Phytoestrogens and Health Effects.

Phytoestrogens are literally estrogenic substances of plant origin. Although these substances are useful for plants in many aspects, their estrogenic properties are essentially relevant to their predators. As such, phytoestrogens can be considered to be substances potentially dedicated to plant-predator interaction. Therefore, it is not surprising to note that the word phytoestrogen comes from the early discovery of estrogenic effects in grazing animals and humans. Here, several compounds whose activities have been discovered at nutritional concentrations in animals and humans are examined. The substances analyzed belong to several chemical families, i.e., the flavanones, the coumestans, the resorcylic acid lactones, the isoflavones, and the enterolignans. Following their definition and the evocation of their role in plants, their metabolic transformations and bioavailabilities are discussed. A point is then made regarding their health effects, which can either be beneficial or adverse depending on the subject studied, the sex, the age, and the physiological status. Toxicological information is given based on official data. The effects are first presented in humans. Animal models are evoked when no data are available in humans. The effects are presented with a constant reference to doses and plausible exposure.

Effects of Isoflavone Supplementation on the Response to Medroxyprogesterone in Premenopausal Women with Nonatypical Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The purpose of this study was to evaluate the impact of isoflavone supplementation compared with placebo on endometrial histology and serum estradiol levels in premenopausal women with nonatypical endometrial hyperplasia. Materials and Methods: The present double-blindplacebo-controlled clinical trial was conducted on 100 women with nonatypical endometrial hyperplasia in the age range of 30 to 45 years. Participants were randomly assigned to receive 50 mg of isoflavone (n = 50) or placebos (n = 50) daily for three months. Both groups received the standard treatment of nonatypical endometrial hyperplasia. Endometrial biopsy and blood samples were taken at the baseline and three months after the intervention. The incidence of drug side effects was assessed as well. Results: After three months, 88.4% of isoflavone-administered subjects had a significant histological improvement compared to 68.9% subjects in the placebo group (P=0.02). There were no significant differences between the two groups in the changes of serum estradiol levels and the incidence of drug side effects. Conclusion: The findings of the present study demonstrated that the coadministration of 50 mg of isoflavones and medroxyprogesterone acetate increases the treatment efficacy in women with nonatypical endometrial hyperplasia. Clinical Trial Registration. This trial was registered on the Iranian website for clinical trial registration (https://www.irct.ir/trial/53553).

Associations between isoflavone exposure and reproductive damage in adult males: evidence from human and model system studies†.

It is controversial whether exposure to isoflavones exerts male reproductive toxicity. The aim of this study was to investigate whether isoflavone exposure during adulthood could have deleterious impacts on male reproductive health by the cross-sectional study, animal experiments, and in vitro tests. In the cross-sectional study, we observed that urinary isoflavones were not significantly associated with semen quality including sperm concentrations, sperm count, progressive motility, and total motility, respectively. However, negative associations were found between plasma testosterone and urinary Σisoflavones, genistein, glycitein, and dihydrodaidzein. In the animal experiments, serum and intratesticular testosterone levels were decreased in mice exposed to several dosages of genistein. Genistein administration caused upregulation of estrogen receptor alpha and downregulation of cytochrome P45017A1 protein levels in testes of mice. In vitro tests showed that genistein caused a concentration-dependent inhibition of testosterone production by TM3 Leydig cells. Elevated protein expression of estrogen receptor alpha and decreased messenger RNA/protein level of cytochrome P45017A1 were also observed in genistein-treated cells. Protein level of cytochrome P45017A1 and testosterone concentration were significantly restored in the estrogen receptor alpha small interferring RNA-transfected cells, compared to cells that treated with genistein alone. The results demonstrate that exposure to isoflavones during adulthood may be associated with alterations of reproductive hormones. Particularly, genistein, which inhibits testosterone biosynthesis through upregulation of estrogen receptor alpha in Leydig cells of mice, might induce the disruption of testosterone production in human. The present study provides novel perspective into potential targets for male reproductive compromise induced by isoflavone exposure.

Bio-enhancement of Soy Isoflavones (Genistein & Daidzein) Using Bacillus coagulans in Letrozole Induced Polycystic Ovarian Syndrome by Regulating Endocrine Hormones in Rats.

