Isoflavones from Red Clover Improve Systemic Arterial Compliance but not Plasma Lipids in Menopausal Women

Abstract & commentary

Synopsis: Arterial compliance was improved in menopausal women who ingested isoflavones derived from red clover. The effect size was comparable to that seen in hormone replacement therapy.

Source: Nestel PJ, et al. J Clin Endocrinol Metab 1999; 84:895-898.

Isoflavones (phytoestrogens) are found in many legumes, including soy. They have been credited with conferring cardioprotection. For example, epidemiological studies suggested the reason Japanese women living in Japan had less cardiovascular disease than Japanese women living in the United States was due to consumption of a diet high in legumes and, therefore, isoflavones. Nestel and associates have performed several studies looking at modification of arterial compliance in postmenopausal women by weight loss, diet, hormone replacement therapy, and soy-derived isoflavones. The present study extended their previous work by examining isoflavones derived from red clover. Specifically, red clover contains genistein, diadzein, and their methylated precursors biochanin A and formononetin. (Soy contains genistein and diadzein.) Twenty-six women began the trial and 13 completed all aspects of the active intervention. Most of the drop-outs were menopausal women who quit their hormone replacement regimen to enroll and then could not tolerate the ensuing hot flashes. Subjects were postmenopausal women younger than 70 years of age who were not currently taking hormones or who had discontinued hormones at least four weeks before the study began. The study involved a three-week observation and dietary training interval followed serially by five weeks of placebo, five weeks of 80 mg of red clover-derived isoflavones, and five weeks of a 160 mg daily dose of isoflavones. Arterial compliance was measured by ultrasound at the end of each treatment window. Decreased arterial compliance is an important risk factor for cardiovascular disease because it leads to systolic hypertension and increased left ventricular work. Compliance was unchanged after placebo and increased after five weeks of either dose of isoflavones. Blood pressure and lipids did not change throughout the study.

Comment By Sarah L. Berga, MD

This study is a good example of what needs to be done to determine the effects of various food supplements now being "hawked" to the American public. In this study, isoflavones derived from red clover had a similar effect upon arterial compliance as did isoflavones derived from soy or flax. Notably, estrogen replacement therapy also had a similar effect upon arterial compliance as did isoflavones. Nestel et al interpret the relatively short response time as evidence for endothelial-related arterial relaxation.

A logical question that one might ask after reading this report is whether isoflavones might be recommended as a substitute for hormone replacement therapy. One needs to keep in mind that the present study only looked at a few cardiovascular end points, so it would not allow one to adequately determine if isoflavones were a substitute for hormones for cardioprotection. Further, based on this report, nothing can be said about the effects of isoflavones upon other tissues and age-related disorders. Thus, it is premature to recommend isoflavones as substitutes for hormones.

This brings me to the next point. Nestel et al should study the effects of isoflavones and estrogens together to see if there is synergism. The rationale for such a study includes the observation that many women were unable to complete the study because of vasomotor symptoms. Clearly, isoflavones will not be a panacea for the spectrum of symptoms linked temporally to menopause. Although isoflavones are referred to as phytoestrogens, they are primarily antioxidants and they do not have the same range of effects upon the brain as do estrogens, which are also antioxidants. The two together might be far better than either one alone. Synergism of this type is the rule rather than the exception. I raise this point because the choice facing patients regarding the use of dietary supplements is often framed as an either/or scenario. The either/or approach is likely to be short-sighted and I recommend abandoning such a simplistic line of reasoning. It reminds me of the old question about whether calcium and exercise could substitute for estrogen use for protection against osteoporosis. We now know that there is synergism between exercise, calcium and vitamin D intake, and estrogen use in bone maintenance. Performing all of these interventions is far better than any one of them alone. I predict we will find similar synergism between estrogens and isoflavones in cardiovascular protection and possibly in protection from dementia. (Dr. Berga is Associate Professor, Departments of Obstetrics, Gynecology, Reproductive Sciences, and Psychiatry, University of Pittsburgh, Pa.)