Early exposure to soy isoflavones and effects on reproductive health: a review of human and animal studies

Soy isoflavones are phytoestrogens with potential hormonal activity due to their similar chemical structure to 17-β-estradiol. The increasing availability of soy isoflavones throughout the food supply and through use of supplements has prompted extensive research on biological benefits to humans in chronic disease prevention and health maintenance. While much of this research has focused on adult populations, infants fed soy protein based infant formulas are exposed to substantial levels of soy isoflavones, even when compared to adult populations that consume a higher quantity of soy-based foods. Infant exposure, through soy formula, primarily occurs from birth to one year of life, a stage of development that is particularly sensitive to dietary and environmental compounds. This has led investigators to study the potential hormonal effects of soy isoflavones on later reproductive health outcomes. Such studies have included minimal human data with the large majority of studies using animal models. This review discusses key aspects of the current human and animal studies and identifies critical areas to be investigated as there is no clear consensus in this research field.     

The spectrum of phytoestrogens in nature: our knowledge is expanding

The classical phytoestrogens, so far known, constitute a group of plant-derived compounds which include mainly isoflavones, lignans, coumestanes, stilbenes and the flavonoids quercetin and kaempherol. The discovery of many more novel estrogen-like compounds in the plant kingdom demonstrates that the spectrum of phytoestrogens in nature is expanding. The classical as well as the novel phytoestrogens show a complex mode of action via interaction with the nuclear estrogen receptor isoforms ERalpha and ERbeta, exhibiting either estrogen-agonist or estrogen-antagonist effects. Their final biological activity, assessed by cell culture assay systems, animal studies and clinical trials, depends on multiple factors such as the chemical structure of the phytoestrogen, the kind of tissue and cell type, the intrinsic estrogenic status, the route of administration, the metabolism as well as the time and the level of exposure. They are characterized by high tissue specificity and dose-dependent activity. However, although phytoestrogen intake as food or dietary supplements, in particular soya products and the isoflavones genistein and daidzein, has been associated with "health promoting effects", some data indicate increased disease risk. Evidently, phytoestrogen supplementation should be viewed with caution until further studies satisfactorily delineate the effects of individual phytoestrogens on human health and disease.     

Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor

Consumption of phytoestrogens and mycoestrogens in food products or as dietary supplements is of interest because of both the potential beneficial and adverse effects of these compounds in estrogen-responsive target tissues. Although the hazards of exposure to potent estrogens such as diethylstilbestrol in developing male and female reproductive tracts are well characterized, less is known about the effects of weaker estrogens including phytoestrogens. With some exceptions, ligand binding to the estrogen receptor (ER) predicts uterotrophic activity. Using a well-established and rigorously validated ER-ligand binding assay, we assessed the relative binding affinity (RBA) for 46 chemicals from several chemical structure classes of potential phytoestrogens and mycoestrogens. Although none of the test compounds bound to ER with the affinity of the standard, 17beta-estradiol (E(2)), ER binding was found among all classes of chemical structures (flavones, isoflavones, flavanones, coumarins, chalcones and mycoestrogens). Estrogen receptor relative binding affinities were distributed across a wide range (from approximately 43 to 0.00008; E(2) = 100). These data can be utilized before animal testing to rank order estimates of the potential for in vivo estrogenic activity of a wide range of untested plant chemicals (as well as other chemicals) based on ER binding.     

Dietary isoflavones: biological effects and relevance to human health

Substantial evidence indicates that diets high in plant-based foods may explain the epidemiologic variance of many hormone-dependent diseases that are a major cause of mortality and morbidity in Western populations. There is now an increased awareness that plants contain many phytoprotectants. Lignans and isoflavones represent two of the main classes of phytoestrogens of current interest in clinical nutrition. Although ubiquitous in their occurrence in the plant kingdom, these bioactive nonnutrients are found in particularly high concentrations in flaxseeds and soybeans and have been found to have a wide range of hormonal and nonhormonal activities that serve to provide plausible mechanisms for the potential health benefits of diets rich in phytoestrogens. Data from animal and in vitro studies provide convincing evidence for the potential of phytoestrogens in influencing hormone-dependent states; although the clinical application of diets rich in these estrogen mimics is in its infancy, data from preliminary studies suggest beneficial effects of importance to health. This review focuses on the more recent studies pertinent to this field and includes, where appropriate, the landmark and historical literature that has led to the exponential increase in interest in phytoestrogens from a clinical nutrition perspective.     