Soy isoflavone (SIF), a natural phytoestrogen, is used in the condition of hormonal imbalance. These isoflavones generally have low solubility resulting in low bioavailability and bioactivity. It is reported that trans-glycosylation by cyclodextrin glycosyltransferase (CGTase) is widely utilized for increasing the solubility and bioavailability of isoflavones. Present investigation was aimed to study the effect of Bacillus coagulans (a probiotic) in potentiating the bioactivity of soy isoflavones in letrozole-induced PCOS. Initial consideration was focused on proving CGTase assay of B. coagulans. After that, animal study was performed to check the enhancement of bioactivity of SIF along with B. coagulans. A total of 36 rats, separated into six groups (6 rats in each), were used. Group I received vehicles, group II received letrozole (1 mg/kg) for 21 days, and group III animals were administered with soy isoflavones (SIF-100 mg/kg). In the case of group IV, V, and VI, animals received SIF (100 mg/kg) along with B. coagulans 0.65, 3.25, and 6.50 mg/kg, respectively. Treatment was given for 2 weeks after induction of disease. All the animals were sacrificed at the end of the study and endpoint parameters were performed. Present investigation revealed that combination of SIF with B. coagulans showed hormone restoration, reduce oxidative stress, recovery in the menstrual cycle, and improvement in ovarian physiology. SIF (genistein & daidzein) together with B. coagulans exhibits a beneficial role in the enhancement of the bioactivity of soy isoflavones. Further, it showed that a higher dose of B. coagulans (6.50 mg/kg) is more effective in ameliorating the PCOS symptoms.

Secondary Hypogonadism due to Excessive Ingestion of Isoflavone in a Man.

A 54-year-old man had been drinking approximately 1.2 L of soy milk (equivalent to approximately 310 mg of isoflavones) per day for the previous 3 years. He then developed erectile dysfunction and gynecomastia. On an examination in our department in May, blood tests showed low gonadotropin and testosterone levels, indicative of secondary hypogonadism. He stopped drinking soy milk on his own in June of that year. When he was admitted in August, blood tests showed an improved gonadal function. Secondary hypogonadism caused by the excessive intake of isoflavones in soy milk was diagnosed. In men, an excessive intake of isoflavones may cause feminization and secondary hypogonadism.

Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: a technical review of the observational and clinical data.

Soybeans are a rich source of isoflavones, which are classified as phytoestrogens. Despite numerous proposed benefits, isoflavones are often classified as endocrine disruptors, based primarily on animal studies. However, there are ample human data regarding the health effects of isoflavones. We conducted a technical review, systematically searching Medline, EMBASE, and the Cochrane Library (from inception through January 2021). We included clinical studies, observational studies, and systematic reviews and meta-analyses (SRMA) that examined the relationship between soy and/or isoflavone intake and endocrine-related endpoints. 417 reports (229 observational studies, 157 clinical studies and 32 SRMAs) met our eligibility criteria. The available evidence indicates that isoflavone intake does not adversely affect thyroid function. Adverse effects are also not seen on breast or endometrial tissue or estrogen levels in women, or testosterone or estrogen levels, or sperm or semen parameters in men. Although menstrual cycle length may be slightly increased, ovulation is not prevented. Limited insight could be gained about possible impacts of in utero isoflavone exposure, but the existing data are reassuring. Adverse effects of isoflavone intake were not identified in children, but limited research has been conducted. After extensive review, the evidence does not support classifying isoflavones as endocrine disruptors.

Calycosin: a Review of its Pharmacological Effects and Application Prospects.

