Soy and Phytoestrogens for Cardiovascular Disease
By Dónal P. O'Mathúna, BS (Pharm), MA, PhD, Dr. O'Mathúna is a lecturer in Health Care Ethics, School of Nursing, Dublin City University, Ireland; he reports no financial relationship relevant to this field of study.
Soy has come a long way since white cubes of tofu were introduced into Western diets in the 1980s. Promoted as a healthy protein substitute for meat, some were convinced right away of its benefit. For others, the food was too bland, although recipes books have since demonstrated how soy can be incorporated into tasty, nutritious meals. Other forms of soy have become available, including tempeh (fermented soybeans), soy flours, and soy milk. Many reports have appeared, claiming many health benefits of replacing animal protein with soy. Since 1999, the FDA has permitted a health claim on foods containing soy.1 The labels may state that consuming 25 grams of soy protein daily, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. In 2000, the American Heart Association released a scientific advisory recommending the inclusion of soy protein in heart-healthy diets.2 In spite of this, only a small proportion of Americans eat soy products at least once a week. For this reason, dietary supplements have been made from soy in the hope that they will have the health benefits of soy.
Soybeans, like most foods, contain a complex mix of compounds. One component is soy protein, which is used to make soy flour, soy milk, tofu, and tempeh. Soy also contains a group of compounds called "isoflavones" that can be isolated from soy and used to make dietary supplements. These compounds are antioxidants and have some weak estrogen-like activity. For this reason, they are also called "phytoestrogens" (phyto means "having to do with plants"). Other products made from soy include soy sauce and soybean oil. The health claims to be discussed here do not apply to these products because they contain very small quantities of soy protein and isoflavones.
Replacing animal protein with soy or taking phytoestrogen supplements is said to have many beneficial health effects. Some of the most commonly cited ones are kidney and gastrointestinal diseases, cancer, osteoporosis, menopausal symptoms, and reproductive problems. This article will examine only the evidence regarding cardiovascular disease (CVD). This group of heart-related conditions is the leading cause of death in women.3 More women die in the United States from CVD than die from all forms of cancer, including breast cancer. Almost half a million women die from CVD, with another 42 million women having various stages of CVD. Safe and effective ways to prevent and treat CVD are urgently needed to promote women's health.
The earliest evidence of a connection between soy and CVD came from epidemiological studies. Some Asian populations have a lower incidence of CVD, which was suggested to be related to their higher consumption of soy. This association has been borne out in several epidemiological studies. For example, the Shanghai Women's Health Study found that women in the highest quartile for soy protein consumption had a 75% lower risk of coronary heart disease and an 86% lower risk of non-fatal myocardial infarctions than women who consumed the least soy protein.4
Controlled studies of soy consumption have largely focused on measuring changes in risk factors for CVD. Numerous early studies found that animals fed protein of animal origin developed high serum cholesterol levels. When the dietary animal protein was replaced by soy protein, blood cholesterol levels were reduced. However, the results were not as beneficial when similar studies were conducted with humans.5
A 1995 meta-analysis shed light on why different studies had such variable results.6 The review identified 38 controlled clinical trials which consistently found that soy reduced total cholesterol and low density lipoprotein (LDL) cholesterol levels. Overall, the meta-analysis found that replacing animal protein with soy protein led to a 9.3% reduction in serum cholesterol, a 12.9% reduction in serum LDL-cholesterol, and a 10.5% reduction in serum triglyceride levels. Serum high density lipoprotein (HDL) cholesterol levels were not significantly differently on the soy diets.
Further analysis of the data revealed that 77% of the variability between studies was accounted for by the initial cholesterol levels of the participants in the studies. Participants with normal or mildly elevated total cholesterol levels had no significant reductions in serum cholesterol when consuming soy. Those with moderate hypercholesterolemia had significant reductions in cholesterol levels (7.4%) and those with severe hypercholesterolemia had even greater reductions (19.6%). A similar pattern was found with the LDL cholesterol levels and the triglyceride levels. This meta-analysis was highly influential in leading the FDA to approve the use of health claims on the labels of soy foods.
