Importantly, the soy variety, environmental conditions of the culture and the processing of soybeans notably influence their isoflavone content [18]. Perna et al. However, the moonlight decreases after the full moon. Regarding endometrial cancer, three prospective and five case-control studies were analyzed, which suggested a lower endometrial cancer risk associated with isoflavone consumption. (2016) published a meta-analysis of 13 case-control and four prospective cohort studies, where the results revealed that soy isoflavone consumption reduced the risk of developing colorectal cancer by 23% [79]. 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]. However, all the authors agree that further studies are necessary so as to confirm these results. Liu J., Yuan F., Gao J., Shan B., Ren Y., Wang H., Gao Y. Indeed, some authors speculate that hepatic and lipoprotein lipase activity may have been altered after variable isoflavone intake from soybean, although no experimental data were provided [67]. All authors have read and agreed to the published version of the manuscript. The main isoflavones found in foodstuffs are daidzein, genistein and glycitein, as well as biochanin A and formononetin [9,12]. Similarly, Li et al. 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. 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). Association between Dietary Isoflavones in Soy and Legumes and Endometrial Cancer: A Systematic Review and Meta-Analysis. The work reported by Lambert 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]. Focusing on the overall intake of isoflavones in humans, several studies have reported varied results. official website and that any information you provide is encrypted Therefore, the authors concluded that the intake of dietary isoflavones paid a protective role against ovarian cancer. The results indicated that the isoflavone intake decreased the ovarian cancer risk by 33%. Further, Chalvon-Demersay et al. 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. 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. and J.T. 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. 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. 19% reduction in endometrial cancer risk. By contrast, the total isoflavone amount is high in soy flour, protein isolate or edamame [19]. Moreover, the authors suggested that ethnicity could have had influenced this association, but studies with larger sample sizes are needed to confirm this hypothesis. That aluminum may be harmful to plants as well as animals. Sfakianos J., Coward L., Kirk M., Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. 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. Applegate C.C., Rowles J.L., Ranard K.M., Jeon S., Erdman J.W. Sirotkin A.V., Harrath A.H. Phytoestrogens and their effects. 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. Moreover, an increase in thyroid hormone levels after isoflavone intake by food supplements has not been observed, and no side effects were confirmed with regard to the endometrial thickness or histopathological changes in the uterus. 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]. Due to a decline in sunlight, the development of leaves . Taken as a whole, all these results suggest that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. The two systematic reviews conclude that isoflavones have an important role in reducing hot flushes [52,53], although some observations need to be pointed out. As with other phenolic compounds, isoflavones can be presented as free forms (aglycones) or conjugated with carbohydrates (glycosides). For this reason, the results should be interpreted with caution, and more randomized clinical trials are imperative. In addition, Qiu et al. This fact suggests that other components, such as fiber in the soy foods, may account for these negative associations. On the contrary, women who were already equol producers did not obtain any additional benefit from supplements of equol or isoflavones. ); sue.uhe@zednanref.oderfla (A.F.-Q. Isoflavone content in soy-derived products is usually lower than in soybeans [17]. Oral isoflavone supplementation on endometrial thickness: A meta-analysis of randomized placebo-controlled trials. Isoflavone glycosides have to be hydrolyzed to the aglycone form prior to its absorption by passive diffusion in the upper small intestine [28]. (2019), included 16 prospective cohort studies involving 11,169 breast cancer cases and 648,913 participants [70]. 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. Ingram D., Sanders K., Kolybaba M., Lopez D. Case-control study of phyto-oestrogens and breast cancer. Proof by rational experiment seems to have been. 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]. You et al. and A.F.-Q. The association between dietary isoflavones intake and gastric cancer risk: A meta-analysis of epidemiological studies. U.S. Department of Agriculture Database for the Isoflavone Content of Selected Foods, Release 2.0. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Prospective study on usual dietary phytoestrogen intake and cardiovascular disease risk in Western women. and Rossi et al. 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. Abshirini M., Omidian M., Kord-Varkaneh H. Effect of soy protein containing isoflavones on endothelial and vascular function in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. (2016) also studied whether there was an association between different types of interventions and the reduction in hot flushes and night sweats [90]. Create your free account or Sign in to continue. 