Introduction: Calycosin (CA), a typical phytoestrogen extracted from root of Astragalus membranaceus. On the basis of summarizing the pharmacological and pharmacokinetic studies of CA in recent years, we hope to provide useful information for CA about treating different diseases and to make suggestions for future research.Areas covered: We collected relevant information (January 2014 to March 2020) on CA via the Internet database. Keywords searched includ pharmacology, pharmacokinetics and toxicology, and the number of effective references was 118. CA is a phytoestrogen with wide range of pharmacological activities. By affecting PI3K/Akt/mTOR, WDR7-7-GPR30, Rab27B-ß-catenin-VEGF, etc. signaling pathway, CA showed the effect of anticancer, anti-inflammatory, anti-osteoporosis, neuroprotection, hepatoprotection, etc. Therefore, CA is prospective to be used in the treatment of many diseases.Expert opinion: Research shows that CA has a therapeutic effect on a variety of diseases. We think CA is a promising natural medicine. Therefore, we propose that the research directions of CA in the future include the following. Carrying out clinical research trials in order to find the most suitable medicinal concentration for different diseases; Exploring the synergistic mechanism of CA in combination with other drugs; Exploring ways to increase the blood circulation concentration of CA.

The effect of hormonal levels and oxidative stress on bisphenol A and soy isoflavone reproductive toxicity in murine offspring.

Previous studies have suggested that human exposure to bisphenol A (BPA) and soy isoflavones (SIFs) can occur during pregnancy. The combination of these chemicals is hypothesized to have a toxic impact on the fetus. While BPA is an industrial chemical used widely in the manufacture of polycarbonate plastics and epoxy resins, SIFs are naturally occurring estrogen­like phytoestrogens. To determine the impact of the combination of BPA and SIFs on fetal development, the body weight, organ weight, anogenital distance and histopathological changes in the testes of F1 offspring were assessed in mice. Hormonal effects were determined by measuring serum levels of estrogen receptor (ESR), follicle­stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T). Additionally, mitochondrial DNA copy numbers, and the serum levels of malondialdehyde and superoxide dismutase, were determined to evaluate alterations in oxidative stress and potential toxicity. Exposure to BPA increased the body weight of the pups and reduced the ratio of anogenital distance to body weight, as well as testes weight. Moreover, BPA exposure also induced testicular lesions. The seminiferous tubules of testis were denatured in varying degrees and the lumen wall structure was disordered. The levels of ESR in all offspring and the T levels in male offspring significantly increased, compared with controls. Co­exposure to BPA and SIFs exacerbated these changes in body weight, testicular lesions and hormonal levels, relative to BPA exposure alone. Additionally, oxidative damage was only induced by high­dose BPA. Collectively, these findings suggested that BPA and SIFs could have synergistic effect on the reproductive system, which could be mediated by the regulation of ESR expression and testosterone release.

Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review.

Dietary phytoestrogens are bioactive compounds with estrogenic activity. With the growing popularity of plant-based diets, the intake of phytoestrogen-rich legumes (especially soy) and legume-derived foods has increased. Evidence from preclinical studies suggests these compounds may have an effect on hormones and health, although the results of human trials are unclear. The effects of dietary phytoestrogens depend on the exposure (phytoestrogen type, matrix, concentration, and bioavailability), ethnicity, hormone levels (related to age, sex, and physiological condition), and health status of the consumer. In this review, we have summarized the results of human studies on dietary phytoestrogens with the aim of assessing the possible hormone-dependent outcomes and health effects of their consumption throughout a lifespan, focusing on pregnancy, childhood, adulthood, and the premenopausal and postmenopausal stages. In pregnant women, an improvement of insulin metabolism has been reported in only one study. Sex hormone alterations have been found in the late stages of childhood, and goitrogenic effects in children with hypothyroidism. In premenopausal and postmenopausal women, the reported impacts on hormones are inconsistent, although beneficial goitrogenic effects and improved glycemic control and cardiovascular risk markers have been described in postmenopausal individuals. In adult men, different authors report goitrogenic effects and a reduction of insulin in non-alcoholic fatty liver patients. Further carefully designed studies are warranted to better elucidate the impact of phytoestrogen consumption on the endocrine system at different life stages.

Effects of soy isoflavones on serum lipids and lipoprotein (a) in peritoneal dialysis patients.

