The American Journal of Medicine
Volume 122, Issue 10 , Pages 939-946.e9 , October 2009

Side Effects of Phytoestrogens: A Meta-analysis of Randomized Trials

  • Clemens B. Tempfer, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • Corresponding Author InformationRequests for reprints should be addressed to Clemens Tempfer, MD, Department of Obstetrics & Gynecology; Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna/Austria
    • ,
  • Georg Froese, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Georg Heinze, PhD

      Affiliations

    • Department of Medical Statistics, Medical University Vienna, Austria
    • ,
  • Eva-Katrin Bentz, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Lukas A. Hefler, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria
    • ,
  • Johannes C. Huber, MD, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, Medical University Vienna, Austria

References 

  1. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137:805–813
  2. Albertazzi P, Purdie D. The nature and utility of the phytoestrogens: a review of the evidence. Maturitas. 2002;42:173–185
  3. 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. 2002;62:2474–2477
  4. Ju YH, Doerge DR, Woodling KA, et al. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) In Vivo. Carcinogenesis. 2008;29:2162–2168
  5. Wagner J, Jiang L, Lehmann L. Phytoestrogens modulate the expression of 17alpha-estradiol metabolizing enzymes in cultured MCF-7 cells. Adv Exp Med Biol. 2008;617:625–632
  6. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289–300
  7. Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric. 2005;8:371–379
  8. Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6–11
  9. Allen JK, Becker DM, Kwiterovich PO, et al. Effect of soy protein-containing isoflavones on lipoproteins in postmenopausal women. Menopause. 2007;14:106–114
  10. Arjmandi BH, Lucas EA, Khalil DA, et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J. 2005;4:8
  11. Arjmandi BH, Khalil DA, Smith BJ, et al. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab. 2003;88:1048–1054
  12. Atkinson C, Oosthuizen W, Scollen S, et al. Modest protective effects of isoflavones from a red clover-derived dietary supplement on cardiovascular disease risk factors in perimenopausal women, and evidence of an interaction with ApoE genotype in 49-65 year-old women. J Nutr. 2004;134:1759–1764
  13. Atteritano M, Marini H, Minutoli L, et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2007;92:3068–3075
  14. Aubertin-Leheudre M, Lord C, Khalil A, Dionne IJ. Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial. Eur J Clin Nutr. 2007;61:1442–1444
  15. Balk JL, Whiteside DA, Naus G, et al. A pilot study of the effects of phytoestrogen supplementation on the postmenopausal endometrium. J Soc Gynecol Investig. 2002;9:238–242
  16. Blum A, Lang N, Peleg A, et al. Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia. Am Heart J. 2003;145(2):e7
  17. Brink E, Coxam V, Robins S, et al. PHYTOS Investigators Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study. Am J Clin Nutr. 2008;87:761–770
  18. Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother. 2002;56:283–288
  19. Campagnoli C, Abba C, Ambroggio S, et al. Polyunsaturated fatty acids (PUFAs) might reduce hot flushes: an indication from two controlled trials on soy isoflavones alone and with a PUFA supplement. Maturitas. 2005;51:127–134
  20. Cancellieri F, De Leo V, Genazzani AD, et al. Efficacy on menopausal neurovegetative symptoms and some plasma lipids blood levels of an herbal product containing isoflavones and other plant extracts. Maturitas. 2007;56:249–256
  21. Casini ML, Marelli G, Papaleo E, et al. Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril. 2006;85:972–978
  22. Chen YM, Ho SC, Lam SS, et al. Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88:4740–4747
  23. Chiechi LM, Secreto G, D'Amore M, et al. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial. Maturitas. 2002;42(4):295–300
  24. Colacurci N, Chiàntera A, Fornaro F, et al. Effects of soy isoflavones on endothelial function in healthy postmenopausal women. Menopause. 2005;12:299–307
  25. D'Anna R, Baviera G, Corrado F, et al. The effect of the phytoestrogen genistein and hormone replacement therapy on homocysteine and C-reactive protein level in postmenopausal women. Acta Obstet Gynecol Scand. 2005;84:474–477
  26. Davis SR, Briganti EM, Chen RQ, et al. The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women (A randomised controlled trial). Med J Aust. 2001;174:68–71
  27. Dodin S, Lemay A, Jacques H, et al. The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab. 2005;90:1390–1397
  28. Faure ED, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomised placebo-controlled study. Menopause. 2002;9:329–334
  29. Frei-Kleiner S, Schaffner W, Rahlfs VW, et al. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas. 2005;51:397–404
  30. Gallagher JC, Satpathy R, Rafferty K, Haynatzka V. The effect of soy protein isolate on bone metabolism. Menopause. 2004;11:290–298
