Soy

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

Common Name(s): Soy , soybean , soya , soy isoflavones

Uses

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.

Dosing

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

Contraindications

Contraindications have not been identified.

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. A decrease in the anticoagulated effect of warfarin has been reported in 1 patient.

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. The plant's isoflavones include genistein and daidzein, the most abundant, as well as glycitein and equol, 5 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 in urine, primarily as glucuronide conjugates. 8

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 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

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

Cancer, prostate

Soy isoflavones have estrogenic, antiandrogenic, and other activities that could 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

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 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

Cardiovascular disease
Animal data

Soy isoflavones exhibit strong biological properties in animals, 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 Association 7 and an expert panel from the American College of Cardiology 32 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. 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

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

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

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

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

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 density 59 , 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 sites, 65 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.

Other effects
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 colic 68 and recurrent abdominal pain in childhood. 69 However, there is no evidence to suggest soy has any beneficial effect in these conditions.

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

Dosage

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 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 An avocado/soybean unsaponifiable fraction has been studied in osteoarthritis at 300 to 600 mg daily. 70 , 71 , 72

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

A subtherapeutic international normalized ratio (INR) was reported in a 70-year-old man stabilized on warfarin after he started drinking soy milk. 74 The INR returned to the therapeutic range when he stopped drinking soy milk.

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 levels, 73 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. Soybeans and peanuts, as well as other beans, are phylogenetically and antigenetically similar. However, 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

