By Pamela Mason, PhD, MRPharmS
Isoflavones are currently being investigated for their protective role in a number of conditions, including cardiovascular disease, cancer and symptoms of the menopause. This article looks at the evidence available to support the various claims made for them
One of the newer dietary supplements to hit the United Kingdom market - isoflavones, which are derived mainly from soya - is generating an enormous amount of consumer interest. Yet, five or more years ago, few people outside the academic community had heard of them. Even now, most of the research in this area is relatively new. Few studies on isoflavones were conducted before 1993 but, during the past five years, well over 2,000 papers have appeared in the literature.
Soya has been consumed in China and other eastern countries for more than 5,000 years but it is relatively new to western countries. It was introduced into the United States less than 200 years ago, when it made up ballast aboard returning clipper ships. The recent interest in the potential health benefits of soya, and hence of isoflavones, arose as a result of epidemiological studies, primarily from Japan where soya consumption is high. These indicated that soya had a protective effect against sex-hormone-dependent cancers, including breast and prostate cancers.1 Currently, soya isoflavones are being investigated to see whether they have a protective role in a range of conditions, including cardiovascular disease, various cancers, osteoporosis and menopausal symptoms. To date, most research on these compounds has been conducted using soya products, as it is not yet clear whether isoflavones are the only potentially beneficial compounds in soya. Investigators are also assessing whether dietary supplements containing isoflavones are of value or not.
What are isoflavones?
Isoflavones belong to a class of compounds known as flavonoids. Products made from them include soya flour, soya milk, tempeh and tofu. They are present in varying amounts, depending on the type of soya product and how it is processed. Isoflavones are also found in dietary supplements, most of which are based on soya, but some come from other plant sources, such as red clover.
The principal isoflavones in the soya bean are genistein, daidzein and glycetin. These are usually found in the form of glycosides, which after ingestion are hydrolysed in the large intestine by the action of bacteria to release isoflavones.
What do they do?
By virtue of their chemical structure, isoflavones are weak estrogens and are also known as phytoestrogens. They are capable of binding to estrogen receptors, where, depending on the hormonal status of the individual, they seem to exert either estrogenic or antiestrogenic effects. This has led to speculation that, premenopausally, isoflavones may be antiestrogenic, whereas postmenopausally they could act as estrogen receptor agonists.
The identification of a second estrogen receptor in the mid-1990s helped to shed light on the possible role of isoflavones. This ?newer? estrogen receptor is known as the beta-receptor, while the ?older? one is known as the alpha-receptor. Different tissues appear to have different ratios of each receptor type. Alpha-receptors appear to predominate in the breast, uterus and ovary, while beta-receptors occur more frequently in prostate, bone and vascular tissue. Phytoestrogens, although far less potent than endogenous or synthetic estrogens, have been shown to bind to beta-estrogen receptors, raising the possibility that they could produce beneficial effects on, for example, bone and vascular tissue, without causing adverse effects on the breast and ovary.
Daidzein can be metabolised by bacteria in the large intestine to form either equol, which is estrogenic, or to o-desmethylangolensin, which is non-estrogenic. Genistein is metabolised to the non-estrogenic p-ethyl phenol. Variation in the ability to metabolise daidzein could, therefore, influence the effects of isoflavones.
Not surprisingly, isoflavones are being promoted as ?natural? hormone replacement therapy (HRT) that has no side effects. However, further research is needed to provide good evidence for the clinical application of isoflavones, and individuals should be discouraged from using these products as HRT until more is known about them.
Although the current interest in isoflavones has been generated by their potential hormonal effects, it has now become apparent that these compounds have a range of physiological effects beyond the purely hormonal. Animal and in vitro evidence indicates that isoflavones arrest the growth of cancer cells through inhibition of DNA replication, interference of signal transduction pathways and reduction in the activity of various enzymes. Isoflavones also exhibit antioxidant effects, suppress angiogenesis (the proliferation of new blood vessels typically seen within malignant tumours) and inhibit the actions of various growth factors and cytokines.2
Soya protein and supplements containing isoflavones have been investigated for their role in cardiovascular risk reduction. Several studies in animals and humans have shown that soya can reduce both total and low- density lipoprotein (LDL) cholesterol, particularly in people with raised cholesterol levels. The mechanisms by which soya foods could reduce cholesterol are being investigated and may include enhancement of bile acid secretion and reduced cholesterol metabolism.
