Mindy Kurzer, PhD
Soy isoflavones are being studied—and marketed—as alternative treatments for menopausal symptoms, cardiovascular conditions, bone loss and breast cancer risk. Mindy S Kurzer, PhD, researches the field.
It is known that women living in Asia have lower risks of heart disease, breast cancer and menopausal symptoms than Western women. These differences in risks, however, disappear within a generation or two after Asian women emigrate to the West. In recent years, researchers have attributed these differences in disease and symptom risks to environmental factors, particularly diet. One of the more promising biochemical factors they have investigated is phyto-oestrogens.
Phyto-oestrogens are weak oestrogens that bind to oestrogen receptors and exert hormonal and anti-hormonal effects.  Isoflavones is a class of phyto-oestrogens that is concentrated in soybeans and also found in plants not typically consumed by humans, such as red clover (Trifolium pratense) and kudzu (Pueraria lobata). A second class of related compounds is the lignans, widespread in plant foods but particularly concentrated in oilseeds, such as flaxseed and whole grains.
Asians typically consume 15-50mg/day isoflavones compared with the typical Western consumption of approximately 1-2mg/day.  Americans consume isoflavones primarily in traditional soy foods, such as tofu (30mg isoflavones per 100g edible portion), miso (40mg per 100g), tempeh (40mg per 100g), soymilk (10mg per 100g) and isolated soy protein (100mg per 100g) added during food processing or consumed as a beverage. 
In addition to being consumed in foods, extracted isoflavones also are marketed in numerous forms as dietary supplements that are regulated in the US under the Dietary Supplements Health and Education Act (DSHEA). A primary market for soy isoflavone supplements is peri- and post-menopausal women who are choosing an alternative to hormone replacement therapy (HRT). Most of these supplements contain isoflavones derived from soybeans or red clover, and some also contain botanicals, such as black cohosh (Cimicifuga racemosa).
Although approved health claims for isoflavones do not currently exist, numerous manufacturers are making structure-function claims. Primary claims for phyto-oestrogen supplements are reduced menopausal symptoms, and improved cardiovascular, bone and breast health. The review that follows summarises recent data regarding the health benefits of soy and isoflavones in each of these areas.
For many women, menopausal hormonal changes lead to uncomfortable vasomotor and other physical and psychological symptoms. The most widely experienced and studied vasomotor menopausal symptoms are hot flushes and night sweats. These symptoms can motivate many women to seek treatment. Oestrogen is the main effective treatment, but increasing numbers of women are avoiding oestrogen therapy due to side effects or fear of increased cancer risk. Therein lies the growing interest in alternative therapies for menopausal symptoms.
Observations that 85 per cent of women in North America report incidences of hot flushes,  whilst only 15-25 per cent of women in Asia report incidences,  have led to the hypothesis that soy isoflavones may exert oestrogenic effects that alleviate menopausal symptoms, so researchers are probing the possible benefits of isoflavones as an alternative therapy.
In fact, the main motivation for phyto-oestrogen supplementation by peri- and post-menopausal women is reduction of the vasomotor symptoms of menopause. The effectiveness of phyto-oestrogens is supported by a prospective study of post-menopausal Japanese women that suggested an inverse association between hot flushes and soy food or isoflavone consumption. In this study, women taking 51mg/day isoflavones were half as likely to have symptoms as those taking 20mg/day. 
In intervention studies, researchers evaluating the effects of soy on menopausal symptoms saw inconsistent results. This is likely due, in part, to the placebo effect, such that symptoms were reduced by 20-50 per cent in both the control and treatment groups. In order to show an independent effect of soy, the reduction in symptoms must be significantly greater in the soy group than in the control group. Nearly all studies reported a 20-30 per cent reduction in symptoms in the placebo group, and additional reductions of 10-20 per cent were seen in intervention studies using soy foods,  soy protein isolate [8,9] and soy extracts [10,11,12] providing 30-100mg/day isoflavones.
Although both placebo and treatment groups have generally shown reductions in symptoms, the treatment groups did not always experience a greater reduction than the placebo group. No benefits beyond the placebo were seen in two studies that each provided about 80mg isoflavones in soy protein isolate, [13,14] or in two studies of breast cancer patients who consumed 90mg/day isoflavones in a soy beverage  or 150mg/day isoflavones in a soy isoflavone extract.  In the latter two studies, some of the women with breast cancer were taking either tamoxifen or raloxifene, which might be expected to negate the effects of the isoflavones. 
