Cholesterol reduction
In 1995, a meta-analysis of clinical studies reported that soy protein lowered LDL-cholesterol by an estimated 12.9%.1 Four years later, the U.S. Food and Drug Administration (FDA) approved an unqualified health claim for soyfoods and coronary heart disease. However, in 20072 the FDA announced its intention to re-evaluate the evidence in support of the claim, and in 20173 it indicated its intention to revoke the claim because of the inconsistent data. The FDA has indicated a decision will be made in September of 2022. Meta-analyses published between 2003 and 2009 show soy protein significantly lowers cholesterol ranging from 3.2-6%.4-11 If the existing claim is revoked, in the opinion of this author, it is likely to be replaced with a strongly worded qualified health claim, similar to that which exists for soybean oil.
Hot flashes
In 1992, isoflavones were hypothesized to prevent the onset of, and/or alleviate, hot flashes.12 Reviews of the many soy/isoflavone-hot flashes trials reached contrasting conclusions. Most suggested isoflavones are not efficacious,13-15 or offered at best modest benefits,16-20 whereas a smaller number have been more supportive of isoflavones.21-25 However, in 2012 a statistical analysis of 13 clinical trials provided support for isoflavones and a possible explanation for the inconsistent data. Trials (n=6) intervening with supplements that had an isoflavone profile (genistein>daidzein>glycitein) similar to that found in soybeans and soyfoods were consistently efficacious, whereas trials (n=7) utilizing supplements providing similar amounts of total isoflavones but that were low in genistein were not.26 Subsequently published trials support this finding.27,28 Studies suggest that about 50mg/d isoflavones, the amount provided by approximately 2 servings of traditional soyfoods, is sufficient for hot flash alleviation.
Osteoporosis
In 1998, isoflavone intake via isoflavone-rich soy protein was found to improve bone mineral density in postmenopausal women.29 In addition, large prospective cohort studies from Shanghai30 and Singapore,31 published in 2005 and 2009, respectively, showed soy intake was associated with a reduced fracture risk among women. In contrast, relatively short-term bone trials published over the past 20 years have produced inconsistent results. In 2021, a meta-analysis of clinical studies concluded that soy isoflavone intake is associated with a trend in increased levels of bone formation markers (osteocalcin and bone alkaline phosphatase), as well as a trend in reduced levels of bone resorption markers (pyridinoline and deoxypyridinoline), based on 8-14 trials per marker.32 However, of the 4 large (n>100), long term (≥2y) trials that evaluated postmenopausal bone mineral density,33-36 only one showed significant benefit.36
Cognitive functionResults of the Honolulu-Asia Aging Study (HAAS) published in 2000 raised concern that soy intake may impair cognitive function.37 In contrast, several small clinical studies published between 2001 and 2006 suggested soy isoflavones exerted cognitive benefits.38-42 In 2008, the controversy ignited by the HAAS was rekindled by the results of a cross-sectional study from Indonesia involving older men and women.43 However, a follow-up study by this research group published in 2011 not only contradicted these findings, but also found positive linear associations of weekly tofu and tempeh consumption with immediate recall.44 Studies in Japan also show conflicting results as one observational study found soy and isoflavone intake decreased risk of cognitive impairment45 whereas another reported an increased risk.46 In 2014, a comprehensive review of the clinical, epidemiologic, and animal data found there was insufficient evidence to draw conclusions about the association between dietary intake of soy isoflavones and cognition in older adults.47 In contrast, a statistical analysis of 16 trials (1,386 participants, mean age: 60 years) published in 2020, found soy isoflavones improved overall cognitive function and memory.48 Interestingly, a recent cross-over study involving older men and women found that the consumption of 67g/d of soynuts that provided ∼25.5g protein and 174mg isoflavones for 16 weeks increased psychomotor speed performance, likely as a result of the increase in cerebral blood flow in 4 brain clusters. However, executive function and memory did not change.49
Prostate cancer
As in the case for breast cancer, prostate cancer incidence rates are low in soyfood-consuming countries relative to the West, though with Westernization of the diet rates have begun to increase.50,51 In 1997, rats fed isoflavone-rich soy protein developed fewer prostate tumors than animals fed casein.52 In addition, early work showed both soy and isoflavones decreased prostate specific antigen (PSA) levels in men with prostate cancer.53 PSA is a marker of prostate tumor growth.54 However, more recent work has not confirmed the results of these initial studies.55-57 In 2018, a statistical analysis of 30 population studies found that the intake of both soyfoods and soy protein was associated with a decrease of prostate cancer risk, but the most robust findings came from case-control, not prospective, studies.58 Another analysis in 2018 found that among Japanese men, plasma isoflavone levels were associated with a decreased prostate cancer risk, although the finding did not quite reach statistical significance.59 Somewhat parenthetically, one study found isoflavones may reduce some of the side effects associated with radiation therapy for prostate cancer treatment.60 Overall, while there is suggestive evidence that soyfoods can reduce risk of developing prostate cancer, the data are too inconsistent to reach firm conclusions.
