Soy

• How It Works

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

  Soy is a plant that is grown worldwide. The beans are rich in protein and other nutrients and are widely consumed as food. Extracts are sold as dietary supplements to treat hot flashes, high cholesterol, and for cancer prevention. Soy contains large amounts of isoflavones that act like estrogen in the body. Studies in animals suggest that soy can prevent or reduce bone loss. In laboratory studies, 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.

• Purported Uses
  • To prevent cancer
    Laboratory and some clinical studies suggest that soy intake was associated with a lower risk of developing breast cancer. High intake of isoflavones may also reduce risk of lung cancer.
  • To prevent heart disease
    Clinical trials show that soy protein, not pills, reduces LDL (bad) cholesterol levels, which may help prevent heart disease.
  • To reduce high cholesterol
    Clinical trials show that soy protein, not 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
    Some clinical trials and animal studies support this use.
• Do Not Take If
  • You are hypersensitive to soy products.
  • You are taking tamoxifen: Animal studies have shown that genistein may reduce the effects of tamoxifen on estrogen-dependent breast cancer.
  • You are taking aromatase Inhibitors: Soy-based supplements may reduce the effects of aromatase inhibitors used in breast cancer treatment.
  • You are taking cytochrome P450 substrate drugs: Soymilk and miso may make them less effective.
  • You are taking P-Glycoprotein substrate drugs: Soymilk and miso may make them less effective.
  • You are taking UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrate drugs: Soy can increase the side effects of these drugs.
• Side Effects
  • Flatulence
  • Allergic reactions

  Case Reports

  • Underactive thyroid: In a 72-year-old woman who had chronic thyroid disease. She had taken a health drink containing soy isoflavones for 6 months. Symptoms improved with medical treatment and discontinuation of the health drink.
  • Breast enlargement: In a 60-year-old man following consumption of soy milk over a period of 6 months. Symptoms resolved after discontinuing use.
  • Abnormal uterine bleeding: In 3 women after a high intake of soy products. Symptoms improved following withdrawal of use.
  • Loss of sex drive and erectile dysfunction: In a 19-year-old diabetic man who was otherwise healthy, following intake of large amounts of soy-based products in a vegan-style diet. Symptoms improved 1 year after discontinuing the diet.
• Special Point

  The isoflavone content is minimal in soy sauce or soy oil.

• Scientific Name

  Glycine max

• Clinical Summary

  Soybeans, derived from Glycine max, 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 exhibit both selective estrogen receptor modulator activity and non-hormonal effects. Studies of soy for menopausal symptoms are inconclusive ^{(2) (3) (4) (5) (6) (7) (8) (9)}. While some trials indicate slower bone density loss ^{(10) (11) (91)}, others report no such effects in postmenopausal women ^(12) (13). But there may be cardiovascular benefits ⁽¹⁷⁾, as soy reduces low-density-lipoprotein (LDL) cholesterol ^(14) (15) along with having beneficial effects on blood pressure in postmenopausal women ^(16) (97) and in healthy adults ⁽⁹⁰⁾. A meta-analysis confirmed that consumption of soy leads to reductions in both total cholesterol and LDL in adults ⁽⁹⁹⁾.

  Soy intake also reduced proteinuria in type 2 diabetic patients with nephropathy ⁽¹⁹⁾. However, conflicting data suggest no protective effects against diabetes ⁽²⁰⁾. Other studies of soy did not find benefit for Alzheimer’s disease ⁽⁹²⁾ or for poorly controlled asthma ⁽⁹³⁾, but soy isoflavone supplementation alone or with Vitamin D improved some symptoms and quality of life in patients with irritable bowel disease ⁽⁹⁴⁾; and lactobacillus-fermented soybean was found to enhance cognitive function in subjects with mild cognitive impairment ⁽¹⁰⁰⁾. In a study of chronic stroke patients, ingesting soymilk immediately following rehabilitation exercise was reported to improve functional outcomes ⁽¹⁰¹⁾; soymilk consumption along with a low-calorie diet had beneficial effects on some metabolic parameters in patients with non-alcoholic fatty liver disease ⁽¹⁰²⁾.

  Soy has been investigated for its anticancer effects as well. Data show that it may reduce the risk of prostate ^{(21) (22) (23)}, lung ^(24) (80), and endometrial ^(25) (26) cancers, but increase risk of bladder cancer ⁽²⁷⁾ and endometrial hyperplasia ⁽²⁸⁾. It may prolong survival among women with lung cancer ⁽⁸¹⁾, reduce mortality ⁽⁸⁹⁾ and breast cancer recurrence regardless of tamoxifen use ⁽⁴²⁾, or prevent breast cancer ^(29) (30). However, long-term supplementation did not affect mammographic density in breast cancer patients or in high-risk women ⁽⁹⁵⁾ and other data suggest adverse effects ^(31) (32) or that supplementation can stimulate over-expression of breast cancer genes in patients with invasive breast cancer ⁽⁸⁷⁾. Preclinical findings indicate that soy consumption may increase metastasis ⁽³³⁾; and daidzin-rich extracts can promote ER-positive breast cancer growth ⁽⁸⁸⁾.