However, this meta-analysis has been strongly criticized for including low- and high-quality studies without discriminating between them. Also, the analysis was carried out before studies identified the phytoestrogen content of soy products. Thus much variability existed in the products used in the early studies. Since the late 1990s, studies have been conducted using soy protein with phytoestrogens removed, soy protein with phytoestrogens, and phytoestrogen supplements (in pill form). A 2006 review found seven studies where animal protein was replaced with soy protein with phytoestrogens removed.5 Only two of the studies showed significant reductions in LDL cholesterol. Combining all the studies, the LDL levels on average dropped 1-2% but this required about 50 g soy per day. This represents half of the average daily protein consumption in the United States.
While this suggests an important role for phytoestrogens in soy's impact on CVD, other studies have not supported this hypothesis. More recent, higher-quality studies of soy protein containing phytoestrogens have found smaller beneficial effects.7 A meta-analysis found that replacing animal protein with 36 g soy protein led to an average 4% reduction in LDL cholesterol and a 3% elevation in HDL cholesterol. However, the results were not affected by the dose of soy protein or phytoestrogens.
Another 19 studies have examined the effects of isolated phytoestrogens on serum lipids.5 Only three of these studies showed reductions in LDL cholesterol, with the overall average effect being no change. Significant changes were not found for HDL cholesterol levels or triglyceride levels, and there was no dose effect.
Six studies have examined the effect of soy protein with phytoestrogens on blood pressure. Only one of six studies found a significant reduction in blood pressure, with the overall average reduction being 1 mmHg.5 Another five studies that examined the effect of phytoestrogens alone on blood pressure found no significant effect.
A comprehensive review of the clinical evidence on soy for all health outcomes was published by the Agency for Healthcare Research and Quality in 2005.8 The report found that CVD was the outcome with most research. However, no controlled studies were found that examined the clinical impact of soy consumption on CVD itself. All the controlled studies measured changes in various CVD risk factors. A total of 68 studies of serum lipid levels were found, with the amount of soy consumed varying considerably. Very few studies were given a "good quality" rating, about half were of fair quality, and another considerable number were of poor quality. The authors concluded that replacing animal protein with soy protein may have a small beneficial effect on serum lipid levels, but much further research is needed before recommendations can be given with confidence.
Soy is generally well tolerated by most people, although a very small number of people can be allergic to it. Soy can cause mild gastrointestinal problems in some people. Those with cancers that are sensitive to estrogen (some breast cancers) should avoid soy.
Concerns have been raised about the long-term effects on infants of consuming large amounts of soy instead of breast milk or dairy products.9 The estrogen-like effects of soy and phytoestrogens can cause developmental damage in certain animals. Such adverse effects have not been shown in humans, though the effects of phytoestrogens on human development remain largely unknown. These concerns led Israel's health ministry in 2005 to warn that soy products should be limited in children and avoided in infants.10 Other countries have issued similar concerns. Current recommendations are that soy infant formula should not be used without medical reasons, such as when infants have an allergy or other medical problem making consumption of cow's milk inadvisable. The breast milk of women consuming large quantities of soy will contain high concentrations of phytoestrogens, although the effects of this are unknown.9
The usual recommendations are to include about 25 g of soy protein in the daily diet. This can be done with four glasses of soy milk, one-third of a brick of tofu, or one serving of soy protein powder. Reported health benefits are based on studies where animal protein was replaced by soy protein. Soy supplements usually recommend 50 mg of phytoestrogens daily. However, labeling of phytoestrogen supplements is not standardized, leading to much variability. Some show the amounts of individual phytoestrogens and others give a combined weight of all phytoestrogens, though calculated in varying ways.
Most people could benefit from replacing some animal protein with soy protein to increase the proportion of plant products in their diet. Early enthusiasm for the cardiovascular benefits of soy has waned as higher quality studies have found fewer beneficial effects. However, some reduction in LDL cholesterol has consistently been demonstrated, though not to the original extent. In contrast, studies with phytoestrogen supplements have consistently found no cardiac benefit. In general, infants should not be fed soy formula unless there is a medical reason to avoid breastfeeding or cow's milk.
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2. 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;102:2555-2559.
3. American Heart Association. Heart disease and stroke statistics: 2007 update. Available at: www.americanheart.org/presenter.jhtml?identifier=3000090. Accessed September 8, 2007.
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10. Siegel-Itzkovich J. Health committee warns of potential dangers of soya. BMJ. 2005;331:254.