Zhong X.S., Ge J., Chen S.W., Xiong Y.Q., Ma S.J., Chen Q. Isoflavone intake in four different European countries: The VENUS approach. Winkel-Shirley B. Biosynthesis of flavonoids and effects of stress. (2019) conducted a meta-analysis where 23 prospective studies with a total of 330,826 participants were included. In this section, 16 meta-analyses have been revised: Nachvack et al. Lu L.J., Anderson K.E. Santo A.S., Santo A.M., Browne R.W., Burton H., Leddy J.J., Horvath S.M., Horvath P.J. For this reason, the bioavailability of isoflavones has been extensively characterized in animal models and humans [25,26,27]. Due to the presence of biologically active compounds, walnut was used in the . Daily et al. Atkinson C., Frankenfeld C.L., Lampe J.W. Presence of four chemical forms of the three isoflavones found in soybeans. Saloniemi H., Whl K., Nyknen-Kurki P., Kallela K., Saastamoinen I. Phytoestrogen content and estrogenic effect of legume fodder. The most significant food source of isoflavones in humans is soy-derived products. 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 et al. The effect of the moon on planting times is stated as a matter of fact in such popular publications as The Old Farmer's Almanac and books such as Gardening and Planting by the Moon 2018, and, of course, calendars such as The Biodynamic Sowing and Planting Calendar 2018. Grosso G., Godos J., Lamuela-Raventos R., Ray S., Micek A., Pajak A., Sciacca S., DOrazio N., Del Rio D., Galvano F. A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations. This meta-analysis included 266,699 participants (21,612 patients with prostate cancer among them). In contrast, it seems that isoflavones do not act on central neurotransmitters directly. Overall, evidence regarding the use of isoflavones in cancer prevention suggests that they may be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, two of the types for which the association between isoflavone intake and cancer risk has been studied more in-depth. The enzymes responsible for the hydrolysis of isoflavone glycosides are glucosidases, which can be produced by the intestinal mucosa or the microbiota [29]. (2017) conducted a meta-analysis with 21 case-control studies and two cohort studies, with a total number of 11,346 cases and 140,177 controls [77]. Consequently, isoflavones can have estrogenic or anti-estrogenic effects [3]. 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. ; WritingOriginal Draft Preparation, S.G.-Z., M.G.-A., A.F.-Q., I.E. Focusing on the overall intake of isoflavones in humans, several studies have reported varied results. In the meta-analysis reported by Applegate et al. aimed to compare the effects of animal and plant-sourced proteins on lipemia and blood pressure [60]. He Bays that his thermometrical instruments were sensibly affected by the moon's rays, even at the lowest of two stations occupied by him at different elevations. Moreover, five studies reported side-effect data, and after the analysis, no significant differences were observed between the two groups. Implications of phytoestrogen intake for breast cancer. Ingram D., Sanders K., Kolybaba M., Lopez D. Case-control study of phyto-oestrogens and breast cancer. van Erp-Baart M.A., Brants H.A., Kiely M., Mulligan A., Turrini A., Sermoneta C., Kilkkinen A., Valsta L.M. 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). In this line, another meta-analysis, which included 52 controlled trials and 5313 patients, shows that soy isoflavones have beneficial effects on bone mineral density in the femur neck, lumbar spine, and hip, regardless of body weight or ethnicity [49]. Thanks for reading Scientific American. . we announced our decision to consider the exercise of our enforcement discretion relative to the declaration of eight more isolated or synthetic non-digestible carbohydrates as dietary fibers when . Hosoda K., Furuta T., Yokokawa A., Ishii K. Identification and quantification of daidzein-7-glucuronide-4-sulfate, genistein-7-glucuronide-4-sulfate and genistein-4,7-diglucuronide as major metabolites in human plasma after administration of kinako. Moreover, even though the binding affinity of isoflavones to the ER receptors is less than that of 17-estradiol, they can also act as estrogenic compounds when the endogenous estradiol is not available [8]. Future research in this field should quantify isoflavones as accurately as possible, analyzing larger cohorts and lengthening the follow-up stage. In general terms, it has been observed that in Asian countries where there is high consumption of soy and its derived foodstuffs, isoflavone intake is high, ranging from 15 to 60 mg/day [20,21], whereas, in western countries, it is notably lower, around 12 mg/day [22,23,24]. The latter is the most common form in foodstuffs, with the exception of fermented soy products, such as miso and tempeh. (2015) concluded that soy isoflavones have both a slight and slow effect in attenuating menopausal hot flushes [87]. 