Soy isoflavones for disease prevention
The health benefits of soybean products have been reported for thousands of years & substantial evidence now supports the effectiveness of soy constituents in cancer, heart disease, osteoporosis, menopausal hot flushes and oxidative stress.
The health benefits of soybean products have been reported for thousands of years and recent research supports this wisdom as justified and very relevant to modern diseases. Conditions that are rife today are those against which soy happens to be most effective. Vegetarians and Asians living by their traditional culture, evidence significantly less heart disease and cancer than Western populations (although they attain similar risk profiles on moving to an industrialised society). It is accepted that soy products are at least partly responsible for the reduced incidence of these diseases.
Substantial evidence now supports the effectiveness of soy constituents in cancer, heart disease, osteoporosis, menopausal hot flushes and oxidative stress.
Tumours (hormone dependent
oestrogen (breast, endometrial, ovarian)
Menopausal or hypo-oestrogenic states
Premenopausal hyperoestrogenic states
Thrombotic tendency (stroke)
Free radical stress
We can group the activity of the soy products into three basic classes:
1. As a regulator of oestrogen activity and inhibitor of environmental oestrogens
2. A lipid (fat) lowering agent
3. Several antitumour mechanisms have been identified for soy
Soya beans contain high amounts of proteins, including all of the amino acids. They are also rich in calcium, iron, zinc, B vitamins, vitamin E and fibre. These factors certainly contribute to the beneficial effects of soy products, but it is the phytochemicals that they contain, which are receiving enormous research attention and appear to be the major disease preventing principles of soy.
The major phytochemicals responsible for the actions of soy are the isoflavones. Isoflavones are sterolic oestrogen-like chemicals, which have a variety of actions. They are found almost exclusively in legumes and with the highest concentrations in soya beans and soya products.
The major isoflavones are genistein and daidzein, with equol, biochanin A and formononetin also having some activity. The properties of these chemicals are covered independently in following sections.
Other health giving chemicals found in soy include:
The saponins have a soap-like nature and are able to quench free radicals due to their antioxidant ability. Other research demonstrates them to have cholesterol lowering potential.
These, like the saponins, are antioxidants that have been seen to protect cellular DNA from attack by carcinogens.
In laboratory studies, phytates inhibit colon cancer and the early stages of breast cancer. They seem to enhance overall immunity by increasing the activity of natural killer cells and also by functioning as antioxidants. As active chelators of iron, phytates prevent excessive iron absorption and generation of free radicals in the gastrointestinal tract.
Useful for the formation of neural tissue, lecithin has been shown to reduce tumour incidence. Lecithin functions as a lipotropic agent so assists fat metabolism.
Omega-3 fatty acids
The essential fatty acids have received a great deal of research attention, which has firmly established them as powerful nutritional tools that dramatically affect a variety of conditions. These include inflammatory conditions, elevated cholesterol and triglycerides, heart disease, thrombosis, eczema, psoriasis and hypertension.
Isoflavones have oestrogenic activity and impact the hormonal system in several beneficial ways. Most potent are genistein and daidzein, although there are others, which have demonstrable activity.
The following benefits have been demonstrated for genistein.
1. As weak oestrogens, the isoflavones are able to block the activity of the more potent, endogenous oestradiol. This provides antioestrogenic activity.
2. Tyrosine kinase is an enzyme produced by the cancer causing genes, oncogenes. The role of tyrosine kinase is to regulate cell cycle, cell survival and cell transformation. The net effect of tyrosine kinase is to activate tumour development and, as a tyrosine kinase inhibitor, genistein has a positive effect on tumour proliferation (as can be seen by the research trials mentioned later).
3. Other enzymes involved in tumour promotion are also inhibited by genistein. These include DNA topoisomerases I and II2 and S6 kinase.
4. Tumour cells continue to grow unchecked because they have failed to differentiate (mature). These immature cells are not programmed to stop proliferating when they touch neighbouring cells. Genistein has been demonstrated to promote tumour cell differentiation, thereby inhibiting tumour proliferation.
