Zaheer K., Humayoun Akhtar M. An updated review of dietary isoflavones: Nutrition, processing, bioavailability and impacts on human health. Therefore, it is necessary to support these results with additional studies. 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. ; Funding Acquisition, M.P.P. In this study, five prospective cohort studies and seven case-control studies, with 6275 cases and 393,776 controls, were included. In like manner, a meta-analysis by Simental-Menda et al. For this reason, the bioavailability of isoflavones has been extensively characterized in animal models and humans [25,26,27]. Sotoca A.M., van den Berg H., Vervoort J., van der Saag P., Strm A., Gustafsson J.A., Rietjens I., Murk A.J. The meta-analysis included 15 studies in which the number of participants ranged from 30 to 252. Regarding the mechanisms by which isoflavones act to alleviate vasomotor symptoms, is has been proposed that they bind to estrogen receptors and activate endothelial nitric oxide synthase (eNOS) transcription, leading to eNOS synthesis and nitric oxide production, the main mediator of vasodilatation, which allows cutaneous heat dissipation [91] (Figure 6). Comparative efficacy of nonhormonal drugs on menopausal hot flashes. Further, Chalvon-Demersay et al. 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]. Daidzein, genistein and glycitein occur naturally in the aglycone form, and thus their absorption is faster than that of others. Effects of isoflavones in cardiovascular disease-related markers. Isoflavone Supplements for Menopausal Women: A Systematic Review. Two of the studies also revealed that women who were able to produce equol or who had received equol supplementation could have had a greater benefit from isoflavones [53]. ), 2CIBEROBN Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, 01006 Vitoria, Spain, 3Bioaraba Health Research Institute, 01002 Vitoria, Spain. Due to the high prevalence of colorectal cancer, three meta-analyses addressing this issue are included in the present review. They also explained that the differences between isoflavones and the rest of the drugs might be because the latter act by modulating central neurotransmitters and, as a consequence, by regulating the central thermoregulatory centers in the hypothalamus. 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. Phytoestrogen Metabolism by Adult Human Gut Microbiota. The .gov means its official. Due to a decline in sunlight, the development of leaves . Nevertheless, this association was not shown when equol or isoflavones were consumed. In this sense, soy isoflavones have been proposed as beneficial because, in theory, they may contribute to the maintenance of good bone health (mass, mineral density and bone structure) in women who are at this stage in their life. The aglycone and conjugate forms of genistein represent up to 60% of total isoflavones, this being up to 30% in the case of daidzein. Thus, soybean can be considered as the best food source. and J.T. The light reflected off the moon has an effect on life on Earth, which isn't surprising, but not every lunar influence is heralded by a wolf's howl. However, the moonlight decreases after the full moon. Potential mechanism of action of isoflavones on bone metabolism. In: Thompson M.J., editor. 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. 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 . van Erp-Baart M.A., Brants H.A., Kiely M., Mulligan A., Turrini A., Sermoneta C., Kilkkinen A., Valsta L.M. Ingram D., Sanders K., Kolybaba M., Lopez D. Case-control study of phyto-oestrogens and breast cancer. Two meta-analyses, which covered prospective cohort studies, showed that soy isoflavone consumption was not associated significantly with mortality linked to cardiovascular events [56,62]. However, a limitation in this field is that there is still a great heterogeneity among studies. This fact suggests that other components, such as fiber in the soy foods, may account for these negative associations. A total of 16 studies were included in their meta-analysis with a range of 24 to 236 subjects. Many females sleep less and have less REM sleep. 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]. Indeed, they reported that an increase of 10 mg/day of soy isoflavones consumption was associated with a 7% lower risk of cancer mortality [62]. Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Gee J.M., DuPont M.S., Day A.J., Plumb G.W., Williamson G., Johnson I.T. However, the authors pointed out several limitations of this study, such as the important source of heterogeneity in their study. Mace T.A., Ware M.B., King S.A., Loftus S., Farren M.R., McMichael E., Scoville S., Geraghty C., Young G., Carson W.E., et al. In this sense, the authors suggested that the composition of the gut microflora may influence isoflavone absorption and metabolism and could affect the production of isoflavone metabolites, which, in turn, could mediate their biological activity. (2020) revised the literature to find randomized controlled trials that evaluated the impact of soy protein supplementation (isoflavone intake ranging from 49.3 to 118 mg/day) on endothelial function parameters in postmenopausal women (n = 802) [58]. Due to its structural similarity to the estrogen-like compound 17-estradiol (Figure 1), they are referred to as phytoestrogens. Scientists not only seek supporting clues, but falsifying clues as well. Sex and long-term soy diets affect the metabolism and excretion of soy isoflavones in humans. As in the previous study, the onset of soy isoflavones was very slow in comparison with other non-hormonal treatments. In the end, isoflavones could be useful in reducing hot flushes associated with menopause. However, more studies are required to provide stronger evidence. 