There were no benefits beyond that of the placebo in two studies involving 30-120mg isoflavones extracted from red clover. [18,19] However, a more recent double-blind, randomised, placebo-controlled study on red clover did show an effect. Here, 30 women took 80mg/day isoflavones (Promensil) and experienced a clinically significant 44 per cent decrease in hot flushes compared with placebo. 
These data taken as a whole suggest that consumption of as little as 30mg/day soy isoflavones, in soy protein or as a soy extract (but not red clover extract), may reduce hot flushes by 30-50 per cent. However, the effect is variable, and how much of that is due to the placebo effect is not easy to determine. The reduction due to the isoflavones may be only 10-20 per cent.
The soy protein does not appear to be required, and the greatest benefit may be realised when the supplement is taken in divided doses throughout the day, and in subjects with the most severe symptoms.  Unlike oestrogen therapy, soy isoflavones do not appear to stimulate the endometrium and should therefore not increase risk of endometrial cancer as does exogenous oestrogen. 
It has been known for some time that consumption of soy protein is beneficial for heart health. In 1999, the US Food and Drug Administration approved the health claim that '25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.'  Since it is possible to consume four servings of a soy food per day, products containing 6.25g soy protein per serving are permitted to use this health claim.
One year later, the American Heart Association issued a statement that concluded, 'It is prudent to recommend including soy protein foods in a diet low in saturated fat and cholesterol to promote heart health.' 
The health claim for soy protein was approved after consideration of numerous studies, including a 1995 meta-analysis of 38 studies reporting that soy protein lowered cholesterol in 34 out of 38 studies.  An average soy protein intake of 47g/day compared with animal protein led to significant average decreases of 9 per cent and 13 per cent, respectively, in concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol, as well as a small non-significant increase in high-density lipoprotein (HDL) cholesterol. Epidemiological studies have suggested that changes of this magnitude could result in a 25-50 per cent decrease in cardiovascular disease risk. Since the meta-analysis was published, additional epidemiological [25,26] and intervention [9,27,28] studies have confirmed the ability of soy protein to favourably affect lipid profiles.
In order to determine whether isoflavones are responsible for soy's lipid-lowering effects, a few studies have compared the effects of an isoflavone-rich soy protein isolate with an isoflavone-depleted soy protein isolate. Results showing that the isoflavone-rich isolate exerts greater effects than the isoflavone-poor isolate suggest that isoflavones are required. In one study, researchers evaluated 13 premenopausal women consuming three isolated soy protein powders providing 10, 65 and 129mg/day isoflavones for three months each.  The highest isoflavone dose resulted in beneficial effects on lipoprotein profiles, with up to 10 per cent declines for LDL cholesterol concentrations and 14 per cent declines in the ratio of LDL to HDL cholesterol. Intermediate effects were seen for the middle dose. Comparable effects were seen in a similarly designed study of 18 post-menopausal women by the same group of investigators.  Interestingly, studies using isoflavone extracts of soy [31,32,33] or red clover [34,35] have not reported these effects on blood lipids.
|For healthy women, consumption of soy foods or isoflavones is likely to confer some health benefits without significant risk|
These results suggest that soy isoflavones lower LDL cholesterol, and probably increase HDL cholesterol, when consumed in soy protein. The effect is greatest in women with high cholesterol levels, although small changes have been reported in women with normal and slightly elevated cholesterol levels. [29,30] Because isoflavone extracts do not exert these effects, it is thought that the cholesterol-lowering is due to an interaction between the isoflavones and soy protein. Isoflavone extracts may exert other benefits on the cardiovascular system, such as improved total systemic arterial compliance (shown with both soy  and red clover  supplements), reduced LDL particle oxidation, [36,37] and improved vascular resistance. 38]
After reaching menopause, women experience up to a 10-fold increase in the rate of bone loss.  Since bone loss is generally thought to be related to the decline in oestrogen levels, there has been great interest in the possibility that soy phyto-oestrogens might exert similar effects as endogenous oestrogen and prevent the development of osteoporosis. Supporting studies have been performed in animals, [40,41] with few human studies in this area.
The few human studies evaluating the effects of soy and isoflavones on bone metabolism have generally found positive benefits. Cross-sectional studies performed on women living in Asia [42,43] and the US  have shown increased bone mineral density (BMD) in women consuming greater quantities of isoflavones.