5. Tumours require a new blood supply to accommodate their increasing mass and volume. Angiogenesis is the growth of new blood vessels into tissue and inhibition of this process greatly inhibits tumour growth.
6. Like most of the other nutritional and chemical constituents of soya beans, genistein is an antioxidant.
7. Evidence is available, which suggests genistein benefits heart disease by its antithrombotic activity and inhibition of platelet aggregation.
The properties shown by genistein explain why it attracts so much interest for treatment of a variety of conditions including cancer, heart disease and osteoporosis.
Daidzein is the next most prominent component of soy and has similar therapeutic potential.
Daidzein's therapeutic effects can be appreciated by its properties:
1. As a weak oestrogenic agent, daidzein has antioestrogenic potential in premenopausal women and oestrogenic activity in menopausal women. This makes daidzein an inhibitor of oestrogen-dependent tumours.
2. The oestrogenic potential of daidzein in postmenopausal women makes it useful for prevention and treatment of osteoporosis and menopausal symptoms.
3. Like genistein it is a potent antioxidant.
4. The antitumour properties of daidzein are general, although data suggests it to be particularly useful in leukaemia, where it induces these tumour cells to differentiate and revert to normal cells.
Other isoflavonoid compounds in soy have similar properties. Glycitein and equol are thought to have contributed to the effects seen in research trials using soy isolates, which concentrate these types of chemicals into a powder.
These research trials show the soy isoflavone concentrate to be beneficial in the following conditions:
Between Western and Asian women, there are large variations in the incidence of menopausal symptomology. Hot flushes are experienced by 70-80% of women in Europe, whereas 18% of Chinese women notice these symptoms and only 14% of Singaporean women are affected.
Supplementation with soy isoflavones has resulted in clinical improvement in hot flushes in menopausal women. Researchers who compared the effects of wheat flour soy and soy flour found that soy flour supplementation resulted in a 25-40% reduction in flushing over a 12 week period.
The isoflavones are partial oestrogen agonists. This means they have an oestrogenic effect but they may block the activity of oestradiol, therefore their net effect is antagonistic to oestrogen.
During the premenopausal years, the administration of phyto-oestrogens, like the isoflavones, is known to increase the length of the menstrual cycle, especially the follicular phase. The perceived benefit of this is that the woman faces a reduced lifetime oestrogen exposure, thereby reducing her risk to oestrogen dependent tumours. Further, if there are severe fluctuations in hormonal levels, these will be tempered by the partial agonist, as would excessive oestrogen levels.
Medical therapy for menopausal conditions and osteoporosis is fraught with side effects and potential negative aspects are yet to be fully evaluated.
The isoflavones from soy appear to be safe in therapeutic doses and to have great promise for retaining bone tissue in those women at risk of developing osteoporosis. Osteoclasts resorb bone tissue. Like tumours, they are dependent on tyrosine kinase. As mentioned earlier, isoflavones are inhibitors of this enzyme and so retard bone resorption. This is one of the proposed mechanisms whereby bone fragility can be prevented.
Recent research has demonstrated genistein and other tyrosine kinase inhibitors to be useful preventers of bone resorption and hold promise for ich are absorbed and enter the circulation have an inhibitory effect on LDL production, probably by binding to the cholesterol receptors in the liver.
The first study to show these effects was by Hughes et. al. in 1967. The optimal scenario for improvement in lipid profile is to totally replace animal protein with soy and those patients with the highest cholesterol have the greatest benefits. The most changes in LDL reductions have been 26% in some individuals. In postmenopausal women, the administration of 40 g of isolated soy protein with 1.39 mg of isoflavones both reduced LDL and increased HDL cholesterol levels.
Lipid lowering drugs are contraindicated in children for as long as possible and medicine can offer little else to lower LDL. Soy protein concentrates have demonstrated ability to modify the blood cholesterol in children. A recent cross-over study showed the potential of soy protein's effect on LDL in children. Compared to a standard low fat diet, which can result in LDL reductions of 7-8%, a diet incorporating approximately 20 g soy protein isolate showed a drop of 16-22%.
