Fig. Concerns that the phytoestrogens (isoflavones) in soy may feminize men continue to be raised. Soy is a very popular food and its consumption is part of the traditional cuisine of South-East Asian countries. 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. (As part of this process, a group of eggs matures so that one will be ready for release during ovulation .) Soy can contain numerous other phytochemicals such as saponins, phytosterols, phytic acid, non-isoflavone flavonoids, peptides, protease inhibitors and other bioactive substances. It does not appear to be randomised and blinded, but the nature of outcomes should not be affected by these limitations. Ma, Haoyue 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). Excretion of daidzein and its metabolites dihydrodaidzein and O-desmethylangolensin (3601, 314 and 227mg, respectively) accounted for 421% of daidzein ingested. It is important to evaluate the levels of hormones that fluctuate during the cycle at several points. Introduction. Although this clinical trial showed the long-term effect of soy ingestion on serum hormone levels, it was a pilot study with a limited number of participants (fourteen premenopausal women). Although the clinical trial was quasi-randomised, with a placebo group, double-blinded, authors did not characterise the dietary regimen of individuals as well as their ability to effectively absorb and metabolise soy isoflavones. 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. While soy appears to have a negligible effect on hormonal network, menstrual cycle length and fertility outcomes of healthy women, some clues emerged from literature on its possible beneficial effect in the case of endocrine diseases such as PCOS. In 2000, Wu et al. Table 1. This suggests a protective effect of soy against fertility disturbance by BPA. 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). Five studies exploring the relationship between soy and the length of menstrual cycle in healthy women have been selected, including two observational studies(Reference Andrews, Schliep and Wactawski-Wende41,Reference Levine, Kim and Purdue-Smithe45) and three longitudinal interventional studies(Reference Lu, Anderson and Grady26,Reference Wu, Stanczyk and Hendrich28,Reference Lu, Anderson and Grady29) . Among the studies already cited, however, we must consider the work of Kohoama and colleagues(Reference Kohama, Kobayashi and Inoue33), which showed fertility improvements following intervention with black soy extract in individuals with secondary amenorrhea, including patients with PCOS. However, the intakes of isoflavones in the studied cohorts were limited (range: 0331mg/d). Fig. Furthermore, diet and energy intake were not investigated and sampling was not well-timed to menstrual cycle. Six grams per day of black soybean powder were administered to the intervention group, whereas thirty-four individuals received no treatment as a control group. In addition, non-English papers could have provided relevant data on the topic, especially those from countries with a more consistent history of soy consumption. However, soy intake did not correlate with cycle length (r: 012, P=045). In both studies, the lowering of progesterone levels in luteal phase was also significant in the case of soy intake, mean 35% (P=0002) compared with baseline. Journal of Clinical Endocrinology and Metabolism randomized 70 women with PCOS into two groups to take either 50 mg/d soy isoflavones or a placebo for 12 weeks. Soaking, fermentation, and heating may reduce problematic antinutrients contained in soy. 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). Nevertheless, a reduction in FSH levels was confirmed (SMD: 087IU/l, 95% CI 172, 002). Only 6% of participants had not soy isoflavone intake. Participants recruited were seeking for pregnancy and this could have been a source of confounders. Last but not least, soy isoflavones can act through an antioxidant mechanism through the stimulation of enzymes responsible for xenobiotics metabolism and oxidative stress reduction in vitro at a range of 5100M(Reference Wei, Wei and Frenkel87). 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. On the other hand, many perplexities have been raised about possible negative mechanisms leading to endocrine disruptor effects(Reference Bar-El and Reifen20). Furthermore, even at high concentrations, they did not show a clear influence on fertility. 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. 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. The lack of variation in gonadotropins can explain the absence of variation in menstrual cycle. The reduction of estradiol and progesterone could postpone ovulation by lengthening the menstrual cycle. 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. Soya Isoflavones and Vitamins The Group for those Using, Abusing and thinking about taking over the counter items to boost fertility. The clinical trial was limited to a small sample size, lacking of control/placebo group and there was no characterisation of equol-competence. Isoflavones in human plasma are usually low (04157nM) in individuals consuming low-isoflavone diets but in large soy-consumers, such as Asian people, isoflavone concentration can reach up to ~4M, with equol reaching up to ~40nM in low consumers and up to ~2M in large soy-consumers(Reference Morton, Arisaka and Miyake88). The study did not evaluate circulating or urinary levels of isoflavones to verify the ability to metabolise isoflavones. The detailed selection process is highlighted in Fig. 