Insights gained from 20 years of soy research

Soyfoods have long been recognized for their high-protein and low-saturated fat content, but over the past 20 y an impressive amount of soy-related research has evaluated the role of these foods in reducing chronic disease risk. Much of this research has been undertaken because the soybean is essentially a unique dietary source of isoflavones, a group of chemicals classified as phytoestrogens. The estrogen-like properties of isoflavones have also raised concern, however, that soyfoods might exert adverse effects in some individuals. There is intriguing animal and epidemiologic evidence indicating that modest amounts of soy consumed during childhood and/or adolescence reduces breast cancer risk. Evidence also suggests that soy reduces prostate cancer risk and inhibits prostate tumor metastasis, but additional clinical support for the chemopreventive effects of soyfoods is needed. Soy protein is modestly hypocholesterolemic and there is suggestive epidemiologic evidence that soyfoods lower risk of coronary heart disease (CHD) independent of effects on cholesterol. In clinical studies, soy favorably affects multiple CHD risk factors; however, with the exception of improved endothelial function, the data are too limited and/or inconsistent to allow definitive conclusions to be made. In regard to bone health, although recent clinical data have not supported the skeletal benefits of isoflavones, 2 large prospective epidemiologic studies found soy intake is associated with marked reductions in fracture risk. Soybean isoflavones also modestly alleviate hot flashes in menopausal women. Finally, other than allergic reactions, there is almost no credible evidence to suggest traditional soyfoods exert clinically relevant adverse effects in healthy individuals when consumed in amounts consistent with Asian intake.     

Phytoestrogens and prostate cancer risk

BACKGROUND: Phytoestrogens are natural plant substances. The four main classes are isoflavones, flavonoids, coumestans, and lignans. Phytoestrogens have anti-carcinogenic potential. For evaluation of the effect of phytoestrogens on prostate cancer risk, we reviewed analytical epidemiological data. METHODS: Up to now, there are few studies that have assessed the direct relation between the individual dietary intake of soy products and other nutrients with phytoestrogens and the risk of prostate cancer. We decided to review analytical epidemiological studies providing data on (a) dietary soy intake or flavonoids intake, (b) urinary excretion of isoflavones or lignans, or (c) blood measurements of isoflavones or lignans. Soy is used as a marker for isoflavone intake. RESULTS: Overall, the results of these studies do not show protective effects. Only four of these studies are prospective, and none of them found statistically significant prostate cancer reductions. Two prospective studies measured flavonoid intake and one reported a preventive effect on prostate cancer for the assumption of myricetin. One study assessed enterolactone concentrations in three different countries and showed no reduction in prostate cancer occurrence. CONCLUSION: Few studies showed protective effect between phytoestrogen intake and prostate cancer risk.     

Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms

Phytoestrogens are phenolic compounds derived from plants and exert an estrogenic as well as an antiestrogenic effect and also various biological efficacies. Chemopreventive properties of phytoestrogens has emerged from epidemiological observations indicating that the incidence of some cancers including breast and prostate cancers is much lower in Asian people, who consume significantly higher amounts of phytoestrogens than Western people. There are 4 main classes of phytoestrogens: isoflavones, stilbenes, coumestans, and lignans. Currently, resveratrol is recognized as another major phytoestrogen present in grape and red wine and has been studied in many biological studies. Phytoestrogens have biologically diverse profitabilities and advantages such as low cytotoxicity to patients, lack of side effects in clinical trials, and pronounced benefits in a combined therapy. In this review, we highlighted the effects of genistein, daidzein, and resveratrol in relation with their anticarcinogenic activity. A lot of in vitro and in vivo results on their chemopreventive properties were presented along with the underlying mechanisms. Besides well-known mechanisms such as antioxidant property and apoptosis, newly elucidated anticarcinogenic modes of action including epigenetic modifications and topoisomerase inhibition have been provided to examine the possibility of phytoestrogens as promising reagents for cancer chemoprevention and/or treatment and to suggest the importance of plant-based diet of phytoestrogens.     

Does equol production determine soy endocrine effects?