  31. Gardner CD, Newell KA, Cherin R, Haskell WL. The effect of soy protein with or without isoflavones relative to milk protein on plasma lipids in hypercholesterolemic postmenopausal women. Am J Clin Nutr. 2001;73:728–735
  32. Garrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas. 2006;54:270–276
  33. González S, Jayagopal V, Kilpatrick ES, et al. Effects of isoflavone dietary supplementation on cardiovascular risk factors in type 2 diabetes. Diabetes Care. 2007;30:1871–1873
  34. Hale G, Paul-Labrador M, Dwyer JH, Merz CN. Isoflavone supplementation and endothelial function in menopausal women. Clin Endocrinol (Oxf). 2002;56:693–701
  35. Hallund J, Tetens I, Bügel S, et al. Daily consumption for six weeks of a lignan complex isolated from flaxseed does not affect endothelial function in healthy postmenopausal women. J Nutr. 2006;136:2314–2318
  36. Han KK, Soares JM, Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99:389–394
  37. Harkness LS, Fiedler K, Sehgal AR, et al. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13:1000–1007
  38. Heyerick A, Vervarcke S, Depypere H, et al. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006;54:164–175
  39. Hidalgo LA, Chedraui PA, Morocho N, et al. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, doubleblind, placebo-controlled study. Gynecol Endocrinol. 2005;21:257–264
  40. Hirata JD, Swiersz LM, Zell B, et al. Does dong quai have estrogenic effects in postmenopausal women? (A double-blind, placebo-controlled trial). Fertil Steril. 1997;68:981–986
  41. Ho SC, Chan AS, Ho YP, et al. Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause. 2007;14(3 Pt 1):489–499
  42. Ho SC, Chen YM, Ho SS, Woo JL. Soy isoflavone supplementation and fasting serum glucose and lipid profile among postmenopausal Chinese women: a double-blind, randomized, placebo-controlled trial. Menopause. 2007;14:905–912
  43. Howes JB, Bray K, Lorenz L, et al. The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women. Climacteric. 2004;7:70–77
  44. Izumi T, Saito M, Obata A, et al. Oral intake of soy isoflavone aglycone improves the aged skin of adult women. J Nutr Sci Vitaminol (Tokyo). 2007;53:57–62
  45. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol. 2001;19:2739–2745
  46. Jayagopal V, Albertazzi P, Kilpatrick ES, et al. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care. 2002;25:1709–1714
  47. Katz DL, Evans MA, Njike VY, et al. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric. 2007;10:500–507
  48. Khaodhiar L, Ricciotti HA, Li L, et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause. 2008;15:125–132
  49. Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric. 2001;4:13–18
  50. Kotsopoulos D, Dalais FS, Liang Y-L, et al. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women. Climacteric. 2000;3:161–167
  51. 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: a randomized controlled trial. JAMA. 2004;292:65–74
  52. Kumar NB, Cantor A, Allen K, et al. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer. 2002;94:1166–1174
  53. Lampe JW, Skor HE, Li S, et al. Wheat bran and soy protein feeding do not alter urinary excretion of the isoflavan equol in premenopausal women. J Nutr. 2001;131:740–744
  54. Lewis JE, Nickell LA, Thompson LU, et al. A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause. Menopause. 2006;13:631–642
  55. Lucas EA, Wild RD, Hammond LJ, et al. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab. 2002;87:1527–1532
  56. Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss—a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004;43:246–257
  57. MacGregor CA, Canney PA, Patterson G, et al. A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer. Eur J Cancer. 2005;41:708–714
  58. Maesta N, Nahas EA, Nahas-Neto J, et al. Effects of soy protein and resistance exercise on body composition and blood lipids in postmenopausal women. Maturitas. 2007;56:350–358
  59. Martini MC, Dancisak BB, Haggans CJ, et al. Effects of soy intake on sex hormone metabolism in premenopausal women. Nutr Cancer. 1999;34:133–139
  60. Maskarinec G, Takata Y, Franke AA, et al. A 2-year soy intervention in premenopausal women does not change mammographic densities. J Nutr. 2004;134:3089–3094
  61. Maskarinec G, Williams AE, Inouye JS, et al. A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev. 2002;11:195–201
  62. Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002;17:1904–1912
  63. Nahas EP, Neto JN, de Luca L, et al. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas. 2004;48:372–380
  64. Nahas EA, Nahas-Neto J, Orsatti FL, et al. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas. 2007;58:249–258
  65. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med. 2006;145:869–879
  66. Nikander E, Kilkkinen A, Metsä-Heikkilä M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220
  67. Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5 Pt 1):1074–1083
  68. Penotti M, Fabio E, Modena AB, et al. Effect of soy-derived isoflavones on hot flushes, endometrial thickness and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117