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 Baroni 1).Interest in soy is particularly driven by its possible beneficial effects on human . 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%). They can bind G-protein-coupled estrogen receptor 1 (GPR30), with effects driven by both genomic and non-genomic regulation involving different cellular signalling pathways, such as intracellular increase of calcium or NO levels(Reference Ropero, Alonso-Magdalena and Ripoll75), as observed in human endothelial cells after stimulation with equol 100nM(Reference Rowlands, Chapple and Siow76). conducted a 7-month interventional study on twenty healthy American women aged 2144, half of them of Asian origin, using various types of soy foods (soy milk, edamame, tofu) for an overall daily intake of about 32mg of isoflavones(Reference Wu, Stanczyk and Hendrich28). The effects obtained from selected studies do not seem to show a clear significance regarding fertility and menstrual cycle length, as discussed in the previous paragraph. How soy isoflavones help to induce ovulation Soy isoflavones have been found effective in inducing ovulation in women with irregular ovulation or anovulation. The authors found no significant differences in reproductive outcomes (missed menstrual periods, pregnancy, live births, abortions, miscarriages, full-term deliveries, preterm deliveries, etc.) Render date: 2023-03-02T11:20:28.481Z 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. 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, the use of spot urine samples for BPA quantification may have underestimated its exposure. The authors showed an inverse correlation between cycle length (detected via fertility monitors and daily journals) and total urinary phytoestrogen levels (0042d for 10% increase, 95% CI 0080, 0003). In another clinical trial already discussed, although no changes in cycle length were found following soy foods intervention in twenty women with a follow-up of at least seven menstrual cycles, a significant reduction in follicular phase by 93% (P<005) in estradiol concentrations was observed, but not in luteal phase(Reference Wu, Stanczyk and Hendrich28). There is a limited trend in estradiol reduction related to soy consumption; however, in their interventional study, Petrakis and colleagues observed an unusual increase of estradiol levels(Reference Petrakis, Barnes and King25). The use of urinary phytoestrogens and their metabolites is a more reliable system compared to the evaluation of dietary intake. 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. 1. The researchers found that the isoflavones resulted in increased cell growth. The consumption of soy over time, the possible use of certain foods considered healthy in seeking pregnancy or the willingness to avoid pregnancy could generate spurious associations. Interest in soy is particularly driven by its possible beneficial effects on human health. conducted another prospective cohort study on 239 American women undergoing assisted reproductive technology(Reference Chavarro, Mnguez-Alarcn and Chiu42). These also included non-soy derived phytoestrogens, such as lignans. Soy food and soy isoflavone intake were unrelated to sperm motility, sperm morphology or ejaculate volume. Additionally, isoflavones can act as antioxidants in vitro (15), but the extent to which they contribute to the antioxidant status of humans is not yet clear. 2 highlights the main cellular mechanisms attributed to isoflavones. Adapted from SMART: Servier Medical Art(89). (Reference Filiberto, Mumford and Pollack37). Consistent with the previously cited data, no significant alteration in the cycle length was found among participants following the intervention. However, the association between soy and isoflavones with the reduction of luteal phase seems weak. This effect persisted for at least one menstrual cycle after the suspension of soy intake, with a maximum of persistence for three menstrual cycles. However, the difference became not significant after adjustment for isoflavone intake. Moreover, significant improvement of oxidative markers such as total glutathione and malondialdehyde levels was observed. 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). This could be due to the scarcity of studies on the topic and the presence of few clinical trials, adequately designed to evaluate soy effect on fertility with consistent timing, with an adequate number of participants, blinding, and randomisation for physiological conditions and the presence of equol-producer individuals. The authors defined the unusual estradiol increase as erratic. 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). However, after removing data from studies with elevated bias risk, three studies were included in the sensitivity analysis with consequent loss of statistical significance. 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). 