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UPDATE ON SOY PRODUCTS:
Are they appropriate for Women Concerned about Breast Cancer?
Soy products are a major nutritional food source in Japan and China. It has been suggested that high levels of consumption of these foods may contribute to certain health benefits, including reduced blood lipids, reduced oxidation of lipids, and improvements in other cardiovascular risk factors. In October 1999, the US Food and Drug Administration authorized the use on food labels of health claims associated with soy protein and the reduced risk of coronary heart disease. Soy protein is one of the most complete proteins of the vegetable kingdom. Soybeans also contain substantial amounts of lecithin and vitamin E, which are understood to be very healthy components of oils. Taken together, the evidence suggests that soybeans and their products can make a good contribution to the human diet.
With regard to women's health, it has been suggested that high soy intake may be associated with reduction of menopausal symptoms and with reduced incidence of breast cancer. These effects, which still need to be elucidated more fully by further studies, are attributed to the soybean isoflavones. The isoflavones are found throughout the legumes (Bean family), but are especially rich in soy beans. In particular, genistein, the dominant isoflavone of soy, is reported to inhibit the growth of cultured cancer cells in the laboratory, including breast cancer cells. Soy isoflavones are reported to reduce hot flashes during menopause more effectively than placebos but not as effectively as hormone replacement therapy (45%, 30%, and 70% effectiveness, respectively). The effects of soy isoflavones on menopausal symptoms are dose dependent, and it is possible that higher rates of effectiveness may be attained with higher isoflavone administration (currently, menopause therapies typically involve 60-80 mg/day of isoflavones).
Raw soybeans may have as much as 150 mg of total isoflavones per 100 grams, and some soy flour products (such as roasted full-flat powder), may have as much as 200 mg isoflavones per 100 grams. By contrast, commonly used soy food products, such as tofu, may provide only about 20-50 mg isoflavones per 100 grams. During the past decade, a number of new soybean products have been designed in which the soy isoflavones are present in quantities as high or higher than in the usual soybean food products, some being comparable to the soy flour products that have the highest naturally-occurring isoflavone content. These new products may have the fat and carbohydrate removed from the soy bean (removal of soy carbohydrates is often regarded as a benefit, as there are polysaccharide components that are difficult for some people to digest). For example, Nutra-Soy (developed by Narula Research) provides 212 mg isoflavones per 100 grams (i.e., 60 mg per one ounce serving) with half of the powder being protein.
The ability to produce soy products in a desirable form with high levels of isoflavones has been made possible by commercial technologies that allow isolation of the isoflavones, which can then be added to soy products (such as soy protein powders) or simply put into capsules and tablets. One reason for this development is that most people who desire the potential benefits of these soy components are unwilling or unable to get the amounts from their diet that are said to be needed, according to research studies, to attain the desired results. Clinical studies using soy isoflavones have involved amounts that typically range from 60-80 milligrams, though higher amounts, up to 200 mg, have been tried and found to be potentially helpful. The typical doses used in such studies correspond to eating a substantial amount of soy products each day; these amounts are attainable by those who have a preference for soy foods, such as tofu, tempeh (a fermented soybean product), soy milk, and soy-based meat substitute products, but not for those who only eat soy foods occasionally or in small amounts.
A growing body of research with soy components, including soy isoflavones, lecithin, vitamin E, soy saponins, and soy protein, have pointed to significant health benefits. However, during the past couple of years, there has been a growing call for caution about consuming soy in any form, particularly in popular literature (newspaper and magazine articles) and on the internet (non-research sites). Much of the concern that has been raised is based on misreading of the literature and on poor studies. Thus, for example, the soy isoflavones are known to be able to inhibit certain enzyme systems and thyroid hormones, a fact which is raised as a serious warning about consuming soy or its isoflavones. However, detrimental effects are not observed in adults: the problem arises when infants are fed solely soy milk formulations to replace mother's milk, cow milk, or non-soy formulations. Infants may face an adverse consequence (related to thyroid inhibition) due to their low body weight, high susceptibility, and the single substance diet. Despite the safety of use in adults, opponents of soy use have warned that this is just one of many problems that needs to concern everyone interested in the health benefits of soy. A nutrition study widely reported in the news media last year suggested that people who consumed more than 2 servings of soy per week had a higher risk of suffering from brain shrinkage as they aged. This study has been soundly criticized with regard to this conclusion, but opponents of soy use have trotted out this inconclusive study so as to bolster a weak case against soy. In fact, other studies suggest that soy helps protect against neurodegeneration.