  69. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol. 2006;24:2836–2841
  70. Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Treatment trial. J Clin Oncol. 2000;18:1068–1074
  71. Rad M, Hümpel M, Schaefer O, et al. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol. 2006;62:288–296
  72. Reimann M, Dierkes J, Carlsohn A, et al. Consumption of soy isoflavones does not affect plasma total homocysteine or asymmetric dimethylarginine concentrations in healthy postmenopausal women. J Nutr. 2006;136:100–105
  73. Ritchie MR, Morton MS, Thompson AM, et al. Investigation of the reliability of 24 h urine excretion as a biomarker of isoflavone exposure over time and over a wide range of isoflavone intakes. Eur J Clin Nutr. 2004;58:1286–1289
  74. Russo R, Corosu R. The clinical use of a preparation based on phytoestrogens in the treatment of menopausal disorders. Acta Biomed. 2003;74:137–143
  75. Samman S, Lyons Wall PM, Chan GS, et al. The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women. Atherosclerosis. 1999;147:277–283
  76. Sammartino A, Di Carlo C, Mandato VD, et al. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol. 2003;17:45–49
  77. Sammartino A, Tommaselli GA, Gargano V, et al. Short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on climacteric-related symptoms in postmenopausal women: a double-blind randomized placebo-controlled trial. Gynecol Endocrinol. 2006;22:646–650
  78. Schult TM, Ensrud KE, Blackwell T, et al. Effect of isoflavones on lipids and bone turnover markers in menopausal women. Maturitas. 2004;48:209–218
  79. Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double blind, randomized study. Maturitas. 2004;47:11–20
  80. Simons LA, von Konigsmark M, Simons J, Celermajer DS. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol. 2000;85:1297–1301
  81. Sites CK, Cooper BC, Toth MJ, et al. Effect of a daily supplement of soy protein on body composition and insulin secretion in postmenopausal women. Fertil Steril. 2007;88:1609–1617
  82. Squadrito F, Altavilla D, Crisafulli A, et al. Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med. 2003;114:470–476
  83. Squadrito F, Altavilla D, Morabito N, et al. The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis. 2002;163:339–347
  84. St Germain A, Peterson CT, Robinson JG, Alekel DL. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause. 2001;8:17–26
  85. Steinberg FM, Guthrie NL, Villablanca AC, et al. Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women. Am J Clin Nutr. 2003;78:123–130
  86. Uesugi T, Fukui Y, Yamori Y. Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal japanese women: a four-week study. J Am Coll Nutr. 2002;21:97–102
  87. Unfer V, Casini ML, Costabile L, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized double-blind placebo-controlled study. Fertil Steril. 2004;82:145–148
  88. Upmalis DH, Lobo R, Bradley L, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter double-blind randomized placebo-controlled study. Menopause. 2000;7:236–242
  89. van de Weijer PHM, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002;42:187–193
  90. van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomised controlled clinical trial. J Clin Oncol. 2002;20:1449–1455
  91. Verhoeven MO, van der Mooren MJ, van de Weijer PHM, et al. Effect of a combination isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12-week randomized, placebo-controlled, double-blind study. Menopause. 2005;12:412–420
  92. Vigna GB, Pansini F, Bonaccorsi G, et al. Plasma lipoproteins in soy-treated postmenopausal women: a double-blind, placebo-controlled trial. Nutr Metab Cardiovasc Dis. 2000;10:315–322
  93. Wiklund IK, Mattsson LA, Lindgren R, Limoni C. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial (Swedish Alternative Medicine Group). Int J Clin Pharmacol Res. 1999;19:89–99
  94. Wu J, Oka J, Higuchi M, et al. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism. 2006;55:423–433
  95. Xu X, Harris KS, Wang HJ, et al. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr. 1995;125:2307–2315
  96. Xu X, Wang HJ, Murphy PA, Hendrich S. Neither background diet nor type of soy food affects short-term isoflavone bioavailability in women. J Nutr. 2000;130:798–801
  97. Ye YB, Tang XY, Verbruggen MA, Su YX. Soy isoflavones attenuate bone loss in early postmenopausal Chinese women: a single-blind randomized, placebo-controlled trial. Eur J Nutr. 2006;45:327–334
  98. Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res. 2007;22:1072–1089
  99. Tempfer CB, Bentz EK, Leodolter S, et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril. 2007;87:1243–1249

 Funding: None.

 Conflict of Interest: Authors CBT and JCH received lecture fees by Apomedica Inc. All other authors report no conflict of interest.

 Authorship: All authors had access to the data and a role in writing the manuscript.

PII: S0002-9343(09)00542-7

doi: 10.1016/j.amjmed.2009.04.018

The American Journal of Medicine
Volume 122, Issue 10 , Pages 939-946.e9 , October 2009

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