Other mechanisms, independent of cholesterol lowering, by which soya could be cardioprotective, include reduction of platelet aggregation and clot formation, and inhibition of atherosclerosis by both an antioxidant effect, and by inhibition of cell adhesion and proliferation in the arteries.2 Preliminary studies in small numbers of subjects have indicated that a diet high in isoflavones could offer protection against LDL oxidation.3,4 This is an interesting finding, given that oxidised LDL may be a more significant risk factor for coronary heart disease (CHD) than LDL alone. However, further studies are required to confirm these possibilities.
A meta-analysis of 38 controlled clinical trials looking at the effects of soya protein on serum lipid levels in humans, showed that there was a statistically significant association between soya protein intake and improvement in serum lipid levels.5 Of the 38 trials, 34 reported a reduction in serum cholesterol and, overall, there was a 9.3 per cent decrease in total cholesterol, a 12.9 per cent decrease in LDL cholesterol and a 10.5 per cent decrease in triacylglycerols. High density lipoprotein (HDL) cholesterol increased but this change was not significant. The improvement in blood lipids seemed to be related to the degree of hypercholesterolaemia in each patient.
More recently, in a double-blind, placebo-controlled trial involving 156 healthy men and women, intake of soya protein providing 62mg isoflavones was associated with a significant reduction in total and LDL cholesterol compared with isoflavone-free soya protein (placebo).6 Moreover, soya protein providing 37mg isoflavones was also associated with a decrease in total and LDL cholesterol but the reduction was significant only in those subjects with a baseline LDL exceeding 4.24mmol/L. However, there was no effect on HDL levels or triacylglycerols. Soya protein providing a lower dose of isoflavones (27mg daily) had no effect on any of the measured indices and, in subjects with baseline LDL levels between 3.62 and 4.24mmol/L, there was no significant effect at any dose of isoflavones.
Other recent studies in men7 and postmenopausal women8 have continued to confirm that soya improves lipid levels in people with hypercholesterolaemia.
However, no significant differences in plasma total and HDL cholesterol, or in platelet aggregation, were seen in two groups of men consuming either a soya protein beverage powder or a control. This was possibly because the men were normocholesterolaemic on entry into the study.9 Nevertheless, soya protein was found to enhance the effect of a low-fat, low-cholesterol diet by reducing serum LDL cholesterol and increasing the ratio of LDL cholesterol to HDL cholesterol in men with both normal and high serum lipid levels.10
Another study, this time in 13 premenopausal women with normal serum cholesterol levels, found that total cholesterol, HDL cholesterol and LDL cholesterol levels changed significantly across menstrual cycle phases.11 During specific phases of the cycle, soya protein providing 128.7mg isoflavones significantly lowered LDL cholesterol by between 7.6 and 10.0 per cent, the ratio of total to HDL cholesterol fell by 10.2 per cent and the ratio of LDL to HDL cholesterol by 13.8 per cent. Despite the high intake of isoflavones, the changes in lipid concentrations were small. However, the authors concluded that, over a lifetime, even the small effects observed could slow the development of atherosclerosis and reduce the risk of CHD in women with normal cholesterol levels.
Whether dietary supplements containing isoflavones are as effective as soya protein in reducing cholesterol levels is an important issue but studies so far where isoflavones have been given in tablet form have yielded less positive results than those using soya protein. Placebo-controlled trials in a mixed group of men and menopausal women,12 premenopausal women13 and postmenopausal women14,15 have shown no significant effects on plasma lipids.
Epidemiological studies have shown that populations with high intakes of soya foods, such as those of China, Japan and other Asian countries, usually have a reduced risk of cancers of the breast, prostate, colon and uterus.16,17 In addition, experimental evidence from in vitro and animal studies on the effects of isoflavones on cancerous cells18-20 has led to the suggestion that isoflavones could reduce the risk of cancer in humans.
Substantial reduction in risk of breast cancer has been reported among women with high intakes of phytoestrogens (as evidenced from urinary excretion).21 Lower urinary daidzein and genistein concentrations were also found in postmenopausal women with recently diagnosed breast cancer compared with controls.22 Isoflavones appear to protect against cancer by their influence on growth factor, malignant cell proliferation and cell differentiation. However, most clinical studies have not specifically examined the relationship between isoflavone intake and cancer risk, so definitive data are not available. Clinical trials in prostate and breast cancer are in progress.
There is some evidence from animal studies that soya isoflavones preserve bone mineral density.23,24 A preliminary study involving 66 hypercholesterolaemic, postmenopausal women supplemented with soy protein (providing either 1.39mg isoflavones/g protein or 2.2mg isoflavones/g protein) or placebo for six months showed that the higher dose of isoflavones was associated with a significant increase in bone mineral density (BMD) at the lumbar spine site.25 The lower dose was not associated with a change in BMD. More recently, a study examined the effects of 24-week consumption of soya protein isolate with isoflavones (80.4mg daily) on bone loss in perimenopausal women.26 This randomised, double-blind study showed that soya isoflavones attenuated the reduction in lumbar spine BMD and bone mineral content, both of which occurred in the control group.
