Perspective: Observational Studies Involving Low-Soy Intake Populations Have Limited Ability for Providing Insight into the Health Effects of Soybean Isoflavones.

Isoflavones are naturally occurring plant compounds found in uniquely high amounts in soybeans and foods made from this legume. These soybean constituents have been proposed to exert several health benefits and as such they have been the subject of an enormous amount of research. This research includes randomized controlled trials (RCTs) and epidemiologic investigations. Although statistically significant associations between isoflavone intake and a wide range of health outcomes have been identified in cohorts involving low-isoflavone intake populations, we suggest that these associations are unlikely to have a causal basis because exposure is too low for isoflavones to exert physiologic effects. In cohorts involving predominantly non-Asian, non-vegetarian populations, the highest isoflavone intake category is typically ≤3 mg/d, an amount of isoflavones provided by ∼30 mL (2 tablespoons) of soymilk made from whole soybeans. In comparison, mean isoflavone intake in the upper intake categories in observational studies involving high-isoflavone intake populations is typically ≥50 mg/d. In RCTs, intervention doses of isoflavones typically range between 40 and 100 mg/d. Health professionals advising patients and clients about soy food and isoflavone intake need to be aware of the limitations of epidemiologic research involving low-isoflavone intake populations. Intake recommendations are best based on the results of RCTs using clinically relevant doses of isoflavones and epidemiologic studies involving populations for whom soy foods are a habitual part of the diet.

Guidance from an NIH workshop on designing, implementing, and reporting clinical studies of soy interventions.

The NIH sponsored a scientific workshop, "Soy Protein/Isoflavone Research: Challenges in Designing and Evaluating Intervention Studies," July 28-29, 2009. The workshop goal was to provide guidance for the next generation of soy protein/isoflavone human research. Session topics included population exposure to soy; the variability of the human response to soy; product composition; methods, tools, and resources available to estimate exposure and protocol adherence; and analytical methods to assess soy in foods and supplements and analytes in biologic fluids and other tissues. The intent of the workshop was to address the quality of soy studies, not the efficacy or safety of soy. Prior NIH workshops and an evidence-based review questioned the quality of data from human soy studies. If clinical studies are pursued, investigators need to ensure that the experimental designs are optimal and the studies properly executed. The workshop participants identified methodological issues that may confound study results and interpretation. Scientifically sound and useful options for dealing with these issues were discussed. The resulting guidance is presented in this document with a brief rationale. The guidance is specific to soy clinical research and does not address nonsoy-related factors that should also be considered in designing and reporting clinical studies. This guidance may be used by investigators, journal editors, study sponsors, and protocol reviewers for a variety of purposes, including designing and implementing trials, reporting results, and interpreting published epidemiological and clinical studies.

Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary.

There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns--based mostly on in vitro and rodent data--that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue.

Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies.

OBJECTIVE: Several reviews have evaluated the clinical evidence relating isoflavone treatment to the relief of menopausal hot flash symptoms. The majority of these reviews included a variety of isoflavone sources, often without discriminating between the identities of individual isoflavones contained in the study product. An evaluation of published studies using well-characterized isoflavone-containing supplements was conducted to determine whether the observed effects, or lack thereof, were attributable to differences in the composition of isoflavones in study products. DESIGN: Eleven studies that met the inclusion criteria were stratified according to specific isoflavone composition. RESULTS: All 11 studies contained similar total isoflavone doses. In five studies, involving a total of 177 treated participants, the study product provided more than 15 mg genistein (calculated as aglycone equivalents) per treatment. Each of these five studies consistently reported a statistically significant decrease in hot flash symptoms. In the six studies involving a total of 201 treated participants that provided less than 15 mg genistein per treatment, only one reported a statistically significant decrease in hot flash symptoms. Thus, the reduction in hot flashes was related to genistein dose, not total isoflavone content of the treatments. CONCLUSION: Reports concluding that isoflavone supplements do not significantly reduce hot flash symptoms may be incorrect. The lack of discrimination between individual isoflavones contained in heterogeneous isoflavone mixtures from differing sources can be misleading when designing studies, interpreting results, and conducting reviews. In light of these observations, evaluation of isoflavone effects should focus greater attention to the specific composition within supplements in future studies.

Emerging evidence on the role of soy in reducing prostate cancer risk.

Soyfoods are a unique dietary source of isoflavones, which have both hormonal and non-hormonal effects relevant to prostate cancer prevention. In vitro, the main soybean isoflavone, genistein, inhibits prostate cancer cell growth; in animals, most but not all studies show isoflavonel rich soy protein and isolated isoflavones inhibit prostate tumor development. Currently, although only limited epidemiologic data indicate soy intake reduces prostate cancer risk, results from a pilot intervention trial suggest isoflavones may be beneficial to prostate cancer patients. For several reasons, men concerned about their prostate health may consider incorporating soy into their diet.

Soy foods and soybean isoflavones and menopausal health.

