Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials

Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials Gabrielle Viscardi, Songhee Back, Amna Ahmed, Shuting Yang, Sonia Blanco Mejia, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3857624/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Despite dietary recommendations to consume more plant foods for public and planetary health and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and their components, especially isoflavones, are a barrier to their intake. Given the cardioprotective effects and ability to alleviate menopausal symptoms, addressing this issue is particularly relevant to women. We therefore undertook a systematic review and meta-analysis of randomized controlled trials in postmenopausal women to determine the effect of soy isoflavones on measures of estrogenicity. Methods MEDLINE, Embase, and Cochrane Library were searched through July 2023 for randomized controlled trials 3-months investigating soy isoflavones versus non-isoflavone controls in postmenopausal women. The four outcomes included endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and estradiol. Independent authors extracted data and assessed risk of bias. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess certainty of evidence. Results We included 40 trials (52 trial comparisons, n=3285) assessing the effect of a median daily dose of 75 mg of soy isoflavones in substitution for non-isoflavone control over a median of 24 weeks. Isoflavones had no statistically significant effects on any of the measures of estrogenicity; ET (mean difference, -0.22mm [95% confidence interval, -0.45 to 0.01mm], P MD =0.059), VMI (2.31 [-2.14 to 6.75], P MD =0.310), FSH (-0.02IU/L [-2.39 to 2.35IU/L], P MD =0.987), and estradiol (1.61pmol/L [-1.17 to 4.38pmol/L], P MD =0.256). The certainty of evidence was high-to-moderate for all outcomes. Conclusion Current evidence provides a good indication that soy isoflavones do not have an estrogenic effect versus non-isoflavone controls on 4 measures of estrogenicity in postmenopausal women. This synthesis supports the classification of soy isoflavones as selective estrogen receptor modulators and that isoflavones differ clinically from the hormone estrogen where no assumptions about the health effects of soy foods or isoflavones should be based on an understanding of the effects of the hormone estrogen. Addressing public health concerns around soy foods may support their intake as high-quality plant protein foods with low environmental impact and cost, especially relevant for postmenopausal women, and aligning with sustainable dietary patterns and guidelines. Registration : PROSPERO (CRD42023439239) Figures Figure 1 Figure 2 INTRODUCTION Despite dietary recommendations to consume more plant foods for public and planetary health( 1 – 5 ) and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and their components, especially soy isoflavones, are a barrier to their intake. The negative views of soy, including a worsening of the prognosis of women with estrogen-sensitive breast cancer( 6 ), are predominately driven by the results of animal studies( 7 – 10 ). These studies have limited implications for human health, in part due to differences in metabolism of soy isoflavones between rodents and humans( 11 – 13 ). In contrast, human studies indicate soy has cardioprotective effects including health claims for soy and cholesterol and coronary heart disease risk reduction( 14 – 16 ). There is also evidence that isoflavones reduce risk of breast( 17 ) and prostate( 18 ) cancer, improve bone health( 19 ) and memory( 20 ), and alleviate menopausal symptoms( 21 ). This issue is thus particularly relevant to women in which cardiovascular disease (CVD), the leading cause of death in both women and globally( 22 ), is underrecognized and undertreated( 23 , 24 ) and up to 80% experience moderate-to-severe vasomotor symptoms and seek an alternative to hormone replacement therapy (HRT), which has been associated with elevated cancer risk( 25 ). Even with the known benefits, there is still public concern about the estrogenicity of soy foods and isoflavones. Although isoflavones are commonly classified as phytoestrogens, they differ from the hormone estrogen at both the molecular and clinical level. For example, isoflavones preferentially bind to estrogen receptor (ER)β in comparison with ERα, whereas estrogen binds with equal affinity to these receptors( 26 , 27 ). These receptors have different tissue distributions and when bound by ligands result in different and sometimes opposite physiological effects( 28 ). In general, activation of ERα and ERβ is seen as exerting proliferative and anti-proliferative effects, respectively( 28 ). Their preferential binding provides a conceptual basis for classifying isoflavones as selective estrogen receptor modulators (SERMs)( 29 ). Given that consumption of soy foods is extremely low in North America with only 3–4% reporting consumption of a soy-containing product on any given day( 30 ), yet both dietary guidance and cardiovascular clinical practice guidelines on nutrition therapy recommend to consume more plant foods( 1 – 5 ) including soy foods, there is a public health need to better understand and characterize soy isoflavones. Addressing public concerns over the estrogenicity of soy foods will also support addressing the gender gap in CVD as this concern is of particular relevance to menopausal women given the increase in CVD risk and vasomotor symptoms, which increased soy consumption may alleviate. We therefore undertook a systematic review and meta-analysis of randomized controlled trials in postmenopausal women to determine the effect of soy isoflavones on four measures of estrogenicity: endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and circulating estradiol. METHODS We followed the Cochrane Handbook for Systematic Reviews of Interventions (version 6.3)( 31 ) for the conduct of our systematic review and meta-analysis and reported our results following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-Equity) guidelines( 32 ). The study protocol was registered on PROSPERO (CRD42023439239). Data sources and search strategy We systematically searched MEDLINE, Embase and the Cochrane Central Register of Controlled Studies from inception through July 20th, 2023. Supplemental Tables 1–2 show the search strategy based on the PICOTS framework without language restrictions. Validated filters from the Cochrane Handbook for Systematic Reviews of Interventions were applied to limit the database search to controlled studies( 33 ). Manual searches of the reference lists of included studies complemented the systematic search. Study selection We included randomized controlled feeding trials in postmenopausal women of all health backgrounds, with intervention periods ≥ 3 months. We included studies that investigated the effect of isoflavones from soy (as either supplements or foods) compared with a suitable non-isoflavone-containing control (such as placebo capsules or soy protein nearly devoid of isoflavones) on measures of estrogenicity. We excluded studies of interventions containing no isoflavones or isoflavones from non-soy sources. In reports containing more than one eligible trial comparison, we included all available trial comparisons. Data extraction and quality assessment At least two independent reviewers (GV, SB, AA) extracted relevant data from eligible studies. Relevant information included the number of participants, age, health status, years since last menses, study design, level of feeding control, intervention