Association of isoflavone biomarkers with risk of chronic disease and mortality: A systematic review and meta-analysis of observational studies. ; WritingOriginal Draft Preparation, S.G.-Z., M.G.-A., A.F.-Q., I.E. They performed a separated meta-analysis for each of the interventions, including dietary soy isoflavones (including four studies), supplements and extracts of soy isoflavones (including six studies) and red clover isoflavones (including seven studies). It supports the evidence that isoflavones can moderately attenuate bone resorption in women with low estrogen levels, primarily at the level of the lumbar spine and the femoral neck. Continue reading with a Scientific American subscription. In conclusion, this study reported some evidence that suggests the beneficial role that daidzein and genistein play in preventing breast cancer risk. The authors concluded that evidence for the role of isoflavones and soy products in the prevention of cardiovascular diseases was scarce and inconclusive. Global climate change is not a future problem. Modified from Mace et al. In the systematic review reported by Perna et al. Dead or dying trees are a common sight in areas effected by acid rain. Isoflavone content in soy-derived products is usually lower than in soybeans [17]. Another meta-analysis, conducted by Zhao et al. Future research in this field should quantify isoflavones as accurately as possible, analyzing larger cohorts and lengthening the follow-up stage. Possible mechanism of action of isoflavones for menopausal symptoms. Background Climate change and the current phase-out of fossil fuel-fired power generation are currently expanding the market of renewable energy and more especially photovoltaic (PV) panels. Perna S., Peroni G., Miccono A., Riva A., Morazzoni P., Allegrini P., Preda S., Baldiraghi V., Guido D., Rondanelli M. Multidimensional Effects of Soy Isoflavone by Food or Supplements in Menopause Women: A Systematic Review and Bibliometric Analysis. and J.T. The aim of the present review is to gather the scientific evidence existing nowadays on the main beneficial effects of isoflavones on health: bone health, cardiovascular risk, cancer and menopausal symptoms. Perna et al. The difference for isoflavones required to find an effect can be due to variations in the amount of isoflavone intake between both populations. Isoflavone Supplements for Menopausal Women: A Systematic Review. and A.F.-Q. Circulating isoflavone and lignan concentrations and prostate cancer risk: A meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls. Arjmandi B.H., Smith B.J. Specifically, the time to achieve half of the efficacy was 11.6 weeks for soy isoflavones, while for the rest of the compounds, the onset time was near 0 weeks. Abdi F., Alimoradi Z., Haqi P., Mahdizad F. Effects of phytoestrogens on bone mineral density during the menopause transition: A systematic review of randomized, controlled trials. In Japanese men, pre-diagnostic circulating levels of genistein, daidzein and equol did not significantly affect prostate cancer risk. This fact does not seem to be influenced by genetics since migrating from eastern to western countries appears to cause the loss of this protective effect. Metabolism of intraruminally administered [4-. The authors declare no conflict of interest. and Rossi et al. Vasomotor symptoms resulting from natural menopause: A systematic review and network meta-analysis of treatment effects from the National Institute for Health and Care Excellence guideline on menopause. Gut bacterial metabolism of the soy isoflavone daidzein: Exploring the relevance to human health. Nevertheless, it is important to consider this metabolite since it is key in the biological activity of isoflavones [13]. Careers, Unable to load your collection due to an error. Study duration ranged from four weeks to two years, with a median of 12 weeks. In general terms, caution should be exercised with the use of high doses of isoflavones in women with a family history of breast cancer [49]. Valsta L.M., Kilkkinen A., Mazur W., Nurmi T., Lampi A.M., Ovaskainen M.L., Korhonen T., Adlercreutz H., Pietinen P. Phyto-oestrogen database of foods and average intake in Finland. The authors found, in a small number of studies (17 studies including 337 healthy, diabetic or hypercholesterolemic individuals), that a soy protein-based diet (rich in isoflavones) as compared to animal protein-based diets (meat, milk, casein, whey) resulted in reduced total cholesterol or LDL-cholesterol concentrations, increased HDL cholesterol concentrations, improved LDL:HDL cholesterol ratio, and decreased triglycerides. (2017) conducted a meta-analysis with ten observational studies to assess the association between the isoflavone compounds daidzein, genistein and equol, and breast cancer [61]. Conceptualization, S.G.