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

American Journal of Medicine

Volumn 122, Issue 10, 2009, Pages

  Tempfer, Clemens B ^a   Froese, Georg ^a   Heinze, Georg ^a   Bentz, Eva Katrin ^a   Hefler, Lukas A ^a   Huber, Johannes C ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Climacteric syndrome; Hormone replacement; Meta analysis; Phytoestrogens; Soy

Indexed keywords

PHYTOESTROGEN; PLACEBO;

ABDOMINAL PAIN; ARTICLE; BLOATING; BREAST CANCER; BREAST DISCHARGE; CLINICAL TRIAL; CONFIDENCE INTERVAL; CONSTIPATION; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; DRUG WITHDRAWAL; DYSPEPSIA; ENDOMETRIUM CANCER; ENDOMETRIUM HYPERPLASIA; EPIGASTRIC PAIN; FEMALE; FLATULENCE; GASTROENTERITIS; GASTROINTESTINAL SYMPTOM; HUMAN; INCIDENCE; MASTALGIA; MENOPAUSAL SYNDROME; META ANALYSIS; MUSCULOSKELETAL DISEASE; NAUSEA; NEUROLOGIC DISEASE; NOCTURIA; PRIORITY JOURNAL; SPOTTING; SYSTEMATIC REVIEW; VAGINA BLEEDING; VOMITING;

BREAST NEOPLASMS; DIETARY SUPPLEMENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; DRUG TOXICITY; ENDOMETRIAL HYPERPLASIA; ENDOMETRIAL NEOPLASMS; ESTROGEN REPLACEMENT THERAPY; FEMALE; FOLLOW-UP STUDIES; GASTROINTESTINAL DISEASES; HUMANS; INCIDENCE; PHYTOESTROGENS; PLANT EXTRACTS; POSTMENOPAUSE; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK ASSESSMENT; UTERINE HEMORRHAGE;

EID: 70349307279     PISSN: 00029343     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.amjmed.2009.04.018     Document Type: Article

References (99)