type, isoflavone dose, comparator, follow-up duration, energy balance, energy control, funding source, and outcome data. Authors were contacted for missing outcome data when it was indicated that relevant outcomes were measured but not reported. In the absence of numerical values for outcomes and inability to obtain the original data from authors, values were extracted from figures using Plot Digitizer where available( 34 ). Included studies were assessed for risk of bias independently by at least two independent reviewers (GV, SB, AA) with the Cochrane Risk of Bias V.2.0 tool( 35 ). Assessment was done across six domains of bias (randomization process, risk of bias arising from period or carryover effects (crossover studies only), deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported results). The tool provides a judgment of ‘low risk of bias’, ‘some concerns’ or ‘high risk of bias’ for each domain based on responses to signaling questions. An overall risk of bias was determined based on judgments from each domain. We resolved discrepancies in data extraction and risk of bias by consensus and review by the senior author (LC). Outcomes The primary outcomes included 4 measures of estrogenicity: ET, VMI, FSH and levels of estradiol. Mean differences (MDs) between the intervention and control arm and respective standard errors were extracted for each trial. If these were not provided, they were derived from available data using published formulas( 31 ). Mean pairwise difference in change-from-baseline values were preferred over end values. When median data was provided, they were converted to mean data with corresponding variances using methods developed by McGrath et al.( 36 ). When no variance data was available, the standard deviation of the MDs was borrowed from a trial similar in size, participants, and nature of intervention. Data synthesis and analysis We used STATA software, version 18.0 (StataCorp, College Station, TX, USA) for all analyses. The principal effect measures were the mean pair-wise differences in change from baseline (or alternatively, end differences) between the intervention arm providing the soy isoflavones and the comparator/control arm in each trial comparison (significance at P MD <0.05). Results are reported as MDs with 95% confidence intervals (95% CI). Data were analyzed using the generic inverse variance method with DerSimonian and Laird random-effects model( 37 ). A fixed effects model was used when the number of trial comparisons was < 5( 38 ). Paired analyses were applied to all crossover trials with the use of a within-individual correlation coefficient between treatment of 0.5 as described by Elbourne et al.( 39 – 41 ). To mitigate a unit-of-analysis error, when arms of trials with multiple intervention or control arms were used more than once, the corresponding sample size was divided by the number of times it was used for calculation of the standard error( 42 ). Each pairwise trial comparison was considered a separate trial for the purpose of this analysis. Heterogeneity was assessed using the Cochran Q statistic and quantified using the I 2 statistic( 43 ). We considered an I 2 ≥ 50% and P Q <0.10 as evidence of substantial heterogeneity( 44 ). Sources of heterogeneity were explored by sensitivity and subgroup analyses. We conducted sensitivity analyses by influence analysis in which each trial was systematically removed from the meta-analysis with recalculation of the summary effect estimate. A trial whose removal explained the heterogeneity or changed the significance, direction, or magnitude (by more than the minimally important difference (MID) for harm set at 0.30 for ET, 3.8 for VMI, 7.4 for FSH and 5.2 for estradiol based on 10% of the baseline mean of 3.0mm, 37.6, 7.4IU/L, and 5.2pmol/L, respectively) of the effect was considered an influential trial. To determine whether the overall results were robust to the use of different correlation coefficients in crossover trials, we also conducted sensitivity analyses using correlation coefficients of 0.25 and 0.75. We also performed sensitivity analyses using fixed effects model. If ≥ 10 trials were available( 45 , 46 ), we conduced subgroup analyses to explore sources of heterogeneity using meta-regression (P Q <0.05). A priori subgroup analyses were conducted by age, participant health status, baseline outcome level, years since last menses, isoflavone dose, intervention type, comparator, follow-up duration, study design, energy balance of the intervention relative to the basal diet (neutral, positive, negative), level of energy control relative to the comparator (substitution, addition, subtraction, ad libitum), feeding control (dietary advice, supplemented, metabolic), funding and risk of bias. Post-hoc subgroup analyses were conducted by type of mean difference (change from baseline or end differences), baseline BMI, comparator by presence of soy protein and by continent where the study was conducted. Meta-regression analyses were used to assess the significance of each subgroup categorically and when possible, continuously. If ≥ 6 trial comparisons are available( 47 ), dose-response analyses were performed using meta-regression to assess linear (by generalized least squares trend estimation models) and non-linear spline curve modelling (by the MKSPLINE procedure with 3 knots( 48 )) dose-response gradients (P < 0.05). If ≥ 10 trials were available( 49 ), we assessed publication bias by inspection of contour enhanced funnel plots and formal testing with the Egger’s and Begg’s tests (P < 0.10)( 50 – 52 ). If there was evidence of publication bias, we adjusted for funnel plot asymmetry by imputing the missing trial data using the Duval and Tweedie trim-and-fill method and assessed for small study effects( 53 ). Certainty of the evidence The certainty of the evidence was assessed using the GRADE approach( 54 ) and software (GRADEpro V.3.2( 55 ). Evidence was rated as high, moderate, low, or very low certainty. The included randomized trials were initially rated as high certainty by default and then downgraded or upgraded based on pre-specified criteria. Reasons for downgrading the evidence included risk of bias (Cochrane Risk of Bias V.2.0 tool( 35 )), inconsistency (substantial unexplained interstudy heterogeneity, I 2 ≥ 50%, P Q <0.10), indirectness (absence or presence of factors limiting the generalizability of results), imprecision (95% CI for pooled effect estimates cross the MID for harm), and publication bias (significant evidence of small study effects). The reason for upgrading the evidence was presence of a significant dose-response gradient( 56 – 63 ). The importance of the magnitude of the pooled estimates was assessed using our prespecified MIDs and the effect size categories according GRADE guidance( 64 – 67 ) as follows: large effect (≥ 5x MID); moderate effect (≥ 2x MID); small important effect (≥ 1x MID); and trivial/unimportant effect (< 1 MID). RESULTS Search results Figure 1 shows the flow of the literature review. We retrieved 5,858 reports from databases and manual searches, 5,636 of which were excluded based on the title or abstract. Of the 224 reports reviewed in full text, 40 reports of randomized trials (52 trial comparisons, N = 3,285) met the eligibility criteria( 68 – 107 ). Trial characteristics Table 1 and Supplemental Table 3 show the trial characteristics. Trial sizes ranged from a median of 50 participants (range 18–245) for FSH to 65 (27–389) for ET. Participants were postmenopausal women with a median age of 54 ( 48 – 71 ) years for VMI, FSH and estradiol to 55 ( 49 – 74 ) years for