Following the removal of eighty-four duplicates, the selection was made through titles, abstracts and full-text reading. A. F. contributed to drafting and revising the manuscript. Although a study in cheetahs suggested that a high intake of phytoestrogens may impair. Furthermore, from the multiple regression analysis of ten women in the second trial(Reference Lu, Anderson and Grady29), the reduction of estradiol in both luteal and follicular phases was positively associated with serum and urinary isoflavone levels but not with individual changes in the intake. The researchers found that the isoflavones resulted in increased cell growth. 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, there was no evaluation of metabolic utilisation capacity of isoflavones and their absorption by measuring serum and urinary levels. In a logical perspective, the effect of soy cannot be attributed to the effect of its isoflavones alone. Introduction. 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) . This could be done by empirically monitoring ovulation to get a real information of menstrual phase, such as quantifying the urinary LH peak as a marker of ovulation, as done by Wu et al. Jamilian and colleagues in 2016 conducted another parallel clinical trial on seventy Iranian women with PCOS, using 50mg/d of soy isoflavones for a 1-month follow-up(Reference Jamilian and Asemi43). Furthermore, no characterisation was made on the possible presence of equol-producers among the participants. 3 Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy. The soy isoflavones block the estrogen receptors in your brain and fool your body into thinking its natural estrogen levels are low. [1] Progesterone and sex hormone-binding globulin (SHGB) levels were not significantly changed by soy intake. These alterations easily lead to hyperandrogenism and irregular menstrual cycles. This suggests a protective effect of soy against fertility disturbance by BPA. Bora, Shabana Soy contains phytoestrogen, a plant-derived estrogen, known as isoflavones. The urinary or serum levels of isoflavones did not affected progesterone levels in the multiple regression analysis. 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. Several studies and case-reports describing feminizing effects including lowering testosterone levels and raising estrogen levels in men have been published. Although some works investigate the relationship between consumption of soy formulations in infancy and age at menarche, as well as the onset of puberty or pre-puberty reproductive organ size, these outcomes are not strictly related to fertility in reproductive age(Reference Andres, Moore and Linam69Reference Sinai, Ben-Avraham and Guelmann-Mizrahi71). However, stratification for the control group or PCOS patients did not show a significant correlation between androgens and equol production. Main cellular mechanism for isoflavones. However, results are questionable due to the lack of hormone level measurements or reproductive functions. The obtained meta-analysis was included in the final summary because it assessed aspects relating to the topic of this review. Adapted from Moher et al. Legumes, particularly soybeans, are the richest . Adapted from Moher et al.(24). Furthermore, the absence of gynecological issues was only based on self-reported information. They may be useful in alleviating menopause symptoms or preventing osteoporosis in postmenopausal women. The article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing. Such shorter menstrual cycle length seemed not clinically relevant because shorter than 1d. Furthermore, for each 1nmol/l increase of genistein, the risk of menstrual cycle irregularities increased (OR: 119, 95% CI 102, 138). Feature Flags: { Recently, the anti-Mllerian hormone (AMH) concentrations have proved to be a useful tool for predicting female fertility, especially because it is independent of the cycle phase(Reference Dewailly and Laven48). (As part of this process, a group of eggs matures so that one will be ready for release during ovulation .) Moreover, difficulties related to data collection about nutritional intakes were available, and individual reporting errors must be taken into account. For this reason, in clinical studies, the nationality and ethnicity of participants may be relevant for the assessment of potential conflicting effects of soy intake. These conclusions cover several physiological aspects, including those concerning women's fertility, consistently with the conclusions of this review that highlighted nine additional articles compared with Messina's selection about the topic. However, even in the West, it is currently widely used, especially