At this time, there are only two known human intervention studies using appropriate control groups in the evaluation of isoflavone effects on bone. [45,46] These two studies compared post-menopausal or peri-menopausal women consuming 80-90mg/day isoflavones for six months in soy protein with women consuming casein, whey protein or 56mg/day isoflavones in soy protein. When compared with the control groups, the women consuming 80-90mg/day isoflavones showed increases in lumbar spine BMD and bone mineral content. These two clinical trials suggest that over the short term, soy isoflavones in soy protein may attenuate lumbar spine bone loss in peri- and post-menopausal women, despite reports that markers of bone metabolism are not altered by isoflavone intake. 
The evidence that isoflavones have clinically important beneficial effects on bone for post-menopausal women is suggestive but not conclusive, and more research in this area is needed. We need well-designed controlled studies to establish whether these effects are sustained over two to three years, and whether isoflavone extracts prevent post-menopausal bone loss. Assessments of BMD, if not occurrence of fractures, would be particularly desirable.
The epidemiological data supporting an inverse association between phyto-oestrogens and breast cancer risk are suggestive of benefits, but not strongly so. A number of case-control studies have reported inverse associations between breast cancer risk and soy food intake [48,49,50] or urinary phytoesterogens, [51-52] but other studies do not confirm these results. [53,54,55] Other population-based studies have shown that soy intake is associated with reduced mammographic density, a potential marker of reduced breast cancer risk. 
Animal studies provide more convincing evidence of the cancer-preventive effects of soy and phyto-oestrogen consumption, although some researchers have concerns about possible stimulation of established tumours. A 2001 meta-analysis concluded that animals consuming soy or purified isoflavones develop fewer tumours than control animals.  At the same time, phyto-oestrogen studies in animals with established tumours have shown both inhibitory  and stimulatory [59,60] effects, and one recent study using a mouse model showed that dietary isoflavone genistein negates the inhibitory effect of tamoxifen. 
The discrepancies among these results may arise because the time-of-life of exposure to phyto-oestrogens determines whether or not the effects on carcinogenesis are beneficial. Studies have shown that the greatest cancer-preventive effects occur in animals exposed during the period of breast development, [62,63] probably because phyto-oestrogens reduce the growth of the terminal end buds, the mammary structure most vulnerable to carcinogenesis. Consistent with this observation is data from an epidemiological study conducted in China, in which researchers reported that women who consumed greater quantities of soy foods as adolescents had lower breast cancer risk as adults.  A study recently performed using Asian-American subjects confirmed these results. 
It thus appears that soy phyto-oestrogens are cancer-preventive, particularly when consumed early in life. Effects in adulthood are less clear, and it is possible that phyto-oestrogens actually stimulate growth of established breast cancer cells.
Soy Meets Girl
Research has shown that soy protein and isoflavones provide a number of benefits for menopausal women beyond the expected nutritional attributes. Consumption of at least 30mg/day soy isoflavones, in soy protein or as an extract, reduces the intensity and frequency of menopausal symptoms by 10-20 per cent, or about 30-50 per cent with the placebo effect included.
Soy protein and isoflavones are both required to lower blood cholesterol concentrations, on the order of 5-15 per cent in people with high cholesterol concentrations. Isoflavone extracts do not lower cholesterol, although they may exert other benefits on the cardiovascular system.
Isoflavones appear to prevent bone loss over the short term, although longer studies are needed to confirm these early studies.
When consumed early in life, isoflavones appear to be cancer-preventive, but a few animal studies showing stimulation of existing tumours raise concerns that phyto-oestrogen supplements should not be recommended for women at high risk of breast cancer.
At the same time, it is unlikely that modest consumption of one or two servings of soy foods or soy protein per day would be harmful. For healthy women, consumption of soy foods or isoflavones is likely to confer some health benefits without significant risk.
Marketing Applications: Health claims and technologies season new products|
The soyfoods industry has changed dramatically in the last three years. Many major food corporations have entered the market as part of their new product development strategy or through acquisitions. One factor accounting for this growth is the US Food and Drug Administration (FDA)-approved heart-health claim, which states that '25 grams of soy protein, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.'
Because of this health claim, awareness by consumers of the heart-healthy benefits of soy is high, nearing 40 per cent. Although many consumers understand the concept, they may not fully understand how to take advantage of soy in their diets. The goal of soy manufacturers and product developers is to deliver soy in a variety of nutritious, great-tasting mainstream food applications such as pastas, cereals, breads, and meat and dairy analogues.
To capitalise on the soy health claim, ADM has created the Soy7 brand, which includes a line of soy-enriched pasta and meat analogues. Every Soy7 product delivers a minimum of seven grams of soy protein per serving and carries the FDA-approved heart-health claim. The premise is that consumers can eat four servings a day of Soy7 foods, thereby giving them 28g of soy protein a day. The ADM Soy7 line provides heart-healthy soy protein that can fit into consumers' diets in products that consumers are already familiar with such as pastas and burgers.