Isoflavones, a group of phytoestrogens, are selective oestrogen receptor (ER) modulators. They may positively impact endocrine-related conditions but the current evidence is sparse. Equol, a non-steroidal oestrogen, is produced by the metabolism of the isoflavone daidzein by intestinal bacteria. In Western countries, 30-50% of individuals metabolize daidzein into equol and are known as equol producers. Equol production may be the source of benefit from isoflavones in endocrine disease.     

Beneficial role of dietary phytoestrogens in obesity and diabetes

Evidence is emerging that dietary phytoestrogens play a beneficial role in obesity and diabetes. Nutritional intervention studies performed in animals and humans suggest that the ingestion of soy protein associated with isoflavones and flaxseed rich in lignans improves glucose control and insulin resistance. In animal models of obesity and diabetes, soy protein has been shown to reduce serum insulin and insulin resistance. In studies of human subjects with or without diabetes, soy protein also appears to moderate hyperglycemia and reduce body weight, hyperlipidemia, and hyperinsulinemia, supporting its beneficial effects on obesity and diabetes. However, most of these clinical trials were relatively short and involved a small number of patients. Furthermore, it is not clear whether the beneficial effects of soy protein and flaxseed are due to isoflavones (daidzein and genistein), lignans (matairesinol and secoisolariciresinol), or some other component. Isoflavones and lignans appear to act through various mechanisms that modulate pancreatic insulin secretion or through antioxidative actions. They may also act via estrogen receptor-mediated mechanisms. Some of these actions have been shown in vitro, but the relevance of these studies to in vivo disease is not known. The diversity of cellular actions of isoflavones and lignans supports their possible beneficial effects on various chronic diseases. Further investigations are needed to evaluate the long-term effects of phytoestrogens on obesity and diabetes mellitus and their associated possible complications.     

Hormonal effects of soy in premenopausal women and men

Over the past few years, there has been increasing interest in the possible hormonal effects of soy and soy isoflavone consumption in both women and men. Soy consumption has been suggested to exert potentially cancer-preventive effects in premenopausal women, such as increased menstrual cycle length and sex hormone-binding globulin levels and decreased estrogen levels. There has been some concern that consumption of phytoestrogens might exert adverse effects on men's fertility, such as lowered testosterone levels and semen quality. The studies in women have provided modest support for beneficial effects. One cross-sectional study showed serum estrogens to be inversely associated with soy intake. Seven soy intervention studies controlled for phase of menstrual cycle. These studies provided 32-200 mg/d of isoflavones and generally showed decreased midcycle plasma gonadotropins and trends toward increased menstrual cycle length and decreased blood concentrations of estradiol, progesterone and sex hormone-binding globulin. A few studies also showed decreased urinary estrogens and increased ratios of urinary 2-(OH) to 16alpha-(OH) and 2-(OH) to 4-(OH) estrogens. Soy and isoflavone consumption does not seem to affect the endometrium in premenopausal women, although there have been weak estrogenic effects reported in the breast. Thus, studies in women have mostly been consistent with beneficial effects, although the magnitude of the effects is quite small and of uncertain significance. Only three intervention studies reported hormonal effects of soy isoflavones in men. These recent studies in men consuming soyfoods or supplements containing 40--70 mg/d of soy isoflavones showed few effects on plasma hormones or semen quality. These data do not support concerns about effects on reproductive hormones and semen quality.     

Epidemiologic evidence suggests that dietary phytoestrogen intake is associated with reduced risk of breast, endometrial, and prostate cancers

Phytoestrogens are natural estrogen-like plant substances. The possible protective effect of phytoestrogens on cancer risk, particularly on hormone-related cancers, has been the focus of many epidemiologic studies during the last 2 decades. We performed a qualitative review of the epidemiologic literature published in the English language and identified on MEDLINE from 1966 until 24 September 2006 on (1) dietary intake of soy, isoflavones, or lignans; (2) urinary excretion of isoflavones or lignans; (3) blood measurements of isoflavones or lignans in relation to breast, prostate, and endometrial cancer risk. Epidemiologic data do seem to support a small protective effect of isoflavones on breast cancer risk, although timing of exposure and the mechanisms of isoflavones at physiologic levels need to be further explored. The epidemiologic evidence to date is conflicting regarding lignans and breast cancer, but recent studies suggest that the effect may be restricted to premenopausal women, differ by estrogen receptor status, and be modified by diet-gene interactions. The 3 case-control studies on dietary intake of phytoestrogens and endometrial cancer risk have provided some evidence for a protective effect, but more prospective data are needed. There is some epidemiologic evidence for a protective effect of soy or isoflavones on prostate cancer, but corresponding data for lignans are inconclusive. Recent data indicate that diet-gene interactions may modify the effect of phytoestrogens on prostate cancer risk. Prospective studies on dietary lignans in relation to prostate cancer risk are lacking.     