Final thoughts
Indications are that soy and its components, especially soy protein and isoflavones, will continue to be heavily researched so greater insights into their health effects can be expected. Given the current state of knowledge, only the results from large, well-designed clinical studies are likely to significantly impact our current understanding of the health effects of soy.
Indications are that soy and its components, especially soy protein and isoflavones, will continue to be heavily researched so greater insights into their health effects can be expected. Given the current state of knowledge, only the results from large, well-designed clinical studies are likely to significantly impact our current understanding of the health effects of soy.
REFERENCES
1. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-82.
2. Department of Health and Human Services, Food and Drug Administration (docket no. 2007N–0464]. Health claims and qualified health claims; dietary lipids and cancer, soy protein and coronary heart disease, antioxidant vitamins and certain cancers, and selenium and certain cancers; reevaluation; opportunity for public comment.
3. US Food and Drug Administration. Food labeling: health claims; Soy protein and coronary heart disease. Fed Reg 2017;82:50324-46.
4. Jenkins DJ, Mirrahimi A, Srichaikul K, Berryman CE, Wang L, Carleton A, Abdulnour S, Sievenpiper JL, Kendall CW, Kris-Etherton PM. Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr 2010;140:2302S-11S.
5. Anderson JW, Bush HM. Soy protein effects on serum lipoproteins: A quality assessment and meta-analysis of randomized, controlled studies. J Am Coll Nutr 2011;30:79-91.
6. Weggemans RM, Trautwein EA. Relation between soy-associated isoflavones and LDL and HDL cholesterol concentrations in humans: a meta-analysis. Eur J Clin Nutr 2003;57:940-6.
7. 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;98:633-40.
8. 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;200:13-27.
9. Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 2005;81:397-408.
10. Benkhedda K, Boudrault C, Sinclair SE, Marles RJ, Xiao CW, Underhill L. Food Risk Analysis Communication. Issued By Health Canada’s Food Directorate. Health Canada’s Proposal to Accept a Health Claim about Soy Products and Cholesterol Lowering. Int Food Risk Anal J 2014;4:22 | doi: 10.5772/59411.
11. Blanco Mejia S, Messina M, Li SS, Viguiliouk E, Chiavaroli L, Khan TA, Srichaikul K, Mirrahimi A, Sievenpiper JL, Kris-Etherton P, et al. A meta-analysis of 46 studies identified by the FDA demonstrates that soy protein decreases circulating LDL and total cholesterol concentrations in adults. J Nutr 2019;149:968-81.
12. Adlercreutz H, Hamalainen E, Gorbach S, Goldin B. Dietary phyto-oestrogens and the menopause in Japan. Lancet 1992;339:1233.
13. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause 2015;22:1155-72; quiz 73-4.
14. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006;113:1034-44.
15. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol 2004;104:824-36.
16. Eden JA. Managing the menopause: phyto-oestrogens or hormone replacement therapy? Ann Med 2001;33:4-6.
17. Stearns V, Hayes DF. Cooling off hot flashes. J Clin Oncol 2002;20:1436-8.
18. Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T. Use of plant-based therapies and menopausal symptoms: A systematic review and meta-analysis. JAMA 2016;315:2554-63.
19. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011;18:732-53.
20. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057-71.
21. Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency. J Med Food 2003;6:1-11.
22. Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause 2010;17:660-6.
23. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 2006;13:831-9.
24. Guo PP, Li P, Zhang XH, Liu N, Wang J, Chen DD, Sun WJ, Zhang W. Complementary and alternative medicine for natural and treatment-induced vasomotor symptoms: An overview of systematic reviews and meta-analyses. Complement Ther Clin Pract 2019;36:181-94.