One interesting development in soyfoods is the difference in market position between the US and Europe. Typically, Europe lags behind the US in market development by about three to five years, but in the case of soyfoods the situation is different. Europe, particularly the UK, enjoys a more advanced soy market. Issues of taste do not drive this as much as consumer suspicion of mainstream meat products compounded by high-profile food scares, the most notable example being bovine spongiform encephalopathy (BSE).
New innovations in both texture and flavour of soyfoods have brought dramatic improvements in recent years. Good examples of this are veggie burgers, in which flavour, taste and texture are now remarkably close to the meat equivalent. In the area of meat analogues, ADM has pioneered 'twin-phase' technology for products in the UK. This is where two different colours, flavours and textures are mixed together in one product. An example of this is a 'pork' or 'lamb'-style cutlet with a 'fat ring' running along the outside of the product, or a 'roast' that has a stuffing mix running through it, thereby simulating the meat equivalent.
Also on the horizon are new extrusion technologies that will lead to a new generation of meat analogues. Other new technologies will also expand the fields of dairy analogues, baked goods and meal replacements by improving soy texture and mouthfeel, increasing soy protein powder dispersion in fluids, and even boosting nutritional content.
director of marketing and soyfoods, ADM
Formulations: Does processing affect isoflavone stability?
Very few studies have examined the effect of food processing on isoflavone content and on their chemical structure. Nutraceu-ticals manufacturers strive to improve the stability and availability of bioactive phytochemicals in foods.
The objective of the current work performed in our lab is to determine the chemical reactions that affect the bioavailability and bioactivity of soy isoflavones. Our central hypothesis is that soy isoflavones react during processing and storage, and that their degradation changes their bioavailability and modifies their bio-activity. Understanding how chemical reactions involving soy isoflavones affect their biological activity will provide a basis for developing new formulations, processes and storage paradigms for foods with high content and beneficial quality of isoflavones.
Researchers have reported that heating daidzein and genistein conjugates under acid conditions released free isoflavones, and that genistein is further degraded. (Wang et al, 1990) High temperatures and pressure reduced the total isoflavone content in corn/soy mixtures. (Singletary, 2000) The effects of processing techniques on the distribution of isoflavones were also investigated in the manufacturing of tempeh, soymilk, tofu and protein isolate. Manufacturing steps, such as soaking, heat processing, coagulation and alkaline extraction caused up to more than 50 per cent losses of isoflavones. (Wang and Murphy, 1996)
However, to date, there are no data available on the kinetics of these changes and the factors affecting them. Moreover, due to the complex composition of isoflavone conjugates in soybeans and soy products, it was pointed out that the chemical form might have potential implications on isoflavone metabolism, bioavailability and biological activity (Barnes et al, 1994).
In our lab, we have studied the kinetics of isoflavone degradation in soymilk and model solutions. In addition, we measured the antioxidant levels of the degradation products, and assessed their bioavailability in vitro. The initial part of our work examined the stability of genistein and daidzein derivatives in soymilk. Soymilk was stored at ambient and elevated temperature range, and change in isoflavone content was monitored with time. Genistein loss in time showed typical first-order kinetics, and the temperature dependence of genistein loss followed the Arhenius relation. In addition, an increase in 6"-O-acetyldaidzin concentration was detected at the early stages of storage, followed by a slow decrease.
The results obtained in this study can serve as a basis for estimating the shelf life of soymilk as related to its genistein content.
Research into the degradation kinetics in model systems used a differential scanning microcalorimeter to study the stability of the isoflavones. Degradation reactions were detected starting at 60°C and up to a maximum ~90°C. Long-time storage of the same model solutions indicated higher degradation rates in alkaline conditions. As for soymilk, all reactions were apparently of the first order. Interestingly, while the antioxidant activity of genistein degradation products was lower than genistein, the products of daidzein decomposition showed significant antioxidant activity. Preliminary bioavailability experiments support previous studies of other researchers, showing a faster absorption rate for deglycosylated isoflavone derivatives.
We hope that the ongoing research will contribute to understanding the effects of processing and storage on soy isoflavones, as well as the effect of these processes on the overall bioactivity of these foods. As a result, better strategies for the application of soy isoflavones in the diet can be developed.
Dr Eyal Shimoni, Department of Food Engineering and Biotechnology, Technion - Israel Institute of Technology, Haifa, Israel
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