There is one area of concern that is very contentious and which currently remains outside of the ability of anyone to form a firm conclusion at this time. Information derived from studies of soy and soy isoflavones have yielded some conflicting implications about the possible effects of soy consumption on the risk of developing breast cancer or its suitability for women who already have breast cancer. For example, at a recent meeting on the subject of breast cancer in Portland, Oregon, two naturopathic physicians (practitioners that specialize in, among other areas, prescription of dietary and nutritional regimens to their patients) offered markedly different views. Both practitioners have a large proportion of patients dealing with breast cancer related issues and have reviewed the literature about soy so as to provide helpful advice. One doctor suggested that so long as the dosage of isoflavones is adequate, they would have a beneficial effect (daily dosage of about 80 mg was suggested). The other doctor suggested that soy isoflavones should be avoided by adult women and that the only possible use for consuming soy regularly in relation to reducing breast cancer risk, at least as he understood the current research results, would be during the early years of life (around puberty).
While the majority of research studies support the use of soy and its isoflavones in relation to breast cancer risk (see: Estrogen dependent tumors and herbs: how modern conditions change traditional practices) the concern expressed by this doctor came primarily from two reports. In one case, involving a clinical evaluation of adult women, the administration of soy led to slight changes (proliferation) in the breast tissue which the researchers felt were consistent with estrogen-like changes that are believed to contribute to the risk of developing of breast cancer (1). The other case was a laboratory animal study in which soy appeared to have a protective anti-cancer effect when administered to young animals (2), whereas such effects are not as evident in studies with older animals. Put together, these two studies could be interpreted as indicating an advantage to using soy in early years that is lost, or even becomes negative, if soy is introduced in later years.
In a recent study of genistein, and the related soy isoflavone genistin, in laboratory cultured breast cancer cells, it was shown that, although these compounds bind very weakly to the cells, they can stimulate their growth at a sufficient dosage. Generally, it is thought that these isoflavones compete for binding sites with estrogen, and thereby prevent the estrogen, which is a much stronger stimulant to breast cancer cells, from having its negative impact. Thus, at the doses normally consumed (via diet or current supplementation practices), the overall risk of inducing breast cancer should be lowered. The debate about the suitability of using soy or soy isoflavones in relation to breast cancer risks is one that probably will not be resolved definitively any time soon, but continuing research appears to lend further support to a benefit of using soy, even in adults and those with breast cancer (see the listing of 5 abstracts at the end of this article). In fact, at this time, the only caution about using soy regularly as an adult appears to be for women who are pregnant, since a high isoflavone intake might have negative consequences for the developing fetus (suggested thus far only by laboratory animal studies). There are no evident problems, in this regard, from normal dietary levels of isoflavones, as are common in Japan.
One of the problems faced with making a definitive interpretation of the data is that breast cancer risk factors are very difficult to determine with specificity. Studies that appear to be conducted properly can present conflicting results with minor changes in design. In the February issue of the Journal of the American Medical Association, there was a review of clinical studies evaluating the risk of breast cancer in relation to consumption of fruits and vegetables (3). The article presented information suggesting that fruit and vegetable consumption had no impact on breast cancer risk. Some early studies and reviews suggested that these foods had a notably favorable impact (more fruits and vegetables meant lower risk). The preliminary results have been one of the reasons why women who wish to avoid breast cancer are advised to eat plenty of fruits and vegetables and even to take supplements that contain what are believed to be active components of these foods (e.g., antioxidants). Similarly, there have been conflicting results regarding the contribution of fats to breast cancer. Early studies seemed to indicate that breast cancer risk was greater with a higher fat diet; more recent evaluations indicated no significant effect (5, 6). The implication that high fat diets contributed to breast cancer risk led to suggestions that women pursue a low fat diet, especially by avoiding large amounts of meat, and thus eating more fruits and vegetables as well as alternative protein sources, such as soy. Additionally, there have been conflicting results from studies about the increased risk of breast cancer posed by using hormone replacement therapy. Some studies find substantial increase in risk (e.g., a one-third increase in risk after using HRT for more than 10 years), others find only a slight increase, and others, still, find no significant change. The hormones do not seem to increase the risk of dying of breast cancer, even if the hormone therapy is given after a diagnosis of breast cancer (6). As pointed out in most modern literature, one of the greatest factors for breast cancer risk is delay of first childbirth or absence of child-bearing; the early differentiation of breast tissue under the hormonal effects of full-term pregnancy apparently confers lasting protection (7).
Based on current research reports, changes in breast cancer risk appear to be quite small regardless of their direction, and most reports suggest there is an improvement with soy isoflavones and soy protein. The scientific literature must still be recognized as presenting preliminary results. However, the overall conclusion that can be derived from a growing body of literature is that the impact of soy isoflavones in relation to health and longevity is a positive one.
On the following pages are five abstracts of recent articles that illustrate the direction of research on soy, where the indications are that soy has a favorable effect, or, at the least, no unfavorable effects related to risk of breast cancer. These abstracts appear in the National Library of Medicine's worldwide web site: http://www4.ncbi.nlm.nih.gov/PubMed.
TITLE: Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. Authors: Shao ZM, Shen ZZ, Fontana JA, Barsky SH. Institution: Department of Surgery, Shanghai Medical University, P. R. China.