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). Sfakianos J., Coward L., Kirk M., Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. (2019) studied whether equol supplementation could benefit equol nonproducer subjects in lowering the incidence and severity of hot flushes [85]. Despite the positive effect of isoflavones, the authors emphasized that the effects took a long time to appear. Presence of four chemical forms of the three isoflavones found in soybeans. 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. Yu Y., Jing X., Li H., Zhao X., Wang D. Soy isoflavone consumption and colorectal cancer risk: A systematic review and meta-analysis. The mean age of women ranged from 49 to 58.3 and 48 to 60.1 years in the placebo and phytoestrogen groups, respectively, and women were followed up for a period of 3 to 12 months. In this sense, Micek et al. Perez-Cornago A., Appleby P.N., Boeing H., Gil L., Kyr C., Ricceri F., Murphy N., Trichopoulou A., Tsilidis K.K., Khaw K.T., et al. 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. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Finally, isoflavones could be useful in reducing hot flushes associated with menopause. 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]. They observed that it was dose-dependent at low to moderate soybean consumption. PV panels have been linked . (2018), 30 articles were included for analysis; 15 of them were case-control studies, eight cohort studies and seven nested case-control studies [76]. 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. Prospective study on usual dietary phytoestrogen intake and cardiovascular disease risk in Western women. 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. ); sue.uhe@ollitrop.yupairam (M.P.P. This fact was not taken into account in previous meta-analyses, and thus it may justify the discrepancies amongst them. 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 et al. Among these, vasomotor symptoms comprising hot flushes and night sweats are the most common and bothersome, which, in turn, have a negative impact on womens quality of life. Thanks for reading Scientific American. As it has been stated in the Bioavailability section, microbiota composition in humans makes equol production very variable, which yields high interindividual differences. No association between isoflavone consumption and gastric cancer risk with the highest versus the lowest categories of dietary isoflavone intake, 30252 perimenopausal or postmenopausal women/report (1753 in total), Reduction of hot flush frequency (vs. placebo), Slight and slow attenuation of hot flushes (vs. estradiol), Slight and slow attenuation of hot flushes (vs. non-hormonal drugs), Soy isoflavones: 33200 mg/day and 6 g soy extract/day, Equol or isoflavone in equol-producers more effective than placebo, Reduction of VSM (hot flushes and night sweats) compared to placebo, Reduction of hot flush frequency by means of dietary isoflavones and supplements), 51403 menopausal and postmenopausal women, Beneficial effects of isoflavones (vs. placebo), 40403 menopausal and postmenopausal women. Gaya P., Medina M., Snchez-Jimnez A., Landete J.M. . 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. Reduction of the endometrial thickness in North American women (for 0.23 mm). Finally, it is important to mention that despite the fact that potential isoflavone adverse effects have been widely studied, little is known about the side effect of the bacterial metabolite equol. Hairi H.A., Shuid A.N., Ibrahim N., Jamal J.A., Mohamed N., Mohamed I.N. Estimated Asian adult soy protein and isoflavone intakes. Karr S.C., Lampe J.W., Hutchins A.M., Slavin J.L. 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. ); sue.uhe@zelaznog.enatiam (M.G.-A. van der Schouw Y.T., Kreijkamp-Kaspers S., Peeters P.H., Keinan-Boker L., Rimm E.B., Grobbee D.E. (2015), the authors examined the efficacy of phytoestrogens in reducing hot flushes [86]. In the aforementioned mechanism, it has been reported that isoflavones bind to both ER and ER, although they present a higher affinity towards ER receptors [7]. Abstract BELIEFS that phases of the moon have a differential effect on the rate of development of plants are both ancient and world-wide. 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]. (2018) performed a meta-analysis of 12 studies, where six were cohort studies, and six case-control studies, with a total of 596,553 participants [81]. 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. Most peculiar is that moonlight exposure causes a rise in blood pressure. 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. 