ET, without diagnosed chronic disease, except for one trial of participants with a history of breast cancer and one with insulin resistance. Years since last menses ranged from a median 5 ( 2 – 19 ) years for trials of FSH and estradiol to a median of 7 ( 2 – 24 ) years for trials of ET. Most trials were performed in North America (29–38%) and Europe (10–43%) and were parallel in design (ranging from 75 to 93% in trials of VMI and ET, respectively). Feeding control was mostly supplemented (88–100%). The median dose of isoflavones ranged from 66mg (36–154) in trials of ET to 77mg (40–600) in trials of FSH. The intervention duration ranged from a median of 13 weeks ( 12 – 104 ) in trials of FSH to 24 weeks (12–156) for ET. Most trials were funded by agency sources (government, not-for-profit health agency, or university sources) (19–43%), followed by both agency and industry sources (7–39%). The comparators included placebo capsules of casein (2%), lactose (7%) and dextrin (%), soy protein nearly devoid of isoflavones (4%), starch (5%), casein-based foods/beverages (10%), usual diet (5%), non-soy-based foods/beverages (2%), soy protein-based foods/beverages nearly devoid of isoflavones (8%), and milk protein-based foods/beverages (8%). Of comparators, most did not include soy protein (88%) whereas a few included soy protein nearly devoid of isoflavones (12%). Table 1 Summary of characteristics of included trial comparisons assessing the effect of soy isoflavones on outcome measures of estrogenicity* Trial characteristics Endometrial thickness Vaginal maturation index Follicle-stimulating hormone Estradiol Trial comparisons (No) 14 8 31 31 Study size (median No (range) of participants) a 65 (27–389) 54 (18–142) 50 (18–245) 56 (18–245) Age (years; median (range)) b 55 (49–74) 54 (49–57) 54 (48–71) 54 (48–71) Health status (%; absence of disease: insulin resistance: history breast cancer) 93:0:7 100:0:0 97:0:3 94:3:3 Years since menopause (years; median (range)) b 7 (2–24) 7 (3–13) 5 (2–19) 5 (2–19) Continent (No of comparisons, and by country) North America = 4 (USA = 4); South America = 3 (Brazil = 3); South Asia = 1 (India = 1); Europe = 6 (Finland = 1; Italy = 4; Sweden = 1) North America = 3 (USA = 3); South America = 2 (Brazil = 2); South Asia = 1 (India = 1); Oceania = 1 (Australia = 1); Europe = 1 (Italy = 1) North America = 12 (USA = 12); South America = 5 (Brazil = 4; Chile = 1); East Asia = 4 (China = 2; Japan = 1; South Korean = 1); South Asia = 4 (India = 4); Oceania = 3 (Australia = 3); Europe = 3 (Finland = 1; Italy = 1; Sweden = 1) North America = 11 (USA = 11); South America = 5 (Brazil = 4; Chile = 1); East Asia = 9 (China = 4; Japan = 4; South Korean = 1); South Asia = 2 (India = 2); Europe = 4 (Finland = 1; Italy = 1; Spain = 1; Sweden = 1) Study design (%; crossover: parallel) 7:93 25:75 13:87 13:87 Feeding control (%; supplemented: ad libitum) 93:7 88:12 100 100 Dose of isoflavones (mg; median (range)) 66 (36–154) 76 (47–200) 77 (40–600) 75 (40–200) Follow-up duration (median No (range) of weeks) 24 (12–156) 20 (12–104) 13 (12–104) 24 (12–104) Funding sources (%; A: I: A, I: NR) f 43:36:7:14 38:25:37:0 19:23:32:26 29:16:39:16 Comparator (No of comparisons) Usual diet = 1; Placebo capsule = 4; Lactose capsule = 1; Soy protein capsule without isoflavone = 1; Calcium supplement = 2 Soy protein-based food/beverage without isoflavone = 1; Milk protein-based food/beverage = 3; Oatmeal beverage = 1 Usual diet = 1; Placebo capsule = 1; Lactose capsule = 1; Calcium supplement = 1; Wheat flour-based food/beverage = 1; Soy protein-based food/beverage without isoflavone = 2; Milk protein-based food/beverage = 1 Casein protein-based food/beverage = 6; Casein capsule = 1; Placebo capsule = 11 Lactose capsule = 2; Soy protein capsule without isoflavone = 1; Dextrin capsule = 1; Wheat flour-based food/beverage = 1; Starch capsule = 2; Non-soy-based food/beverage = 1; Soy protein-based food/beverage without isoflavone = 2; Milk protein-based food/beverage = 2; Oatmeal beverage = 1 Usual diet = 2; Casein protein-based food/beverage = 2; Casein capsule = 1; Placebo capsule = 11; Lactose capsule = 2; Soy protein capsule without isoflavones = 1; Dextrin capsule = 4; Starch capsule = 2; Non-soy-based food/beverage = 1; No capsule = 1; Soy protein-based food/beverage without isoflavone = 2; Milk protein-based food/beverage = 1; Oatmeal beverage = 1 Soy protein containing comparator (%; non-soy protein-containing: soy protein-containing 86:14 75:25 90:10 90:10 Intervention (No of interventions) Isoflavone capsule = 9; Soy protein-based beverage/food = 4; Isoflavone containing beverage = 1 Isoflavone capsule = 2; Soy protein powder = 1; Soy protein-based beverage/food = 5 Isoflavone capsule = 19; Soy protein powder = 1; Soy protein-based beverage/food = 9; Isoflavone containing beverage = 2 isoflavone capsule = 24 Soy protein-based beverage/food = 6 isoflavone containing beverage = 1 Setting (%; outpatient: inpatient) 100:0 100:0 100:0 100:0 Baseline BMI (kg/m 2 ; median (range)) b 26.3 (24.9–29.1) 25.8 (25.2–29.0) 25.6 (22.6–29.1) 25.2 (21.1–29.1) Baseline outcome (median (range)) b,c 3.1 (2.2–4.1) 41.8 (27.4–49.0) 76.0 (40.7–108.8) 44.2 (12.8–133.5) Energy balance (%; neutral: positive: negative) d 64:36:0 25:75:0 65:35:0 77:23:0 Energy control (%; substitution: addition: subtraction) e 86:14:0 50:50:0 84:13:3 90:10:0 Type MD (%; CFB: ED) 93:7 100:0 94:6 90:10 A, agency; BMI, body mass index; CFB, change from baseline; ED, end difference; I, industry; MD, mean difference * All numbers with the exception of baseline values were rounded to the nearest whole number to improve readability. a All sample sizes reflect participants included in the data analysed. b Not all trials reported baseline values. Baseline values were not reported for: age (n = 6), years since menopause (n = 17), and baseline BMI (n = 8) c Not all trials reported baseline outcome measures. Baseline outcome measures were not reported for: vaginal maturation index (n = 1). d Neutral energy balance refers to the maintenance of usual energy intake. Positive energy balance refers to a greater than normal energy intake. Negative energy balance refers to a deficit in normal energy intake. e Energy control refers to the energy intake of the intervention group compared to the control group where substitution refers to energy matched between intervention and comparator, addition refers to excess energy between intervention and comparator, and subtraction refers to deficit in energy between intervention and comparator. f Agency funding is that from government, university, or not-for-profit sources. The majority of industry funding is that from trade organisations that obtain revenue from the sale of products. Risk of bias Supplemental Figs. 1–2 show a summary of the ROB assessments. Across outcomes, most trials were assessed as having low ROB in the randomization (86–97%), missing (63–87%), measurements (100%), and selection (71–88%) domains, and some concerns in the deviations (35–42%) domain. Fewer trials were assessed as having high ROB ranging from 3% in the randomization and measurements domains, to 16–38% in the deviations domain, and 13–38% in the missing domain. Most trials were judged overall as low (32–39%) or some (25–48%) concerns, with fewer as high ROB (19–38%). Primary outcomes Figure 2 and Supplemental Figs. 3–6 present the effect of soy isoflavones on ET, VMI, FSH and estradiol. Isoflavones had no statistically significant effects on any of the measures of estrogenicity; ET (14 trials; MD: -0.22mm; 95% CI: -0.45 to 0.01mm, P MD =0.059; substantial heterogeneity, I 