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. Jun S., Shin S., Joung H. Estimation of dietary flavonoid intake and major food sources of Korean adults. 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. He et al. (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]. Beneficial role of dietary phytoestrogens in obesity and diabetes. Matulka R.A., Matsuura I., Uesugi T., Ueno T., Burdock G. Developmental and Reproductive Effects of SE5-OH: An Equol-Rich Soy-Based Ingredient. HRT: hormone replacement therapy, RCT: randomized controlled trial, VSM: vasomotor symptoms. Reproductive and developmental toxicity studies have stated that 1 g and 2 g of equol per day is safe [96], although further studies are required [92]. Proof by rational experiment seems to have been. Yu Y., Jing X., Li H., Zhao X., Wang D. Soy isoflavone consumption and colorectal cancer risk: A systematic review and meta-analysis. Considering the isoflavone chemical structure, potential health adverse effects of these compounds related to their estrogenic activity have been postulated, despite the scientific opinion offered by EFSA indicating that isoflavone intake was safe. (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]. On the contrary, a systematic review and meta-analysis reported by Man et al. In addition, Qiu et al. Yan Z., Zhang X., Li C., Jiao S., Dong W. Association between consumption of soy and risk of cardiovascular disease: A meta-analysis of observational studies. Zaheer K., Humayoun Akhtar M. An updated review of dietary isoflavones: Nutrition, processing, bioavailability and impacts on human health. The .gov means its official. (2020) carried out their meta-analysis of 63 controlled trials, including 6427 postmenopausal women and concluded that isoflavones improve bone density at the lumbar spine, femoral neck and the distal radius in menopausal women [50]. Changes to Earth's climate driven by increased human emissions of heat-trapping greenhouse gases are already having widespread effects on the environment: glaciers and ice sheets are shrinking, river and lake ice is breaking up earlier, plant and animal geographic ranges are shifting, and plants and trees are blooming sooner. Chen L.R., Ko N.Y., Chen K.H. Liu J., Yuan F., Gao J., Shan B., Ren Y., Wang H., Gao Y. In fact, all the body fluids, as the tides, were controlled by the lunar phases. Moreover, this association was more prominent among postmenopausal women than premenopausal women. U.S. Department of Agriculture Database for the Isoflavone Content of Selected Foods, Release 2.0. In this regard, it has been reported that isoflavones have a higher affinity to the -estrogen receptor [7], which, contrary to the -estrogen receptor, inhibits cell proliferation and stimulates apoptosis [84]. Furthermore, soy protein has been linked to an improvement in nitric oxide production and contributes to increased arterial compliance [65]. Lu D., Gigure V. Requirement of Ras-dependent pathways for activation of the transforming growth factor beta3 promoter by estradiol. Isoflavones were the phytoestrogens used in most of the studies; therefore, the meta-analysis only included outcomes regarding isoflavones, while outcomes with other phytoestrogens were not included. Apparently, soy isoflavones modified adhesion molecules by binding to vascular endothelium and mimicking the effect of a modulator of estrogen receptors [64]. 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. Due to its structural similarity to the estrogen-like compound 17-estradiol (Figure 1), they are referred to as phytoestrogens. The water in the ocean on the side of the Earth closest to the moon experiences a larger gravitational attraction than the water on the opposite side. Simental-Menda L.E., Gotto A.M., Atkin S.L., Banach M., Pirro M., Sahebkar A. Lastly, Abshirini et al. Chalvon-Demersay T., Azzout-Marniche D., Arfsten J., Egli L., Gaudichon C., Karagounis L.G., Tom D. A Systematic Review of the Effects of Plant Compared with Animal Protein Sources on Features of Metabolic Syndrome. The main isoflavones found in foodstuffs are daidzein, genistein and glycitein, as well as biochanin A and formononetin [9,12]. 