative breast cancer, regardless of tamoxifen use.
These data suggest that soy intake is safe and can benefit women with breast cancer.

Azadbakht L, Kimiagar M, Mehrabi Y, et al. Dietary soya intake alters plasma antioxidant status and lipid peroxidation in postmenopausal women with the metabolic syndrome. Br J Nutr. 2007;98(4):807-13.
The effect of soy consumption on metabolic syndrome parameters was analyzed in 42 postmenopausal women in this randomized crossover study. Women consumed a control diet, which consisted of the Dietary Approaches to Stop Hypertension (DASH) diet, the DASH diet with soy protein in place of red meat, or the DASH diet with soy nut in place of red meat for 8 weeks each with 4-week washout periods. All the diets reduced fasting blood glucose, LDL cholesterol, total cholesterol, fasting insulin, and insulin resistance (as assessed by the homeostasis model assessment for insulin resistance, HOMA-IR), but the soy nut diet most greatly improved fasting blood glucose levels, HOMA-IR scores, and LDL levels as compared with the soy protein diet, indicating that differences in soy products may influence metabolic syndrome improvements. The authors surmise that greater unsaturated fat and isoflavone content in soy nuts may mediate these improvements.

Schabath M, Hernandez L, Wu X, et al. Dietary phytoestrogens and lung cancer risk. JAMA. 2005;294(12):1493-504.
In a large case-control study that involved over 1,600 lung cancer patients and approximately equal number of healthy controls, the consumption of phytoestrogens has been shown to reduce the risk of lung cancer. High intake of soy isoflavones has the most significant protective effect, 72% for men and 44% for women. It is unclear if life style or dietary variations between groups contributed to this reduction in risk. This is the strongest evidence ever presented to support the use of soy as a chemopreventive agent. However, the authors cautioned against over interpretation of the findings and suggested further large-scale studies to confirm these results.

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women. JAMA. 2004;292:65-74.
In this double-blind randomized trial, 202 healthy postmenopausal women were randomly administered either 25.6g of soy protein or placebo on a daily basis for 12 months. Subjects who took soy protein did not show any improvement in cognitive function, bone mineral density, or plasma lipids when compared with those who took placebo. Researchers concluded that soy protein does not have any effect on cognitive function, bone mineral density, or plasma lipids in postmenopausal women when started at the age of 60 years or later.

Van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 2002;20:1449-55.
A prospective, randomized, double-blind evaluation of soy milk containing 90 mg isoflavones on post-menopausal breast cancer patients’ 4-month status post treatment experiencing hot flashes. Patients consumed 250 ml of soy milk (n=59) or placebo rice milk (n=64) twice daily for 12 weeks. The study allowed patients to take prescription medications and complementary therapies for hot flashes, provided the dose was stable for ≥4 months. Primary outcome was the number of hot flashes as recorded by patients in a daily menopause diary. Of 157 randomized patients, 9 were ineligible after randomization for reasons unknown, and 25 dropped out for various reasons including 10 patients intolerant to the study drug (soy n=7, placebo n=3). Both the active and placebo group demonstrated a reduction in number of hot flashes per day, 54% and 58% respectively. Adverse events were primarily gastrointestinal in nature, including abdominal bloating and flatulence. The authors suggest that soy milk delivering 90 mg per day isoflavones is no more effective than placebo for the management of hot flashes experienced by post-menopausal breast cancer patients.

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Dosage (Inside MSKCC Only)
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References
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  77. Chandrareddy A, Muneyyirci-Delale O, McFarlane SI, et al. Adverse effects of phytoestrogens on reproductive health: a report of three cases. Complement Ther Clin Pract. May 2008;14(2):132-135.
  78. Siepmann T, Roofeh J, Kiefer FW, et al. Hypogonadism and erectile dysfunction associated with soy product consumption. Nutrition. Jul-Aug 2011;27(7-8):859-862.
  79. Furukawa S, Takaya A, Nakagawa T, et al. Fatal hypernatremia due to drinking a large quantity of shoyu (Japanese soy sauce). J Forensic Leg Med. Feb 2011;18(2):91-92.
  80. Yang WS, Va P, Wong MY, et al. Soy intake is associated with lower lung cancer risk: results from a meta-analysis of epidemiologic studies. Am J Clin Nutr. 2011 Dec;94(6):1575-83.
  81. Gong Yang, Xiao-Ou Shu, Hong-Lan Li, et al. Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women. J Clin Oncol. 2013. Published Ahead of Print on March 25, 2013 as 10.1200/JCO.2012.43.0942
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Consumer Information

How It Works

Bottom Line: Whether soy helps relieve menopausal symptoms is still unclear. It may reduce risk of some cancers.

