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Menopause Matters

Soy Consumption and Cholesterol Levels

Thomas B. Clarkson, DVM

After the initial flurry over research associating soy isoflavone consumption with coronary health—especially in postmenopausal women—a closer examination of the data has led to its effectiveness being questioned.

Based on animal research and human epidemiologic evidence, many experts felt that consumption of soy protein and soy isoflavones could potentially reduce plasma cholesterol concentrations and prevent coronary heart disease (CHD). In 2001, the American Heart Association (AHA) issued guidelines recommending dietary soy protein and isoflavones for decreasing the risk of CHD.1 More recently, however, the AHA reversed its recommendation and concluded that soy/soy isoflavones had such small effects on plasma lipid profiles it probably did not reduce CHD risk.2 The new AHA advisory was followed by a review article by Dewell et al3 in which research from several medical and scientific databases was reevaluated and the conclusion was that there was little evidence to suggest that soy or soy isoflavones reduced CHD risk.3

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THE CONTROVERSY

Dewell et al3 speculated that statistical variation in hypocholesterolemic effects, rather than actual quantitative differences, appeared to account for the initial favorable findings. This was the basis of their conclusion that the role of soy protein and isoflavones in lowering plasma cholesterol concentrations may not be clinically important.

One of the early and influential papers in the field was a meta-analysis of 38 studies concluding that consumption of 31 to 47 g/d of soy protein could reduce plasma concentrations of both total cholesterol and low-density lipoprotein cholesterol (LDL-C).4 The review by Dewell et al3 showed that changes in cholesterol concentrations were modest and occurred only among subjects with high initial concentrations. It also cited additional confounding factors in the meta-analysis—ie, the trials used different varieties of soy proteins and amounts of isoflavones, and had different study designs and populations.

Dewell et al3 looked at the effects of soy protein and soy isoflavones on plasma lipid profiles, largely in postmenopausal women. They considered 17 studies involving soy protein and nine studies focusing on soy isoflavone extracts. The authors concluded that both soy protein and soy isoflavone extracts caused only very small reductions in total plasma cholesterol concen- trations—primarily LDL-C values—and no changes in high-density lipoprotein cholesterol (HDL-C) levels, and that these decreases were likely too small to be clinically beneficial. This conclusion is consistent with the AHAÍs recent advisory on soy and cardiovascular health,2 which reviewed 22 randomized trials to compare isolated soy-protein isoflavones to milk and other proteins. It was found that soy reduced plasma concentrations of LDL-C about 3% on average, with no significant effects on HDL-C, triglycerides, lipoprotein(a), or blood pressure. The panel also considered 19 studies involving purified soy isoflavone extract, and found no consistent effects on LDL-C or other plasma lipid risk factors. The overall conclusion was that any cardiovascular benefit from soy protein or isoflavone supplements would be "minimal at best."2

Much of the emerging conundrum can be attributed to species differences in soy isoflavone metabolism between animal and human models. Recently, Wake Forest University collaborated with the Arkansas ChildrenÍs Nutrition Center (Little Rock, Ark) and the Yerkes National Primate Center/Emory University (Atlanta, Ga) to determine soy isoflavone phenotypes among female rats, pigs, and monkeys compared with women.5 When female monkeys were compared with women, monkey urine contained high concentrations of aglycones, whereas women excreted isoflavones mainly as glucuronides; the metabolic significance of this difference remains to be clarified. In addition, monkeys convert nearly all of the soy isoflavone daidzein to the potent metabolite equol, whereas only about 35% of human subjects convert daidzein to equol, and in much smaller quantities. Setchell et al6 have suggested that women who are equol producers derive plasma lipid benefits from soy treatment, while nonproducers do not. The author has explored the similarity in plasma lipid changes due to isoflavone-containing soy protein consumption in equol-producing women and cynomolgus monkeys.7 It has not been established that equol production by monkey models accounts for their robust plasma lipid benefits, although eliminating the gut flora (the source of daidzein-to-equol conversion) reduced the plasma lipid benefits of a soy diet.8