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. Kelly G.E., Nelson C., Waring M.A., Joannou G.E., Reeder A.Y. The effect of soy isoflavones on arterial stiffness: A systematic review and meta-analysis of randomized controlled trials. Chadha R., Bhalla Y., Jain A., Chadha K., Karan M. Dietary Soy Isoflavone: A Mechanistic Insight. Phenolic compounds are secondary metabolites, which are produced by plants as a defense mechanism against infection, water stress, cold stress, ultraviolet radiation and high visible light, among others [1,2]. Their meta-analysis included five studies with a total of 728 menopausal women between 50.5 and 58.5 years old and concluded that women who are not able to produce equol could benefit from equol supplementation. Soy isoflavones osteoprotective role in postmenopausal women: Mechanism of action. Some gardening folklore suggests that planting crops according to the phases of the moon will give you a better harvest, but there is little scientific evidence to back this up. 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. The most significant food source of isoflavones in humans is soy-derived products, soybeans, soy flour, soy flakes, soy beverages and fermented soy products such as miso and tempeh, among others [9]. The four chemical forms of the three most abundant isoflavones. In the same line, Yu et al. Kov L., Dadkov K., Kaparovsk J., Kaparovsk T. Isoflavones. (2019), included 16 prospective cohort studies involving 11,169 breast cancer cases and 648,913 participants [70]. With regard to isoflavone content in foodstuffs, it has been observed that in soybeans, the amount of these phenolic compounds ranges from 1.2 to 4.2 mg per g on dry weight, whereas in red clover, the amount varies between 10 and 25 mg per g on dry weight [15,16]. While a moderate intake of soy isoflavones did not significantly affect breast cancer risk, a significant reduction was shown when the intake was high. Zamora-Ros R., Knaze V., Rothwell J.A., Hmon B., Moskal A., Overvad K., Tjnneland A., Kyr C., Fagherazzi G., Boutron-Ruault M.C., et al. (2018) showed no effect of soy isoflavones on plasma concentrations of lipoprotein a (Lpa), a low-density lipoprotein associated with increased cardiovascular risk due to its pro-thrombotic and atherogenic properties [63]. 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. During menopause, there is a loss of bone density that can cause osteoporosis. Lambert M.N.T., Hu L.M., Jeppesen P.B. In this revision, three systematic reviews and five meta-analyses were included to explore the association of isoflavones and markers related to CVDs (Table 3). It is also important to mention that isoflavones could act as potential anticancer compounds due to their antioxidant role in malignant cell proliferation and differentiation (Figure 5). By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. This is mainly due to their potential adverse effects, which range from increased coronary heart disease to stroke and cancer [53,85]. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. Regarding breast cancer (Table 4), the same increase in soy isoflavone intake (10 mg/day) was related to a 9% lower risk of breast cancer mortality. Modified from Mace et al. 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]. Effects of isoflavones in bone health maintenance. Arjmandi B.H., Smith B.J. Watanabe S., Yamaguchi M., Sobue T., Takahashi T., Miura T., Arai Y., Mazur W., Whl K., Adlercreutz H. Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako). Kurzer M.S., Xu X. Dietary phytoestrogens. 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. Akhlaghi M., Ghasemi Nasab M., Riasatian M., Sadeghi F. Soy isoflavones prevent bone resorption and loss, a systematic review and meta-analysis of randomized controlled trials. You J., Sun Y., Bo Y., Zhu Y., Duan D., Cui H., Lu Q. In fact, the number of isoflavones present was very variable among the different soy food types. In the systematic review reported by Perna et al. Chang H.H., Robinson A.R., Common R.H. Excretion of radioactive diadzein and equol as monosulfates and disulfates in the urine of the laying hen. Acid rain also removes minerals and nutrients from the soil that trees need to grow. In a study conducted by Karr et al., the authors analyzed the urinary excretion of genistein, daidzein, equol and O-DMA in fourteen young men and women [47]. The lunar effect is a purported unproven correlation between specific stages of the roughly 29.5-day lunar cycle and behavior and physiological changes in living beings on Earth, including humans. However, the authors pointed out several limitations of this study, such as the important source of heterogeneity in their study. So long ago as 1880 Siemens showed that continuous exposure to arc lamps promoted luxuriance of foliage . Soy products (0.05130 g/day) and total isoflavones (0.28 to 63 mg/day). Sansai et al. 1Nutrition and Obesity Group, Department of Pharmacy and Food Science, University of the Basque Country (UPV/EHU) and Lucio Lascaray Research Institute, 01006 Vitoria, Spain; sue.uhe@zemog.aoias (S.G.