Soy isoflavones and bone health: the relationship is still unclear

Evidence of the effect of purified soy isoflavones and soy protein isolates containing isoflavones on bone health in rats and in humans is inconsistent. Differences may be because of synergies or antagonisms among the isoflavones, threshold or biphasic dose effects, life stage of animals or human subjects, estrogen status, and environment-genetic interactions, including the ability to produce metabolites upon ingestion of isoflavones. At this time, the benefits of soy protein and isoflavones on bone health are inconclusive. This overview will summarize these discrepancies and will suggest future studies to clarify the conditions under which these dietary substances can be helpful for bones.     

Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study(1-4)

Many plants that are consumed contain phytoestrogens. Only a few published studies have examined the dietary intake of phytoestrogens in the general Western population. The potentially positive health effects of phytoestrogens might be of relevance to postmenopausal women. The aim of the present study was to estimate the intake of dietary isoflavones, coumestans and lignans by healthy Western postmenopausal women. For this purpose, we studied 964 postmenopausal, Caucasian women who participated in the Framingham Offspring Study and completed the Willett food-frequency questionnaire (FFQ). By searching the medical and agricultural literature and contacting experts, we identified food sources of phytoestrogens. The concentrations of the different isoflavones, coumestrol and lignans in each food in the FFQ were scored in seven categories and multiplied by the serving size of the food and the frequency of its consumption. The estimated daily median intake of the isoflavone daidzein was 39 microg (24-57 microg); of genistein, 70 microg (28-120 microg); of formononetin, 31 microg (13-44 microg); and of biochanin A, 6 microg (2-11 microg). Median total intake of isoflavones was 154 microg (99-235 microg). The main sources of isoflavones were beans and peas. The estimated daily intake of coumestans was 0.6 microg (0.2-1.7 microg), with broccoli as the main source. The estimated daily median intake of matairesinol was 19 microg (12-28 microg) and of secoisolariciresinol 560 microg (399-778 microg). The median total intake of lignans was 578 microg (416-796 microg). The main source of the lignans was fruits. The daily dietary intake of phytoestrogens in healthy postmenopausal Caucasian women in the United States is <1 mg.     

Phytoestrogens in food--a review]

The steroid hormone estrogen influences female and male reproductive system, 17-beta-oestradiol is the major human oestrogen. Phytoestrogens are naturally occurring oestrogens in many foods of plant origin. They are structurally and functionally similar to 17-beta-oestradiol or produce estrogenic effects. It is suggested that phytoestrogens could lower risk of diseases accompanied woman in meno- and postmenopausal stage. They are consider to decrease risk of breast, endometrial and ovarian cancer, osteoporosis, cardiovascular disease. This report presents the literature review on nutritious and health aspects connected with phytoestrogens. Generally authors confirm the possibility of beneficial health effects of phytoestrogens in humans.     

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.     

Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer

Although many dietary studies have focused on breast cancer risk, few have examined dietary influence on tumor characteristics such as estrogen receptor (ER) status. Because phytoestrogens may modulate hormone levels and ER expression, we analyzed ER status and phytoestrogen intake in a case-case study of 124 premenopausal breast cancer patients. We assessed intake with a food-frequency questionnaire and obtained ER status from medical records. Rather than focusing on risk, we evaluated whether low intakes were more strongly associated with ER-negative tumors than with ER-positive disease. In logistic regression adjusting for potential confounders, threefold greater risks of ER-negative tumors relative to ER-positive tumors were associated with low intake of the isoflavones genistein (odds ratio, OR=3.50; 95% confidence interval, CI=1.43-8.58) and daidzein (OR=3.10; 95% CI=1.31-7.30). Low intake of the flavonoid kaempferol (OR=0.36; 95% CI=0.16-0.83), the trace element boron (OR=0.33; 95% CI=0.13-0.83), and the phytosterol beta-sitosterol (OR=0.42; 95% CI=0.18-0.98) were associated with decreased risk of ER-negative tumors relative to ER-positive disease. Other phytoestrogens were not significantly associated with ER status. Thus, in premenopausal patients, some phytoestrogens may affect breast carcinogenesis by influencing ER status. Such findings suggest new directions for mechanistic research on dietary factors in breast carcinogenesis that may have relevance for prevention and clinical treatment.     

