Phytoestrogens: End of a tale?

Figures & data

Figure 1 Chemical structures of major phytoestrogens compared to 17β‐estradiol. Genistein and the chemically related isoflavones daidzein and glycitein are the most widely used compounds. Genistein, daidzein and glycitein are generally labelled as “phytoestrogens” and they are thus the major topic of the present review article.

Table I. Summary of randomized clinical studies investigating the effect of isolated phytoestrogens or low versus high phytoestrogen‐containing soy on risk factors for cardiovascular disease.

Source	Design	Subjects	Intervention	Results	Conclusion
Nestel et al. 1997 29	Placebo‐controlled cross‐over, 5–10 week treatments	21 women	Phytoestrogens (80 mg/day) and placebo	No effect on plasma lipids but significant improvement in systemic arterial compliance in phytoestrogen group compared with placebo	Phytoestrogens did not improve plasma lipids but improved measures of arterial health
Hodgson et al. 1998 30	Parallel, randomized, double‐blind, placebo‐controlled, 8 weeks	46 men and 13 postmenopausal women not receiving hormone replacement therapy	Phytoestrogen tablets (55 mg/day) or placebo tablets	Serum lipids did not differ significantly between groups	In subjects with average serum cholesterol levels phytoestrogens do not beneficially modify serum lipids
Samman et al. 1999 54	Randomized cross‐over, four menstrual cycles (∼ 4 months)	14 healthy pre‐menopausal women	Phytoestrogens (86 mg/day) and placebo	Phytoestrogen intake did not lead to changes in LDL oxidizability or plasma levels of total cholesterol or triacylglycerols	Did not support hypothesis that phytoestrogens are a major active hypocholesterolemic agent
Simons et al. 2000 47	Double‐blind, placebo‐controlled, randomized crossover, 8 weeks each treatment	20 healthy, post‐menopausal women, with evidence of endothelial dysfunction	Soy phytoestrogen tablets (80 mg/day) or placebo	Blood pressure, plasma lipids and flow‐mediated endothelium‐dependent dilatation were not affected by phytoestrogens	No significant effect of phytoestrogens on plasma lipids or endothelial function
Wiseman et al. 2000 53	Randomized, crossover, 17 days each treatment	24 subjects (men and women aged 19–40 years)	Soy diets low (1.9 mg/day) or high (56 mg/day) in phytoestrogens	Biomarkers of in vivo lipid peroxidation lower and lag time for copper‐ion‐induced LDL oxidation longer after high phytoestrogen soy	High phytoestrogen soy demonstrated increased antioxidant action
Dewell et al. 2002 31	Parallel, randomized, 8 weeks	36 moderately hypercholesterolemic, elderly, postmenopausal women	Phytoestrogen (150 mg/d) or placebo	No effects on serum lipids	Phytoestrogens may not be effective at reducing cardiovascular disease risk in the population tested
Squadrito et al. 2002 45	Parallel, double‐blind, placebo controlled, randomized, 6 months	60 healthy postmenopausal women	Genistein (54 mg/day) or placebo	Genistein led to increased level of nitrites/nitrates, decreased level of plasma endothelin‐1 and increased flow‐mediated, endothelium‐dependent vasodilatation	Flow‐mediated endothelium dependent vasodilatation was improved by phytoestrogen therapy
Squadrito et al. 2003 46	Parallel, double‐blind, controlled, randomized, 1 year	79 healthy postmenopausal women	Genistein (54 mg/d), estrogen/progestin therapy or placebo	Genistein increased levels of nitrites/nitrates, decreased plasma endothelin‐1 levels and improved brachial artery flow‐mediated dilation similarly to estrogen/progestin therapy	Genistein and estrogen/progestin improve endothelium function to a similar extent
Vega‐Lopez et al. (2005) 56	Randomized crossover design	42 hypercholesterolemic men and postmenopausal women aged >50 years	Soy protein (trace or 50 mg phytoestrogens/ 1000 kcal) or animal protein (trace or 50 mg phytoestrogens/1000 kcal)	No significant effect of phytoestrogens on LDL oxidation, urinary F(2)‐isoprostanes, or protein carbonyl groups	Plasma antioxidant capacity and biomarkers of oxidative stress are not modified by soy‐derived phytoestrogens

Table II. Summary of randomized clinical studies investigating the effect of phytoestrogens on osteoporosis and bone metabolism markers.