BACKGROUND AND AIM: Lipid abnormalities are common in peritoneal dialysis (PD) patients and no effective treatment to decrease serum lipoprotein (a) [Lp(a)] in dialysis patients is known so far. Therefore, this research was designed to investigate the effects of soy isoflavone supplement on serum lipids and Lp(a) in PD patients. METHODS & RESULTS: In this randomized, double-blind, placebo-controlled trial, 40 PD patients were randomly assigned to either the isoflavone or the placebo group. The patients in the isoflavone group received 100 mg soy isoflavone daily for 8 weeks, whereas the placebo group received corresponding placebos. At baseline and the end of the 8th week, 7 mL of blood was obtained from each patient and serum triglycerides, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and Lp(a) were measured. Serum Lp(a) reduced significantly up to 10% in the isoflavone group at the end of week 8 compared to baseline (P < 0.05), and the reduction was significant in comparison with the placebo group (P < 0.05). Serum HDL-C increased significantly up to 11.5% in the isoflavone group at the end of week 8 compared to baseline (P = 0.05), and the increment was significant in comparison with the placebo group (P < 0.05). There were no significant differences between the two groups in mean changes of serum triglycerides, total cholesterol, and LDL-C. CONCLUSIONS: This study indicates that daily administration of 100 mg soy isoflavones reduces serum Lp(a) and increases HDL-C concentration which are two determinants of cardiovascular disease in PD patients. CLINICALTRIALS.GOV: NCT03773029. REGISTRATION NUMBER AND DATE: NCT03773029 - 2018.

Isoflavone Intake and the Risk of Coronary Heart Disease in US Men and Women: Results From 3 Prospective Cohort Studies.

BACKGROUND: Whether soy products confer health benefits related to coronary heart disease (CHD) remains controversial because of inconsistent evidence. METHODS: A total of 74 241 women from the NHS (Nurses' Health Study; 1984-2012), 94 233 women from the NHSII (Nurses' Health Study II; 1991-2013), and 42 226 men from the Health Professionals Follow-Up Study (1986-2012), who were free of cardiovascular disease and cancer at baseline, were included in the present analysis. Dietary data were updated every 2 to 4 years using a validated food frequency questionnaire. Nonfatal myocardial infarction and CHD deaths were adjudicated through reviewing medical records, death certificates, and other medical documents. RESULTS: In these cohorts, 8359 incident CHD cases were documented during 4 826 122 person-years of follow-up. In multivariable-adjusted analyses, isoflavone intake was inversely associated with CHD (pooled hazard ratio [HR] comparing the extreme quintiles: 0.87 [95% CI, 0.81-0.94]; P=0.008). Consumption of tofu, but not soy milk, was inversely associated with the risk of CHD, with pooled HRs (95% CIs) of 0.82 (0.70-0.95; P=0.005) and 0.87 (0.69-1.10; P=0.41), respectively, comparing ≥1 serving/week with <1 serving/month. Further analyses showed that, in women, the favorable association of tofu was primarily driven by stronger inverse association of tofu intake observed in younger women before menopause and postmenopausal women without hormone use (Pinteraction=0.002). CONCLUSIONS: Higher intake of isoflavones and tofu was associated with a moderately lower risk of developing CHD, and in women the favorable association of tofu were more pronounced in young women or postmenopausal women without hormone use.

Maternal Consumption of a Low-Isoflavone Soy Protein Isolate Diet Accelerates Chemically Induced Hepatic Carcinogenesis in Male Rat Offspring.

It has been reported that maternal nutrition determines the offspring's susceptibility to chronic diseases including cancer. Here, we investigated the effects of maternal diets differing in protein source on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in adult rat offspring. Dams were fed a casein (CAS) diet or a low-isoflavone soy protein isolate (SPI) diet for two weeks before mating and throughout pregnancy and lactation. Offspring were weaned to and fed a chow diet throughout the study. From four weeks of age, hepatocellular carcinomas (HCC) were induced by intraperitoneal injection of DEN once a week for 14 weeks. The SPI/DEN group exhibited higher mortality rate, tumor multiplicity, and HCC incidence compared with the CAS/DEN group. Accordingly, altered cholesterol metabolism and increases in liver damage and angiogenesis were observed in the SPI/DEN group. The SPI/DEN group had a significant induction of the nuclear factor-κB-mediated anti-apoptotic pathway, as measured by increased phosphorylation of IκB kinase ß, which may lead to the survival of precancerous hepatocytes. In conclusion, maternal consumption of a low-isoflavone soy protein isolate diet accelerated chemically induced hepatocarcinogenesis in male rat offspring in the present study, suggesting that maternal dietary protein source may be involved in DEN-induced hepatocarcinogenesis in adult offspring.

