4 Center for Complementary Medicine, Department of Internal Medicine II, Faculty of Medicine, University of Freiburg, Freiburg, Germany. The use of surveys only through self-administered questionnaires, although validated, is easily exposed to self-reporting errors or incompleteness and misclassifications derived from the database used for food intake quantification. Green, Eulalee However, the evaluation of ability to absorb and metabolise isoflavones was lacking in the present study. The phytoestrogen actions of soy isoflavones may increase estrogen levels in the body and induce ovulation in women, thus, may speed up the process of pregnancy. The authors responsibilities were as follows: G. R. study conception and drafting the manuscript. 16 Although much of the concern is based on animal research, 16 a sufficient amount of fertility-relevant human research, including both epidemiologic and clinical studies, has been conducted; therefore, conclusions about the impact of soy on fertility can be Furthermore, even at high concentrations, they did not show a clear influence on fertility. Despite the significant increase in FSH, LH and estradiol in both intervention arms, the endometrial thickness (assessed by transvaginal sonography) had a major improvement in the intervention group compared with placebo. The concomitant treatment with soybean phytoestrogens significantly increased the implantation rate (254% v. 202%; P<005), the pregnancy rate (393% v. 209%; P<005) and the pregnancy-to-delivery rate (303% v. 162%; P<005) compared with placebo. The beneficial efficacy of soy is often attributed to the presence of isoflavones, capable of mitigating the excesses of endogenous estrogens, through the competition with estrogen receptors or by the activation of receptors, in the presence of low levels of endogenous estrogens. The obtained results were evaluated for duplicates and then screened for titles and abstracts information. The possibility of a sexual development disorder as a neonatal programming effect is an often raised hypothesis because circulating levels of isoflavones are higher in soy-fed infants compared with cow milk formula or breastfed infants(Reference Andres, Moore and Linam69). No changes were highlighted for DHEA, DHEAS, dihydrotestosterone (DHT) concentration or LH:FSH ratio. Presumably, treatment with pharmacological concentrations of soy phytoestrogens allows mitigating the negative effect of clomiphene citrate on endometrial tissue, thus facilitating embryo implantation. Participants were divided into four categories: non-consumers and tertiles of soy intake. The advantages of observational cohort studies include longer times and wider population samples. WHAT IS IT? A slight increase of approximately 1d (MD: 105, 95% CI 013, 197) was seen compared with the control, with no significant effects in the length of luteal and follicular phases. Days Soy Isoflavones were taken: 2-6 Dosage on those days: 120mg Side effects: bad: hot flushes, headaches, disturbed sleep. However, the intakes of isoflavones in the studied cohorts were limited (range: 0331mg/d). Adapted from Moher, Main cellular mechanism for isoflavones. Fig. Several studies and case-reports describing feminizing effects including lowering testosterone levels and raising estrogen levels in men have been published. The estrogen-like effects of isoflavones underlie concerns about soy and fertility. The authors of this recent literature review of available evidence from observational and interventional studies concluded that soy and its components cannot be classified as an endocrine disruptor. Based on our literature search, we also identified two observational studies: a cross-sectional study published in 1997 by Nagata et al. One of the first research papers to look directly at soy and fertility outcomes was from the Adventist Health Study-2. For example, it should be identified whether the interest is related to pharmacological effect, thus implying the use of high concentrations of soy components, or if the aim is to investigate soy functional effects that can be obtained mimicking eating habits, thus providing soy foods with realistic intake levels. In particular, among selected studies, only the intervention study by Haudum and colleagues explored the stratification of participants for equol-competence(Reference Haudum, Lindheim and Ascani46). This may have influenced the presence of large confidence intervals. Using food frequency questionnaires, researchers found that women with high isoflavone intake ( 40 mg/day) had a 3% lower lifetime probability of giving birth to a live child compared to women with a low intake (< 10mg/day). Main characteristics of selected studies. 3 Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy. Metabolic, endocrine, inflammation, and oxidative stress . Consequently, the absence of fertility, called infertility, is a disease characterised by the failure to establish a clinical pregnancy and it can depend on various factors including predisposition and behavioural/environmental aspects. hasContentIssue true, Proposed mechanisms of isoflavones action, This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, Copyright The Author(s), 2022. A total of 834 entries were obtained following search engine queries (PubMed: 381; ScienceDirect: 392; Cochrane Library Trials: 30 and ClinicalTrials.gov: 31). The urinary or serum levels of isoflavones did not affected progesterone levels in the multiple regression analysis. In the study by Nagata and colleagues, fifty Japanese women were enrolled to evaluate the association between soy intake (using an FFQ) and hormone levels. Moreover, urinary concentrations seem to reflect the isoflavone intakes in a short time window. The evaluation of isoflavones