Source	Design	Subjects	Intervention	Results	Conclusion
Potter et al. 1998 101	Parallel double blind, 6 months	66 free‐living postmenopausal women	40 g protein/day ‐ either casein or isolated soy protein (1.39 or 2.25 mg phytoestrogens/g protein)	Significant increases in bone mineral content and density in the lumbar spine but not elsewhere for higher phytoestrogen group only	Only the higher phytoestrogen level protected against spinal bone loss.
Wangen et al. 2000 102	Randomized, cross‐over, 3 month each treatment	30 pre‐ and post‐menopausal women	3 soy protein isolates containing 8, 65, and 130 mg/day phytoestrogens	Only small, not clinically relevant changes observed in markers of bone turnover	Did not provide evidence that phytoestrogens beneficially affect bone turnover
Alekel et al. 2000 104	Parallel, 24 weeks	69 perimenopausal women	Phytoestrogen‐rich (80.4 mg/d) soy, phytoestrogen‐poor soy or whey control	High phytoestrogen treatment had a positive effect on lumbar spine bone mineral density and content	Lumbar spine bone loss slower due to phytoestrogens
Lydeking‐Olsen et al. 2004 105	Double‐blind parallel, 2 years	89 postmenopausal women with established osteoporosis or at least 3 risk‐factors	Soy containing phytoestrogens (76 mg/day), transdermal progesterone, the combination of the above two or placebo	Lumbar spine bone mineral density and content lost in placebo and combination group but not in soy containing phytoestrogen and progesterone group	Phytoestrogens prevented lumbar spine bone loss alone but not in combination with progesterone
Chen et al. 2004 106	Parallel, randomized, 1 year	203 postmenopausal women	Mid‐dose phytoestrogens (40 mg/day), high‐dose (80 mg/day) and placebo	Significant beneficial effect of phytoestrogens on bone mineral content (total hip and trochanter) in late postmenopausal women with lower body weight or lower calcium intake	Beneficial effects of phytoestrogens increased in low body weight and low calcium intake women and those in later menopause
Spence et al. 2005 110	Randomized, crossover design, 1 month each treatment	15 postmenopausal women	Soy protein isolate with phytoestrogens, soy protein isolate devoid of phytoestrogens, and dairy protein diets	Urinary calcium excretion was significantly less on either of the soy diets. Fractional calcium absorption, total fecal calcium excretion, bone deposition and resorption, and calcium retention were unaffected by treatment	Soy phytoestrogens did not significantly affect calcium metabolism.
Arjmandi et al. 2005 109	Parallel, randomized, 1 year	87 postmenopausal women	Soy‐containing foods (60 mg phytoestrogens/day) or control foods with no soy	Both soy and control foods reduced whole body and lumbar bone mineral density and content but positively affected markers of bone formation	Results do not support a role of soy or its phytoestrogens in bone protection

Table III. Summary of randomized clinical studies investigating the effect of phytoestrogens on menopausal vasomotor symptoms.

