[Soyfoods Symposium 1997 Home Page] Soy as a Possible Alternative to Hormone Replacement Therapy
By Mark Messina, Ph.D.
Nutrition Matters, Inc.Introduction
Soyfoods are no longer consumed only by health food enthusiasts and vegetarians. Soyfoods are becoming mainstream. There are reportedly 26 million soyfood consumers in this country. Increased interest in soyfoods stems in part from the general shift in American eating habits toward a diet more focused on plant foods and more importantly, because of the hypothesized health effects of soybeans and soybean components.
Protein, Fat, and the Glycemic Index
From a nutrient profile perspective, soybeans are quite impressive. Not only are soybeans higher in protein than other beans, most beans are 20-30% protein on a caloric basis whereas soybeans are about 35% protein, but the quality of soy protein is superior to that of plant proteins. However, the quality of soy protein has been under appreciated until recently. This is because the protein efficiency ratio (PER), which is based on the growth of laboratory animals, most commonly rats, has been the standard method for evaluating protein quality until recently. Rats have a methionine requirement that is approximately 50% higher than the human methionine requirement. Consequently, because bean proteins are relatively low in sulfur amino acids, the PERs of beans is quite low.
However, the World Health Organization and the U.S. Food and Drug Administration have adopted an alternative method for evaluating protein quality called the Protein Digestibility Corrected Amino Acid Score (PDCAAS). This method uses the amino acid score (based on the FAO estimated amino acid requirement for 2-5 year old children) and a correction factor for digestibility to arrive at a value for protein quality. Some types of soy protein products have a PDCAAS of close to one, the highest value possible. Soy protein has an amino acid pattern that permits optimal endogenous protein synthesis thus, using somewhat outdated and inappropriate terminology, soy protein is considered a complete protein.
Soybeans also stand out from other beans on the basis of their fat content. Most beans are very low in fat, generally about 5% on a caloric basis. In contrast, soybeans are over 40% fat. The predominant fatty acid in soybeans is the essential fatty acid, linoleic acid, an omega-6 fatty acid. But soybeans are also relatively high in the other essential fatty acid, the omega-3 fatty acid linolenic acid (7-8% of total fat). There are relatively few good plant sources of linolenic acid. Omega-3 polyunsaturated fatty acids are being studied for their health benefits particularly related to heart disease and cancer.
Soybeans have a very low glycemic index. The glycemic index refers to the postprandial glucose response following the consumption of a given amount of carbohydrate. Although neither the American Diabetes Association nor the American Dietetic Association endorse the glycemic index as a tool for constructing diets for individuals with diabetes, research published during the past decade makes for a persuasive argument for the glycemic index of foods being one factor affecting the overall quality of the diet. The low glycemic index of soyfoods suggests they may be particularly important for individuals with diabetes and those with an elevated risk of developing diabetes.
Isoflavones
Although the high protein quality, fatty acid composition and low glycemic index of soybeans is impressive, these attributes alone could not account for all of the attention soyfoods are receiving from consumers and health professionals. The reason for this attention is that soybeans are, for practical purposes, a unique dietary source of a group of phytochemicals called isoflavones. Soybeans and soy products contain roughly 1-3 mg of isoflavones per gram of protein, one serving of traditional soyfoods provides about 25-40 mg of isoflavones. The
two primary isoflavones in soybeans are genistein and daidzein. Isoflavones have received considerable attention in recent years and are being studied for their potential role in the prevention and treatment of a number of chronic diseases including certain forms of cancer, osteoporosis and heart disease, and also for their ability to relieve menopause symptoms.Relative to physiologic estrogens, isoflavones (phytoestrogens) are quite weak, possessing between 1 x 10-4 and 1 x 10-3 the activity of estradiol. Despite their relatively low potency, isoflavones are likely to exert physiological effects since serum levels of isoflavones in people consuming soyfoods are several orders of magnitude higher than the physiologic estrogens. Studies have found that in response to the consumption of soyfoods, blood isoflavone levels can reach the low umolar range.
Although isoflavones are weak estrogens, more than 30 years ago it was shown in animals that isoflavones could function as an antiestrogens. The prevailing hypothesis has been that isoflavones exert antiestrogenic effects when placed in a high estrogen environment, such as in premenopausal women, and estrogenic effects in a low estrogen environment, such as in postmenopausal women. In addition to competing with endogenous estrogens for binding to the estrogen receptor, there are a number of potential mechanisms by which the isoflavones may exert antiestrogenic effects. However, there are conflicting results about when isoflavones and/or soy exert hormonal effects and whether these effects are estrogenic or antiestrogenic in nature.