2 = 69.3%, P Q <0.001), VMI (8 trials; MD: 2.31; 95% CI: -2.14 to 6.75, P MD =0.310; no substantial heterogeneity, I 2 = 1.3%, P Q =0.420), FSH (31 trials; MD: -0.02IU/L; 95% CI: -2.39 to 2.35IU/L, P MD =0.987; substantial heterogeneity, I 2 = 51.9%, P Q <0.001), and estradiol (31 trials; MD: 1.61pmol/L; 95% CI: -1.17 to 4.38pmol/L, P MD =0.256; no substantial heterogeneity, I 2 = 23.5%, P Q =0.121). Adverse events and acceptability Supplemental Table 4 presents the data reported in 5 trials on acceptability and 18 trials on adverse events. All trials reported data descriptively except for one trial. Of the 5 trials reporting acceptability, women in the intervention groups mainly reported a dislike for taste or volume of food, with Knight et al. 2001( 107 ) reporting a tendency to dislike the taste of the soy isoflavone beverage compared to control (P = 0.07). Among the 18 trials reporting adverse events, gastrointestinal upset was the most common reported symptom, where it was experienced to a similar extent in both those in the intervention and control groups. Sensitivity analyses Supplemental Figs. 7–10 present the individual trial influence analyses for each outcome. Removal of either Atteritano et al. 2007( 68 ), Kenny et al. 2009 (control + isoflavone)( 74 ), Nahas et al. 2007( 81 ), or Upmalis et al. 2000( 90 ) resulted in a gain of significance for a decrease in ET. Removal of either Jassi et al. 2010( 73 ) or Kim et al. 2013( 76 ) provided a partial explanation of the evidence of substantial heterogeneity for FSH. Supplemental Table 5 shows sensitivity analyses for the different correlation coefficients (0.25 and 0.75) used in paired analyses of crossover trials for each outcome. The use of these different correlation coefficients did not alter the direction, magnitude, or significance of the effect or evidence for heterogeneity. Supplemental Figs. 11–14 present the sensitivity analyses where fixed effects models were used. The use of a fixed effects model resulted in isoflavones showing a significant reduction on ET (14 trials; MD: -0.12mm; 95% CI: -0.24 to -0.01mm, P MD =0.032; substantial heterogeneity, I 2 = 69.34%, P Q <0.001). Subgroup analyses Supplemental Figs. 15–23 present the subgroup analyses and continuous meta regression analyses for the effect of isoflavones on ET, FSH and estradiol as there were ≥ 10 trial comparisons. There was significant effect modification by years since menopause (trials with median < 5 years tending towards a reduction, while trials with a median ≥ 5 years tending towards an increase in FSH), continent (with neither continental subgroup showing statistical significance) and intervention type and energy control, however the latter 2 were driven by 1 trial in which soy protein powder showed a greater reduction than other trials examining FSH. In continuous subgroup analyses, follow-up duration was significant (β = 0.09 [0.00–0.18], P = 0.044). These subgroups partially explained evidence of substantial heterogeneity for FSH (residual I 2 = 25–48%). There was also significant effect modification by comparator for estradiol, however this was driven by 1 trial where the comparator was soy protein capsules without isoflavones that showed an increase in estradiol. Dose response analyses Supplemental Figs. 24–27 present linear and non-linear dose-response analyses. There was no dose response for the effect of isoflavones on any measure of estrogenicity. Small-study effects Supplemental Figs. 28–30 present the contour-enhanced funnel plots and publication bias assessments for all outcomes with ≥ 10 trials available. There was no evidence of funnel plot asymmetry for any outcome. Note that publication bias was not assessed for VMI as < 10 trial comparisons were available (n = 8). GRADE assessment Figure 2 and Supplemental Table 6 present the GRADE assessments. The certainty of evidence for the effect of isoflavones was moderate for ET (no effect), owing to a downgrade for inconsistency due to unexplained heterogeneity, moderate for VMI (no effect) owing to a downgrade for imprecision, and high for FSH (no effect) and estradiol (no effect). DISCUSSION This systematic review and meta-analysis included 40 trials (52 trial comparisons) involving 3,285 postmenopausal women, who were predominantly middle aged, without diagnosed chronic disease and a median 5–6 years since last menses. We showed that consumption of soy isoflavones does not affect 4 measures of estrogenicity. These measures were chosen because they are known to be affected by the hormone estrogen and were evaluated in many trials involving isoflavones. The median intervention duration ranged from 13 (FSH) to 24 weeks (ET, estradiol). The lack of estrogenic effect was robust to sensitivity and subgroup analyses. The median dose of isoflavones ranged from 66mg/d (range 36-154mg) in trials of ET to 77mg/d (40-600mg) in trials of FSH. Findings in the context of literature The lack of estrogenic effect on ET in the current analysis is consistent with a 2016 systematic review and meta-analysis of trials ≥ 3 months( 108 ), which examined the effects of isoflavones from red clover and soy, in peri- and postmenopausal women. They found there was no significant change in ET when all women were included in the analysis (23 trials, 2,167 participants, standardized mean difference (SMD): -0.05, 95% CI: -0.23 to 0.13, P = 0.60). However, a daily dose of more than 54mg decreased ET by 0.26mm (10 trials, 984 participants, SMD: -0.26, 95% CI: -0.45 to -0.07, P = 0.007). This finding suggests that higher isoflavone doses, by reducing ET, could potentially reduce risk of developing endometrial cancer, a suggestion for which there is some epidemiological support( 108 ). Additionally, Li et al. 2010( 109 ) found that when trials were stratified according to study location, isoflavone supplementation significantly decreased ET by 0.23mm in North American trials (N = 7, 726 participants, SMD: -0.23, 95% CI: -0.44 to -0.01, P = 0.04), but tended to increase ET in Asian trials (N = 3, 128 participants, SMD: 0.23; 95% CI: -0.04 to 0.50, P = 0.10). The non-significant increase in ET observed in Asian trials, albeit based on only 3, may result from ethnic differences in isoflavone metabolism wherein Asians are more likely to host intestinal bacteria that convert daidzein into equol( 110 ), which has a much higher receptor binding affinity for both ERs than its parent isoflavone daidzein( 111 ). However, observational studies involving Asians show soy or isoflavone intake is associated with a decreased risk of endometrial cancer( 112 ). Our analyses did not demonstrate effect modification on ET by continent, where the lack of effect was consistent across trials from varying continents. The lack of effect on circulating estradiol and FSH levels is consistent with the findings of a 2009 systematic review and meta-analysis of trials ≥ 4 weeks( 113 ). In their meta-analysis, neither soy nor isoflavone consumption affected estradiol, estrone, FSH or luteinizing hormone levels in pre- (6–11 trials per comparison) or postmenopausal (21 trials per comparison) women. No previously published meta-analysis has explored the effects of isoflavones on VMI. Although only 8 trials examined this endpoint, the lack of effect is consistent with the results of the other 3 measures of estrogenicity considered in the current analysis. The lack of estrogenic effects of isoflavones on ET, VMI, FSH and estradiol in the current analysis, does not rule out these soybean constituents from exerting estrogen-like effects on other tissues and measures or endpoints. As noted