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). This allowed to exclude the already summarised articles in meta-analysis from a detailed discussion. 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) . In a logical perspective, the effect of soy cannot be attributed to the effect of its isoflavones alone. Regarding the two mentioned studies, the use of very high amounts of isoflavones is noteworthy because it is not possible to obtain such a dose through diet, therefore the effects found can be interpreted as a pharmacological and not nutritional intervention. In order to assess the association between urinary isoflavones and fertility, adjustment for various confounding factors including ethnicity, supplement use, nutrients and lifestyle aspects was applied. 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 changes may have resulted in the mild, non-clinically relevant prolongation of menstrual cycle, as discussed in the previous section. (Reference Moher, Liberati and Tetzlaff24). They may be useful in alleviating menopause symptoms or preventing osteoporosis in postmenopausal women. The lack of variation in gonadotropins can explain the absence of variation in menstrual cycle. 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. Isoflavones concentrations did not show significant differences between participants at baseline. 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. Results from a pilot study, Effect of soy phytoestrogen on metabolic and hormonal disturbance of women with polycystic ovary syndrome, Usual dietary isoflavone intake and reproductive function across the menstrual cycle, Soy isoflavone intake and the likelihood of ever becoming a mother: the adventist health study-2, Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy, Soy food intake and treatment outcomes of women undergoing assisted reproductive technology, Dietary factors and luteal phase deficiency in healthy eumenorrheic women, Soy intake modifies the relation between urinary bisphenol A concentrations and pregnancy outcomes among women undergoing assisted reproduction, The effects of soy isoflavones on metabolic status of patients with polycystic ovary syndrome, Dietary phytoestrogen intakes of adult women are not strongly related to fecundability in 2 preconception cohort studies, Urinary phytoestrogens and relationship to menstrual cycle length and variability among healthy, eumenorrheic women, Impact of short-term isoflavone intervention in polycystic ovary syndrome (PCOS) patients on microbiota composition and metagenomics, Fecundity and natural fertility in humans, Isolation and determination of anthocyanins in seed coats of black soybean (, Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome, The influence of religious affiliation on participant responsiveness to the complete health improvement program (CHIP) lifestyle intervention, Health beliefs, behavior, spiritual growth, and salvation in a global population of seventh-day adventists, A brief historical overview of the past two decades of soy and isoflavone research, The utility of menstrual cycle length as an indicator of cumulative hormonal exposure, Menstrual cycle length in reproductive age women is an indicator of oocyte quality and a candidate marker of ovarian reserve, Prospective evaluation of luteal phase length and natural fertility, Menstrual cycle characteristics and fecundability in a North American preconception cohort, A prospective cohort study of menstrual characteristics and time to pregnancy, Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis, Hormonal effects of soy in premenopausal women and men, Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature, Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome, The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome, Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis, Dietary patterns and outcomes of assisted reproduction, Compared with feeding infants breast milk or cow-milk formula, soy formula feeding does not affect subsequent reproductive organ size at 5 years of age, Early-life soy exposure and age at menarche, Consumption of soy-based infant formula is not associated with early onset of puberty, Cellular and biochemical mechanisms by which environmental oestrogens influence reproductive function, Steroid hormone activity of flavonoids and related compounds, Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta, Rapid endocrine disruption: Environmental estrogen actions triggered outside the nucleus, Equol-stimulated mitochondrial reactive oxygen species activate endothelial nitric oxide synthase and redox signaling in endothelial cells: roles for F-actin and GPR30, Genistein, a specific inhibitor of tyrosine-specific protein kinases, Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes, Bacterial metabolite S-equol modulates glucagon-like peptide-1 secretion from enteroendocrine L cell line GLUTag cells via actin polymerization. However, soy intake did not correlate with cycle length (r: 012, P=045). Isoflavones are plant-based compounds found almost exclusively in beans, like soybeans, that mimic the action of the hormone estrogen. A weak, not clinically relevant effect has been highlighted on cycle length and hormonal status. For these reasons, results should be interpreted with caution. Available from: Lin, Jing From a sub-analysis on ethnic characteristics, it was further highlighted that only Asian women showed a significant reduction in follicular estradiol from baseline (174%). 