Source	Design	Subjects	Intervention	Results	Conclusion
Murkies et al. 1995 119	Parallel, randomized, double blind, 12 weeks	58 postmenopausal women with at least 14 hot flushes per week	Soy flour (phytoestrogen level not reported) versus wheat flour	Hot flushes reduced by 45% in soy and 25% in wheat flour groups. Increased urinary excretion of phytoestrogens in soy group	Both soy (presumably containing phytoestrogens) and wheat flour significantly reduced hot flushes
Albertazzi et al. 1998 122	Parallel double‐blind, multicenter, randomized placebo‐controlled, 12 weeks	104 postmenopausal women	40 g of isolated soy protein (76 mg phytoestrogens) or 60 g of casein placebo daily	Soy significantly reduced hot flushes by 45% versus 30% with the placebo	Soy protein isolate added daily to the diet substantially reduced the frequency of hot flushes
Washburn et al. 1999 126	Randomized, double‐blind crossover, 6 weeks each treatment	51 perimenopausal women	20 g/day of soy protein (34 mg/day of phytoestrogens) given in a single dose or split into two doses versus 20 g/day carbohydrate placebo	Significant improvement in severity of vasomotor symptoms in the twice‐daily soy group compared with carbohydrate placebo group.	Soy with phytoestrogens gave significant improvements in perceived severity of vasomotor symptoms.
Baber et al. 1999 131	Randomized cross‐over, 12 week and 14 week treatments	51 postmenopausal women	Phytoestrogen tablets (40mg/day) and placebo	No significant difference between phytoestrogen and placebo groups in the reduction in hot flushes	Phytoestrogens did not provide a therapeutic benefit to hot flushes
Knight et al. 1999 132	Parallel, randomized, double‐blind, placebo‐controlled, 12 weeks	37 postmenopausal women with symptoms of estrogen deficiency	Phytoestrogen tablets (40 or 160 mg/day) or placebo	No significant difference in hot flushes between groups	Large placebo response may have obscured effect of phytoestrogens
Quella et al. 2000 123	Randomized, double‐blind crossover, 4 weeks each treatment	177 breast cancer survivors with substantial hot flushes	Soy‐derived phytoestrogen tablets (150 mg/day) or placebo	No difference between soy and placebo periods for hot flushes	Phytoestrogens did not reduce hot flushes in the breast cancer survivors
Van Patten et al. 2001 124	Parallel, randomised, placebo‐controlled, double‐blind, 12 weeks	123 postmenopausal women with moderate hot flushes previously treated for early‐stage breast cancer	Soy beverage (90 mg phytoestrogens/day) or placebo rice beverage	No significant differences in the number or severity of hot flushes. Strong placebo effect	In women with breast cancer, soy beverage with phytoestrogens did not reduce hot flushes any more than the placebo
Faure et al. 2002 127	Parallel, multicenter, randomized, double‐blind, placebo‐controlled, 16 weeks	75 women in natural or surgical menopause with at least seven hot flushes per day	Soy phytoestrogen extract (70 mg/day) or placebo	Patients taking soy extract 61% reduction in hot flushes versus 21% reduction with placebo	Phytoestrogens may help to reduce the frequency of hot flushes
Han et al. 2002 128	Parallel, double‐blind, placebo‐controlled, 16 weeks	80 postmenopausal women	Soy phytoestrogens (100 mg/day) and placebo	Significantly lower menopausal symptoms in phytoestrogen than placebo group	Phytoestrogens may be an effective treatment for menopausal symptoms
Colacurci et al. 2004 129	Parallel, randomised, 12 weeks	75 postmenopausal women	Phytoestrogens (50 or 75 mg/day orally or 6 or 12 mg/day transdermally), and a control group of no treatment.	Phytoestrogens gave significant reduction in hot flushes (except 6 mg/day transdermally)	Phytoestrogens given orally and transdermally reduce menopausal neurovegetative symptoms slightly or moderately
Petri Nahas et al. 2004 130	Parallel, double‐blind placebo‐controlled, 6 months	50 postmenopausal women	Soy germ phytoestrogen capsules (60 mg/day) and placebo	The reduction in hot flushes was significantly greater for the phytoestrogen than the placebo groups	Beneficial effects on vasomotor symptoms are provided by soy germ phytoestrogens
McGregor et al. 2005 125	Parallel, randomized, 12 weeks	72 postmenopausal women diagnosed with breast cancer having menopausal symptoms	Soy phytoestrogen capsules (70 mg/day) or placebo	No statistical difference in menopausal symptom scores between two treatments	No benefit of phytoestrogen supplementation compared to placebo

Nestel P. J., Yamashita T., Sasahara T., Pomeroy S., Dart A., Komesaroff P. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol 1997; 17: 3392–8

 PubMed Web of Science ®Google Scholar

Hodgson J. M., Puddey I. B., Beilin L. J., Mori T. A., Croft K. D. Supplementation with isoflavonoid phytoestrogens does not alter serum lipid concentrations: a randomized controlled trial in humans. J Nutr 1998; 128: 728–32

 PubMed Web of Science ®Google Scholar

Samman S., Lyons Wall P. M., Chan G. S., Smith S. J., Petocz P. The effect of supplementation with isoflavones on plasma lipids and oxidizability of low density lipoprotein in premenopausal women. Atherosclerosis 1999; 147: 277–83

 PubMed Web of Science ®Google Scholar

Simons L. A., van Konigsmark M., Simons J., Celermajer D. S. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol 2000; 85: 1297–301

 PubMed Web of Science ®Google Scholar

Wiseman H., O'Reilly J. D., Adlercreutz H., Mallet A. I., Bowey E. A., Rowland I. R. Isoflavone phytoestrogens consumed in soy decrease F2‐isoprostane concentrations and increase resistance of low‐density lipoprotein to oxidation in humans. Am J Clin Nutr 2000; 72: 395–400

 PubMed Web of Science ®Google Scholar

Dewell A., Hollenbeck C. B., Bruce B. The effects of soy‐derived phytoestrogens on serum lipids and lipoproteins in moderately hypercholesterolemic postmenopausal women. J Clin Endocrinol Metab 2002; 87: 118–21