25. Chen LR, Ko NY, Chen KH. Isoflavone supplements for menopausal women: A systematic review. Nutrients 2019;11.
26. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-90.
27. Chi X-X, Zhang T. The effects of soy isoflavone on bone density in north region of climacteric Chinese women. Journal of clinical biochemistry and nutrition 2013;53:102–7.
28. Bitto A, Arcoraci V, Alibrandi A, D'Anna R, Corrado F, Atteritano M, Minutoli L, Altavilla D, Squadrito F. Visfatin correlates with hot flashes in postmenopausal women with metabolic syndrome: effects of genistein. Endocrine 2017;55:899-906.
29. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW, Jr. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68:1375S-9S.
30. Zhang X, Shu XO, Li H, Yang G, Li Q, Gao YT, Zheng W. Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch Intern Med 2005;165:1890-5.
31. Koh WP, Wu AH, Wang R, Ang LW, Heng D, Yuan JM, Yu MC. Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am J Epidemiol 2009;170:901-9.
32. Kanadys W, Baranska A, Blaszczuk A, Polz-Dacewicz M, Drop B, Malm M, Kanecki K. Effects of soy isoflavones on biochemical markers of bone metabolism in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health 2021;18.
33. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, Kurzer MS, Peterson CT. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr 2010;91:218-30.
34. Tai TY, Tsai KS, Tu ST, Wu JS, Chang CI, Chen CL, Shaw NS, Peng HY, Wang SY, Wu CH. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study. Osteoporos Int 2012;23:1571-80.
35. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med 2011;171:1363-9.
36. Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano V, Minutoli L, Atteritano M, Levy RM, D'Anna R, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab 2008;93:4787-96.
37. White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. Brain aging and midlife tofu consumption. J Am Coll Nutr 2000;19:242-55.
38. File SE, Jarrett N, Fluck E, Duffy R, Casey K, Wiseman H. Eating soya improves human memory. Psychopharmacology (Berl) 2001;157:430-6.
39. File SE, Hartley DE, Elsabagh S, Duffy R, Wiseman H. Cognitive improvement after 6 weeks of soy supplements in postmenopausal women is limited to frontal lobe function. Menopause 2005;12:193-201.
40. Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause 2003;10:196-202.
41. Duffy R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacol Biochem Behav 2003;75:721-9.
42. Casini ML, Marelli G, Papaleo E, Ferrari A, D'Ambrosio F, Unfer V. Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril 2006;85:972-8.
43. Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord 2008;26:50-7.
44. Hogervorst E, Mursjid F, Priandini D, Setyawan H, Ismael RI, Bandelow S, Rahardjo TB. Borobudur revisited: soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res 2011;1379:206-12.
45. Nakamoto M, Otsuka R, Nishita Y, Tange C, Tomida M, Kato Y, Imai T, Sakai T, Ando F, Shimokata H. Soy food and isoflavone intake reduces the risk of cognitive impairment in elderly Japanese women. Eur J Clin Nutr 2018;72:1458-62.
46. Svensson T, Sawada N, Mimura M, Nozaki S, Shikimoto R, Tsugane S. Midlife intake of the isoflavone genistein and soy, and the risk of late-life cognitive impairment: the JPHC Saku Mental Health Study. J Epidemiol 2021.
47. Soni M, Rahardjo TB, Soekardi R, Sulistyowati Y, Lestariningsih, Yesufu-Udechuku A, Irsan A, Hogervorst E. Phytoestrogens and cognitive function: a review. Maturitas 2014;77:209-20.
48. Cui C, Birru RL, Snitz BE, Ihara M, Kakuta C, Lopresti BJ, Aizenstein HJ, Lopez OL, Mathis CA, Miyamoto Y, et al. Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2020;78:134-44.
49. Kleinloog JPD, Tischmann L, Mensink RP, Adam TC, Joris PJ. Longer-term soy nut consumption improves cerebral blood flow and psychomotor speed: results of a randomized, controlled crossover trial in older men and women. Am J Clin Nutr 2021.
50. Sim HG, Cheng CW. Changing demography of prostate cancer in Asia. Eur J Cancer 2005;41:834-45.
51. Zhang J, Dhakal IB, Zhao Z, Li L. Trends in mortality from cancers of the breast, colon, prostate, esophagus, and stomach in East Asia: role of nutrition transition. Eur J Cancer Prev 2012;21:480-9.