SOURCE: Anticancer Research 2000 Jul-Aug; 20(4): 2409-16.
ABSTRACT (emphasis added): Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention.
TITLE: Soy consumption alters endogenous estrogen metabolism in postmenopausal women. Authors: Xu X, Duncan AM, Wangen KE, Kurzer MS. Institution: Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota.
SOURCE: Cancer Epidemiology Biomarkers, 2000; 9(8):781-786.
ABSTRACT (emphasis added): Isoflavones are soy phytoestrogens that have been suggested to be anticarcinogenic. Our previous study in premenopausal women suggested that the mechanisms by which isoflavones exert cancer-preventive effects may involve modulation of estrogen metabolism away from production of potentially carcinogenic metabolites [16alpha-(OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol] (X. Xu et al., Cancer Epidemiol. Biomark. Prev., 7: 1101-1108, 1998). To further evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 18 healthy postmenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for 93 days, during which subjects consumed their habitual diets supplemented with soy protein isolate providing 0.1 (control), 1, or 2 mg isoflavones/kg body weight/day (7.1 +/- 1.1, 65 +/- 11, or 132 +/- 22 mg/day). A 72-h urine sample was collected 3 days before the study (baseline) and days 91-93 of each diet period. Urine samples were analyzed for 10 phytoestrogens and 15 endogenous estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Compared with the soy-free baseline and very low isoflavone control diet, consumption of 65 mg isoflavones increased the urinary 2/16alpha-(OH) estrone ratio, and consumption of 65 or 132 mg isoflavones decreased excretion of 4-(OH) estrone. When compared with baseline values, consumption of all three soy diets increased the ratio of 2/4-(OH) estrogens and decreased the ratio of genotoxic: total estrogens. These data suggest that both isoflavones and other soy constituents may exert cancer-preventive effects in postmenopausal women by altering estrogen metabolism away from genotoxic metabolites toward inactive metabolites.
TITLE: Modest hormonal effects of soy isoflavones in postmenopausal women. Authors: Duncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR, Kurzer MS. Institution: Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota.
SOURCE: Journal of Clinical Endocrinology and Metabolism 1999; 84(10): 3479-3484.
ABSTRACT (emphasis added): Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to bodyweight [control: 0.11 +/- 0.01; low isoflavone (low-iso): 1.00 +/- 0.01; high isoflavone (high-iso): 2.00 +/- 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36-38, 64-66, and 92-94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.
TITLE: Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity-a controlled crossover trial. Authors: Jenkins DJ. Kendall CW. Garsetti M. Rosenberg-Zand RS. Jackson CJ. Agarwal S. Rao AV. Diamandis EP. Parker T. Faulkner D. Vuksan V. Vidgen E. Institution: Clinical Nutrition and Risk Factor Modification Center, St. Michael's Hospital, Toronto, Ontario, Canada.
SOURCE: Metabolism: Clinical and Experimental, 2000; 49(4):537-543.
ABSTRACT (emphasis added): Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/day and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control. The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (and the ratio of conjugated dienes to LDL cholesterol, even in subjects already using vitamin E supplements (400 to 800 mg/day). No significant difference was detected in excreted (ex vivo) sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers.
TITLE: Effects of genistein and synergistic action in combination with eicosapentaenoic acid on the growth of breast cancer cell lines. Authors: Nakagawa H, Yamamoto D, Kiyozuka Y, Tsuta K, Uemura Y, Hioki K, Tsutsui Y, Tsubura A. Institution: Department of Surgery II, Kansai Medical University, Moriguchi, Osaka, Japan.
SOURCE: Journal of Cancer Research and Clinical Oncology 2000; 126(8):448-454.
ABSTRACT (emphasis added): Genistein, a prominent isoflavone in soy products, produced dose- and time-dependent in vitro growth inhibition at high concentrations (at least 185 microM) with an IC50 of 7.0-274.2 microM after 72 h incubation in four breast cancer cell lines (DD-762, Sm-MT, MCF-7 and MDA-MB-231) and one breast epithelial cell line (HBL- 100) of human and animal origin; it stimulated estrogen-receptor-positive MCF-7 cells at low concentrations (3.7 nM-37 microM). Genistein-exposed cells underwent apoptosis, confirmed by G2/M arrest followed by the appearance of a sub-G1 fraction in cell-cycle progression, and by a characteristic cell ultrastructure. The apoptosis cascade was due to up-regulation of Bax protein, down-regulation of Bcl-XL protein, and activation of caspase-3. Genistein acted in synergism with eicosapentaenoic acid (EPA), a fish oil component, on human breast cancer MCF-7 cells (genistein > 93.2 microM and EPA > 210.9 microM) and on MDA-MB-231 cells (genistein > 176.1 microM and EPA > 609.3 microM). Dietary intake of genistein in combination with EPA may be beneficial for breast cancer control.