Bibliography

1. Ensminger AH, Ensminger ME, Konlande JE, Robson JR. Foods & Nutrition Encyclopedia . Vol. 2. 2nd ed. Boca Raton, FL: CRC Press; 1994:2017-2035.
2. Glycine max . USDA, NRCS. 2011. The PLANTS database ( http://plants.usda.gov , September 2011). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
3. Polunin M. Healing Foods . New York, NY: DK Publishing; 1997:70.
4. Craig S, Haigh J, Harrar S. The Complete Book of Alternative Nutrition . Emmaus, PA: Rodale Press; 1997:278-279.
5. Messina MJ, Loprinzi CL. Soy for breast cancer survivors: a critical review of the literature. J Nutr . 2001;131(11)(suppl):3095S-3108S.
6. Garcia MC, Torre M, Marina ML, Laborda F. Composition and characterization of soyabean and related products. Crit Rev Food Sci Nutr . 1997;37(4):361-391.
7. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M; American Heart Association Nutrition Committee. Soy protein, isoflavones, and cardiovascular health: an American Heart Association science advisory for professionals from the nutrition committee. Circulation . 2006;113(7):1034-1044.
8. Barnes S, Coward L, Kirk M, Sfakianos J. HPLC-mass spectrometry analysis of isoflavones. Proc Soc Exp Biol Med . 1998;217(3):254-262.
9. Messina M, McCaskill-Stevens W, Lampe JW. Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J Natl Cancer Inst . 2006;98(18):1275-1284.
10. Enderlin CA, Coleman EA, Stewart CB, Hakkak R. Dietary soy intake and breast cancer risk. Oncol Nurs Forum . 2009;36(5):531-539.
11. Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat . 2011;125(2):315-323.
12. de Lemos ML. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother . 2001;35(9):1118-1121.
13. Bolca S, Urpi-Sarda M, Blondeel P, et al. Disposition of soy isoflavones in normal human breast tissue. Am J Clin Nutr . 2010;91(4):976-984.
14. Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update . 2010;16(6):745-760.
15. Messina MJ. Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr Rev . 2003;61(4):117-131.
16. Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular diseases, cancer, climacteric symptoms and osteoporosis. Drug Saf . 2001;24(9):665-682.
17. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest . 2003;21(5):744-757.
18. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. Am J Clin Nutr . 2009;89(4):1155-1163.
19. Hwang YW, Kim SY, Jee SH, Kim YN, Nam CM. Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer . 2009;61(5):598-606.
20. 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.
21. Sharma P, Wisniewski A, Braga-Basaria M, et al. Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy. J Urol . 2009;182(5):2265-2272.
22. deVere White RW, Tsodikov A, Stapp EC, Soares SE, Fujii H, Hackman RM. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer . 2010;62(8):1036-1043.
23. Katdare M, Osborne MP, Telang NT. Inhibition of aberrant proliferation and induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural phytochemicals. Oncol Rep . 1998;5(2):311-315.
24. Record IR, Broadbent JL, King RA, Dreosti IE, Head RJ, Tonkin AL. Genistein inhibits growth of B16 melanoma cells in vivo and in vitro and promotes differentiation in vitro. Int J Cancer . 1997;72(5):860-864.
25. Zhou Y, Lee AS. Mechanism for the suppression of the mammalian stress response by genistein, and anticancer phytoestrogen from soy. J Natl Cancer Inst . 1998;90(5):381-388.
26. Myung SK, Ju W, Choi HJ, Kim SC; Korean Meta-Analysis (KORMA) Study Group. Soy intake and risk of endocrine-related gynaecological cancer: a meta-analysis. BJOG . 2009;116(13):1697-1705.
27. Hedelin M, Löf M, Andersson TM, Adlercreutz H, Weiderpass E. Dietary phytoestrogens and the risk of ovarian cancer in the women's lifestyle and health cohort study. Cancer Epidemiol Biomarkers Prev . 2011;20(2):308-317.
28. Kim J, Kang M, Lee JS, Inoue M, Sasazuki S, Tsugane S. Fermented and non-fermented soy food consumption and gastric cancer in Japanese and Korean populations: a meta-analysis of observational studies. Cancer Sci . 2011;102(1):231-244.
29. Yan L, Spitznagel EL, Bosland MC. Soy consumption and colorectal cancer risk in humans: a meta-analysis. Cancer Epidemiol Biomarkers Prev . 2010;19(1):148-158.
30. Anthony MS, Clarkson TB, Williams JK. Effects of soy isoflavones on atherosclerosis: potential mechanisms. Am J Clin Nutr . 1998;68(6)(suppl):1390S-1393S.
31. Clarkson TB, Anthony MS, Morgan TM. Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab . 2001;86(1):41-47.