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]. Isoflavones (high dose: 0.675.5 mg/day; and low dose: 0.0120.1 mg/day). Saloniemi H., Whl K., Nyknen-Kurki P., Kallela K., Saastamoinen I. Phytoestrogen content and estrogenic effect of legume fodder. 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. In view of the results gathered in the present review, we can conclude that there is scientific evidence that reveals the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis in postmenopausal women. . Implications of phytoestrogen intake for breast cancer. Zaheer K., Humayoun Akhtar M. An updated review of dietary isoflavones: Nutrition, processing, bioavailability and impacts on human health. The authors found a statistical inverse association between isoflavone consumption and colorectal cancer risk in case-control studies, although not in cohort studies. (2018) published a meta-analysis of seven prospective cohort studies (two studies from Japan with 241 cases and 503 controls, and five studies from Europe with 2828 cases and 5593 controls) [75]. With regard to the mechanisms by which isoflavones act to reduce cancer risk, it has been suggested that the effects are due to the similarity of the isoflavone molecule to estradiol. The majority of the studies that used display stimuli, such as photos, 3D images, virtual reality, and videos of natural landscapes, confirmed that viewing natural scenery led to more relaxed body responses than viewing the control. A total of 16 studies were included in their meta-analysis with a range of 24 to 236 subjects. 8600 Rockville Pike Wang X., Dykens J.A., Perez E., Liu R., Yang S., Covey D.F., Simpkins J.W. 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. Zhong et al. Grosso et al. (2017) also analyzed eight studies of prostate cancer, and they found an association between isoflavone intake and prostate cancer risk [61]. 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. However, the authors acknowledged several limitations to their study, such as the small sample size in the meta-analysis (middle-aged 276 women and 209 men), and recognized that a large number of subjects as well as a lengthier intervention are needed to investigate whether supplementation of soy isoflavones actually improves these outcomes. Gaya P., Medina M., Snchez-Jimnez A., Landete J.M. [12,42]. Thanks for reading Scientific American. The authors indicated that high concentrations of daidzein and genistein (no specific values concerning these concentrations were available) were related to 34% and 28% reduction in breast cancer risk, respectively, whereas no association with equol was found. Licensee MDPI, Basel, Switzerland. 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. Thus, soybean can be considered as the best food source. Treutter D. Significance of flavonoids in plant resistance and enhancement of their biosynthesis. Study duration ranged from four weeks to two years, with a median of 12 weeks. Thus, its consumption, according to epidemiological and clinical studies, has been postulated to be related to a decrease in the risk of different diseases. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. For this reason, the results should be interpreted with caution, and more randomized clinical trials are required. After this, each metabolite undergoes its own metabolic pathway [40]. and J.T. Concerning this issue, six meta-analyses and two systematic reviews are included in the present review (Table 5). From laboratory experiments, it's known that light intensities as low as 0.1 lux (approximately 0.01 foot-candle) during the night can influence photoperiodic time measurement in some plants and animals. Produced metabolites appear in plasma at variable concentrations and can enter enterohepatic circulation [28]. With regard to prostate cancer, it has been proposed that it might be affected by isoflavone consumption due to its effect on hormone metabolism. These two associations were significant for postmenopausal participants. Analysis of isoflavones in Foods. The authors studied all possible correlations between isoflavone consumption and the risk of breast cancer. Nevertheless, it is important to consider this metabolite since it is key in the biological activity of isoflavones [13]. However, a limitation in this field is that there is still a great heterogeneity among studies. Karr S.C., Lampe J.W., Hutchins A.M., Slavin J.L. 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. Lastly, Zhang et al. Sulfation of the isoflavones genistein and daidzein in human and rat liver and gastrointestinal tract. 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]. Bethesda, MD 20894, Web Policies For their meta-analysis, Jiang et al. A significant 19% reduction of the risk was found at high concentrations of daidzein, but not at genistein or equol concentrations. 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. Plants grow best when the moon is in the waxing phase, when its gravitational pull is strongest. In addition, it is important to highlight that interindividual differences in gut bacterial populations are responsible for the diverse effects of isoflavones in humans. Soy products (0.05130 g/day) and total isoflavones (0.28 to 63 mg/day). (At least not real scientists.) By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. In fact, all the body fluids, as the tides, were controlled by the lunar phases. The authors found a significant inverse association between isoflavone intake and both overall mortality and breast cancer recurrence. 