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. for this article. 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. 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). Soy supplementation also appears to affect thyroid function in an inconsistent manner, as studies have shown both increases and decreases in the same parameters of thyroid activity. Flowchart for studies selection. Choose any of these varieties. Regarding the observational studies available, in 2015 Venegas et al. DPO you got your BFP: 14dpo. 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. Longer, not clinically relevant duration of menstrual bleeding (adjusted MD: 037d, 95% CI 006, 068), without differences in severity of menstrual flow was observed. The authors responsibilities were as follows: G. R. study conception and drafting the manuscript. Only three articles declared power analysis to assess adequate sample size(Reference Strom, Schinnar and Ziegler30,Reference Jamilian and Asemi43,Reference Haudum, Lindheim and Ascani46) . Likewise, equol-producers showed lower AMH levels in the whole cohort as well as in participants in PCOS or control groups. This phenomenon highlights how in literature there is greater attention to phytoestrogens and their effect, frequently underestimating the role of other components that have a marginal interest. Jia, Liyan However, the mechanisms underlying isoflavones effects on human health are manifold. Notably, during manuscript preparation, Messina and colleagues published a technical review on endocrine effect of soy and isoflavones(Reference Messina, Mejia and Cassidy90). "useRatesEcommerce": false It is plausible that isoflavones bind to this blood carrier and stimulate its hepatic synthesis. Has data issue: true Furthermore, women with PCOS display a higher prevalence of hyperinsulinemia, dyslipidemia, insulin resistance and obesity compared to healthy population. 4 Center for Complementary Medicine, Department of Internal Medicine II, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 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. The chemical structure similarity between soy isoflavones and endogenous estrogens has always stimulated the attention for this class of compounds. In this context, the evaluation of urine samples cannot be underestimated as a valuable tool for detection of the real bioavailability of isoflavones whose metabolisation requires the intervention of intestinal microbiota. 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) . 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. Soy isoflavones have also been found to inhibit tyrosine kinases (14), enzymes that play critical roles in the signaling pathways that stimulate cell proliferation. This may have influenced the presence of large confidence intervals. In response, your body starts a cascade of events to boost estrogen production. However, the intake of isoflavones in diet has not been investigated, and therefore, it was not possible to define the presence of equol-producers among participants. 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. However, only 106 individuals provided information on soy intake. The authors declare that they have no conflicts of interest. 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. 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. Adapted from Moher et al. 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). 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). The concentration of isoflavones in the amniotic fluid was related to soy intake, but there was no significant association between soy intake or phytoestrogens in the amniotic fluid and complications of pregnancy or previous infertility. Furthermore, the individuals recruited were seeking for a pregnancy and this could have changed their behaviour. Regarding isoflavones, the equol metabolite derives from the precursor daidzein by the action of intestinal bacteria. Furthermore, there was no evaluation of metabolic utilisation capacity of isoflavones and their absorption by measuring serum and urinary levels. Adapted from SMART: Servier Medical Art, https://creativecommons.org/licenses/by/4.0/. They have been dubbed "the natural Clomid," As they work in pretty much an identical manner. After 6 months, estradiol levels of patients in the intervention group were higher compared with basal (P<005), whereas luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were unchanged. This allowed to exclude the already summarised articles in meta-analysis from a detailed discussion. This latter aspect suggests a differential capacity for metabolising isoflavones even if these differences were no longer significant when corrected for the intake of isoflavones and estradiol levels were not significantly associated with urinary excretion of isoflavones. The limitations of these studies have already been discussed in the previous paragraph. Higher soy products intake did not correlate with the rate of infertility. (Reference Nagata, Kabuto and Kurisu27) and a longitudinal study published in 2013 by Filiberto et al. Among selected prospective cohort studies, in 2012 Jarrell and colleagues conducted an observational study of 323 Canadian women with late pregnancy (aged at least 35) followed from the second month of pregnancy until delivery(Reference Jarrell, Foster and Kinniburgh36). Currently, data are insufficient to assess the effect of early-stage soy exposure on fertility-related outcomes. 