Some studies conducted with ipriflavone, a synthetic isoflavone available as a dietary supplement and as a licensed product in some European countries, found that it reduced bone loss in postmenopausal women.27-29 Currently, further studies are under way looking at the effect of soya protein and isoflavone supplements on bone health.
Reduction of estrogen production in middle-aged women is associated with symptoms of the menopause, such as hot flushes, vaginal dryness and atrophic vaginitis. These symptoms were thought to occur universally. However, women in some countries, such as Japan, appear to experience symptoms less frequently than women in western countries,30 despite the fact that far fewer use hormone replacement therapy postmenopausally.31
Several preliminary studies with soya isoflavones indicate a possible benefit on menopausal symptoms but, overall, the evidence is inconclusive. One study involved 58 postmenopausal women with an average of at least 14 hot flushes a week.32 They received either 45g soya flour or wheat flour each day as a supplement to their regular diet over 12 weeks in a randomised, double-blind design. Hot flushes decreased in both groups (45 per cent in the soya group and 25 per cent in the controls), with a rapid response in the soya group at six weeks. Other menopausal symptoms decreased significantly in both the treated and placebo groups. The authors concluded that the lack of difference between the two groups could be due either to a strong placebo effect or a decline in symptoms with time. Another study provides slightly more persuasive information. One hundred and forty-five postmenopausal women were randomised to receive either three servings of soya foods daily or a control for 12 weeks.33 Menopausal symptom scores, hot flushes and vaginal dryness decreased by 50, 54 and 60 per cent, respectively, in women on the soya diet. These three parameters also fell in the control group, but only significantly for the reduction in menopausal symptom score.
More recently, a double-blind, placebo-controlled study involved 104 postmenopausal women who were randomised to receive 60g soya protein isolate (containing 76mg isoflavones) or a control.34 In comparison with placebo, subjects on the soya supplement reported statistically fewer hot flushes per 24 hours after four, eight and 12 weeks. By week three the treated group experienced a 26 per cent reduction in the mean number of hot flushes, a 33 per cent reduction by week four and, by week 12, a 45 per cent reduction compared with 30 per cent in the control group
Soya foods have been consumed in Asian cultures for centuries. However, studies to assess the long-term safety of supplemental soya protein isolates or isoflavone supplements are lacking, and much needed if safety is to be assured. Isoflavones are estrogenic, albeit weakly, and there is some evidence that they may stimulate cancer cell proliferation in women with breast cancer.35 Until more is known about these compounds, women with breast cancer should consult their pharmacists or doctors before taking isoflavones.
Not enough is known about isoflavones to be able to recommend a daily amount but consumption in Asian countries varies between 25 and 200mg a day. Doses used in clinical studies have been in the same range. As a rule of thumb, 250ml soya milk or yoghurt, or 50g soya flour, cooked soya beans or textured vegetable protein (TVP) provide approximately 50mg isoflavones. Soya sauce and soya bean oil contain almost no isoflavones. Most isoflavone supplements provide 25-100mg total isoflavones.
Many studies have evaluated the effects of isoflavones on cardiovascular disease, cancer, osteoporosis and menopausal symptoms. However, data are inconclusive as to whether potential beneficial effects are attributable to isoflavones alone or to other components in the foods that contain them. The most convincing data, to date, relate to the effect of soya foods containing isoflavones (rather than dietary supplements) on plasma lipid levels. These effects seem to be greater in individuals with high cholesterol levels than in those with levels in the normal range
Data on the ability of isoflavones to protect against various cancers and osteoporosis are, as yet, inconclusive. Some research results support the value of isoflavones in reducing menopausal symptoms but several studies have found no differences between those treated with isoflavones and controls. Claims have been made for supplements containing these compounds but there is insufficient evidence to say that they can be used as a substitute for hormone replacement therapy during the menopause.
Indeed, additional clinical trials are needed before specific recommendations can be made about taking supplements or large amounts of foods containing isoflavones for any indication. However, this story is not over yet.
1.Department of Health. Health Information for Overseas Travel 2000. London: Stationery Office; 2000.
2.Salisbury D, Begg N, editors. Immunisation against infectious diseases. London: Stationery Office; 1996.
3.Kassianos GC. Immunisation: childhood and travel health. Oxford: Blackwell Science; 1998.
Dr Mason is a pharmacist with a postgraduate qualification in nutrition
Citation: The Pharmaceutical Journal URI: 20003979
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