Phytoestrogènes et os : de nouvelles données

Osteoporosis is a greater public health problem.Ecological studies have shown that femoral neck fractures was lesser in asian populations.It has been suggested that diet might play a role in this observation. Among foods, soybean and soyfoods seemed able to play this role because of their isoflavones content. They are experimentally weak estrogens which may bind to bone estrogen receptors (β especially). They also probably act through others mechanisms such as enzymes, particularly tyrosine kinase.In vitro studies and in vivo studies in animal models and in humans have shown two kinds of effects, a bone resorption inhibiting effect and a bone formation stimulating effect. A beneficial effect is not observed in non human female primate.Observational studies give inconsistent results, according to age, kind of bone, population, isoflavones dosage. Asian epidemiologic studies, and in a lesser extend western studies, show within these populations a positive correlation between isoflavones intakes and bone mineral density. Recently a Chinese prospective study has established a relationship between isoflavones intakes and bone fracture during a four years follow-up.Some clinical trials with defectives methodology demonstrate a lack of effect on bone mineral density; most of clinical trials show favourable results on femoral and spinal bone mineral density, sometimes on forearm, never of calcaneum. Two recent studies with red clover are also positive. Results in clinical trials are provided with higher dosages than in epidemiologic studies. The variability of observed effects could be due to producers or non-equol producers. These data are discussed.However we are still lacking for histological and histomorphometric data and for clinical trials on the fractures’ risk.To-day phytoestrogens cannot be considered as an anti-osteoporotic treatment. But it is not excluded than soy and/or soy isoflavones may become future means used in bone-loss prevention.     

How should we assess the effects of exposure to dietary polyphenols in vitro?

Human intervention studies have provided clear evidence that dietary polyphenols (eg, flavonoids--eg, flavonols--and isoflavones) are at least partly absorbed and that they have the potential to exert biological effects. Biological activity of polyphenols is often assessed by using cultured cells as tissue models; in almost all such studies, cells are treated with aglycones or polyphenol-rich extracts (derived from plants and foods), and data are reported at concentrations that elicited a response. There are 2 inherent flaws in such an approach. First, plasma and tissues are not exposed in vivo to polyphenols in these forms. Several human studies have identified the nature of polyphenol conjugates in vivo and have shown that dietary polyphenols undergo extensive modification during first-pass metabolism so that the forms reaching the blood and tissues are, in general, neither aglycones (except for green tea catechins) nor the same as the dietary source. Polyphenols are present as conjugates of glucuronate or sulfate, with or without methylation of the catechol functional group. As a consequence, the polyphenol conjugates are likely to possess different biological properties and distribution patterns within tissues and cells than do polyphenol aglycones. Although deconjugation can potentially occur in vivo to produce aglycone, it occurs only at certain sites. Second, the polyphenol concentrations tested should be of the same order as the maximum plasma concentrations attained after a polyphenol-rich meal, which are in the range of 0.1-10 micromol/L. For correct interpretation of results, future efforts to define biological activities of polyphenols must make use of the available data concerning bioavailability and metabolism in humans.     

植物雌激素对动物和人体健康的影响

植物雌激素是一类具有类似动物雌激素生物活性的天然植物成分,它们在结构和功能上与动物雌激素相似.实验室研究和流行病学调查显示,植物雌激素存在着广泛的生物学效应,初步的人类临床试验研究也表明,植物雌激素对激素相关疾病有较大作用.近年来,植物雌激素对动物和人体健康的影响受到广泛的关注.该文对植物雌激素在激素相关类癌症、心血管疾病、骨质疏松症和生殖功能等方面的研究进展作了详细评述,并提出了今后主要研究方向.