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. In contrast, red clover was not associated with changes in the hot flush frequency. 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. Despite the positive effect of isoflavones, the authors emphasized that the effects took a long time to appear. Conceptualization, S.G.-Z. government site. 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 tropical climates meat which is exposed to the moonlight rapidly becomes putrid ; and in the Indies, the negroes who will lie sweltering and unoovered beneath the full glare of a tropical sun, carefully muffle their heads and faces when exposed to the moonbeams, which they believe will cause swelling and distortion of the features, and sometimes even blindness. Murota K., Nakamura Y., Uehara M. Flavonoid metabolism: The interaction of metabolites and gut microbiota. 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. 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. 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]. In another systematic review of three observational studies (including 68,748 participants), low evidence of isoflavones was shown in the prevention of cardiovascular diseases [61]. The Sun ruled our heart, blood circulation and spine, while the Moon had influence on growth, fertility, breasts, stomach, uterus and menstrual flow. In this sense, it has been described that both isoflavones and other estrogenic molecules could mediate their beneficial effects due to two different mechanisms: the classical estrogen receptor (ER)-mediated signaling pathway and the activation of intracellular pathways such as protein tyrosine kinase, phospholipase C and mitogen-activated protein kinase (MAPK) [5,6]. Determination of total soy isoflavones in dietary supplements, supplement ingredients, and soy foods by high-performance liquid chromatography with ultraviolet detection: Collaborative study. 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]. Winkel-Shirley B. Biosynthesis of flavonoids and effects of stress. 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. Isoflavones have received attention due to their putative healthy properties. On the contrary, a systematic review and meta-analysis reported by Man et al. 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]. (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]. The authors suggested that this difference could be due to different genetic backgrounds and dietary patterns among Asian and Western populations. The main forms of conjugates in soybeans are the malonyl derivatives [14]. Interestingly, soy protein isolate (void of isoflavones through alcoholic extraction during the protein solation phase) did not show these effects. Atkinson C., Frankenfeld C.L., Lampe J.W. However, the intake of specific isoflavones, genistein and daidzein, was indeed significantly associated with a reduced risk of this type of cancer. Modified from Mace et al. The authors observed that soy isoflavone consumption was inversely associated with cancer deaths. In the end, isoflavones could be useful in reducing hot flushes associated with menopause. This fact was not taken into account in previous meta-analyses, and thus it may justify the discrepancies amongst them. Nevertheless, the results do not seem entirely conclusive, as there are discrepancies among the studies included in the systematic reviews and in the meta-analyses, probably related to their experimental designs. Equol has been considered as the most interesting colonic metabolite due to its beneficial biological activity, which differs from that of its precursor, daidzein [13,38,39]. In this systematic review, 123 studies were included, with a total number of 516,330 participants. Most would agree that the daily rising and falling of the moon, along with the monthly waxing and waning cycles, have effects on our oceans and seas. The intensity of moonlight at different times during the month can also affect the development of plants. The light of the moon also influences animals that are active in daytime. Gruber C.J., Tschugguel W., Schneeberger C., Huber J.C. Production and actions of estrogens. 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. In: Thompson M.J., editor. 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). 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). An official website of the United States government. Furthermore, soy protein has been linked to an improvement in nitric oxide production and contributes to increased arterial compliance [65]. Kurzer M.S., Xu X. Dietary phytoestrogens. Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Ten studies reported a significant reduction in hot flush frequency in the phytoestrogen group when compared with the placebo group. Possible mechanism of action of isoflavones for cancer prevention. It follows that additional high-quality, large-scale randomized controlled trials are needed. In a study reported by Ko et al., the authors quantified the plasma concentrations of daidzein, genistein, glycitein and equol in Korean men and women [36]. Chadha R., Bhalla Y., Jain A., Chadha K., Karan M. Dietary Soy Isoflavone: A Mechanistic Insight. 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. This metabolite since it is important to consider this metabolite since it is key in the soy variety, conditions... 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