Soy Phytoestrogens, Lipid Reductions, and Atherosclerosis Delay in Ovariectomized Primates

B. Anderson;

Department of Nutrition Schools of Public Health and Medicine University of North Carolina Chapel Hill, North Carolina 27599-7400 and Sanford C. Garner Department of Surgery Duke University Medical Center Durham, North Carolina

Address correspondence and requests for reprints to: John Anderson, Ph.D., Department of Nutrition, Schools of Public Health and Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7400. E-mail: jjb_anderson{at}unc.edu


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Phytoestrogens have become an alternative therapy for many western diseases, as used by consumers, but not yet recommended by practitioners. Increasing evidence is accruing that phytoestrogens may provide health benefits if consumed at sufficient levels (1, 2). The results of a prospective, placebo-controlled investigation of ovariectomized, postmenopausal cynomologus monkeys by Clarkson et al. (3), in this issue of the journal, provide convincing evidence of the effectiveness of soy protein plus soy isoflavones, one type of phytoestrogens (SPE), in lowering the risk of atherosclerotic disease and its sequelae, coronary heart disease and stroke. The study was conducted for almost 36 months following ovariectomy in this postmenopausal animal model.

The significant cardio-protective effects in monkeys treated with soy protein plus SPE compared with control animals given soy protein without the isoflavones were generally intermediate to the findings for monkeys treated with conjugated equine estrogens (CEEs). To enhance the chance of these monkeys developing atherosclerosis, animals in all three groups were fed an atherogenic diet (42% fat by calories). The specific findings of the monkeys treated with SPE compared with control animals were: 1) significant reduction in total cholesterol; 2) significant elevation in high-density lipoprotein cholesterol; 3) significant reduction in low-density lipoprotein cholesterol plus very low density lipoprotein cholesterol and triglycerides; 4) significant lowering of the ratio of total cholesterol to high-density lipoprotein cholesterol; and 5) reduction in atherosclerotic lesions in the common iliac and other arteries that were significant in the common and internal carotid arteries. Also, a significant lowering of serum estradiol concentration was found in the SPE-treated compared with the CEE-treated primates. The findings in the animals treated with CEE were similar to those reported for postmenopausal women on hormone replacement therapy.

Primates are not, however, humans! If the same results of the SPE-treated primates had come from a prospective human trial, much more enthusiasm would be generated for the use of soy isoflavones in treating postmenopausal women because of the presumed reduction of risk of both reproductive cancers and osteoporosis, which were not the focus of the present study. Because greater numbers of postmenopausal women are refusing treatment with CEE (Premarin) and similar forms of estrogens for fear of breast, uterine, and, possibly, ovarian cancer, the time seems propitious to consider mounting a well-designed, national, multicenter trial to test the efficacy of soy isoflavones, with or without the soy protein, in a large sample of postmenopausal women. Sufficient statistical power would need to be assured to find meaningful statistical differences. In addition, several doses of isoflavones should be used to establish any dose-related effects in tissues other than the liver and arteries. For example, the single dose used in the present study yielded the significant findings enumerated above in the monkeys, but it was not sufficient to show an effect in improving bone mineral density in another primate study (4). A few human trials have also found lipid-lowering effects of isoflavones with soy protein (5, 6, 7).

Several uncertainties remain in the use of soy isoflavones in a randomized, placebo-controlled human trial, if such is warranted. First, soy proteins with the enriched isoflavone content need to be compared with soy isoflavones alone to establish whether the soy protein is an essential component for benefiting cardiovascular, skeletal, and other tissues. Secondly, a study design involving several dosage levels of isoflavones (with and without the soy protein) is needed to find potential effects on the skeleton, which apparently require higher doses than used in the present study (5, 6, 8, 9). In one study of bone markers in pre- and postmenopausal women, a dose of 130 mg/day of soy isoflavones did not yield any changes in bone biomarkers (10). Consideration of the effects of isoflavones on climacteric symptoms, cognition, and other potential outcomes needs to be factored into such a study design.

In conclusion, the study by Clarkson et al. (3) should stimulate considerable new research because of the strength of not only the cardio-protective effects in this report, but also because of the potential benefits of isoflavones in humans on other tissues. The work of Clarkson et al. (3) provides a high-level example of the value of experimental models used for the advancement of human health.

Received November 14, 2000.

Accepted November 15, 2000.


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  1. Adlercreutz H, Mazur W. 1997 Phyto-oestrogens and western diseases. Ann Med. 2:95–120.
  2. Anderson JJB, Garner, SC. 1998 Phytoestrogens and bone. Balliere’s Clin Endocrinol Metab. 12:543–557.[Medline]
  3. Clarkson T, Anthony M, Morgan TM. 2001 Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab. 86:41–47.[Abstract/Free Full Text]
  4. Lees CJ, Ginn TA. 1998 Soy protein isolate diet does not prevent cortical bone turnover in ovariectomized macaques. Calcif Tissue Int. 62:557–558.[CrossRef][Medline]
  5. Potter SM, Baum JA, Teng H, et al. 1998 Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr. 68(Suppl):1375S–1379S.
  6. Alekel DL, St Germain A, Peterson CT, et al. 2000 Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr. 72:844–852.[Abstract/Free Full Text]
  7. Wong WW, Smith EO, Stuff JE, et al. 1998 Cholesterol-lowering effect of soy protein in normocholesterolemic and hypercholesterolemic men. Am J Clin Nutr. 68(Suppl):1385S–1389S.
  8. Horiuchi T, Onouchi T, Takahashi M, et al. 2000 Effect of soy protein on bone metabolism in postmenopausal Japanese women. Osteoporosis Int. 11:721–724.[CrossRef][Medline]
  9. Atkinson C, Compston JE, Robins SSP, Bingham SA. 2000 The effects of isoflavone phytoestrogens on bone: preliminary results from a large randomized controlled trial. Proceedings of the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada; p.43.
  10. Wangen KE, Duncan AM, Merz-Demlow BE, et al. 2000 Effects of soy isoflavones on markers of bone turnover of premenopausal and postmenopausal women. J Clin Endocrinol Metab. 85:3043–3048.[Abstract/Free Full Text]