Despite Dewell et alÍs review3 and the latest AHA advisory,3 health care professionals should not rush to judgment about whether soy has cardiovascular benefits, as the clinical picture is still evolving. In addition, plasma lipid concentrations are but one surrogate marker for atherosclerosis progression and the development of CHD. For example, Nestel et al9 found that while isoflavone treatment of postmenopausal women did not improve plasma lipid profiles, there was significant improvement in arterial compliance—a measurement closely associated with degree of atherosclerosis. This observation was confirmed by van der Schouw et al,10 where isoflavone intake was associated with decreased aortic stiffness. Furthermore, the presence of oxidized LDL in artery walls enhances the accumulation of macrophage-derived foam cells in the atherosclerotic plaque, resulting in more complex and possibly less stable plaques. Interestingly, studies have found reductions in markers of LDL oxidation in humans consuming soy protein with isoflavones or isoflavone pills.11-15

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CONCLUSION

Experts are now awaiting the conclusion of the first prospective, randomized, double-blind, placebo-controlled trial to determine whether treatment with isoflavone-containing soy protein reduces the progression of ath-erosclerosis in postmenopausal women. The National Institutes of Health’s Center for Complementary and Alternative Medicine, the Office of Dietary Supplements, the Office of Research on Women’s Health, and the Solae Company are supporting the Women’s Isoflavone Soy Health trial, which will last for 2.5 years with a primary endpoint focusing on change in carotid artery intima-media thickness.

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Thomas B. Clarkson, DVM, is professor of comparative medicine, Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC.

References

1. Erdman JW Jr. AHA Science Advisory: Soy protein and cardiovascular disease: A statement for healthcare professionals from the nutrition committee of the AHA. Circulation. 2000;102(20):2555-2559.
2. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M; American Heart Association Nutrition Committee. Soy protein, iso- flavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation. 2006;113(7):1034-1044.
3. Dewell A, Hollenbeck PL, Hollenbeck CB. Clinical review: a critical evaluation of the role of soy protein and isoflavone supplementation in the control of plasma cholesterol concentrations. J Clin Endocrinol Metab. 2006;91(3):772-780.
4. 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(5):276-282.
5. Gu L, House SE, Prior RL, et al. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr. 2006;136(5):1215-1221.
6. Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol„a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002;132 (12):3577-3584.
7. Clarkson TB, Appt SE. Cardiovascular effects of dietary soy. In: Watson RR, Preedy VR, eds. Nutrition and Heart Disease: Causation and Prevention. Boca Raton, Fla: CRC Press; 2004:215-236.
8. Blair RM, Appt SE, Franke AA, Clarkson TB. Treatment with antibiotics reduces plasma equol concentration in cynomolgus monkeys (Macaca fascicularis). J Nutr. 2003;133(7):2262-2267.
9. Nestel PJ, Yamashita T, Sasahara T, et al. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol. 1997;17(12):3392-3398.
10. van der Schouw YT, Pijpe A, Lebrun CE, et al. Higher usual dietary intake of phytoestrogens is associated with lower aortic stiffness in postmenopausal women. Arterioscler Thromb Vasc Biol. 2002;22(8):1316-1322.
11. Jenkins DJ, Kendall CW, Garsetti M, et al. Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity—a controlled crossover trial. Metabolism. 2000;49(4):537-543.
12. Jenkins DJ, Kendall CW, Vidgen E, et al. Effect of soy-based breakfast cereal on blood lipids and oxidized low-density lipoprotein. Metabolism. 2000;49(11):1496-1500.
13. Tikkanen MJ, Wahala K, Ojala S, Vihma V, Adlercreutz H. Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. Proc Natl Acad Sci USA. 1998;95(6):3106-3110.
14. Wiseman H, OÍReilly JD, Adlercreutz H, et al. Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr. 2000;72(2):395-400.
15. Samman S, Lyons Wall PM, Chan GS, Smith SJ, Petocz P. The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women. Atherosclerosis. 1999;147(2):277-283.

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