52. Pollard M, Luckert PH. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr Cancer 1997;28:41-5.
53. Messina M, Kucuk O, Lampe JW. An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J AOAC Int 2006;89:1121-34.
54. Pentyala S, Whyard T, Pentyala S, Muller J, Pfail J, Parmar S, Helguero CG, Khan S. Prostate cancer markers: An update. Biomed Rep 2016;4:263-8.
55. Bosland MC, Kato I, Zeleniuch-Jacquotte A, Schmoll J, Enk Rueter E, Melamed J, Kong MX, Macias V, Kajdacsy-Balla A, Lumey LH, et al. Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial. JAMA 2013;310:170-8.
56. Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J, Hersey K, Farley A, Jansz K, Siemens DR, Trpkov K, et al. Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium. J Clin Oncol 2011;29:2386-90.
57. Ratha P, Neumann T, Schmidt CA, Schneidewind L. Can isoflavones influence prostate specific antigen serum levels in localized prostate cancer? A systematic review. Nutr Cancer 2021;73:361-8.
58. Applegate CC, Rowles JL, Ranard KM, Jeon S, Erdman JW. Soy consumption and the risk of prostate cancer: An updated systematic review and meta-analysis. Nutrients 2018;10.
59. Perez-Cornago A, Appleby PN, Boeing H, Gil L, Kyro C, Ricceri F, Murphy N, Trichopoulou A, Tsilidis KK, Khaw KT, et al. Circulating isoflavone and lignan concentrations and prostate cancer risk: a meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls. Int J Cancer 2018;143:2677-86.
60. Ahmad IU, Forman JD, Sarkar FH, Hillman GG, Heath E, Vaishampayan U, Cher ML, Andic F, Rossi PJ, Kucuk O. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer 2010;62:996-1000.
1. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-82.
2. Department of Health and Human Services, Food and Drug Administration (docket no. 2007N–0464]. Health claims and qualified health claims; dietary lipids and cancer, soy protein and coronary heart disease, antioxidant vitamins and certain cancers, and selenium and certain cancers; reevaluation; opportunity for public comment.
3. US Food and Drug Administration. Food labeling: health claims; Soy protein and coronary heart disease. Fed Reg 2017;82:50324-46.
4. Jenkins DJ, Mirrahimi A, Srichaikul K, Berryman CE, Wang L, Carleton A, Abdulnour S, Sievenpiper JL, Kendall CW, Kris-Etherton PM. Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr 2010;140:2302S-11S.
5. Anderson JW, Bush HM. Soy protein effects on serum lipoproteins: A quality assessment and meta-analysis of randomized, controlled studies. J Am Coll Nutr 2011;30:79-91.
6. Weggemans RM, Trautwein EA. Relation between soy-associated isoflavones and LDL and HDL cholesterol concentrations in humans: a meta-analysis. Eur J Clin Nutr 2003;57:940-6.
7. 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;98:633-40.
8. 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;200:13-27.
9. Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 2005;81:397-408.
10. Benkhedda K, Boudrault C, Sinclair SE, Marles RJ, Xiao CW, Underhill L. Food Risk Analysis Communication. Issued By Health Canada’s Food Directorate. Health Canada’s Proposal to Accept a Health Claim about Soy Products and Cholesterol Lowering. Int Food Risk Anal J 2014;4:22 | doi: 10.5772/59411.
11. Blanco Mejia S, Messina M, Li SS, Viguiliouk E, Chiavaroli L, Khan TA, Srichaikul K, Mirrahimi A, Sievenpiper JL, Kris-Etherton P, et al. A meta-analysis of 46 studies identified by the FDA demonstrates that soy protein decreases circulating LDL and total cholesterol concentrations in adults. J Nutr 2019;149:968-81.
12. Adlercreutz H, Hamalainen E, Gorbach S, Goldin B. Dietary phyto-oestrogens and the menopause in Japan. Lancet 1992;339:1233.
13. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause 2015;22:1155-72; quiz 73-4.
14. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006;113:1034-44.
15. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol 2004;104:824-36.
16. Eden JA. Managing the menopause: phyto-oestrogens or hormone replacement therapy? Ann Med 2001;33:4-6.
17. Stearns V, Hayes DF. Cooling off hot flashes. J Clin Oncol 2002;20:1436-8.
18. Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T. Use of plant-based therapies and menopausal symptoms: A systematic review and meta-analysis. JAMA 2016;315:2554-63.
19. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011;18:732-53.
20. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057-71.
21. Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency. J Med Food 2003;6:1-11.
22. Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause 2010;17:660-6.
23. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 2006;13:831-9.
24. Guo PP, Li P, Zhang XH, Liu N, Wang J, Chen DD, Sun WJ, Zhang W. Complementary and alternative medicine for natural and treatment-induced vasomotor symptoms: An overview of systematic reviews and meta-analyses. Complement Ther Clin Pract 2019;36:181-94.
25. Chen LR, Ko NY, Chen KH. Isoflavone supplements for menopausal women: A systematic review. Nutrients 2019;11.
26. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-90.
27. Chi X-X, Zhang T. The effects of soy isoflavone on bone density in north region of climacteric Chinese women. Journal of clinical biochemistry and nutrition 2013;53:102–7.
28. Bitto A, Arcoraci V, Alibrandi A, D'Anna R, Corrado F, Atteritano M, Minutoli L, Altavilla D, Squadrito F. Visfatin correlates with hot flashes in postmenopausal women with metabolic syndrome: effects of genistein. Endocrine 2017;55:899-906.
29. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW, Jr. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68:1375S-9S.
30. Zhang X, Shu XO, Li H, Yang G, Li Q, Gao YT, Zheng W. Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch Intern Med 2005;165:1890-5.
31. Koh WP, Wu AH, Wang R, Ang LW, Heng D, Yuan JM, Yu MC. Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am J Epidemiol 2009;170:901-9.
32. Kanadys W, Baranska A, Blaszczuk A, Polz-Dacewicz M, Drop B, Malm M, Kanecki K. Effects of soy isoflavones on biochemical markers of bone metabolism in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health 2021;18.
33. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, Kurzer MS, Peterson CT. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr 2010;91:218-30.
34. Tai TY, Tsai KS, Tu ST, Wu JS, Chang CI, Chen CL, Shaw NS, Peng HY, Wang SY, Wu CH. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study. Osteoporos Int 2012;23:1571-80.
35. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med 2011;171:1363-9.
36. Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano V, Minutoli L, Atteritano M, Levy RM, D'Anna R, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab 2008;93:4787-96.
37. White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. Brain aging and midlife tofu consumption. J Am Coll Nutr 2000;19:242-55.
38. File SE, Jarrett N, Fluck E, Duffy R, Casey K, Wiseman H. Eating soya improves human memory. Psychopharmacology (Berl) 2001;157:430-6.
39. File SE, Hartley DE, Elsabagh S, Duffy R, Wiseman H. Cognitive improvement after 6 weeks of soy supplements in postmenopausal women is limited to frontal lobe function. Menopause 2005;12:193-201.
40. Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause 2003;10:196-202.
41. Duffy R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacol Biochem Behav 2003;75:721-9.
42. Casini ML, Marelli G, Papaleo E, Ferrari A, D'Ambrosio F, Unfer V. Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril 2006;85:972-8.
43. Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord 2008;26:50-7.
44. Hogervorst E, Mursjid F, Priandini D, Setyawan H, Ismael RI, Bandelow S, Rahardjo TB. Borobudur revisited: soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res 2011;1379:206-12.
45. Nakamoto M, Otsuka R, Nishita Y, Tange C, Tomida M, Kato Y, Imai T, Sakai T, Ando F, Shimokata H. Soy food and isoflavone intake reduces the risk of cognitive impairment in elderly Japanese women. Eur J Clin Nutr 2018;72:1458-62.
46. Svensson T, Sawada N, Mimura M, Nozaki S, Shikimoto R, Tsugane S. Midlife intake of the isoflavone genistein and soy, and the risk of late-life cognitive impairment: the JPHC Saku Mental Health Study. J Epidemiol 2021.
47. Soni M, Rahardjo TB, Soekardi R, Sulistyowati Y, Lestariningsih, Yesufu-Udechuku A, Irsan A, Hogervorst E. Phytoestrogens and cognitive function: a review. Maturitas 2014;77:209-20.
48. Cui C, Birru RL, Snitz BE, Ihara M, Kakuta C, Lopresti BJ, Aizenstein HJ, Lopez OL, Mathis CA, Miyamoto Y, et al. Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2020;78:134-44.
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