-Z. Another meta-analysis explored the effects of several pharmacological and non-pharmacological treatments in the relief of vasomotor symptoms, taking into account not only hot flushes but also night sweats [89]. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. The conclusion was that isoflavones exerted little influence over bone mineral density and thus over bone health during menopause, although not all the studies observed the same effect. 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. Modified from Wang et al., 2006 [4]. But that doesn't mean that they dig in their heels and argue about it. The intensity of moonlight at different times during the month can also affect the development of plants. 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. ; Funding Acquisition, M.P.P. The same results were reported in another meta-analysis published by the same authors a year later (Li et al., 2016), when they compared the efficacy of several non-hormonal drugs on hot flushes, including selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), gabapentin, clonidine and soy isoflavones [88]. In addition, several studies have observed that the urine excretion of daidzein metabolites is notably higher than that of genistein metabolites [44,45,46]. This finding suggests that bacterial deglycosylation contributes significantly to isoflavone absorption [32]. Franco O.H., Chowdhury R., Troup J., Voortman T., Kunutsor S., Kavousi M., Oliver-Williams C., Muka T. Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis. Since hepatic lipase and lipoprotein lipase hydrolyze triglycerides into their constituents glycerol and fatty acids, their activation results in the delivery of the fatty acids to tissues such as muscle and adipose tissue. Isoflavones could be used as an alternative therapy for pathologies dependent on hormonal disorders such as breast and prostate cancer, cardiovascular diseases, as well as to minimize menopausal symptoms. In like manner, a meta-analysis by Simental-Menda et al. Although results vary greatly, most of these applications are supported by at least a few clinical studies. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, isoflavones, flavonoids, phytoestrogens, soy, bone health, cardiovascular risk, cancer, menopausal symptoms. Isoflavone Supplements for Menopausal Women: A Systematic Review. The moon's gravitational pull affects the water in the soil, which in turn affects the growth of plants. The authors suggested that this difference could be due to different genetic backgrounds and dietary patterns among Asian and Western populations. The authors found a statistical inverse association between isoflavone consumption and colorectal cancer risk in case-control studies, although not in cohort studies. That aluminum may be harmful to plants as well as animals. Thirty-nine studies were included with a sample size of 200 women per trial, in which the intervention period ranged from two to 96 weeks (median 12 weeks). Zhong et al. Isoflavones could be used as an alternative therapy for pathologies dependent on hormonal disorders such as breast and prostate cancer, cardiovascular diseases, as well as to minimize menopausal symptoms. Batterham T.J., Shutt D.A., Braden A.W.H., Tweeddale H.J. This study was supported by Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007, Basque Government under Grant PA20/04 and the University of the Basque Country under Grant GIU18-173. Furthermore, among the four studies of breast cancer recurrence, three studies found that isoflavone intake decreased the risk of breast cancer recurrence, although further studies are required to confirm this finding [82]. Further, Chalvon-Demersay et al. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin. 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. However, the moonlight decreases after the full moon. (2016) included 17 studies (nine case-control studies and eight cohort studies) [80]. 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