  Genistein, the most estrogenic isoflavone ⁽³⁴⁾, has been reported to improve fasting blood glucose, insulin levels, and insulin resistance in postmenopausal women ⁽¹⁸⁾. It also demonstrated antiproliferative effects in multiple cell lines, including breast cancer (ER+/-) ⁽³⁵⁾, prostate cancer (androgen-dependent/-independent) ⁽³⁶⁾, nasopharyngeal carcinoma ⁽³⁷⁾, neuroblastoma, sarcoma, and retinoblastoma cells ⁽³⁶⁾. However, animal studies show that it antagonizes the effects of tamoxifen ^(38) (39) and promotes tumor progression in advanced prostate cancer ⁽⁴⁰⁾. In addition, supplementation may decrease serum PSA levels in prostate cancer patients before ⁽⁴¹⁾, but not after ⁽⁸²⁾, prostatectomy. Further research is needed to evaluate the role of genistein in cancer prevention.

  Isoflavone supplementation may reduce side effects associated with chemo- or radiotherapy ^(43) (44), but when used with vitamin E and selenium, did not prevent prostate cancer progression ⁽⁴⁵⁾. It was also ineffective in reducing hot flashes in patients with prostate cancer ⁽⁸³⁾. Patients should consult their physicians about the use of soy supplements, whose long term-safety remains to be determined.

• 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.

• Purported Uses
  • Cancer prevention
  • Cardiovascular disease
  • High cholesterol
  • Menopausal symptoms
  • Osteoporosis
• Mechanism of Action

  Animal studies suggest that genistein and daidzein can 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⁾. Isoflavones may inhibit oxidation of LDL and 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⁾.

  In addition, several mechanisms have been proposed for soy’s anticancer effects. Genistein affects microRNA expression-targeted translation inhibitors for multiple proteins implicated in regulating various pathobiological processes ⁽⁵²⁾. It also 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 cells, genistein acts as an agonist to estrogen receptor (ER)-alpha in ER-alpha-predominant 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, genistein induces estrogen-dependent MCF-7 tumor cell growth and increases breast cancer-associated aromatase expression/activity, suggesting that soy-based supplements may affect aromatase inhibitor efficacy ⁽⁵⁵⁾. Genistein is also known to negate tamoxifen’s inhibitory effect 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 the epigenetic level ^{(47) (48) (49)}.

  In prostate tumors, soy protein was shown to reduce androgen receptor expression ⁽⁵⁷⁾. 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⁾.

• Contraindications
  • Contraindicated in patients who are hypersensitive to soy products.
• Adverse Reactions
  • Flatulence, allergic reactions

  Case Reports

  • Severe hypothyroidism: In a 72-year-old woman with chronic thyroid disease who consumed a health drink for 6 months that contained soy isoflavone powder extracts ⁽⁹⁶⁾.
  • Gynecomastia: In a 60-year-old man following consumption of soy milk over a period of 6 months. Symptoms resolved after discontinuing use ⁽⁷⁶⁾.
  • Abnormal uterine bleeding: With endometrial pathology in 3 women after a high intake of soy products. Symptoms improved following withdrawal of use ⁽⁷⁷⁾.
  • Loss of libido and erectile dysfunction: In a 19-year-old diabetic man who was otherwise healthy, following intake of large amounts of soy-based products in a vegan-style diet. Symptoms improved 1 year after discontinuing the diet ⁽⁷⁸⁾.
• Herb-Drug Interactions
  • Tamoxifen: Animal studies suggest that genistein may antagonize the effects of tamoxifen on estrogen-dependent breast cancer (MCF-7) ^(38) (39). Relevance in humans has yet to be determined.
  • Aromatase inhibitors: Genistein induced MCF-7 tumor cell growth and increased breast cancer-associated aromatase expression and activity, in vitro, suggesting that soy-based supplements may affect the efficacy of aromatase inhibitors used in breast cancer treatment ⁽⁵⁵⁾.
  • Cytochrome P450 substrates: Soymilk and miso were shown to induce CYP3A4 in vivo, and may affect the intracellular concentration of drugs metabolized by this enzyme ⁽⁸⁶⁾.
  • P-Glycoprotein: Soymilk and miso were shown to induce P-Gp in vivo, and can affect the intracellular concentration of certain drugs ⁽⁸⁶⁾.
  • Uridine 5’-diphospho-glucuronosyltransferase (UGT) substrates: Soy modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them ⁽⁷⁵⁾.
  • Membrane organic anion-transporting polypeptides (OATPs): Soy isoflavones and their metabolites were shown to affect transport of drugs across tissue barriers via human OATP2B1, in vitro. Clinical relevance is not known ⁽⁹⁸⁾.
• References

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  3. Cassidy A, Bingham S, Setchell KD. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr. Sep 1994;60(3):333-340.

  4. Han KK, Soares JM, Jr., Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. Mar 2002;99(3):389-394.

  5. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. Dec 19 2006;145(12):869-879.

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  37. Han H, Zhong C, Zhang X, et al. Genistein induces growth inhibition and G2/M arrest in nasopharyngeal carcinoma cells. Nutr Cancer. 2010;62(5):641-647.

  38. Ju YH, Doerge DR, Allred KF, et al. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. May 1 2002;62(9):2474-2477.

  39. Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res. Feb 1 2005;65(3):879-886.

  40. Nakamura H, Wang Y, Kurita T, et al. Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PloS one. 2011;6(5):e20034.

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  43. Tacyildiz N, Ozyoruk D, Yavuz G, et al. Soy isoflavones ameliorate the adverse effects of chemotherapy in children. Nutr Cancer. 2010;62(7):1001-1005.

  44. Ahmad IU, Forman JD, Sarkar FH, et al. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer. 2010;62(7):996-1000.

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