Cancer
There are literally hundreds of in vitro studies showing genistein inhibits the growth of a wide range of both hormone dependent and hormone independent cancer cells including breast, prostate, colon, and skin cells. Furthermore, in vitro, genistein inhibits the metastatic activity of both breast and prostate cancer cells independent of effects on cell growth. The potential antiestrogenic effects of isoflavones could not account for the effect of genistein on hormone independent cancer cells. In fact, much of the excitement over the potential anticancer effects of genistein is because of its effects on signal transduction. Genistein's inhibits the activity of several enzymes intimately involved in controlling cell growth and regulation, including tyrosine protein kinases, MAP kinase and ribosomal S6 kinase among others.
Soy and Breast Cancer
The relationship between soy intake and cancer risk initially focused primarily on cancer of the breast. In large part, interest in this relationship was due to two observations: 1) the potential antiestrogenic effects of isoflavones and 2) the relatively low breast cancer mortality rates in Asian countries where soyfoods are commonly consumed. In Japan for example, the breast cancer mortality rate is only about 1/4 the U.S. rate.
Although the notion that soy intake reduces breast cancer risk is an intriguing hypothesis, it remains quite speculative. The epidemiologic data are conflicting, although there is more support for soy lowering the risk of premenopausal breast cancer than postmenopausal breast cancer. There are very provocative data suggesting that the early consumption of soyfoods by young girls may reduce breast cancer development later in life. Early exposure (during the neonatal or prepubertal period of life) to genistein (s.c. administration) inhibits the development of chemically induced mammary tumors in rodents and increases the latency period. Although it is not clear to what extent this experimental model and the dose of genistein used in these studies are relevant to humans, these findings are certainly the basis for an intriguing line of investigation.
Soy and Prostate Cancer
As is the case for breast cancer, prostate cancer mortality rates vary markedly among countries. An interesting observation related to the occurrence of prostate cancer is that clinical prostate cancer rates vary much more than the rates of latent prostate cancer. This suggests that in some populations such as the Japanese, the growth of prostate tumors is slower and/or that the onset of prostate tumors occurs later in life. Delaying the appearance of clinical prostate tumors by even a few years could have a marked impact on mortality since prostate cancer typically occurs in older men. There is speculation that the intake of soyfoods may be a factor contributing to the low Japanese prostate cancer mortality rate. However the data in support of this hypothesis, while intriguing, are limited.
Genistein inhibits the growth of both androgen dependent and androgen independent prostate cancer cells in vitro. In addition to the effects of genistein on signal transduction noted previously, there are several other mechanisms by which genistein/isoflavones could reduce prostate cancer risk. For example, even though the precise role of estrogen in prostate cancer is not well defined, the potential estrogenic effects of isoflavones may be protective effects since estrogens have been used successfully as a form of hormone therapy for metastatic prostate cancer. Genistein may also inhibit the conversion of testosterone into the active form of testosterone, dihydrotestosterone (DHT). Increased levels of DHT may increase prostate cancer risk.
Recently, several studies have found that soy/isoflavones delay the occurrence of prostate tumors in animals and that genistein administration can inhibit the growth of prostate cells implanted into rodents. Not surprisingly, there are limited human data upon which to evaluate the soy-prostate cancer hypothesis although a prospective study found that the consumption of tofu was associated with a markedly reduced risk of prostate cancer. Of potential relevance to the effects of isoflavones on prostate cancer risk is the finding that isoflavones appear in the prostatic fluid, and that levels are highest in men from soyfood consuming countries. Furthermore, relative to plasma levels, isoflavones are concentrated several fold in prostatic fluid. Interestingly, a recent case study reported significant apoptosis in the prostatic specimen from a man with adenocarcinoma who had taken isoflavones (160 mg/day) derived from red clover one week prior to surgery. This red clover extract contains both genistein and daidzein as well as the methylated isoflavones, biochanin-A and formononetin from which genistein and daidzein, respectively, are derived.
Cancer Treatment
There has been some speculation that soy/isoflavones could be used in the treatment of existing tumors either alone or in conjunction with conventional chemotherapeutic agents. Support for this speculation comes from work showing that in vitro genistein inhibits angiogenesis or blood vessel growth. Development of anti-angiogenesis agents is a highly promising area of cancer treatment since inhibiting the tumor stimulated growth of new blood vessels prevents tumors from becoming larger than 1-2 mm. Tumors limited to this size are clinically insignificant. There is some preliminary in vivo support for the anti-angiogenic potential of soy. In a small study of patients with hereditary hemorrhagic telangiectasia (HHT), soy intake led to a marked reduction in nose bleeds and gastrointestinal bleeding. This suggests soy consumption inhibits blood vessel growth.