32. Vogel JH, Bolling SF, Costello RB, et al. American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). Integrating complementary medicine into cardiovascular medicine. (A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents [Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine]). J Am Coll Cardiol . 2005;46(1):184-221.
33. Taku K, Umegaki K, Sato Y, Taki Y, Endoh K, Watanabe S. Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials [published correction appears in Am J Clin Nutr . 2007;86(3):809]. Am J Clin Nutr . 2007;85(4):1148-1156.
34. Harland JI, Haffner TA. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis . 2008;200(1):13-27.
35. Reynolds K, Chin A, Lees KA, Nguyen A, Bujnowski D, He J. A meta-analysis of the effect of soy protein supplementation on serum lipids. Am J Cardiol . 2006;98(5):633-640.
36. Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr . 2008;88(1):38-50.
37. Taku K, Lin N, Cai D, et al. Effects of soy isoflavone extract supplements on blood pressure in adult humans: systematic review and meta-analysis of randomized placebo-controlled trials. J Hypertens . 2010;28(10):1971-1982.
38. Maki KC, Butteiger DN, Rains TM, et al. Effects of soy protein on lipoprotein lipids and fecal bile acid excretion in men and women with moderate hypercholesterolemia. J Clin Lipidol . 2010;4(6):531-542.
39. Santo AS, Santo AM, Browne RW, et al. Postprandial lipemia detects the effect of soy protein on cardiovascular disease risk compared with the fasting lipid profile. Lipids . 2010;45(12):1127-1138.
40. Beavers KM, Serra MC, Beavers DP, Hudson GM, Willoughby DS. The lipid-lowering effects of 4 weeks of daily soymilk or dairy milk ingestion in a postmenopausal female population. J Med Food . 2010;13(3):650-656.
41. Campbell SC, Khalil DA, Payton ME, Arjmandi BH. One-year soy protein supplementation does not improve lipid profile in postmenopausal women. Menopause . 2010;17(3):587-593.
42. Ricci E, Cipriani S, Chiaffarino F, Malvezzi M, Parazzini F. Effects of soy isoflavones and genistein on glucose metabolism in perimenopausal and postmenopausal non-Asian women: a meta-analysis of randomized controlled trials. Menopause . 2010;17(5):1080-1086.
43. Liu ZM, Chen YM, Ho SC. Effects of soy intake on glycemic control: a meta-analysis of randomized controlled trials. Am J Clin Nutr . 2011;93(5):1092-1101.
44. Liu ZM, Chen YM, Ho SC, Ho YP, Woo J. Effects of soy protein and isoflavones on glycemic control and insulin sensitivity: a 6-mo double-blind, randomized, placebo-controlled trial in postmenopausal Chinese women with prediabetes or untreated early diabetes. Am J Clin Nutr . 2010;91(5):1394-1401.
45. Christie DR, Grant J, Darnell BE, Chapman VR, Gastaldelli A, Sites CK. Metabolic effects of soy supplementation in postmenopausal Caucasian and African American women: a randomized, placebo-controlled trial. Am J Obstet Gynecol . 2010;203(2):153.e1-153.e9.
46. Muraro MA. Soy and other protein sources. Pediatr Allergy Immunol . 2001;12(suppl 14):85-90.
47. Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev . 2006;(4):CD003741.
48. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev . 2007;(4):CD001395.
49. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med . 2002;137(10):805-813.
50. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol . 2004;104(4):824-836.
51. Bolaños R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause . 2010;17(3):660-666.
52. Hooper L, Ryder JJ, Kurzer MS, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update . 2009;15(4):423-440.
53. Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas . 2010;67(3):262-269.
54. Levis S, Strickman-Stein N, Doerge DR, Krischer J. Design and baseline characteristics of the soy phytoestrogens as replacement estrogen (SPARE) study—a clinical trial of the effects of soy isoflavones in menopausal women. Contemp Clin Trials . 2010;31(4):293-302.
55. Gallo D, Zannoni GF, Apollonio P, et al. Characterization of the pharmacologic profile of a standardized soy extract in the ovariectomized rat model of menopause: effects on bone, uterus, and lipid profile. Menopause . 2005;12(5):589-600.
56. Breitman PL, Fonseca D, Ward WE. Combinations of soy protein and high dietary calcium on bone biomechanics and bone mineral density in ovariectomized rats. Menopause . 2005;12(4):428-435.
57. Nakai M, Cook L, Pyter LM, et al. Dietary soy protein and isoflavones have no significant effect on bone and a potentially negative effect on the uterus of sexually mature intact Sprague-Dawley female rats. Menopause . 2005;12(3):291-298.
58. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab . 2003;88(9):4362-4370.
59. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women: meta-analysis of randomized controlled trials. Clin Nutr . 2008;27(1):57-64.
60. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. Eur J Clin Nutr . 2008;62(2):155-161.
61. Liu J, Ho SC, Su YX, Chen WQ, Zhang CX, Chen YM. Effect of long-term intervention of soy isoflavones on bone mineral density in women: a meta-analysis of randomized controlled trials. Bone . 2009;44(5):948-953.
62. Taku K, Melby MK, Kurzer MS, Mizuno S, Watanabe S, Ishimi Y. Effects of soy isoflavone supplements on bone turnover markers in menopausal women: systematic review and meta-analysis of randomized controlled trials. Bone . 2010;47(2):413-423.
63. Darling AL, Millward DJ, Torgerson DJ, Hewitt CE, Lanham-New SA. Dietary protein and bone health: a systematic review and meta-analysis. Am J Clin Nutr . 2009;90(6):1674-1692.
64. Alekel DL, Van Loan MD, Koehler KJ, et al. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr . 2010;91(1):218-230.
65. Wong WW, Lewis RD, Steinberg FM, et al. Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial. Am J Clin Nutr . 2009;90(5):1433-1439.
66. Shedd-Wise KM, Alekel DL, Hofmann H, et al. The soy isoflavones for reducing bone loss study: 3-yr effects on pQCT bone mineral density and strength measures in postmenopausal women. J Clin Densitom . 2011;14(1):47-57.
67. Vanderhoof JA, Murray ND, Paule Cl, Ostrom KM. Use of soy fiber in acute diarrhea in infants and toddlers. Clin Pediatr (Phila). 1997;36(3):135-139.
68. Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, van Geldrop WJ, Neven AK. Effectiveness of treatments in infantile colic: systematic review [published correction appears in BMJ . 1998;317(7152):171]. BMJ . 1998;316(7144):1563-1569.
69. Huertas-Ceballos A, Macarthur C, Logan S. Dietary interventions for recurrent abdominal pain (RAP) in childhood. Cochrane Database Syst Rev . 2002;(2):CD003019.
70. Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage . 2008;16(4):399-408.
71. Maheu E, Mazières B, Valat JP, et al. Symptomatic efficacy in avocado/soybean unsaponpifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum . 1998;41(1):81-91.
72. Ernst E. Avocado-soybean unsaponifiables (ASU) for osteoarthritis—a systematic review. Clin Rheumatol . 2003;22(4-5):285-288.
73. Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ. Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis. Fertil Steril . 2010;94(3):997-1007.
74. Cambria-Kiely JA. Effect of soy milk on warfarin efficacy. Ann Pharmacother . 2002;36(12):1893-1896.
75. Steinberg FM, Murray MJ, Lewis RD, et al. Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women. Am J Clin Nutr . 2011;93(2):356-367.
76. Bluck LJ, Bingham SA. Isoflavone content of breast milk and soy formulas: benefits and risk. Clin Chem . 1997;43(5):851-852.
77. Huggett AC, Pridmore S, Malnoë A, Haschke F, Offord EA. Phyto-oestrogens in soy-based infant formula. Lancet . 1997;350(9080):815-816.
78. Beaton LK, McVeigh BL, Dillingham BL, Lampe JW, Duncan AM. Soy protein isolates of varying isoflavone content do not adversely affect semen quality in healthy young men. Fertil Steril . 2010;94(5):1717-1722.
79. Sathyapalan T, Manuchehri AM, Thatcher NJ, et al. The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab . 2011;96(5):1442-1449.
80. Fitzpatrick M. Soy formulas and the effects of isoflavones on the thyroid. N Z Med J . 2000;113(1103):24-26.
81. National Toxicology Program. NTP brief on soy infant formula September 16, 2010. National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services. Available at: http://ntp.niehs.nih.gov/ntp/ohat/genistein-soy/SoyFormulaUpdt/FinalNTPBriefSoyFormula_9_20_2010.pdf .
82. Codina RM, Calderón E, Lockey RF, Fernández-Caldas E, Rama R. Specific immunoglobulins to soybean hull allergens in soybean asthma. Chest . 1997;111(1):75-80.
83. Sicherer SH, Sampson HA, Burks AW. Peanut and soy allergy: a clinical and therapeutic dilemma. Allergy . 2000;55(6):515-521.
84. Inomata N, Osuna H, Yanagimachi M, Ikezawa Z. Late-onset anaphylaxis to fermented soybeans: the first confirmation of food-induced, late-onset anaphylaxis by provocation test. Ann Allergy Asthma Immunol . 2005:94(3):402-406.

Copyright © 2009 Wolters Kluwer Health

Hide
(web1)