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 The individual conversion capacity, equol-competence, offers a useful tool for estimating the biological effect of these compounds(Reference Zubik and Meydani15). 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. Regarding isoflavones, the equol metabolite derives from the precursor daidzein by the action of intestinal bacteria. Metabolic, endocrine, inflammation, and oxidative stress . One of the first research papers to look directly at soy and fertility outcomes was from the Adventist Health Study-2. For this reason, the clinical data were meta-ana Individuals who are not equol-producers have likely limited response to isoflavone intake(Reference Iino, Shimoyama and Iino16). Flowchart for studies selection. 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). [cited 2021 Jul 26]. The duration of menstrual cycle, especially in luteal phase, can also have a direct influence on the mammary gland proliferation, through a reduction in exposure of the epithelium to proliferative hormones. No correlation with specific isoflavones such as equol, daidzein and O-DMA was found. The significant inverse association between dietary isoflavone intake and live births (3% reduction, 95% CI 0, 7, P=005) was highlighted. Furthermore, the possible ameliorative influence of soy or its components in the case of assisted reproduction techniques outcomes and pregnancy seeking appears promising and worthy of interest. The generalisation of these results is complex due to the type of study, which does not allow to define a causal relationship. Furthermore, there was no characterisation of dietary regimen, although it was a standard hospital diet. M. L. contributed to drafting and revising the manuscript. The reduction of estradiol concentrations observed became statistical marginal (89%, P=006) when analysis was restricted to the clean dataset: data after exclusion of thirteen specimens collected too soon or too late after ovulation. Soya Isoflavones are derived from soya beans. The clinical trial was limited to a small sample size, lacking of control/placebo group and there was no characterisation of equol-competence. SHBG levels were not associated with the intake of soy foods, except in the case of miso intake on the 22nd day of cycle (r: 036, P=002). 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 two observational studies also show different limitations, in particular, one of these studies uses a follow-up of only 2 months. The study involved a large number of couples seeking pregnancy. 1. Following the removal of eighty-four duplicates, the selection was made through titles, abstracts and full-text reading. Soaking, fermentation, and heating may reduce problematic antinutrients contained in soy. 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). Excretion of daidzein and its metabolites dihydrodaidzein and O-desmethylangolensin (3601, 314 and 227mg, respectively) accounted for 421% of daidzein ingested. The ethnicity assessment of participants was useful in identifying, as might be expected, a greater consumption of soy foods by Asian individuals. Among the studies discussed to evaluate menstrual cycle length, three interventional studies also evaluated the levels of circulating hormones following soy intake in healthy women(Reference Lu, Anderson and Grady26,Reference Wu, Stanczyk and Hendrich28,Reference Lu, Anderson and Grady29) . (Reference Nagata, Kabuto and Kurisu27) and a longitudinal study published in 2013 by Filiberto et al. You should take them like Clomid hun so cd 1-5, 2-6, 3-7, 4-8 or 5-9. Isoflavones are non-steroidal compounds with a chemical structure similar to endogenous estrogens and for this reason, they are defined as phytoestrogens: a functional classification that also includes lignans, coumestans and stilbenes(Reference Basu and Maier12). However, the sampling during the various days of the cycle allowed a detailed characterisation of serum LH surge day. In the previously mentioned meta-analysis by Hooper and colleagues(Reference Hooper, Ryder and Kurzer59), reduction of about 22% of FSH (SMD: 045UI/l, 95% CI 079, 011, P=001) and of about 4% of LH (SMD: 034IU/l, 95% CI 068, 001, P=005) were related to the intake of soy or isoflavones. A list of the selected clinical studies with their characteristics is summarised in Table 1. The study did not evaluate circulating or urinary levels of isoflavones to verify the ability to metabolise isoflavones. Moreover, difficulties related to data collection about nutritional intakes were available, and individual reporting errors must be taken into account. The authors responsibilities were as follows: G. R. study conception and drafting the manuscript. Fig. Good: strong ovulation pains and increased ewcm. Since there are no scientific studies on the effects of soy isoflavones and ovulation, these are just general guidelines. 