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]. Produced metabolites appear in plasma at variable concentrations and can enter enterohepatic circulation [28]. Association of isoflavone biomarkers with risk of chronic disease and mortality: A systematic review and meta-analysis of observational studies. Although results vary greatly, most of these applications are supported by at least a few clinical studies. Although the mechanisms of action of isoflavones are not completely understood, it seems that isoflavones not only reduce the rate of bone resorption but also increase the rate of bone formation. Chen M.N., Lin C.C., Liu C.F. Messina M.J. Legumes and soybeans: Overview of their nutritional profiles and health effects. The specific mechanisms of action underlying these effects and the reported side effects derived from their consumption. 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. (2016) included 17 studies (nine case-control studies and eight cohort studies) [80]. Zhao T.T., Jin F., Li J.G., Xu Y.Y., Dong H.T., Liu Q., Xing P., Zhu G.L., Xu H., Miao Z.F. 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. aimed to compare the effects of animal and plant-sourced proteins on lipemia . The intensity of moonlight at different times during the month can also affect the development of plants. Regarding endometrial cancer, three prospective and five case-control studies were analyzed, which suggested a lower endometrial cancer risk associated with isoflavone consumption. In the meta-analysis reported by Applegate et al. In this line, three meta-analyses were conducted to study isoflavone consumption and endometrial cancer risk. In this systematic review, 123 studies were included, with a total number of 516,330 participants. Similarly, Li et al. Lund S., Holman G.D., Schmitz O., Pedersen O. 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). ; Project Administration, M.P.P. After this, each metabolite undergoes its own metabolic pathway [40]. Gruber C.J., Tschugguel W., Schneeberger C., Huber J.C. Production and actions of estrogens. They are present in several vegetables, mainly in legumes such as soy, white and red clover, alfalfa and beans. Is equol production beneficial to health? In fact, the number of isoflavones present was very variable among the different soy food types. Potential health adverse effects in the intake of isoflavones have been postulated due to their estrogenic activity, especially in relation to breast cancer. (At least not real scientists.) Thanks for reading Scientific American. 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]. The tides are crucial to life: tidal pools, sheltered and renewed in rhythm with these cycles, catalyzed some of the first stable ecologies and still represent unique niches. Isoflavones have received attention due to their putative healthy properties. In addition, several studies have observed that the urine excretion of daidzein metabolites is notably higher than that of genistein metabolites [44,45,46]. Bustamante-Rangel M., Delgado-Zamarreo M.M., Perez-Martin L., Rodriguez-Gonzalo E., Dominguez-Alvarez J. Lastly, Zhang et al. Global climate change is not a future problem. Therefore, the authors concluded that the intake of dietary isoflavones paid a protective role against ovarian cancer. In the meta-analysis reported by Chen et al. (2018) revised 13 epidemiologic studies involving 178,947 participants: 7067 cases and 171,880 controls; among them, three were prospective cohort studies, and ten were population-based case-control studies [71]. Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Xu B., Chibber R., Ruggiero D., Kohner E., Ritter J., Ferro A., Ruggerio D. Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. Consequently, isoflavones can have estrogenic or anti-estrogenic effects [3]. 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]. It is well-known that some of the most accurate BP readings occur right as someone wakes up and at that event, the BP will be shown for the most part to stay lower than that of a daily average. That's what behavioral ecologist Jenny York learned while studying white-browed sparrow weavers . According to the results gathered in the present review, it can be stated that there is scientific evidence showing the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis on postmenopausal women, although the results do not seem entirely conclusive as there are discrepancies among the studies, probably related to their experimental designs. However, it is important to point out that the beneficial effects of soy isoflavone consumption have been exhibited by women with estrogen receptor-negative breast cancer, but not by women with receptor-positive breast cancer, who present a better prognosis [62]. The Sun ruled our heart, blood circulation and spine, while the Moon had influence on growth, fertility, breasts, stomach, uterus and menstrual flow. Isoflavone excretion occurs mainly through urine and feces, primarily in the conjugate forms, and up to 95% takes place in 24 h [43]. Daily J.W., Ko B.S., Ryuk J., Liu M., Zhang W., Park S. Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. At high elevations, acidic fog and clouds might . For the development of this section, the meta-analyses and systematic reviews published between 2015 and 2020 were taken into account. Lastly, the association between dietary isoflavone intake and the risk of developing gastric cancer has also been analyzed. It follows that additional high-quality, large-scale randomized controlled trials are needed. Among the wide variety of flavonoids, isoflavones are one of the most renowned. 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. 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