previously, isoflavones are classified as SERMs. By definition, SERMs have tissue-specific effects. For example, tamoxifen exerts an anti-estrogenic effect on breast tissue, but an estrogenic effect on endometrial tissue( 29 ). Therefore, the current analysis does not undermine findings that isoflavones alleviate menopausal symptoms( 21 ), reduce bone loss( 19 ) and improve memory( 20 ) in postmenopausal women; effects thought to result from the interaction between isoflavones and ERs. Similarly, they do not rule out isoflavones from exerting estrogenic effects on breast tissue, although substantial clinical evidence indicates this is not the case( 114 , 115 ). Nor do they rule out isoflavones from having anti-estrogenic effects. In premenopausal women, genistein (a soybean isoflavone accounting for approximately 50% of total isoflavone content of the soybean( 116 )) has demonstrated inhibitory effects on endometrial hyperplasia, a precancerous condition indicated by an irregular thickening of the endometrial wall( 117 ). Furthermore, soy isoflavones have been shown to reduce the risk of breast cancer recurrence in postmenopausal women with estrogen-dependent cancer taking anastrozole, an estrogen-lowering therapy( 118 ). However, the findings of the current systematic review and meta-analysis serve to illustrate that isoflavones differ clinically from the hormone estrogen. This difference is evident when comparing the effect of soy isoflavones to that of HRTs ( Supplemental Table 7 ). In systematic reviews and meta-analyses of the effect of HRTs on measures of estrogenicity, they demonstrate increases in ET, VMI and estradiol and reductions in FSH, which contrast with the lack of effects of isoflavones observed in the present analysis. Furthermore, these differences were also observed in a head-to-head comparison between HRT with soy isoflavones( 97 ). This differentiation is important because safety concerns raised about isoflavones are based on their similarity to estrogen. Implications Although most trials in the present analysis provided isoflavones as capsules, the results of these trials did not differ from those trials in which isoflavones were provided as soy protein-based beverages or foods (approximately 30%). Furthermore, mean isoflavone intake in the included trials (median 66-77mg/d) was higher than the typical isoflavone intake among older Japanese women (30-50mg/d)( 119 , 120 ) and the typical amount associated with a range of beneficial effects in observational studies where a systematic review and meta-analysis demonstrated each 10 mg/d increment of soy isoflavones intake was significantly associated with a 4% lower risk of overall cancer incidence( 18 ). The intake of soy isoflavones per capita in the United States( 121 – 123 ) and Europe( 124 , 125 ) is no more than 6 mg/d and most likely fewer than 3 mg. Traditional Asian soy foods (e.g., tofu, miso, soymilk) contain approximately 3.5 mg isoflavones/g protein, thus a typical serving of tofu or soymilk which provides ~ 8g protein may contain ~ 28mg soy isoflavones, while foods made from soybeans using concentrated sources of soy protein such as soy protein isolates or soy protein concentrates, where as much as 90% of isoflavone content can be lost during the processing of soybeans, may contain lower concentrations of isoflavones. Thus, given the intake of soy foods is extremely low, our results may help to allay safety concerns about soy foods and isoflavones and support consumption of soy foods as high-quality plant protein foods with low environmental impact and cost. These data support the translation of dietary guidance and cardiovascular dietary guidelines for sustainable plant-based dietary patterns( 1 – 5 ). The results of these data also support addressing the gender gap in CVD as this concern is of particular relevance to menopausal women given the fact that as the leading cause of death in women( 22 ) which is underrecognized and undertreated( 23 , 24 ), encouraging an increased intake of soy foods can reduce cardiovascular risk, as evident in health claims( 14 – 16 ). The current findings are also particularly relevant to menopausal women since soy foods have been shown to alleviate menopausal symptoms and up to 80% experience moderate-to-severe vasomotor symptoms, diminishing quality of life, and seek an alternative to hormone replacement therapy (HRT) due to its association with elevated cancer risk( 25 ). Strengths and limitations The strengths of the analyses include a comprehensive identification of all eligible studies resulting from a rigorous search and selection strategy; inclusion of primarily high quality trials providing the highest protection against bias; use of intention to treat data, when available, providing more conservative pooled estimates( 126 ), and using the GRADE approach to assess the overall certainty of evidence. Limitations of the analysis include the evidence indicating serious inconsistency for the effect of isoflavones on ET and serious imprecision in the pooled estimate for VMI where the 95% CIs were wide and could not rule out evidence of effect. Although the present analyses cannot necessarily be extrapolated to tissues and endpoints not examined in the current analysis, they do address the 4 measures of estrogenicity related to endometrial tissues. Weighing these strengths and limitations, we graded the certainty in the evidence as high for FSH and estradiol and moderate for ET and VMI. CONCLUSION In conclusion, our synthesis demonstrates that in postmenopausal women, consumption of soy isoflavones results in no effects on 4 measures of estrogenicity, ET, VMI, FSH and estradiol. Certainty in the evidence was high for FSH and estradiol and moderate for ET and VMI. The main sources of uncertainty, inconsistency for ET and imprecision for VMI, should be considered by future large high-quality trials. Therefore, based on the current findings, isoflavones differ from the hormone estrogen and thus, no assumptions about the health effects of soy foods or isoflavones should be based on an understanding of the effects of the hormone estrogen. Addressing public health concerns around soy foods may support their intake as high-quality plant protein foods with low environmental impact and cost, aligning with dietary guidelines. Abbreviations CI, confidence interval; ET, endometrial thickness; ER, estrogen receptor; FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; MD, mean difference; MID, minimally important difference; ROB, risk of bias; SERM, selective estrogen receptor modulator; SMD, standardized mean difference; VMI, vaginal maturation index Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Availability of data and materials: All data generated or analyzed during this study are available in the article, additional files, or from the corresponding author upon reasonable request. The study protocol can be accessed on PROSPERO (CRD42023439239). Conflicts of Interest: AZ is a part-time research associate at INQUIS Clinical Research Ltd, a contract research organization, and has received consulting fees from Glycemic Index Foundation. TAK has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. He has received funding from the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. MM was employed by the Soy Nutrition Institute Global, an organization that receives funding from the United Soybean Board (USB) and from members involved in the soy industry. CWCK has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate & Lyle, Unilever and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. DJAJ has received research