The dual roles of calycosin in growth inhibition and metastatic progression during pancreatic cancer development: A "TGF-ß paradox".

BACKGROUND: Calycosin is a bioactive isoflavonoid of the medicinal plant Astragalus membranaceus that exhibits a wide range of pharmacological properties. In the present study, we have attempted to explore the anti-tumorigenic potential of calycosin in pancreatic cancer. METHODS: MTT assay was used to determine cancer cell viability. Cell cycle analysis and detection of apoptosis were performed using flow cytometry. A wound healing assay was employed to study the migratory activity of cancer cells. Western blotting and RT-PCR were used to explore the mechanism by assessing the target proteins and genes. An orthotopic tumor xenograft mouse model was also used to study the drug effects in vivo. RESULTS: Calycosin inhibited the growth of pancreatic cancer cells by inducing p21Waf1/Cip1-induced cell cycle arrest and caspase-dependent apoptosis. Alternatively, it also promoted MIA PaCa-2 cell migration by eliciting epithelial-mesenchymal transition (EMT) and matrix metalloproteinase activation. In vivo study has confirmed that calycosin would provoke the pro-invasive and angiogenic drive and subsequent EMT in pancreatic tumors. Further mechanistic study suggests that induction of the Raf/MEK/ERK pathway and facilitated polarization of M2 tumor-associated macrophage in the tumor microenvironment both contribute to the pro-metastatic potential of calycosin. These events appear to be associated with increased expression of TGF-ß1 at both transcriptional and post-translational levels, which may explain the paradoxical drug actions since TGF-ß has been implicated to play dual roles as both tumor suppressor and tumor promoter in pancreatic cancer development. CONCLUSION: Findings of this study provide innovative insights about the impact of calycosin in pancreatic cancer progression through induction of cell cycle arrest and apoptosis while possessing certain tumor-promoting property by modulation of the tumor microenvironment.

Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.

OBJECTIVE: PhytoSERM is a selective estrogen receptor beta (ERß) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS: In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS: Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION: Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Soy and Isoflavone Consumption and Multiple Health Outcomes: Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies and Randomized Trials in Humans.

SCOPE: To assess the existing evidence of associations between consumption of soy and isoflavone and multiple health outcomes. METHODS AND RESULTS: This is an umbrella review of meta-analyses and systematic reviews of randomized trials and observational studies in humans. 114 Meta-analyses and systematic reviews are identified with 43 unique outcomes. Soy and isoflavone consumption seems more beneficial than harmful for a series of health outcomes. Beneficial associations are identified for cancers, cardiovascular disease, gynecological, metabolic, musculoskeletal, endocrine, neurological, and renal outcomes, particularly in perimenopausal women. Harmful association is only found for gastric cancer (RR: 1.17, 95% CI: 1.02-1.36) for high intake of miso soup (1-5 cups per day) in male. CONCLUSION: Generally, soy and isoflavone consumption is more beneficial than harmful. The results herein support promoting soy intake as part of a healthy diet. Randomized controlled trials are necessary to confirm this finding.

Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study.

BACKGROUND: Soy-based dietary supplements have been promoted as natural alternatives to menopausal hormone therapy, but their potential effect on breast cancer development is controversial. OBJECTIVES: We examined the relation between the consumption of soy supplements and the risk of breast cancer, overall and by tumor hormone receptor status, among women aged >50 y. METHODS: In total, 76,442 women from the Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, born between 1925 and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed every 2-3 y. HRs of breast cancer were estimated with the use of multivariable Cox models. RESULTS: Compared with never using soy supplements, the HRs associated with current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95% CI: 0.60, 0.99) for estrogen receptor (ER)-positive, and 2.01 (95% CI: 1.41, 2.86) for ER-negative breast cancers. There was no association between past use of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI: 0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family history of breast cancer, respectively (P-interaction = 0.03) and 1.06 (95% CI: 0.87, 1.30) ≥5 y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in premenopause or ≤5 y postmenopause (P-interaction = 0.04). CONCLUSIONS: In this cohort of women aged >50 y, we report opposing associations of soy supplements with ER-positive and ER-negative breast cancer risk. Our results also caution against the use of these supplements in women with a family history of breast cancer. Whether the risk profile of soy supplements could be more favorable among premenopausal or recently postmenopausal women deserves further investigation.