due to its versatility in plant-based products for health purposes and vegetarian diets(Reference Rizzo and Baroni1). The same type of soy phytoestrogen intervention was subsequently used by Unifer and colleagues in a second clinical trial on 213 infertile women undergoing in vitro fertilisation with embryo transfer cycles after intramuscular progesterone treatments (50mg/d) with or without (placebo) 1500mg/d of soy isoflavones intake(Reference Unfer, Casini and Gerli32). A total of 834 entries were obtained following search engine queries (PubMed: 381; ScienceDirect: 392; Cochrane Library Trials: 30 and ClinicalTrials.gov: 31). Hostname: page-component-7fc98996b9-pxj8b The present paper aims to conduct a review of available data on the effect of soy, soy foods and soy components on women's fertility and related outcomes. Soaking, fermentation, and heating may reduce problematic antinutrients contained in soy. Main characteristics of selected studies. Fig. Presumably, treatment with pharmacological concentrations of soy phytoestrogens allows mitigating the negative effect of clomiphene citrate on endometrial tissue, thus facilitating embryo implantation. Improvements were observed only in lipid profile (circulating total cholesterol, LDL and LDL/HDL ratio and triglycerides). Adapted from Moher, Main cellular mechanism for 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. Similar significant association was observed for peak luteal progesterone 10ng/ml (aOR: 140, 95% CI 100, 196, P=005). It is important to evaluate the levels of hormones that fluctuate during the cycle at several points. However, the mechanisms underlying isoflavones effects on human health are manifold. Publication types Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't MeSH terms However, in the work of Filiberto and colleagues(Reference Filiberto, Mumford and Pollack37), even if the correlation between isoflavones and the increase in SHBG was highlighted, the dosage of estradiol and free estradiol did not show significant correlations, although the estimate of free estradiol was done through Sodergard's formula(Reference Sdergrd, Bckstrm and Shanbhag61), so a direct dosage would be more reliable. Soya Isoflavones and Vitamins The Group for those Using, Abusing and thinking about taking over the counter items to boost fertility. There was no evaluation of dietary habits and the determination of hormone levels was performed using non-validated ELISA kits, due to limited budget. Recently, Wesselink and colleagues evaluated the fertility of 7778 healthy American or Canadian women in two cohort studies that followed participants for 12 months or until pregnancy(Reference Wesselink, Hatch and Mikkelsen44). Other weak aspects of the population sample characterisation are given by a lack of stratification by ethnicity and equol-producers. The study did not evaluate circulating or urinary levels of isoflavones to verify the ability to metabolise isoflavones. Live birth odds in the multivariable-adjusted analysis was higher among women in the second tertile of soy intake, consuming 264755mg/d of soy isoflavones (OR: 187; 95% CI 112, 314) and among women in the third tertile of soy intake, consuming 7562789mg/d of isoflavones (OR: 177; 95% CI 103, 303) compared with no consumption, but without a significant linear trend. [cited 2021 Jul 26]. Sampling involved synchronisation on the third day of menstrual cycle follicular phase, spontaneous or pharmacologically induced. Luteal phase deficiency can represent a relevant aspect for pregnancy outcomes and fertility disorders. These mechanisms involve genomic regulation with activation of both receptor's subtypes at 1M as seen in 293 human embryonal kidney cells in transient gene expression assay(Reference Kuiper, Lemmen and Carlsson74). Soy isoflavones have repeatedly shown a mild estrogenic effect but at high concentrations they may have enough power to act on hypothalamus and pituitary gland, reducing the ovarian synthesis of estrogens. However, the work had several strengths: the real evaluation of luteal and follicular phase through the dosage of urinary LH:creatinine ratio, the characterisation of sampling according to the cycle; the evaluation of isoflavone content in foods used for the intervention and quantification of urinary isoflavones to check compliance; the use of soy foods and not supplements or extracts to approach a real-life pattern; the characterisation of diet at various steps of clinical trial to avoid confounding mechanisms; the stratification by ethnicity which indirectly showed the effect on equol-producer individuals. They evaluated the hormonal variations during menstrual cycle through the composite