grants from Saskatchewan & Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg's Company, Canada, Quaker Oats, Canada, Procter & Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut & Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker's panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter & Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael's Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael's Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan. JLS has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund which has received donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and vegan grants through the Karuna Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Inquis Clinical Research, Ingredion, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. LC has received research support from Protein Industries Canada (a Government of Canada Global Innovation Clusters). GV, SB, AA, SY, SBM, and AS have no conflicts of interest to disclose. Funding: This work was supported by the United Soybean Board (the United States Department of Agriculture soy check-off program) and the Canadian Institutes of Health Research (funding reference number, 129920) through the Canada-wide Human Nutrition Trialists' Network (NTN). The Diet, Digestive tract, and Disease (3D) Centre, funded through the Canada Foundation for Innovation and the Ministry of Research and Innovation’s Ontario Research Fund, provided the infrastructure for the conduct of this work. GV was funded by a CIHR Canada Graduate Scholarship and Toronto 3D Summer Scholarship award. SB was funded by an Undergraduate Student Research Program scholarship. AA was funded by a Charles Hollenburg Summer Scholarship. AZ was funded by a Toronto 3D Postdoctoral Fellowship Award. LC was funded by a Toronto 3D New Investigator Award. None of the sponsors had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. But one of the co-authors, Mark Messina, who was not involved in data collection or analysis, is the Director of Nutrition Science and Research at the Soy Nutrition Institute Global, an organization that receives partial funding from the principal funder, the United Soybean Board (USB). Author’s contributions: LC, AS, MM, CWCK, DJAJ and JLS designed the research (project conception, development of overall research plan, and study oversight). GV, SB, AA and SY conducted the research (hands-on conduct of the experiments and data collection). GV, SB, TAK, and AZ analyzed data or performed statistical analysis. LC wrote the paper. LC had primary responsibility for the final content and takes responsibility for the integrity of the data and the accuracy of the data analysis. All the authors contributed to the critical revision of the manuscript for important intellectual content, read and approved the final manuscript. LC supervised the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Acknowledgements: Not applicable References Health Canada. Canada's Food Guide [Available from: https://food-guide.canada.ca/en/ . Willett W, Rockstrom J, Loken B, Springmann M, Lang T, Vermeulen S, et al. Food in the Anthropocene: the EAT-Lancet Commission on healthy diets from sustainable food systems. Lancet. 2019;393(10170):447–92. Pearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P, Dayan N, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021;37(8):1129–50. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376–414. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA et al. /ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e143. Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor- positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 1998;58(17):3833–8. Carter MW, Matrone G, Smart WW. Jr. Effect of genistin on reproduction of the mouse. J Nutr. 1955;55(4):639–45. Carter MW, Smart WW Jr., Matrone G. Estimation of estrogenic activity of genistein obtained from soybean meal. Proc Soc Exp Biol Med. 1953;84(2):506–8. Cheng E, Story CD, Yoder L, Hale WH, Burroughs W. Estrogenic activity of isoflavone derivatives extracted and prepared from soybean oil meal. Science. 1953;118(3058):164–5. Ginsburg J. Tackling environmental endocrine disrupters. Lancet. 1996;347(9014):1501–2. Gu L, House SE, Prior RL, Fang N, Ronis MJ, Clarkson TB, et al. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr. 2006;136(5):1215–21. Setchell KD, Brown NM, Zhao X, Lindley SL, Heubi JE, King EC, et al. Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011;94(5):1284–94. Soukup ST, Helppi J, Muller DR, Zierau O, Watzl B, Vollmer G, et al. Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: a cross-species and sex comparison. Arch Toxicol. 2016;90(6):1335–47. Health Canada. Summary of Health Canada's Assessment of a Health Claim about Soy Protein and Cholesterol Lowering. https://www.canada.ca/en/health-canada/services/food-nutrition/food-labelling/health-claims/assessments/summary-assessment-health-claim-about-protein-cholesterol-lowering.html . Accessed December 12, 2023. [December 12, 2023]. U.S, Food. & Drug Administration. Code of Federal Regulations. 21 CFR 101.82 Health claims: Soy protein and risk of coronary heart disease (CHD). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-E/section-101.82 . Accessed December 12, 2023. Blanco Mejia S, Messina M, Li SS, Viguiliouk E, Chiavaroli L, Khan TA, et al. A Meta-Analysis of 46 Studies Identified by the FDA Demonstrates that Soy Protein Decreases Circulating LDL and Total Cholesterol Concentrations in Adults. J Nutr. 2019;149(6):968–81. Yang J, Shen H, Mi M, Qin Y. Isoflavone consumption and risk of breast cancer: An updated systematic review with meta-analysis of observational studies. Nutrients. 2023;15(10). Fan Y, Wang M, Li Z, Jiang H, Shi J, Shi X, et al. Intake of Soy, Soy Isoflavones and Soy Protein and Risk of Cancer Incidence and Mortality. Front Nutr. 2022;9:847421. Kanadys W, Baranska A, Blaszczuk A, Polz-Dacewicz M, Drop B, Malm M et al. Effects of soy isoflavones on biochemical markers of bone metabolism in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health. 2021;18(10). Cui C, Birru RL, Snitz BE, Ihara M, Kakuta C, Lopresti BJ, et al. Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2020;78(2):134–44. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012;19(7):776–90. Mensah GA, Fuster V, Murray CJL, Roth GA, Global Burden of Cardiovascular D, Risks C. Global Burden of Cardiovascular Diseases and Risks, 1990–2022. J Am Coll Cardiol. 2023;82(25):2350 – 473. Maas AH, Appelman YE. Gender differences in coronary heart disease. Neth Heart J. 2010;18(12):598–602. Ryczkowska K, Adach W, Janikowski K, Banach M, Bielecka-Dabrowa A. Menopause and women's cardiovascular health: is it really an obvious relationship? Arch Med Sci. 2023;19(2):458–66. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85(2):304–13. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138(3):863–70. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998;139(10):4252–63. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64(1):423–8. Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med. 2008;74(13):1656–65. Mudryj AN, Aukema HM, Yu N. Intake patterns and dietary associations of soya protein consumption in adults and children in the Canadian Community Health Survey, Cycle 2.2. Br J Nutr. 2015;113(2):299–309. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 2022 [Available from: https://training.cochrane.org/handbook/current . Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf MI et al. Searching for and selecting studies. Cochrane Handbook for systematic reviews of interventions. 