circulating levels and their urinary excretion allowed to show a wide inter-individual variation of metabolic and absorption capacity. Published by Cambridge University Press on behalf of The Nutrition Society. Additionally, the enrolment criteria included only women who had stopped oral contraception less than 2 months earlier, so highly fertile individuals could have been excluded. The length of menstrual cycle may represent an indirect marker of ovarian function and reproductive health(Reference Mumford, Steiner and Pollack54,Reference Vassena, Vidal and Coll55) . Furthermore, phytoestrogens appear to act on SHBG synthesis by altering mRNA levels in hepatocarinoma human cells treated with genistein 20M(Reference Mousavi and Adlercreutz85), and modulating the balance between bound and free steroids or competing with endogenous sex hormones for the active site binding of the carrier(Reference Dchaud, Ravard and Claustrat86). A. F. contributed to drafting and revising the manuscript. They may be useful in alleviating menopause symptoms or preventing osteoporosis in postmenopausal women. In the present study, the intervention group showed improvements in hormonal circulating levels compared with baseline, which consisted in the reduction of LH levels (94%, P=0000), testosterone (56%, P=0000) and DHEAS (87%, P=0000), with no significant changes in the control group. Moreover, couples with male infertility issues were excluded. As expected, women with the highest soy consumption were more likely to be of Asian descent. and After the soy intervention, the length of menstrual cycle marginally increased (from 28319 to 31851d, P=006). It would have been useful to have retrospective information on soy consumption to assess the potential effect on previous fertility problems. These alterations easily lead to hyperandrogenism and irregular menstrual cycles. The effects of phytoestrogen genistein on steroidogenesis and estrogen receptor expression in porcine granulosa cells of large follicles, Endocrine-disrupting chemicals as modulators of sex steroid synthesis, Amplification of HSD17B1 and ERBB2 in primary breast cancer, Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione, Genistein is an effective stimulator of sex hormone-binding globulin production in hepatocarcinoma human liver cancer cells and suppresses proliferation of these cells in culture, Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG), Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein, Phytoestrogen concentrations in serum from Japanese men and women over forty years of age, Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: a technical review of the observational and clinical data, Flowchart for studies selection. No restrictions were applied using filters and results were collected from search engines by the inception through 4 April 2021. . Concerns that the phytoestrogens (isoflavones) in soy may feminize men continue to be raised. DOI: 10.1017/jns.2022.15. (Reference Filiberto, Mumford and Pollack37). Consequently, it is plausible that research efforts have been aimed at evaluating the effects of soy, especially isoflavones, on human fertility and hormonal regulation. While the observational data better reflect the effects of diet in free-living conditions compared with experimental settings of clinical trials, the use of food frequency questionnaires exposes to possible misclassification and measurement errors. 2 highlights the main cellular mechanisms attributed to isoflavones. There was a significant correlation between dietary soy consumption and fertilisation rate (77% v. 71%, P=0004), age-adjusted pregnancy (52% v. 41%, P=003) or age-adjusted live birth rate (44% v. 31%, P=0007) among soy consumers compared with non-consumers. 1. Furthermore, women with PCOS display a higher prevalence of hyperinsulinemia, dyslipidemia, insulin resistance and obesity compared to healthy population. Moreover, isoflavones act as selective estrogen receptor modulators (SERMs) showing both agonist and antagonist effects on ER, with subsequent estrogenic, anti-estrogenic or even neutral effects(Reference Liu, Li and Chen14). Soy isoflavones are generally considered safe .Numerous randomized controlled trials in menopausal women reported that side effects were not significantly different between soy isoflavone and placebo groups .Adverse events were generally mild and included gastrointestinal and musculoskeletal complaints .One systematic review of over 100 studies in patients with or at risk of breast cancer . The intervention period was extended only to one menstrual cycle. After adjustments, an inverse correlation between estradiol and soy intake was highlighted on the 22nd day of menstrual cycle (r: 032, P=004) but not on the 11th. Similar to the previous trial, the number of participants was limited. Even if serum AMH concentrations appear as a useful tool for predicting female fertility, only one study from our selection used them(Reference Haudum, Lindheim and Ascani46). However, urinary phytoestrogen levels were only detected at baseline and this increased the correlation uncertainty. Furthermore, there was no characterisation of dietary regimen, although it was a standard hospital diet. Notably, during manuscript preparation, Messina and colleagues published a technical review on endocrine effect of soy and isoflavones(Reference Messina, Mejia and Cassidy90). Similarly, a significant correlation between isoflavone intake and nulligravidity emerged (P=003) with a 13% higher risk but with a wide range of confidence interval (95% CI 2, 26) in women with intake 40mg/d compared with lower intakes (<10mg/d). Recently, in a prospective study by Levine et al., 326 American women eumenorrheic aged 1840 were followed for 12 months or until pregnancy(Reference Levine, Kim and Purdue-Smithe45). 