Having elevated LDL alone does not necessarily predispose to a greater risk of heart disease. Oxidation of the LDL particle seems more important. Being a lipid-laden molecule, LDL is at risk of oxidation by free radicals. When it is oxidised, it becomes highly atherogenic.
The LDL particle normally passes into and then out of the blood vessel wall, delivering cholesterol. The oxidised LDL passes into but does not leave this tissue, because macrophages recognise that it has become damaged and invaginate it. The accumulation of macrophages, full of oxidised LDL, is the initial lesion of an atherosclerotic plaque. This is why antioxidants are useful in preventing atherosclerosis and heart disease. Research has demonstrated soy protein to have a significant protective effect against LDL oxidation.
Kanazawa has recently shown that the LDL of patients with myocardial infarction, cerebral infarction or familial hypercholesterolaemia shows a higher degree of oxidation and has a greater ability to cause platelets to aggregate. LDL particles also tended to be larger than normal. Soy was seen to prevent oxidation of the LDL particle, diminish platelet aggregatory tendency and to reduce the size of the LDL particles in these patients.
Tempeh is a fermented soy product, which has been used in Asian cuisine for centuries. It is a source of vitamin B12, superoxide dismutase and isoflavone. Supplementation of diets of rats with tempeh resulted in a reduction of total lipid peroxidation, as demonstrated by reduced malondialdehyde (an indication of lipid oxidation). Compared with a casein diet, cholesterol and triglycerides were also lowered in those animals taking tempeh.
Many cardiovascular events are precipitated by thrombus formation, which occludes blood vessels to tissues, including the heart and brain.
Thrombus formation is dependent upon the coalescing of platelets to form an aggregate. Platelets aggregate to form a blood clot in response to several stimuli. Free radical exposure is a potent stimulus to platelets. Experiments on platelets exposed to collagen show that the platelets produce reactive oxygen species and become aggregatory.
Administration of genistein demonstrated a significant antioxidative capacity and anti-aggregatory ability of this isoflavone.
Other studies have shown isoflavones to inhibit the production of an enzyme, phospholipase D, which is involved in platelet aggregation. Induction of aggregation of platelets by pervanadate was inhibited by isoflavones and the production of phospholipase was seen to be significantly reduced.
The role of isoflavones as promoters of cellular differentiation appears to be a major factor in their observed effect on tumours. The oestrogenic properties of isoflavones also contribute to its effects on oestrogen-dependent tumours.
Some research shows that environmental oestrogens (xenooestrogens) are strong contributors to a variety of oestrogen mediated disorders. These oestrogens are consumed in foods (dairy and meats) and are leached from plastics. Some environmental chemicals, especially pesticides, have an oestrogenic effect.
The effect of the xenooestrogens is to elevate women's total lifetime oestrogenic exposure, so they have increased risk of oestrogen-dependent tumours. It is also thought that in girls, these environmental hormones promote premature menarche, so that they start to produce their own oestrogen at a younger age. The role of phytooestrogens here is to bind to oestrogen receptors, without eliciting a strong response, thereby inhibiting the xenooestrogenic effect.
At the same time, as mentioned earlier, tumours require a variety of enzymes for initiation and proliferation e.g. tyrosine kinase, and inhibitors of these factors may reduce cancer formation. Those factors with immunostimulatory potential would have obvious benefits against tumour development, as do the many antioxidants present in soy concentrates.
A recent meta-analytical study investigated the role of soy in cancer and determined that a protective effect of soy on hormonal and nonhormonal tumours is significant. There has been no indication in any studies of a negative effect of isoflavones on tumour promotion.
Breast cancer is the most common tumour in females and is the second leading cause of cancer death among women. Asian women have a low incidence, although this protection is lost when they move to a Western environment. It is likely that soy protein is a protective mechanism.
Constantinou studied animal models of mammary carcinoma and the effect of genistein on cellular differentiation. An interesting feature of genistein is that the dose either had an effect to promote differentiation and return to normal cell types, or induced apoptosis, programmed cell death, to abort tumour development. The higher doses induced cell death, whereas the lower concentrations induce maturation of the mammary cancer cells.