2019:67–107. SourceForge. Plot Digitizer 2001 [updated 24-Oct-2015. Available from: http://plotdigitizer.sourceforge.net/ . Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366. McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A, Collaboration DSD. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Methods Med Res. 2020;29(9):2520–37. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. Tufanaru C, Munn Z, Stephenson M, Aromataris E. Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc. 2015;13(3):196–207. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol. 2002;31(1):140–9. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45(7):769–73. Balk EM, Earley A, Patel K, Trikalinos TA, Dahabreh IJ. Empirical assessment of within-arm correlation imputation in trials of continuous outcomes. 2012. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 2019 [updated July 2019. Available from: . Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. Cochrane Handbook for Systematic Reviews of Interventions. 2011 [updated March 2011. Available from: . Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;21(11):1559–73. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis: John Wiley & Sons; 2011. Fu R, Gartlehner G, Grant M, Shamliyan T, Sedrakyan A, Wilt TJ, et al. Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011;64(11):1187–97. Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New-York: Springer; 2001. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–29. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61(10):991–6. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994:1088 – 101. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–63. GRADE Handbook. 2013 [updated October 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html . GRADEpro GDT. GRADEpro Guideline Development Tool [Software] McMaster University2020 [developed by Evidence Prime, Inc.]. Available from: https://gradepro.org/ . Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013;66(2):173–83. Guyatt GH, Oxman AD, Schunemann HJ. GRADE guidelines-an introduction to the 10th-13th articles in the series. J Clin Epidemiol. 2013;66(2):121–3. Brunetti M, Shemilt I, Pregno S, Vale L, Oxman AD, Lord J, et al. GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence. J Clin Epidemiol. 2013;66(2):140–50. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013;66(2):158–72. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol. 2013;66(2):151–7. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. Andrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck-Ytter Y, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013;66(7):719–25. Santesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol. 2020;119:126–35. Santesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol. 2020;119:126–35. Schünemann HBJ, Guyatt GOA. GRADE Handbook [Internet]. 2013 [cited 2018 Nov 10]. Available from: https://gdt.gradepro.org/app/handbook/handbook.html . Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6. Atteritano M, Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2007;92(8):3068–75. Garrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas. 2006;54(3):270–6. Han KK, Soares JM Jr., Haidar MA, de Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99(3):389–94. Harkness LS, Fiedler K, Sehgal AR, Oravec D, Lerner E. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13(9):1000–7. Huang HY, Yang HP, Yang HT, Yang TC, Shieh MJ, Huang SY. One-year soy isoflavone supplementation prevents early postmenopausal bone loss but without a dose-dependent effect. J Nutr Biochem. 2006;17(8):509–17. Jassi HK, Jain A, Arora S, Chitra R. Effect of soy proteins Vs soy isoflavones on lipid profile in postmenopausal women. Indian J Clin Biochem. 2010;25(2):201–7. Kenny AM, Mangano KM, Abourizk RH, Bruno RS, Anamani DE, Kleppinger A, et al. Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr. 2009;90(1):234–42. Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause. 2008;15(1):125–32. Kim J, Lee H, Lee O, Lee KH, Lee YB, Young KD, et al. Isoflavone supplementation influenced levels of triglyceride and luteunizing hormone in Korean postmenopausal women. Arch Pharm Res. 2013;36(3):306–13. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363–9. Llaneza P, Gonzalez C, Fernandez-Inarrea J, Alonso A, Diaz-Fernandez MJ, Arnott I, et al. Soy isoflavones, Mediterranean diet, and physical exercise in postmenopausal women with insulin resistance. Menopause. 2010;17(2):372–8. Mittal N, Hota D, Dutta P, Bhansali A, Suri V, Aggarwal N, et al. Evaluation of effect of isoflavone on thyroid economy & autoimmunity in oophorectomised women: a randomised, double-blind, placebo-controlled trial. Indian J Med Res. 2011;133(6):633–40. Petri Nahas E, Nahas Neto J, De Luca L, Traiman P, Pontes A, Dalben I. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas. 2004;48(4):372–80. Nahas EA, Nahas-Neto J, Orsatti FL, Carvalho EP, Oliveira ML, Dias R. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas. 2007;58(3):249–58. Nikander E, Kilkkinen A, Metsa-Heikkila M, Adlercreutz H, Pietinen P, Tiitinen A, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101(6):1213–20. Nikander E, Rutanen EM, Nieminen P, Wahlstrom T, Ylikorkala O, Tiitinen A. Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal women. Fertil Steril. 2005;83(1):137–42. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79(5):1112–7. Pop EA, Fischer LM, Coan AD, Gitzinger M, Nakamura J, Zeisel SH. Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women: a phase I clinical trial. Menopause. 2008;15(4 Pt 1):684–92. Rios DR, Rodrigues ET, Cardoso AP, Montes MB, Franceschini SA, Toloi MR. Lack of effects of isoflavones on the lipid profile of Brazilian postmenopausal women. Nutrition. 2008;24(11–12):1153–8. Sammartino A, Di Carlo C, Mandato VD, Bifulco G, Di Stefano M, Nappi C. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol. 2003;17(1):45–9. Steinberg FM, Murray MJ, Lewis RD, Cramer MA, Amato P, Young RL, et al. Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women. Am J Clin Nutr. 2011;93(2):356–67. Uesugi T, Toda T, Okuhira T, Chen JT. Evidence of estrogenic effect by the three-month-intervention of isoflavone on vaginal maturation and bone metabolism in early postmenopausal women. Endocr J. 2003;50(5):613–9. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7(4):236–42. Villa P, Costantini B, Suriano R, Perri C, Macri F, Ricciardi L, et al. The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: relationship with the metabolic status. J Clin Endocrinol Metab. 2009;94(2):552–8. Wu J, Oka J, Higuchi M, Tabata I, Toda T, Fujioka M, et al. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism. 2006;55(4):423–33. Wu J, Oka J, Ezaki J, Ohtomo T, Ueno T, Uchiyama S, et al. Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial. Menopause. 2007;14(5):866–74. Ye YB, Wang ZL, Zhuo SY, Lu W, Liao HF, Verbruggen M, et al. Soy germ isoflavones improve menopausal symptoms but have no effect on blood lipids in early postmenopausal Chinese women: a randomized placebo-controlled trial. Menopause. 2012;19(7):791–8. Arjmandi BH, Lucas EA, Khalil DA, Devareddy L, Smith BJ, McDonald J, et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J. 2005;4:8. Basaria S, Wisniewski A, Dupree K, Bruno T, Song MY, Yao F, et al. Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women. J Endocrinol Invest. 2009;32(2):150–5. Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas. 2010;67(3):262–9. Chiechi LM, Secreto G, Vimercati A, Greco P, Venturelli E, Pansini F, et al. The effects of a soy rich diet on serum lipids: the Menfis randomized trial. Maturitas. 