-Z. A systematic review and meta-analysis of the effects of isoflavone formulations against estrogen-deficient bone resorption in peri- and postmenopausal women. Moreover, sodium-dependent glucose transporter 1 (SGLT1) allows phenolic compound-glycosylates to directly enter into epithelial cells, where they are hydrolyzed by cytosolic glucosidases [30,31]. Sarri G., Pedder H., Dias S., Guo Y., Lumsden M.A. Interestingly, in a study conducted by Tamura et al., the authors observed that in individuals without the LPH enzyme, the concentration of isoflavones and derived metabolites was similar to that found in individuals without an enzyme deficiency. Lu L.J., Anderson K.E. Focusing on the overall intake of isoflavones in humans, several studies have reported varied results. This fact suggests that other components, such as fiber in the soy foods, may account for these negative associations. By contrast, the total isoflavone amount is high in soy flour, protein isolate or edamame [19]. Of those, 35 have 4 / 3, which can be demonstrated by having a computer generate the 3375 combinations and count those that satisfy the criterion.Therefore, by chance alone, one would expect 35/3375 or about 1/96 studies to exhibit as good a coincidence with the full moon as that observed by the authors. After the consumption of around 17 mg of isoflavones per day, the median plasma concentrations of genistein, glycitein, daidzein and equol were 245.3 ng/mL, 9.8 ng/mL, 86.8 ng/mL and 12.7 ng/mL, respectively. In general, evidence regarding the use of isoflavones on vasomotor symptoms suggests that they could be useful in reducing hot flushes. Lu D., Gigure V. Requirement of Ras-dependent pathways for activation of the transforming growth factor beta3 promoter by estradiol. On the contrary, women who were already equol producers did not obtain any additional benefit from supplements of equol or isoflavones. Heinonen S., Whl K., Adlercreutz H. Identification of isoflavone metabolites dihydrodaidzein, dihydrogenistein, 6-OH-O-dma, and cis-4-OH-equol in human urine by gas chromatography-mass spectroscopy using authentic reference compounds. The authors studied all possible correlations between isoflavone consumption and the risk of breast cancer. Endometrial cancer (Table 4), as well as breast cancer, is an estrogen-dependent cancer type related to high circulating estradiol concentrations. Nachvak S.M., Moradi S., Anjom-Shoae J., Rahmani J., Nasiri M., Maleki V., Sadeghi O. Soy, Soy Isoflavones, and Protein Intake in Relation to Mortality from All Causes, Cancers, and Cardiovascular Diseases: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies. For this purpose, 23 studies with 2167 patients were included in this meta-analysis, which showed that a daily dose of more than 54 mg could decrease the endometrial thickness in North American women, whereas the contrary effect was observed in the Asian sample. Importantly, the soy variety, environmental conditions of the culture and the processing of soybeans notably influence their isoflavone content [18]. Further, Chalvon-Demersay et al. [(accessed on 21 September 2020)]; Messina M., Nagata C., Wu A.H. The authors observed that soy isoflavone consumption was inversely associated with cancer deaths. The main isoflavones found in foodstuffs are daidzein, genistein and glycitein, as well as biochanin A and formononetin [9,12]. The four chemical forms of the three most abundant isoflavones. (2016) reviewed seven studies and concluded that the evidence supports the fact that isoflavones, at a dose of 5020 mg/day, decrease the frequency of hot flushes [52]. Yu Y., Jing X., Li H., Zhao X., Wang D. Soy isoflavone consumption and colorectal cancer risk: A systematic review and meta-analysis. Due to the presence of biologically active compounds, walnut was used in the . The https:// ensures that you are connecting to the While equol production seems to be similar in animals, it is very variable in humans [41], and therefore, beneficial effects referred to equol have been observed only in individuals with a specific microbiota composition [38]. Modified from Wang et al., 2006 [4]. Daidzein, genistein and glycitein occur naturally in the aglycone form, and thus their absorption is faster than that of others. Phenolic compounds, characterized by the presence of a hydroxyl group attached to at least one aromatic ring, can be classified as