Itoh has shown soybean and miso to be preventative of several tumours, including breast and liver. By incorporating these factors into the diet, significant reduction in tumour incidence was seen for several tumours.
Human studies show positive effects of the isoflavones. Studies looking at consumption of soy products correlate inversely with breast tumour incidence for Chinese, Japanese, Filipino and American women. This indicates that those women who consume the least soy products, also have the highest risk of breast cancer. A similar result was seen in a study of British women. Healthy control women had significantly higher serum levels of daidzein and genistein than either previously treated or new breast cancer cases.
The researchers suggest that low serum phytooestrogen levels are a marker for increased risk of breast cancer and may be useful in breast cancer prevention.
An interesting study on transforming growth factor beta (TGBb) and breast cancer showed that part of the effect of genistein on breast cancer inhibition may be due to its promotion of TGBb production. TGBb has been shown to have growth inhibitory effects on human mammary tumour cells. When genistein is added to cells with anti-TGBb antibodies, the effect of the isoflavone is reduced, suggesting this is a primary mode of action.
Colonic carcinoma is preceded by colonic adenoma. Prior to both of these tumours are the preneoplastic aberrant crypt foci. In these stages, the undifferentiated cells are about to become cancerous and agents, which promote cellular differentiation, can abort the cancer development.
Soy flakes, soy flour and genistein have all been shown to reduce the total number of these crypts in animals exposed to carcinogenic chemicals. Colonic cancer was initiated by subcutaneous injection of azoxymethane. The genistein concentrate reduced the crypt formation by 40%, while the soy flour group experienced a 35% reduction in crypt number.
Interestingly, oestrogen, progesterone and dihydrotestosterone receptors have been found on colon cancer tumours and it is thought that the sex hormones play a prominent role in cancer of the colon. As applies to other conditions, which appear to be affected by the soya isoflavones, colon cancer incidence is less in Asian countries and in societies which adhere to a soy based diet.
Dietary fibre has also been isolated as a protector against these tumours and this may be another mechanism of action of soya beans as antitumour agents. The fibre is thought to bind luminal oestrogens and other carcinogenic principles, whilst providing substrate for short-chain fatty acid synthesis, which promotes differentiation of colonic cells.
Research has shown a tendency for increased soya consumption to be associated with a reduced risk for colon carcinogenesis. In vitro studies on well-differentiated adenocarcinoma type colorectal cells show a positive effect of biochanin A, genistein and daidzein. These isoflavones inhibited tumour cell proliferation, probably via an apoptotic process. Apoptosis is the natural suicidal process of cells that are dysfunctional or metastatic.
Several large trials of the ability of soy to prevent colonic cancer are underway.
The study of the role of phytooestrogens as tumour inhibitors has largely focused on female cancers and for obvious reasons. The phytooestrogens though may be more accurately described as phytohormones, as they have similar action on androgen receptors. Therefore, tumours specific to males seem to benefit from the anticarcinogenic properties of soy constituents.
Human prostatic cancer is seen to be inhibited by genistein. In a double-blind clinical trial, the exposure of prostatic tumour cells to genistein resulted in a reduction in the proliferation of these cells.
Hempstock has examined biochanin A, daidzein and genistein and their potential to inhibit three human prostatic cancer cell lines. Compared to controls, the isoflavones induced a strong inhibition, ranging from 42 to 78%, of all cancer cell types.
Animal studies show similar inhibition. Rats administered a transplantable prostate carcinoma were given genistein at 50 mg/kg. A substantial inhibition of the growth of the carcinoma was seen in the prostate. Furthermore, fewer animals developed invasive tumours and compared to the control group, there were fewer cases with lymph node metastases. No genistein-treated animals developed lung metastases.
Approximating an Asian diet by supplementing a Western diet with soy isoflavone concentrate or consuming greater quantities of soya based products, is likely to improve the risk profile we face against degenerative disease so prevalent in our society.