Soy contains large amounts of substances known as isoflavones, also called phytoestrogens. These substances act in a similar way as estrogen in the body and may also be antioxidants. The effects of soy are weak in younger women because estrogen is abundant. At menopause, however, the effects of soy may increase due to the decrease in estrogen. Studies in animals suggest that soy can prevent or reduce bone loss by acting like estrogen and by reducing loss of calcium.

In laboratory studies, soy isoflavones slowed down the growth of several different types of cancer cells, including breast and prostate cancers. Animal studies showed that genistein, one of the isoflavones, may interfere with tamoxifen that is used for breast cancer. But a new study showed that soy foods can benefit women with breast cancer.

Patients should consult their physicians about use of soy supplements.

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Purported Uses
  • To prevent cancer
    Laboratory and some clinical studies suggest that women with high soy intake have a lower risk of developing breast cancer. High intake of soy isoflavones can also reduce risk of lung cancer.
  • To prevent heart disease
    Clinical trials show that soy protein (not soy pills) reduces LDL (bad) cholesterol levels, which may help prevent heart disease.
  • To reduce high cholesterol
    Clinical trials show that soy protein (not soy pills) reduces LDL (bad) cholesterol levels and may increase HDL (good) cholesterol levels.
  • To treat menopause symptoms such as hot flashes, vaginal dryness, sleep disturbances, mood problems
    Clinical studies have conflicting results.
  • To prevent bone loss (osteoporosis)
    Some clinical trials and animal studies support this use.
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Research Evidence

Menopausal symptoms
In a clinical trial of post-menopausal breast cancer patients with hot flashes, 59 patients drank 250 ml of soy milk twice daily (containing 90 mg of isoflavones) while 64 patients drank 250 ml placebo rice milk for 12 weeks. Both groups experienced a similar decrease in hot flashes, around 60%, showing that soy milk works no better than placebo in reducing hot flashes. However, patients were allowed to use other therapies and medicines to treat their hot flashes, which may have interfered with the study's results.

Cholesterol levels and bone density
In a study of the effect of diet and soy intake on cholesterol and bone density, 66 patients with high cholesterol followed a low-fat, low-cholesterol diet (“Step 1 diet”) for two weeks. At this point, patients were split into three groups and for six months followed either: 1) the Step 1 diet with 40 g of placebo protein daily, 2) the Step 1 diet with 40 g of low-isoflavone soy protein daily, or 3) the Step 1 diet with 40 g of high-isoflavone soy protein. HDL (“good”) cholesterol rose in groups 2 and 3, but total cholesterol did not decrease. Group 3 had a large increase in bone mineral content compared to group 1.

Breast cancer prevention
In a case-control study, 144 women with newly diagnosed breast cancer were matched (by age, where they lived, etc.) with women without breast cancer. Their intake of phytoestrogens was monitored. Women who consumed a high level of phytoestrogens had a lower risk of developing both premenopausal and postmenopausal breast cancer.

In a large, population-based cohort study of 5042 female breast cancer survivors conducted in China, information about cancer diagnosis, treatment, lifestyle changes, and disease progression was collected at 6 months after diagnosis with three follow-up points at 18, 36, and 60 months. Researchers observed that consumption of soy foods reduced the risk of mortality and breast cancer recurrence. Further, this association was seen in women with both estrogen receptor-positive or negative breast cancer, regardless of tamoxifen use.
These data suggest that soy intake is safe and can benefit women with breast cancer.

Lung cancer prevention
In a large case-control study of 1674 lung cancer patients and 1735 healthy controls, high soy isoflavone intake has been shown to lower the risk of lung cancer by 61%.

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Do Not Take If
  • You are hypersensitive to soy products.
  • You are taking drugs that are substrates of UGT (Uridine 5'-diphospho-glucuronosyltransferase) enzymes (Soy may increase the risk of side effects of these drugs).
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Side Effects
  • Flatulence
  • Allergic reactions
  • Case Reports
  • A 60-year-old man developed gynecomastia following consumption of soy milk over a period of six months. His symptoms resolved after discontinuing soy use.
  • Three women experienced abnormal uterine bleeding with endometrial pathology after high intake of soy products. Their symptoms improved following withdrawal of soy use.
  • A 19-year-old type diabetic but otherwise healthy man experienced sudden onset of loss of libido and erectile dysfunction following consumption of large amounts of soy-based products in a vegan-style diet. His symptoms improved one year after discontinuing the vegan diet.
  • A 55-year-old woman died from salt poisoning following consumption of a large quantity of Japanese soy sauce, shoyu.
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Last updated: March 26, 2013
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