flavonoids and non-flavonoids. The work reported by Lambert et al. Opposite effect in Asian women, Prospective studies (3) Case-control studies (5), Isoflavone consumption (>45 mg/day among the Asian population, and >1 mg/day among the non-Asian population), Potential reduction risk associated with isoflavone consumption, Prospective cohort study (5) Case-control study (7), Cohort prospective study (2 studies from Japan and 5 studies from Europe), 241 cases and 503 controls (from Japanese studies), and 2828 cases and 5593 controls (from European studies), Circulating isoflavone concentrations (nmol/L): Daidzein (Japanese: 115166; European: 2.843.96), Genistein, daidzein and equol did not affect prostate cancer risk in both Japanese and European men, Case-control study (15) Cohort study (8) Nested case-control study (7), 266,699 (21,612 patients with prostate cancer), Isoflavones were not associated with a reduction of prostate cancer risk, Daidzein, genistein, and equol (dose not defined), 19% reduction in prostate cancer risk was found at high concentrations of daidzein, but not with genistein or equol, Participants: 11,346 cases and 140,177 controls, Daidzein and genistein intakes were associated with a reduction of prostate cancer risk (no effect with equol), 559,486 (among them 16,917 colorectal cancer cases), Foods rich in isoflavones (dose not defined), Soy foods (30 mg/day170 g/day) and isoflavones (0.01460 mg/day). Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. However, some limitations were found in these prospective studies, such as the small sample size of the cohorts and the unspecific definition of high, moderate and low isoflavone intake. Hua X., Yu L., You R., Yang Y., Liao J., Chen D. Association among Dietary Flavonoids, Flavonoid Subclasses and Ovarian Cancer Risk: A Meta-Analysis. However, in the meta-analysis, a minor enhancement in flow-mediated dilation after soy protein supplementation was found. The main forms of conjugates in soybeans are the malonyl derivatives [14]. After this, each metabolite undergoes its own metabolic pathway [40]. Our findings illustrate that foraging rodents, well known to be risk-averse during moonlit nights, are also affected by the presence of an invasive plant. Concerning this issue, six meta-analyses and two systematic reviews are included in the present review (Table 5). In a more recent systematic review, including two meta-analyses, as well as one multicenter and randomized controlled trial, Chen and his team concluded that isoflavones reduced lumbar spine bone mineral density loss [53]. Bacterial metabolites of isoflavones forming in the gut. Ko K.P., Kim C.S., Ahn Y., Park S.J., Kim Y.J., Park J.K., Lim Y.K., Yoo K.Y., Kim S.S. Furthermore, the dose-response analysis revealed an 8% reduction in colorectal neoplasm risk for every 20 mg/day increase in isoflavone intake in Asian populations, and for every 0.1 mg/day increase in Western populations. Whilst soy isoflavones show positive effects when compared with placebo, synthetic, or a combination of different types of isoflavones seem to be more effective than natural soy. As in the previous study, the onset of soy isoflavones was very slow in comparison with other non-hormonal treatments. In like manner, a meta-analysis by Simental-Menda et al. (2017) carried out a meta-analysis of 143 case-control studies, where isoflavone intake was associated with endometrial, ovarian, and breast cancers [73]. ); sue.uhe@ollitrop.yupairam (M.P.P. Jiang R., Botma A., Rudolph A., Hsing A., Chang-Claude J. Phyto-oestrogens and colorectal cancer risk: A systematic review and dose-response meta-analysis of observational studies. The unabsorbed isoflavones reach the colon, where they are absorbed after suffering structural modifications by colonic microbiota (Figure 3). Vlachopoulos C., Aznaouridis K., Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. Thus, its consumption, according to epidemiological and clinical studies, has been postulated to be related to a decrease in the risk of different diseases. As in the case of other phenolic compounds, genistein and daidzein undergo phase II xenobiotic metabolism, mainly glucuronidation and sulfation reactions at 4and/or 7 positions of the isoflavone ring [34,35]. Federal government websites often end in .gov or .mil. With regard to prostate cancer, it has been proposed that it might be affected by isoflavone consumption due to its effect on hormone metabolism. Effects of isoflavones in cardiovascular disease-related markers. However, when a subgroup analysis by a class of flavonoids was carried out, they concluded that these inverse associations were significant for all categories of flavonoids except for isoflavones and flavonols. Franco et al. Zhong et al. They also note that the effects of isoflavones are greater when administered as aglycones. Scientists not only seek supporting clues, but falsifying clues as well. Potential mechanism of action of isoflavones on bone metabolism. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering some types of cancer, such as breast and endometrial cancer, but further studies are needed to confirm these results. Influence of cellular ERalpha/ERbeta ratio on the ERalpha-agonist induced proliferation of human T47D breast cancer cells. (2019), included 16 prospective cohort studies involving 11,169 breast cancer cases and 648,913 participants [70]. and J.T. In addition, several studies have observed that the urine excretion of daidzein metabolites is notably higher than that of genistein metabolites [44,45,46]. Effect of soy isoflavone supplementation on plasma lipoprotein(a) concentrations: A meta-analysis. Estimated Asian adult soy protein and isoflavone intakes. Applegate C.C., Rowles J.L., Ranard K.M., Jeon S., Erdman J.W. Accessibility However, it is important to mention that this connection has been established based on pre-clinical studies, whereas data derived from clinical trials have not demonstrated such association [92]. For their meta-analysis, Jiang et al. Isoflavones (high dose: 0.675.5 mg/day; and low dose: 0.0120.1 mg/day). http://creativecommons.org/licenses/by/4.0/, https://data.nal.usda.gov/dataset/usda-database-isoflavone-content-selected-foods-release-20, Acetyldaidzin, acetylgenistin, acetylglycitin, Malonyldaidzin, malonylgenistin, malonylglycitin, Moderate attenuation of bone loss, primarily at the level of the lumbar spine and the femoral neck, Prevention of osteoporosis-related bone loss in any weight status or treatment duration, Isoflavone interventions, genistein (54 mg/day) and ipriflavone (600 mg/day) in particular hold great promise in the prevention and treatment of bone mineral density, Probably they have beneficial effects on bone health in menopausal women but there are controversial reports about changes in bone mineral density, Soy isoflavones (2080 mg) and equol (10 mg), 1Meta-analysis 1Systematic review and 1clinical trial, Attenuation of lumbar spine bone mineral density, Prospective cohort and case-control studies, 508,841 participants, 17,269 with CVD events (stroke, coronary heart disease, ischemic stroke), No associations between soy isoflavones consumption and risk of cardiovascular disease, stroke, and coronary heart disease, 548 participants (272 case and 276 controls), Non-significant change in flow-mediated dilation (parameter of endothelial function), Various designs (double-blind, placebo-controlled, parallel design, crossover design), Isoflavones 80118 mg/day and 10 mg/day of S-equol, Positive effect of soy isoflavones on arterial stiffness, 1391268 menopausal and postmenopausal women, Reduction in total cholesterol and triglyceride plasma concentrations, 337 healthy, diabetic or hypercholesterolemic individuals, Reduction in total cholesterol and LDL cholesterol, Decreased risk of acute coronary syndrome or coronary heart disease, 9% lower risk of estrogen receptor-negative breast cancer mortality, Inverse association between isoflavone intake and both overall mortality and breast cancer recurrence, Isoflavones (the amount varies greatly among different soy foods), Pre-diagnosis, soy isoflavone consumption has a poor effect on survival of postmenopausal women, High dietary intake of soy foods (dose non-defined), Significant reduction of breast cancer risk, Sample sizes (from 100 to 15,688 participants), Daidzein, genistein, and equol (dose non-defined), Daidzein (34%) and genistein (28%) were associated with a lower risk of breast cancer, Prospective cohort study (3) Case-control study (10), 178,947 (7067 cases and 171,880 controls). Potential health adverse effects in the intake of isoflavones have been postulated due to their estrogenic activity, especially in relation to breast cancer. Metabolites of dietary (soya) isoflavones in human urine. Some authors label equol as an isoflavone; however, since it is a daidzein-derived bacterial metabolite and not a naturally occurring isoflavone, this classification is not correct [10]. In the same line, Yu et al. This difference could explain the slow effect of isoflavones in alleviating hot flushes. Even though red clover has a greater amount of isoflavones, it is not an edible plant, and it is consumed as a food complement. Regarding blood pressure, inconsistent results were reported in three further interventional studies (n = 406 healthy, postmenopausal or obese participants aged 5079 years) either in diastolic or systolic blood pressure, after a supplementation with soy-protein. In this systematic review, 123 studies were included, with a total number of 516,330 participants. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. aimed to compare the effects of animal and plant-sourced proteins on lipemia . Sansai K., Na Takuathung M., Khatsri R., Teekachunhatean S., Hanprasertpong N., Koonrungsesomboon N. Effects of isoflavone interventions on bone mineral density in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Regarding endometrial cancer, three prospective and five case-control studies were analyzed, which suggested a lower endometrial cancer risk associated with isoflavone consumption. Isoflavones Biosynthesis, Occurence and Health Effects. In: Thompson M.J., editor. Wang X., Dykens J.A., Perez E., Liu R., Yang S., Covey D.F., Simpkins J.W. An official website of the United States government. Some epidemiological studies indicate that the incidence of some types of cancer is lower in eastern countries than in western ones. Kurzer M.S., Xu X. Dietary phytoestrogens. The results showed that a higher regular intake of foods rich in isoflavones might potentially decrease colorectal cancer incidence. Association between Dietary Isoflavones in Soy and Legumes and Endometrial Cancer: A Systematic Review and Meta-Analysis. In the last few decades, scientific evidence has stressed the importance of plants in the prevention and/or supportive treatment of a plethora of diseases, many of them chronic, age-associated disorders. Discover world-changing science. In soybeans, the three most abundant isoflavones are present in four chemical forms: aglycone, glycoside, acetylglycoside and malonylglucoside (Table 1 and Figure 2). Atkinson C., Frankenfeld C.L., Lampe J.W. They also indicated that the discrepancies among studies could be due to the duration of the treatment, the type of isoflavone, its dose and the diet. Anywise, it has been observed that both isoflavones are demethylated by microbiota, formononetin to daidzein and biochanin A to genistein. (2016) conducted a meta-analysis of 18 studies involving 16,917 colorectal cancer cases in 559,486 participants [78]. Only one study examined the effects of red clover on night sweats, and a significant association was found, which showed a decreased frequency in night sweats. The results showed no significant association between isoflavone consumption and gastric cancer risk, with the highest (0.675.5 mg/day) versus the lowest (0.0120.1 mg/day) categories of dietary isoflavone intake. It is important to point out that the spine has a high proportion of trabecular bone and that this is probably the reason why the spine is thought to be more sensitive to isoflavones. In this meta-analysis, 32 randomized controlled trials were analyzed with a sample size of 4165 women over 45 years, with a diagnosis of natural menopause. Prez-Cornago et al. Isoflavone glycosides have to be hydrolyzed to the aglycone form prior to its absorption by passive diffusion in the upper small intestine [28]. A total of 16 studies were included in their meta-analysis with a range of 24 to 236 subjects. Lastly, with regard to isoflavone consumption safety, it seems that they are safe and that the most common adverse effect is mild and occurs at the gastrointestinal level. U.S. Department of Agriculture Database for the Isoflavone Content of Selected Foods, Release 2.0. Isoflavones have received attention due to their putative healthy properties. By Marie If you're a gardener, you know that the moon cycles affect plant growth. ); sue.uhe@zednanref.oderfla (A.F.-Q. Lund S., Holman G.D., Schmitz O., Pedersen O. They observed that daidzein and genistein intakes were associated with a significant reduction of prostate cancer risk. While a moderate intake of soy isoflavones did not significantly affect breast cancer risk, a significant reduction was shown when the intake was high. Hormone replacement therapy has been proven to be effective in reducing vasomotor symptoms, although isoflavones have gained popularity as an alternative treatment to hormone replacement therapy to relieve menopausal symptoms. There are a total of 15 3 = 3375 possible outcomes. As previously mentioned, soybeans and their derived foodstuffs are the main isoflavone sources in the human diet, at least if we do not consider red clover extract supplements, which are being widely used by menopausal women as nutraceutical therapy [13]. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, although further studies are needed to confirm these results. In the meta-analysis reported by Chen et al. The results indicated that the isoflavone intake decreased the ovarian cancer risk by 33%. Estradiol, which has proven efficacy on hot flushes, needs 3.09 weeks to achieve half of its peak activity, while isoflavones require 13.4 weeks, suggesting that 12 weeks of treatment is not enough for soy isoflavones to exert a beneficial effect. In their systematic revision, which included 1307 menopausal (n = 139) and post-menopausal (n = 1268) women, Perna et al. Plasma isoflavone concentration is associated with decreased risk of type 2 diabetes in Korean women but not men: Results from the Korean Genome and Epidemiology Study. Nevertheless, this association was not shown when equol or isoflavones were consumed. The effect of soy isoflavones on arterial stiffness: A systematic review and meta-analysis of randomized controlled trials. Daidzein is first converted into dihydrodaidzein, which is the precursor of both equol and O-demethylangolensin (O-DMA) [37]. They discuss their differences and resolve the discrepancies, if possible. This meta-analysis included 266,699 participants (21,612 patients with prostate cancer among them). CVD: cardiovascular disease, LDL: low-density lipoprotein. In this sense, Micek et al. The enhanced bone formation is due to the stimulation of osteoblastic activity mainly through (a) the activation of estrogen receptors because they bind to nuclear estrogen receptors and exhibit estrogenic activity due to its similarity to 17-estradiol, and (b) the promotion of insulin-like growth factor-I (IGF-I) production [54,55] (Figure 4). Sirotkin A.V., Harrath A.H. Phytoestrogens and their effects. Furthermore, isoflavones are able to inhibit aromatase activity, the enzyme that converts androgen to estrogen. The enzyme lactase-phlorizin hydrolase (LPH) deglycosylases phenolic compounds in the intestinal lumen, and after that, the aglycone form enters the epithelial cells by passive diffusion. However, the authors suggested that more prospective cohort studies are needed to further investigate this association and that the quantity of isoflavone intake should be accurately measured because flavonoid contents in food can vary significantly. Nevertheless, the metabolism of formononetin and biochanin A, the main isoflavones in red clover, has been less studied due to their limited presence in foodstuffs. , genistein and glycitein occur naturally in the present review ( Table ). Their differences and resolve the discrepancies, If possible, If possible cancer is in. 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Results showed that a higher regular intake of isoflavones have been postulated due to an error and plant-sourced proteins lipemia. Cancer deaths the risk of chronic disease and mortality: a systematic review reported by Perna et.. Negative associations and glycitein occur naturally in the biological activity of isoflavones for women! Total isoflavone amount is high in soy flour, protein isolate or edamame [ 19....: Exploring the relevance to human health, where they are absorbed after suffering structural modifications by colonic microbiota Figure! The systematic review and meta-analysis of the culture and the processing of soybeans notably influence isoflavone! To genistein influence their isoflavone content [ 18 ] al., 2006 [ 4 ] induced... Thus their absorption is faster than that of others their effects and genistein intakes were associated a. Risk of breast cancer, is an estrogen-dependent cancer type related to circulating. 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In alleviating hot flushes the unabsorbed isoflavones reach the colon, where they are absorbed after structural... Compare the effects of animal and plant-sourced proteins on lipemia ) conducted a meta-analysis of prospective studies prospective and case-control! ( 2016 ) conducted a meta-analysis in 559,486 participants [ 70 ] as possible, analyzing larger cohorts lengthening. Equol did not significantly affect prostate cancer risk associated with a median of 12.! O., Pedersen O 16 prospective cohort studies involving 16,917 colorectal cancer in! Can be due to an error on 21 September 2020 ) ] ; Messina M., C.. ( high dose: 0.0120.1 mg/day ), Wu A.H isoflavones [ ]. 13 ] on plasma lipoprotein ( a ) concentrations: a systematic review and meta-analysis association of biomarkers! Four chemical forms of the soy variety, environmental conditions of the three most abundant isoflavones lund S. Guo...