construct that considered the cumulative information of the day of menstrual cycle for specimens. Although isoflavones can be found in many foods, not soy foods can be considered negligible sources of these compounds. The study must be considered exploratory, because of the limited number of luteal phase deficiency cycles and a small number of fertility-related outcomes. Conclusions: These data suggest that higher intake of soy foods and soy isoflavones is associated with lower sperm concentration. Concerns that the phytoestrogens (isoflavones) in soy may feminize men continue to be raised. The authors found no significant differences in reproductive outcomes (missed menstrual periods, pregnancy, live births, abortions, miscarriages, full-term deliveries, preterm deliveries, etc.) It affects one out of every six couples and affects the majority women aged between 15 to 44 years. Isoflavone genistein inhibited the enzyme tyrosine kinase in human A431 cell membranes at 07g/ml, a very high, non-physiological concentration(Reference Akiyama, Ishida and Nakagawa77) and act as a ligand for peroxisome proliferator-activated receptors (PPARs) in cultured astrocytes at 500nM(Reference Valles, Dolz-Gaiton and Gambini78). Major equol production was associated with a reduction in androgens levels (total testosterone, free testosterone and androstenedione), in the whole cohort. The results of selected manuscripts were grouped according to the outcomes used, for a clear comparison. However, the evaluation of ability to absorb and metabolise isoflavones was lacking in the present study. Furthermore, the nutritional habits of Adventists differ from the Western population ones and they show soy consumption more similar to populations in South-East Asia(Reference Messina53). Soy has been used to treat certain symptoms of menopause (such as hot flashes) and to help prevent bone loss ( osteoporosis ).Some supplement products have been found to contain possibly . 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. Phytoestrogens and breast cancer promoters or protectors? Pending further confirmation, soy and its components do not appear to have a clinically relevant influence on menstrual cycle in healthy women. (Reference Nagata, Kabuto and Kurisu27) and a longitudinal study published in 2013 by Filiberto et al. Higher soy products intake did not correlate with the rate of infertility. Likewise, equol-producers showed lower AMH levels in the whole cohort as well as in participants in PCOS or control groups. Moreover, significant improvement of oxidative markers such as total glutathione and malondialdehyde levels was observed. Fig. In the ten women who participated in the second study(Reference Lu, Anderson and Grady29), there were no significant changes in the levels of luteinizing and follicle-stimulating hormones. Qin, Zhen In particular, soy contains numerous non-isoflavone constituents such as phytic acid, triterpenes and sterols, BowmanBirk protease inhibitors, unsaturated fatty acids, saponins, inositol phosphates, proteins, peptides such as lunasin;(Reference Kang, Badger and Ronis10) nevertheless, soy isoflavones have attracted much attention in the last years for its estrogenic as well as non-hormonal properties(Reference Aulisa, Binda and Padua11). Despite the 6-month duration of the clinical trial, the lack of a placebo group, the absence of characterisation of equol-competence among individuals and the limited number of participants reduced the strength of the results obtained. In the only clinical trial available, even if it is considered a pilot study, it emerges that a significant role could be played not only by isoflavones, but also by phytochemicals present in soy, particularly in black soy. The procedure was carried out following the most recent PRISMA guidelines(Reference Liberati, Altman and Tetzlaff23). The evaluation at two different times of menstrual cycle allowed to discriminate the effect between luteal and follicular phases but not day by day hormonal fluctuations. The same authors admitted that they had no information on the type of soy used and about the last ingestion. The diagnosis of PCOS occurs in the presence of at least two of the three Rotterdam Criteria: oligo or anovulation, polycystic ovary morphology and biochemical or clinical hyperandrogenism(Reference Pfieffer67). Go. These changes may have resulted in the mild, non-clinically relevant prolongation of menstrual cycle, as discussed in the previous section. With regards to available clinical trials, Lu and colleagues conducted two interventional studies using 36 Oz of soy milk (about one litre) divided into three daily intakes for a total daily intake of about 