Soybeans are a natural dietary source of isoflavones, which have estrogen-like properties. Therefore, it is worthwhile to consider the implications for soy of the recently published findings of the Heart and Estrogen/Progestin Replacement Study (HERS) I/II and the Women's Health Initiative (WHI). The WHI found coronary heart disease (CHD) risk to be increased in women receiving hormone replacement therapy, and both studies found increases in venous thromboembolic disease in such women. Additionally, stroke and breast cancer risk were increased in the WHI, although risk of colorectal cancer and fracture was decreased. Because research suggests that it is the combination of estrogen plus progestin, and not estrogen alone, that increases breast cancer risk, soy seems unlikely to increase risk because it has no progestin activity. Similarly, there is no evidence to suggest that soy will increase venous thromboembolic disease or stroke; however, only limited data are available in this area. There are promising data suggesting that soy may decrease CHD risk, although studies conducted thus far have examined only markers of risk and not actual CHD events. Similarly, short-term studies generally suggest that soy reduces bone loss in postmenopausal women; however, such effects have been noted primarily only at the spine, and longer-term studies are needed. Finally, very limited human research suggests that soy may decrease colon cancer risk, but this is highly speculative. The results of HERS I/II and WHI suggest that soy may have some of the advantages, but not the disadvantages, of combined hormone replacement therapy (at least with respect to the specific hormones and doses used in the HERS I/II and WHI), but that large, long-term intervention studies examining disease outcome are needed before definitive conclusions can be drawn. Nevertheless, the evidence warrants recommendations that menopausal women include soy in their diets.

Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk.

BACKGROUND: Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. OBJECTIVE: The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. DESIGN: Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. RESULTS: The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was <1% in steady state and <2% at peak concentrations. By contrast, rodents fed soy-containing diets conjugate isoflavones less efficiently. The plasma percentages of unconjugated genistein concentrations in Sprague-Dawley rats and C57BL/6, nude, and transgenic AngptL4B6 mice were 4.0 ± 0.6%, 4.6 ± 0.6%, 11.6 ± 0%, and 30.1 ± 4.3%, respectively, which represent 20, 23, 58, and 150 times that in humans. CONCLUSION: The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue.

Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis.

OBJECTIVE: To determine whether isoflavones exert estrogen-like effects in men by lowering bioavailable T through evaluation of the effects of soy protein or isoflavone intake on T, sex hormone-binding globulin (SHBG), free T, and free androgen index (FAI) in men. DESIGN: PubMed and CAB Abstracts databases were searched through July 1, 2008, with use of controlled vocabulary specific to the databases, such as soy, isoflavones, genistein, phytoestrogens, red clover, androgen, testosterone, and SHBG. Peer-reviewed studies published in English were selected if [1] adult men consumed soy foods, isolated soy protein, or isoflavone extracts (from soy or red clover) and [2] circulating T, SHBG, free T, or calculated FAI was assessed. Data were extracted by two independent reviewers. Isoflavone exposure was abstracted directly from studies. MAIN OUTCOME MEASURE(S): Fifteen placebo-controlled treatment groups with baseline and ending measures were analyzed. In addition, 32 reports involving 36 treatment groups were assessed in simpler models to ascertain the results. RESULT(S): No significant effects of soy protein or isoflavone intake on T, SHBG, free T, or FAI were detected regardless of statistical model. CONCLUSION(S): The results of this meta-analysis suggest that neither soy foods nor isoflavone supplements alter measures of bioavailable T concentrations in men.

Soy consumption, adhesion molecules, and pro-inflammatory cytokines: a brief review of the literature.

Given the interest in the vascular effects of both soyfoods and soy isoflavones, the purpose of this short review is to evaluate clinical trials that have examined the effects of isoflavone-rich soy products on the novel cardiovascular risk factors, cellular adhesion molecules, and pro-inflammatory cytokines. A total of 14 randomized clinical studies were assessed. From the data evaluated, evidence suggests that neither soyfoods nor soy isoflavones affect IL-6 or TNF-alpha expression. In contrast, the effects of soy on cellular adhesion molecules are mixed. Study design characteristics possibly contributing to the inconsistent data are discussed and recommendations for future research in this area are presented.

Food, plant food, and vegetarian diets in the US dietary guidelines: conclusions of an expert panel.

We summarize conclusions drawn from a panel discussion at the "Fifth International Congress on Vegetarian Nutrition" about the roles of and emphasis on food, plant food, and vegetarianism in current and future US dietary guidelines. The most general recommendation of the panel was that future dietary guidelines, following the lead of the 2005 Dietary Guidelines Advisory Committee, should emphasize food-based recommendations and thinking to the full extent that evidence allows. Although nutrient-based thinking and Dietary Reference Intakes (DRIs) may help ensure an adequate diet in the sense that deficiency states are avoided, the emphasis on DRIs may not capture many important nutritional issues and may inhibit a focus on foods. More generally, in the context of the conference on vegetarian nutrition, this report focuses on the history and structure of the Dietary Guidelines Advisory Committee, on various plant food-oriented recommendations that are supported by literature evidence, and on mechanisms for participating in the process of forming dietary guidelines. Among recommendations that likely would improve health and the environment, some are oriented toward increased plant food consumption and some toward vegetarianism. The literature on health effects of individual foods and whole lifestyle diets is insufficient and justifies a call for future food-oriented research, including expanding the evidence base for plant-based and vegetarian diets. The Dietary Guidelines Advisory Committee's role should be carried forward to creation of a publicly accessible icon (eg, the current pyramid) and related materials to ensure that the science base is fully translated for the public.