Scandenolone from Cudrania tricuspidata fruit extract suppresses the viability of breast cancer cells (MCF-7) in vitro and in vivo.

Scandenolone, an isoflavone, has shown anti-cancer potential. In this study, we extracted scandenolone from Cudrania tricuspidata fruit and evaluated its anti-breast cancer effects as well as toxicity in cell and animal models. In cell model, scandenolone suppressed the breast cancer MCF-7 cells viability, ceased mitotic cell cycle, decreased mitochondrial membrane potential, up-regulated cleaved caspase-3 and promoted the phosphorylation of p53. Additionally, this isoflavone promoted cell apoptosis and induced a sustained activation of the phosphorylation of p38 and ERK, but not JNK and Akt. The effects were further verified in a human MCF-7 breast cancer xenograft model, where scandenolone efficiently suppressed the cancer growth and increased apoptotic cells in tumor tissue. However scandenolone has also shown certain toxicity to normal hepatocytes and breast epithelial cells. It could be concluded that scandenolone suppressed the growth of breast cancer cells, but its toxicity towards normal cells might limit its potential clinical use.

Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies.

BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. CONCLUSIONS: The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.

Soy Isoflavone Intake and Bladder Cancer Risk in Japan: From the Takayama Study.

Background: There is growing evidence suggesting that soy isoflavones play a protective role in the development of cancer. However, few epidemiological studies have investigated the association between soy isoflavone intake and bladder cancer.Methods: We evaluated the associations of soy and isoflavone intakes with bladder cancer incidence in a population-based prospective study in Japan. Subjects were 14,233 men and 16,584 women age 35 years or older in September 1992. Soy and isoflavone intakes were assessed via a validated food-frequency questionnaire, while controlling for total energy intake. Cancer incidence was mainly confirmed through regional population-based cancer registries. Bladder cancer was defined as code C67 according to the International Classification of Diseases and Health Related Problems, 10th Revision.Results: During mean follow-up of 13.6 years, 120 men and 41 women had developed bladder cancer. After adjustments for multiple confounders, compared with the lowest quartile of soy food intake, the estimated hazard ratios for the second, third, and highest quartiles of soy food intake were 0.74, 0.52, and 0.55, respectively, in men (P-trend: 0.023). The corresponding values were 0.60, 0.75, and 0.64, respectively, in women (P-trend: 0.43). Similar inverse associations were observed between isoflavone intake and bladder cancer risk.Conclusions: A significant decreased risk of bladder cancer was observed among men who had higher intakes of total soy and isoflavones.Impact: Our finding on the potential benefit of consuming soy foods against bladder cancer is promising and warrants further studies. Cancer Epidemiol Biomarkers Prev; 27(11); 1371-5. ©2018 AACR.

Effects of isoflavones on breast tissue and the thyroid hormone system in humans: a comprehensive safety evaluation.

Isoflavones are secondary plant constituents of certain foods and feeds such as soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations are marketed as food supplements and so-called dietary food for special medical purposes to alleviate health complaints of peri- and postmenopausal women. Based on the bioactivity of isoflavones, especially their hormonal properties, there is an ongoing discussion regarding their potential adverse effects on human health. This review evaluates and summarises the evidence from interventional and observational studies addressing potential unintended effects of isoflavones on the female breast in healthy women as well as in breast cancer patients and on the thyroid hormone system. In addition, evidence from animal and in vitro studies considered relevant in this context was taken into account along with their strengths and limitations. Key factors influencing the biological effects of isoflavones, e.g., bioavailability, plasma and tissue concentrations, metabolism, temporality (pre- vs. postmenopausal women), and duration of isoflavone exposure, were also addressed. Final conclusions on the safety of isoflavones are guided by the aim of precautionary consumer protection.