 PubMed Web of Science ®Google Scholar

Squadrito F., Altavilla D., Morabito N., Crisafulli A., D'Anna R., Corrado F. The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin‐1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis 2002; 163: 339–47

 PubMed Web of Science ®Google Scholar

Squadrito F., Altavilla D., Crisafulli A., Saitta A., Cucinotta D., Morabito N. Effect of genistein on endothelial function in postmenopausal women: a randomized, double‐blind, controlled study. Am J Med 2003; 114: 470–6

 PubMed Web of Science ®Google Scholar

Vega‐Lopez S., Yeum K‐J., Lecker J. L., Ausman L. M., Johnson E. J., Devaray S. Plasma antioxidant capacity in response to diets high in soy or animal protein with or without isoflavones. Am J Clin Nutr 2005; 81: 43–9

 PubMed Web of Science ®Google Scholar

Potter S. M., Baum J. A., Teng H. Soy protein and isoflavones: their effects on blood lipids and bone density in post‐menopausal women. Am J Clin Nutr 1998; 68: 1375S–9

 PubMed Web of Science ®Google Scholar

Wangen K. E., Duncan A. M., Merz‐Demlow B. E., Xu X., Marcus R., Phipps W. R. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000; 85: 3043–8

 PubMed Web of Science ®Google Scholar

Alekel D. L., Germain A. S., Peterson C. T., Hanson K. B., Stewart J. W., Toda T. Isoflavone‐rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr 2000; 72: 844–52

 PubMed Web of Science ®Google Scholar

Lydeking‐Olsen E., Beck‐Jensen J‐E., Setchell K. D. R., Holm‐Jensen T. Soymilk or progesterone for prevention of bone loss. A 2 year randomized, placebo‐controlled trial. Eur J Nutr 2004; 43: 246–57

 PubMed Web of Science ®Google Scholar

Chen Y. M., Ho S. C., Lam S. S., Ho S. S., Woo J. L. Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double‐blind, randomized, controlled trial. Menopause 2004; 11: 246–54

 PubMed Web of Science ®Google Scholar

Spence L. A., Lipscomb E. R., Cadogan J., Martin B., Wastney M. E., Peacocock M. The effect of soy protein and soy isoflavones on calcium metabolism in postmenopausal women: a randomized crossover study. Am J Clin Nutr 2005; 81: 916–22

 PubMed Web of Science ®Google Scholar

Arjmandi B. H., Lucas E. A., Khalil D. A., Devareddy L., Smith B. J., McDonald J. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J 2005; 4: 8

 PubMed Web of Science ®Google Scholar

Murkies A. L., Lombard C., Strauss B. J. G., Wilcox G., Burger H. G., Morton M. S. Dietary flour supplementation decreases post‐menopausal hot flushes: effect of soy and wheat. Maturitas 1995; 21: 189–95

 PubMed Web of Science ®Google Scholar

Albertazzi P., Pansini F., Bonaccorsi G., Zanotti L., Forini E., De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998; 91: 6–11

 PubMed Web of Science ®Google Scholar

MacGregor C. A., Canney P. A., Patterson G., McDonald R., Paul J. 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: 708–14

 PubMed Web of Science ®Google Scholar

Han K. K., Soares J. M, Jr., Haidar M. A., de Lima G. R., Baracat E. C. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 2002; 99: 389–94

 PubMed Web of Science ®Google Scholar

Colacurci N., Zarcone R., Borrelli A., De Franciscis P., Fortunato N., Cirillo M. Effects of soy isoflavones on menopausal neurovegetative symptoms. Minerva Ginecologica 2004; 56: 407–12

 PubMedGoogle Scholar

Quella S. K., Loprinzi C. L., Barton D. L., Knost J. A., Sloan J. A., LaVasseur B. I. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 2000; 18: 1068–74

 PubMed Web of Science ®Google Scholar

Van Patten C. L., Olivotto I. A., Chambers G. K., Gelmon K. A., Hislop T. G., Templeton E. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 2002; 20: 1449–55

 PubMed Web of Science ®Google Scholar

Washburn S., Burke G. L., Morgan T., Anthony M. Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 1999; 6: 7–13

 PubMed Web of Science ®Google Scholar

Faure E. D., Chantre P., Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double‐blind, randomized, placebo‐controlled study. Menopause 2002; 9: 329–34

 PubMed Web of Science ®Google Scholar

Petri Nahas E., Nahas Neto J., De Luca L., Traiman P., Pontes A., Dalben I. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas 2004; 48: 372–80

 PubMed Web of Science ®Google Scholar