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). The results of selected manuscripts were grouped according to the outcomes used, for a clear comparison. Furthermore, no characterisation was made on the possible presence of equol-producers among the participants. In the second study by Lu and colleagues(Reference Lu, Anderson and Grady29), ten American women aged 2342 who did not consume soy regularly were followed for the duration of a menstrual cycle, during which nutritional intervention with soy was performed (36 Oz/d soy drink; 113207mg/d IF), without observing significant changes in cycle length compared to baseline and with a marginal shortening of luteal phase (6%, P=007). Total loading time: 0 Table 1. Soy consumption was not related to estradiol levels or endometrial thickness. There was no dose-response relation in either cohort. No changes were highlighted for DHEA, DHEAS, dihydrotestosterone (DHT) concentration or LH:FSH ratio. Furthermore, even at high concentrations, they did not show a clear influence on fertility. 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). SMART [Internet]. 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. Higher soy products intake did not correlate with the rate of infertility. Regarding observational studies, in 2015 Andrews and colleagues conducted a prospective cohort study on 246 American women with normal menstrual cycle, aged 1844 and with 13% of participants of Asian ethnicity, for a follow-up of 12 whole menstrual cycles(Reference Andrews, Schliep and Wactawski-Wende41). Soy consumption is supposed to have protective effects against cardiovascular disease by cholesterol-lowering and blood pressure improvement action and in the prevention of cancer or diabetes and it also supports bone health and the management of menopause symptoms(Reference Ding, Pan and Manson2Reference Mosallanezhad, Mahmoodi and Ranjbar8). These enzymes convert estrone and androstenedione into estrogen and testosterone(Reference Gunnarsson, Ahnstrm and Kirschner83,Reference Thompson and Siiteri84) . In the first clinical trial by Unifer and colleagues, 1500mg/d of isoflavones from soy or placebo were administered for 10d to 134 women who had been infertile for at least 2 years, undergoing intrauterine insemination after 100mg/d for 5d of clomiphene citrate treatments (an ovulation inducer)(Reference Unfer, Casini and Costabile31). PMCID: PMC8922143. These substances could play a role in the ovaries circulatory functions(Reference Oyawoye, Abdel Gadir and Garner50). A systematic consultation of literature was launched on four search engines (PubMed, ScienceDirect, Cochrane Trials Library and ClinicalTrials.gov) using the following keywords: (Soy OR Soy Foods OR Soybeans OR Genistein OR Daidzein OR Isoflavones OR Phytoestrogens) AND (Fertility OR Infertility OR Fecundability). conducted another prospective cohort study on 239 American women undergoing assisted reproductive technology(Reference Chavarro, Mnguez-Alarcn and Chiu42). Get the latest business insights from Dun & Bradstreet. For these reasons, studies that evaluated the ovarian hormones secretion were aimed at exploring the potential beneficial effect of soy on breast cancer prevention, but they were not designed for the evaluation of endocrine consequences, including fertility. Similar to the previous trial, the number of participants was limited. 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). 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. Recently, Haudum and colleagues conducted a longitudinal case-control clinical trial on forty-four Australian patients (twenty-four PCOS and twenty healthy controls) using 400ml/d of soy milk (containing approximately 50mg of isoflavones, 132g protein) for a 3-d pilot study(Reference Haudum, Lindheim and Ascani46). Microbial alpha diversity and glucose homeostasis improved in PCOS group after isoflavone intervention, resembling the control group profile at baseline. Soy contains numerous phytochemicals that can be responsible for these positive effects through multiple mechanisms. Manuscripts exploring multiple aspects were discussed in different paragraphs, where deemed necessary. The purpose of this review is to collect currently available data in literature, summarising the possible interaction between soy, soy foods and components of soy (in particular isoflavones) on aspects concerning women's fertility and related outcomes. Flowchart for studies selection. These alterations easily lead to hyperandrogenism and irregular menstrual cycles. It is important to evaluate the levels of hormones that fluctuate during the cycle at several points. Articles concerning reviews, case series, case studies, non-human studies, in vitro studies, studies on males, editorials, letters to editor, conference abstracts, book's chapters, non-English papers, studies with no-soy isoflavones and studies with outcomes not pertinent to fertility were excluded. It affects one out of every six couples and affects the majority women aged between 15 to 44 years. Based on our literature search, we also identified two observational studies: a cross-sectional study published in 1997 by Nagata et al. In addition, equol acts on incretins levels in endocrine L cell line GLUTag cells at concentration ranging from 50 to 300M, with long-term metabolic consequences(Reference Harada, Sada and Sakaguchi79). PMID: 35320928. 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Multiple aspects were discussed in the previous trial, the number of couples seeking pregnancy from detailed...

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