1. Kronenberg F., and Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 137 (2002) 805-813
2. Albertazzi P., and Purdie D. The nature and utility of the phytoestrogens: a review of the evidence. Maturitas 42 (2002) 173-185
3. Ju Y.H., Doerge D.R., Allred K.F., 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 62 (2002) 2474-2477
4. Ju Y.H., Doerge D.R., Woodling K.A., 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 29 (2008) 2162-2168
5. Wagner J., Jiang L., and Lehmann L. Phytoestrogens modulate the expression of 17alpha-estradiol metabolizing enzymes in cultured MCF-7 cells. Adv Exp Med Biol 617 (2008) 625-632
6. Benjamini Y., and Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 57 (1995) 289-300
7. Albertazzi P., Steel S.A., and Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric 8 (2005) 371-379
8. Albertazzi P., Pansini F., Bonaccorsi G., et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 91 (1998) 6-11
9. Allen J.K., Becker D.M., Kwiterovich P.O., et al. Effect of soy protein-containing isoflavones on lipoproteins in postmenopausal women. Menopause 14 (2007) 106-114
10. Arjmandi B.H., Lucas E.A., Khalil D.A., et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J 4 (2005) 8
11. Arjmandi B.H., Khalil D.A., Smith B.J., 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 88 (2003) 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 134 (2004) 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 92 (2007) 3068-3075
14. Aubertin-Leheudre M., Lord C., Khalil A., and Dionne I.J. Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial. Eur J Clin Nutr 61 (2007) 1442-1444
15. Balk J.L., Whiteside D.A., Naus G., et al. A pilot study of the effects of phytoestrogen supplementation on the postmenopausal endometrium. J Soc Gynecol Investig 9 (2002) 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 145 2 (2003) 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 87 (2008) 761-770
18. Burke B.E., Olson R.D., and Cusack B.J. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 56 (2002) 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 51 (2005) 127-134
20. Cancellieri F., De Leo V., Genazzani A.D., et al. Efficacy on menopausal neurovegetative symptoms and some plasma lipids blood levels of an herbal product containing isoflavones and other plant extracts. Maturitas 56 (2007) 249-256
21. Casini M.L., 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 85 (2006) 972-978
22. Chen Y.M., Ho S.C., Lam S.S., 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 88 (2003) 4740-4747
23. Chiechi L.M., Secreto G., D'Amore M., et al. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial. Maturitas 42 4 (2002) 295-300
24. Colacurci N., Chiàntera A., Fornaro F., et al. Effects of soy isoflavones on endothelial function in healthy postmenopausal women. Menopause 12 (2005) 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 84 (2005) 474-477
26. Davis S.R., Briganti E.M., Chen R.Q., et al. The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women. A randomised controlled trial. Med J Aust 174 (2001) 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 90 (2005) 1390-1397
28. Faure E.D., Chantre P., and Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomised placebo-controlled study. Menopause 9 (2002) 329-334
29. Frei-Kleiner S., Schaffner W., Rahlfs V.W., et al. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas 51 (2005) 397-404
30. Gallagher J.C., Satpathy R., Rafferty K., and Haynatzka V. The effect of soy protein isolate on bone metabolism. Menopause 11 (2004) 290-298
31. Gardner C.D., Newell K.A., Cherin R., and Haskell W.L. The effect of soy protein with or without isoflavones relative to milk protein on plasma lipids in hypercholesterolemic postmenopausal women. Am J Clin Nutr 73 (2001) 728-735
32. Garrido A., De la Maza M.P., Hirsch S., and Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas 54 (2006) 270-276
33. González S., Jayagopal V., Kilpatrick E.S., et al. Effects of isoflavone dietary supplementation on cardiovascular risk factors in type 2 diabetes. Diabetes Care 30 (2007) 1871-1873
34. Hale G., Paul-Labrador M., Dwyer J.H., and Merz C.N. Isoflavone supplementation and endothelial function in menopausal women. Clin Endocrinol (Oxf) 56 (2002) 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 136 (2006) 2314-2318
36. Han K.K., Soares J.M., Haidar M.A., et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 99 (2002) 389-394
37. Harkness L.S., Fiedler K., Sehgal A.R., et al. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt) 13 (2004) 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 54 (2006) 164-175
39. Hidalgo L.A., Chedraui P.A., 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 21 (2005) 257-264
40. Hirata J.D., Swiersz L.M., Zell B., et al. Does dong quai have estrogenic effects in postmenopausal women?. A double-blind, placebo-controlled trial. Fertil Steril 68 (1997) 981-986
41. Ho S.C., Chan A.S., Ho Y.P., et al. Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause 14 3 Pt 1 (2007) 489-499
42. Ho S.C., Chen Y.M., Ho S.S., and Woo J.L. Soy isoflavone supplementation and fasting serum glucose and lipid profile among postmenopausal Chinese women: a double-blind, randomized, placebo-controlled trial. Menopause 14 (2007) 905-912
43. Howes J.B., Bray K., Lorenz L., et al. The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women. Climacteric 7 (2004) 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) 53 (2007) 57-62
45. Jacobson J.S., Troxel A.B., 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 19 (2001) 2739-2745
46. Jayagopal V., Albertazzi P., Kilpatrick E.S., et al. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care 25 (2002) 1709-1714
47. Katz D.L., Evans M.A., Njike V.Y., et al. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric 10 (2007) 500-507
48. Khaodhiar L., Ricciotti H.A., Li L., et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause 15 (2008) 125-132
49. Knight D.C., Howes J.B., Eden J.A., and Howes L.G. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric 4 (2001) 13-18
50. Kotsopoulos D., Dalais F.S., Liang Y.-L., et al. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women. Climacteric 3 (2000) 161-167