Soy and Bone Health
The similarity in structure between the isoflavones and estrogen and the knowledge that isoflavones possess weak estrogenic properties, as demonstrated in various experimental models, provided the initial basis for speculation that isoflavones may promote bone health. An additional observation supporting the potential benefits of soybean isoflavones is their similarity in chemical structure with the synthetic isoflavone, 7-isopropoxyisoflavone (ipriflavone), which has been shown to increase bone mass in postmenopausal women. Interestingly, for ipriflavone to be maximally effective, it requires metabolism; one of the metabolites of ipriflavone is the soybean isoflavone, daidzein.
Until recently there were no direct data indicating the soybean isoflavones affected bone density. In 1996, soy protein when fed to ovariectomized rats was shown to increase bone density relative to rats fed casein. Later work found that the isoflavones were directly responsible for this effect. Two human studies examining the effects of soy consumption on bone loss in postmenopausal women have been reported but thus far only in abstract form. In both studies, soy was associated with favorable effects on bone density but the results of these studies should be considered very preliminary. In one of the human studies, approximately 90 mg of total isoflavones (the amount found in about 3 servings of tofu) was required to exert protective effects.
Some insight into the possible mechanism(s) for the effect of isoflavones on bone health observed in rats has been gained. There are data to suggest that isoflavones may both stimulate bone formation and inhibit bone resorption. Genistein has been shown to increase osteoblast number and serum osteocalcin levels in rats and to inhibit osteoclast protein synthesis.
In addition to the isoflavones directly affecting bone health, soy protein when substituted for animal protein may also play a role. Protein causes an increase in calcium excretion, an effect thought to be due at least in part to the metabolism of the sulfur amino acids (SAAs). The skeletal system serves as one of the main buffering systems in the body. As a result, the hydrogen ions produced from the metabolism of the SAAs causes bone to be demineralized and calcium to be excreted. Human studies have shown that the consumption of soy protein is associated with a markedly lower urinary calcium excretion in comparison to the consumption of similar amounts animal protein. The nutritional significance of substituting soy protein for animal protein on bone health will, of course, depend upon the relative level of intake.
The relationship between soy/isoflavones and bone health is provocative. However, before firm conclusions can be drawn, long term human studies examining the effects of soy and/or isoflavones on bone density and fracture risk are needed. Fortunately, because of the number of studies underway, it is likely that a much better understanding of this area will be obtained within a relatively short period of time.
Soy and Menopause Symptom Relief
In comparison to Western women, far fewer Japanese women report symptoms of menopause such as hot flashes. It has been hypothesized that at least one reason Japanese women report fewer symptoms is because they consume soyfoods. The drop in blood estrogen levels as a women goes through menopause is thought to be responsible for many of the symptoms of menopause. Since isoflavones are weak estrogens, it has been suggested that soyfoods contain enough estrogen activity to compensate for the lack of estrogen production by the ovaries.
In 1995, the consumption of soy flour was associated with a marked decrease in hot flashes and a general improvement in menopause symptoms. However, the control group in this study also experienced improvement. Since 1995, several researchers have examined the effects of soy on menopause symptoms. The results are somewhat equivocal, some studies showing benefit, others showing no effect. It may be that some women are more sensitive to soy than others, and that for a subset of the menopausal population, soy is very effective. It is clear however, that there is a large placebo effect, and that studies examining the effect of soy on menopause symptoms need to be well designed in order to achieve the expected improvement in the control (nonsoy) group. Unlike cancer and osteoporosis, any change in symptoms in response to soy consumption can be directly experienced. It is certainly reasonable for women to try soyfoods for the relief of menopause symptoms even though the existing literature on this subject is inconsistent.
Conclusion
From a nutritional profile perspective, soybeans and soyfoods have much to offer, being high in protein, low in saturated fat, and high in complex carbohydrate. Soybeans are also a good source of several micronutrients and phytochemicals. Soybeans are unique among the legumes because they are a concentrated source of isoflavones. Isoflavones have been hypothesized to reduce the risk of cancer, heart disease and osteoporosis and to help relieve menopause symptoms. Although there is much to learn about the effects of isoflavones this area of research holds considerable potential. Even with so many questions remaining, it is clear that soyfoods warrant a bigger role in the American diet than they currently have.
[Soyfoods Symposium 1997 Home Page]