1 The FDA based this decision on clinical studies showing that at least 25 g of soy protein per day lowered . Instead, in the cohort study by Filiberto and colleagues, 259 American women were followed for at least 2 menstrual cycles. The dietary intake of isoflavones did not appear to be associated with fertility in the two cohorts but some marginal evidence of amelioration of fertility was related to a higher intake of isoflavones among 30 years old individuals after age stratification (Fecundability Ratios: 112, 95% CI 994, 134 and 119, 95% CI 092, 155 in the two cohorts comparing 90th with <24th percentile). Soy is a very popular food and its consumption is part of the traditional cuisine of South-East Asian countries. Main cellular mechanism for isoflavones. Longer, not clinically relevant duration of menstrual bleeding (adjusted MD: 037d, 95% CI 006, 068), without differences in severity of menstrual flow was observed. These also included non-soy derived phytoestrogens, such as lignans. In a logical perspective, the effect of soy cannot be attributed to the effect of its isoflavones alone. Regarding the observational studies available, in 2015 Venegas et al. In 2000, Wu et al. [cited 2021 Jul 26]. These changes may have resulted in the mild, non-clinically relevant prolongation of menstrual cycle, as discussed in the previous section. The use of urinary phytoestrogens and their metabolites is a more reliable system compared to the evaluation of dietary intake. Finally, they show antioxidant activity: a shared property among polyphenols(Reference Patel, Boersma and Crawford19). CA. Soy can contain numerous other phytochemicals such as saponins, phytosterols, phytic acid, non-isoflavone flavonoids, peptides, protease inhibitors and other bioactive substances. Conclusions: These data suggest that higher intake of soy foods and soy isoflavones is associated with lower sperm concentration. Any later it delays ovulation. conducted another prospective cohort study on 239 American women undergoing assisted reproductive technology(Reference Chavarro, Mnguez-Alarcn and Chiu42). Han, Jing Only 6% of participants had not soy isoflavone intake. Moreover, two recent observational cohort studies by Chavarro and colleagues evaluated the association between soy consumption and in vitro fertilisation outcomes(Reference Vanegas, Afeiche and Gaskins40,Reference Chavarro, Mnguez-Alarcn and Chiu42) . A total number of twenty-two experimental articles plus a meta-analysis was used for the final synthesis. Furthermore, no characterisation was made on the possible presence of equol-producers among the participants. Genistein treatment reduced LDL cholesterol and triglycerides levels. Correction for covariates included demographics, education, income, lifestyle, dietary and behavioural factors. The present study has numerous strengths: a large sample of participants with good adherence to the study, a detailed assessment of dietary habits, and comprehensive sampling during all phases of menstrual cycle. This could favour the bioavailability of sex hormones(Reference Kurzer60). However, levels of progesterone, estradiol, free estradiol, estrone and SHBG did not show significant differences. There was no dose-response relation in either cohort. The lack of variation in gonadotropins can explain the absence of variation in menstrual cycle. The generalisation of these results is complex due to the type of study, which does not allow to define a causal relationship. Participants were classified by ethnicity; however, the population sample size did not allow to perform stratification of outcomes based on this aspect. The fertility concept differs from the fecundity one, which refers to reproductive potential and depends on reproductive physiology, from the production of gametes phase to the ability to carry a pregnancy to term. Pending further confirmation, soy and its components do not appear to have a clinically relevant influence on menstrual cycle in healthy women. In 2015, a longitudinal study found no differences in sexual organ development at 5 years of age between cow milk formula, breast milk and soy formula feeding(Reference Andres, Moore and Linam69). However, a clear effect on reproductive system has never been highlighted, especially due to the absence of observational studies designed for this purpose. Introduction. Soaking, fermentation, and heating may reduce problematic antinutrients contained in soy. Shop Soy Isoflavones Menopause Relief and read reviews at Walgreens. Even if the exact conversion mechanism has not been characterised yet, a limited conversion capacity in Western populations (about 25%) has been highlighted, as opposed to the greater competence of Asian populations (50%), estimated through urinary equol excretion(Reference Setchell, Brown and Lydeking-Olsen17). The influence of high-dose of isoflavones on fertility emerging from the studies is difficult to be transferred to other groups of individuals with other ethnicity or different treatments. There are clues about the association between soy intake and the increase in SHBG levels. No correlation with specific isoflavones such as equol, daidzein and O-DMA was found. From the general linear model of the analysis of covariance, the intervention with soy reduced free androgen index (0020005 v. +0010005, P<0001), total testosterone (01005 v. +01005ng/ml, P=0008) and increased SHBG levels (+4008 v. 1408nmol/l, P<0001) compared with placebo (adjusted for baseline values). Fig. Soy isoflavones have also been found to inhibit tyrosine kinases (14), enzymes that play critical roles in the signaling pathways that stimulate cell proliferation. 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