51. Kreijkamp-Kaspers S., Kok L., Grobbee D.E., 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 292 (2004) 65-74
52. Kumar N.B., Cantor A., Allen K., et al. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer 94 (2002) 1166-1174
53. Lampe J.W., Skor H.E., Li S., et al. Wheat bran and soy protein feeding do not alter urinary excretion of the isoflavan equol in premenopausal women. J Nutr 131 (2001) 740-744
54. Lewis J.E., Nickell L.A., Thompson L.U., 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 13 (2006) 631-642
55. Lucas E.A., Wild R.D., Hammond L.J., et al. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab 87 (2002) 1527-1532
56. Lydeking-Olsen E., Beck-Jensen J.E., Setchell K.D., and Holm-Jensen T. Soymilk or progesterone for prevention of bone loss-a 2 year randomized, placebo-controlled trial. Eur J Nutr 43 (2004) 246-257
57. MacGregor C.A., Canney P.A., 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 41 (2005) 708-714
58. Maesta N., Nahas E.A., Nahas-Neto J., et al. Effects of soy protein and resistance exercise on body composition and blood lipids in postmenopausal women. Maturitas 56 (2007) 350-358
59. Martini M.C., Dancisak B.B., Haggans C.J., et al. Effects of soy intake on sex hormone metabolism in premenopausal women. Nutr Cancer 34 (1999) 133-139
60. Maskarinec G., Takata Y., Franke A.A., et al. A 2-year soy intervention in premenopausal women does not change mammographic densities. J Nutr 134 (2004) 3089-3094
61. Maskarinec G., Williams A.E., Inouye J.S., et al. A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev 11 (2002) 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 17 (2002) 1904-1912
63. Nahas E.P., Neto J.N., de Luca L., et al. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas 48 (2004) 372-380
64. Nahas E.A., Nahas-Neto J., Orsatti F.L., et al. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas 58 (2007) 249-258
65. Newton K.M., Reed S.D., LaCroix A.Z., et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med 145 (2006) 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 101 (2003) 1213-1220
67. Osmers R., Friede M., Liske E., et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 105 5 Pt 1 (2005) 1074-1083
68. Penotti M., Fabio E., Modena A.B., et al. Effect of soy-derived isoflavones on hot flushes, endometrial thickness and the pulsatility index of the uterine and cerebral arteries. Fertil Steril 79 (2003) 1112-1117
69. Pockaj B.A., Gallagher J.G., Loprinzi C.L., 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 24 (2006) 2836-2841
70. Quella S.K., Loprinzi C.L., Barton D.L., 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 18 (2000) 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 62 (2006) 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 136 (2006) 100-105
73. Ritchie M.R., Morton M.S., Thompson A.M., 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 58 (2004) 1286-1289
74. Russo R., and Corosu R. The clinical use of a preparation based on phytoestrogens in the treatment of menopausal disorders. Acta Biomed 74 (2003) 137-143
75. Samman S., Lyons Wall P.M., Chan G.S., et al. The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women. Atherosclerosis 147 (1999) 277-283
76. Sammartino A., Di Carlo C., Mandato V.D., et al. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol 17 (2003) 45-49
77. Sammartino A., Tommaselli G.A., 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 22 (2006) 646-650
78. Schult T.M., Ensrud K.E., Blackwell T., et al. Effect of isoflavones on lipids and bone turnover markers in menopausal women. Maturitas 48 (2004) 209-218
79. Secreto G., Chiechi L.M., Amadori A., et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double blind, randomized study. Maturitas 47 (2004) 11-20
80. Simons L.A., von Konigsmark M., Simons J., and Celermajer D.S. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol 85 (2000) 1297-1301
81. Sites C.K., Cooper B.C., Toth M.J., et al. Effect of a daily supplement of soy protein on body composition and insulin secretion in postmenopausal women. Fertil Steril 88 (2007) 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 114 (2003) 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 163 (2002) 339-347
84. St Germain A., Peterson C.T., Robinson J.G., and Alekel D.L. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 8 (2001) 17-26
85. Steinberg F.M., Guthrie N.L., Villablanca A.C., 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 78 (2003) 123-130
86. Uesugi T., Fukui Y., and 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 21 (2002) 97-102
87. Unfer V., Casini M.L., Costabile L., et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized double-blind placebo-controlled study. Fertil Steril 82 (2004) 145-148
88. Upmalis D.H., 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 7 (2000) 236-242
89. van de Weijer P.H.M., and Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 42 (2002) 187-193
90. van Patten C.L., Olivotto I.A., Chambers G.K., et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomised controlled clinical trial. J Clin Oncol 20 (2002) 1449-1455
91. Verhoeven M.O., van der Mooren M.J., van de Weijer P.H.M., 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 12 (2005) 412-420
92. Vigna G.B., Pansini F., Bonaccorsi G., et al. Plasma lipoproteins in soy-treated postmenopausal women: a double-blind, placebo-controlled trial. Nutr Metab Cardiovasc Dis 10 (2000) 315-322
93. Wiklund I.K., Mattsson L.A., Lindgren R., and 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 19 (1999) 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 55 (2006) 423-433
95. Xu X., Harris K.S., Wang H.J., et al. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr 125 (1995) 2307-2315
96. Xu X., Wang H.J., Murphy P.A., and Hendrich S. Neither background diet nor type of soy food affects short-term isoflavone bioavailability in women. J Nutr 130 (2000) 798-801
97. Ye Y.B., Tang X.Y., Verbruggen M.A., and Su Y.X. Soy isoflavones attenuate bone loss in early postmenopausal Chinese women: a single-blind randomized, placebo-controlled trial. Eur J Nutr 45 (2006) 327-334
98. Zhang G., Qin L., and 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 22 (2007) 1072-1089
99. Tempfer C.B., Bentz E.K., Leodolter S., et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 87 (2007) 1243-1249