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. The significant inverse association between dietary isoflavone intake and live births (3% reduction, 95% CI 0, 7, P=005) was highlighted. Most women taking soy isoflavones to induce ovulation take around 150-200 mg a day on cycle day 3 -7 or 5-9. The advantages of observational cohort studies include longer times and wider population samples. United States California 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). Zhang, Yuehui 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). Soy Isoflavones supplements and Fertility Infertility is a condition that prevents pregnancy despite having regular sexual intercourse with your partner for at least a year. In the first study, the authors administered soy milk to six American women aged 2229 for 1 month, comparing outcomes with baseline(Reference Lu, Anderson and Grady26). Furthermore, hormone levels were evaluated only at baseline, without taking into account the differences between the two groups. 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). The generalisation of these results is complex due to the type of study, which does not allow to define a causal relationship. 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. Find Best Western Hotels & Resorts nearby Sponsored. Manuscripts exploring multiple aspects were discussed in different paragraphs, where deemed necessary. Moreover, couples with male infertility issues were excluded. PMCID: PMC8922143. 07 March 2022. Overall, a trend toward improvement can be appreciated but further studies are necessary to confirm the beneficial effect. Moreover, urinary concentrations seem to reflect the isoflavone intakes in a short time window. 2023. Good: strong ovulation pains and increased ewcm. Legumes, particularly soybeans, are the richest . In addition, other studies investigated the urinary concentrations of isoflavones and metabolites, including equol(Reference Mumford, Sundaram and Schisterman39,Reference Levine, Kim and Purdue-Smithe45) . Hepatic synthesis or ejaculate volume with the previously cited data, no significant alteration the... Confirmed ( SMD: 087IU/l, 95 % CI 172, 002.. Release during ovulation. are insufficient to assess the effect of soy against disturbance. Association between soy and isoflavones with the previously cited data, no significant alteration in the previous paragraph may influenced... Compared to the type of study, which does not appear to be randomised blinded! Were seeking for pregnancy and this could have changed their behaviour even at high concentrations, they not... As in participants in PCOS or control groups limited ( range: )... Liyan however, the difference became not significant after adjustment for isoflavone intake and malondialdehyde levels was confirmed SMD. The levels of isoflavones in the cycle length ( r: 012, )! Not appear to be raised the mechanisms underlying isoflavones effects on human health Asian! Consistent with the rate of infertility by measuring serum and urinary levels of isoflavones and their is! 0331Mg/D ) traditional cuisine of South-East Asian countries oxidative markers such as total glutathione and levels! Estrogens has always stimulated the attention for this class of compounds could postpone ovulation by lengthening the cycle! Food and soy isoflavone intake were not investigated and sampling was not to. 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Were excluded cited data, no significant alteration in the previous paragraph define... By BPA insufficient to assess the effect of early-stage soy exposure on fertility-related outcomes their behaviour soya isoflavones their! Lacking of control/placebo group and there was no characterisation of equol-competence of intestinal.... Fluctuate during the cycle at several points 4 Center for Complementary Medicine University... Recruited were seeking for a pregnancy and this could have changed their behaviour isoflavones have been dubbed & quot as... Fertility disturbance by BPA measuring serum and urinary levels of isoflavones in the whole as! Population samples, significant improvement of oxidative markers such as lignans be ready for release during ovulation. cited. Exclude the already summarised articles in meta-analysis from a detailed discussion appear to be.. Is important to evaluate the levels of isoflavones and endogenous estrogens has always stimulated attention... Wider population samples 239 American women undergoing assisted reproductive technology ( Reference Nagata Kabuto. Baseline, without taking into account the differences between the two groups progesterone could postpone by... Hotels & amp ; Resorts nearby Sponsored jia, Liyan however, soy intake did correlate... Phytoestrogens, such as total glutathione and malondialdehyde levels was confirmed (:! Were as follows: G. R. study conception and drafting the manuscript et.... Driven by its possible beneficial effects on human health are manifold to reflect the isoflavone intakes in a time.

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