200mg of isoflavones(Reference Lu, Anderson and Grady26,Reference Lu, Anderson and Grady29) . Mildly increased levels of SHBG were associated with higher dietary isoflavone intakes (Q4 [16788mg/d] v. Q1 [0003mg/d]) in the adjusted linear mixed model (: 009, 95% CI 002, 016), but no correlation was found for estradiol, progesterone, LH, FSH levels or anovulatory events. . In two studies, women having fertility treatment took part in research looking at the amount of soya they ate, and whether that affected the success of their treatment. However, urinary phytoestrogen levels were only detected at baseline and this increased the correlation uncertainty. Flowchart for studies selection. The possible correlation between menstrual cycle length and soy does not seem convincing either. Table 2 summarises main limitations about the studies discussed. 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. From obtained data, it seems likely that soy consumption, not only in the form of isoflavones in pharmacological quantities, could have a beneficial effect on fertility, especially in those individuals with fertility problems. The clinical studies selection included one retrospective study, two cross-sectional studies, eight longitudinal cohort studies, five parallel-designed interventional studies and six longitudinal interventional studies. Isoflavones are produced via a branch of the general phenylpropanoid pathway that produces flavonoid compounds in higher plants. Corrections for confounding factors, such as diet, demographics, lifestyle factors, age, body composition and ethnicity, indicated reliable analysis. Soy can contain numerous other phytochemicals such as saponins, phytosterols, phytic acid, non-isoflavone flavonoids, peptides, protease inhibitors and other bioactive substances. 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. In addition, in the work of Kohama and colleagues, an increase in estradiol levels following intervention with soy compared with baseline was shown(Reference Kohama, Kobayashi and Inoue33). Longer, not clinically relevant duration of menstrual bleeding (adjusted MD: 037d, 95% CI 006, 068), without differences in severity of menstrual flow was observed. In particular, information about the adequate choice of updated nutritional tables as well as specific nutritional choices, such as increased soy consumption due to pre-existing socio-cultural and physiological aspects should be collected. No significant differences were found in the spontaneous abortion rate, the number and quality of embryos transferred or oocytes fertilised. However, levels of progesterone, estradiol, free estradiol, estrone and SHBG did not show significant differences. In the meta-analysis by Hooper and colleagues(Reference Hooper, Ryder and Kurzer59) from the evaluation of eleven studies on premenopausal women, ten studies were included to clarify the effect of soy on menstrual cycle length. Similarly, the stratification by ethnicity and equol-producers may suggest the nature of interactions between soy and fertility. 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. Manuscripts exploring multiple aspects were discussed in different paragraphs, where deemed necessary. Black soy, in addition to the content of isoflavones, is known to be rich in antioxidant substances, especially in external seed integuments, which are rich in anthocyanins(Reference Choung, Baek and Kang49). Despite the sample size and full follow-up for endpoints evaluation, the study displays limitations. RANCHO CUCAMONGA. The use of urinary phytoestrogens and their metabolites is a more reliable system compared to the evaluation of dietary intake. Day 22 should correspond to the mid-luteal phase, however, the authors pointed out that participants exhibited different lengths of menstrual cycle and this could have been a source of heterogeneity that was used as a covariate in the regression model. Emerged clinical trials display several limitations including small sample size as well as the longitudinal design without a parallel control group, placebo or a cross-over design consistently limiting the strength of these pilot studies. However, the intakes of isoflavones in the studied cohorts were limited (range: 0331mg/d). Although this was a randomised, placebo-controlled and double-blinded trial with a sample size appropriate to the power of detection, there was no evaluation of serum and urinary levels of isoflavones and/or metabolites. As total glutathione and malondialdehyde levels was performed Using non-validated ELISA kits, to., San Raffaele Roma Open University, 00166 Rome, Italy the multiple regression.. 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