2002;41(2):97–104. Chiechi LM, Putignano G, Guerra V, Schiavelli MP, Cisternino AM, Carriero C. The effect of a soy rich diet on the vaginal epithelium in postmenopause: a randomized double blind trial. Maturitas. 2003;45(4):241–6. Duncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR, Kurzer MS. Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab. 1999;84(10):3479–84. Murkies AL, Lombard C, Strauss BJ, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21(3):189–95. Persky VW, Turyk ME, Wang L, Freels S, Chatterton R Jr., Barnes S, et al. Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr. 2002;75(1):145–53. Quaas AM, Kono N, Mack WJ, Hodis HN, Felix JC, Paulson RJ, et al. Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial. Menopause. 2013;20(8):840–4. Radhakrishnan G, Rashmi, Agarwal N, Vaid NB. Evaluation of Isoflavone Rich Soy Protein Supplementation for Postmenopausal Therapy. Pak J Nutr. 2009;8(7):1009–17. Teede HJ, Dalais FS, McGrath BP. Dietary soy containing phytoestrogens does not have detectable estrogenic effects on hepatic protein synthesis in postmenopausal women. Am J Clin Nutr. 2004;79(3):396–401. Cheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM. Isoflavone treatment for acute menopausal symptoms. Menopause. 2007;14(3 Pt 1):468–73. Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric. 2001;4(1):13–8. Liu J, Yuan F, Gao J, Shan B, Ren Y, Wang H, et al. Oral isoflavone supplementation on endometrial thickness: a meta-analysis of randomized placebo-controlled trials. Oncotarget. 2016;7(14):17369–79. Li SH, Liu XX, Bai YY, Wang XJ, Sun K, Chen JZ, et al. Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials. Am J Clin Nutr. 2010;91(2):480–6. Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr. 2010;140(7):1355S–62S. Jiang Y, Gong P, Madak-Erdogan Z, Martin T, Jeyakumar M, Carlson K, et al. Mechanisms enforcing the estrogen receptor beta selectivity of botanical estrogens. FASEB J. 2013;27(11):4406–18. Zhong XS, Ge J, Chen SW, Xiong YQ, Ma SJ, Chen Q. Association between Dietary Isoflavones in Soy and Legumes and Endometrial Cancer: A Systematic Review and Meta-Analysis. J Acad Nutr Diet. 2018;118(4):637–51. Hooper L, Ryder JJ, Kurzer MS, Lampe JW, Messina MJ, Phipps WR, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update. 2009;15(4):423–40. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst. 1991;83(8):541–6. Messina M, Messina V. Increasing use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc. 1991;91(7):836–40. Murphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;777(1–2):129–38. Bitto A, Granese R, Triolo O, Villari D, Maisano D, Giordano D, et al. Genistein aglycone: a new therapeutic approach to reduce endometrial hyperplasia. Phytomedicine. 2010;17(11):844–50. Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010;182(17):1857–62. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006;55(1):1–12. Konishi K, Wada K, Yamakawa M, Goto Y, Mizuta F, Koda S, et al. Dietary soy intake is inversely associated with risk of type 2 diabetes in Japanese women but not in men. J Nutr. 2019;149(7):1208–14. Bai W, Wang C, Ren C. Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr. 2014;65(1):9–20. Sebastian RS, Wilkinson Enns C, Goldman JD, Martin CL, Steinfeldt LC, Murayi T, et al. A new database facilitates characterization of flavonoid intake, sources, and positive associations with diet among US adults. J Nutr. 2015;145(6):1239–48. Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007;137(5):1244–52. Zamora-Ros R, Ferrari P, Gonzalez CA, Tjonneland A, Olsen A, Bredsdorff L, et al. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Breast Cancer Res Treat. 2013;139(1):163–76. Ziauddeen N, Rosi A, Del Rio D, Amoutzopoulos B, Nicholson S, Page P, et al. Dietary intake of (poly)phenols in children and adults: cross-sectional analysis of UK National Diet and Nutrition Survey Rolling Programme (2008–2014). Eur J Nutr. 2019;58(8):3183–98. Porta N, Bonet C, Cobo E. Discordance between reported intention-to-treat and per protocol analyses. J Clin Epidemiol. 2007;60(7):663–9. Additional Declarations Competing interest reported. AZ is a part-time research associate at INQUIS Clinical Research Ltd, a contract research organization, and has received consulting fees from Glycemic Index Foundation. TAK has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. He has received funding from the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. MM was employed by the Soy Nutrition Institute Global, an organization that receives funding from the United Soybean Board (USB) and from members involved in the soy industry. CWCK has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate & Lyle, Unilever and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. DJAJ has received research grants from Saskatchewan & Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg's Company, Canada, Quaker Oats, Canada, Procter & Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut & Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker's panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter & Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael's Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael's Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan. JLS has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund which has received donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and vegan grants through the Karuna Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Inquis Clinical Research, Ingredion, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. LC has received research support from Protein Industries Canada (a Government of Canada Global Innovation Clusters). GV, SB, AA, SY, SBM, and AS have no conflicts of interest to disclose. 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Chiavaroli","email":"data:image/png;base64,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","orcid":"","institution":"University of Toronto","correspondingAuthor":true,"prefix":"","firstName":"Laura","middleName":"","lastName":"Chiavaroli","suffix":""}],"badges":[],"createdAt":"2024-01-12 16:44:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3857624/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3857624/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50795081,"identity":"3eb49822-ea39-4256-911a-c94b8614669b","added_by":"auto","created_at":"2024-02-07 11:48:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":567000,"visible":true,"origin":"","legend":"\u003cp\u003eFlow of literature for the effect of soy isoflavones on measures of estrogenicity.\u003c/p\u003e","description":"","filename":"Viscardietal.Figure1.FlowDiagramDec1920231.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3857624/v1/06e8084e5f5d50b824aa327e.jpg"},{"id":50795083,"identity":"f7b4b365-8de9-4817-b3c1-6c48fbeaa9a7","added_by":"auto","created_at":"2024-02-07 11:48:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":494911,"visible":true,"origin":"","legend":"\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e For the interpretation of the magnitude, we used the MIDs (see a above) to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. We then used the MIDs to assess the importance of the magnitude of our point estimates using the effect size categories according GRADE guidance (54-57) as follows: large effect (≥5 MID); moderate effect (≥2 MID); small important effect (≥1 MID); and trivial/unimportant effect (\u0026lt;1 MID).\u003c/p\u003e\n\u003cp\u003eSummary plot of the effect of soy isoflavones on measures of estrogenicity in post-menopausal women.\u003c/p\u003e\n\u003cp\u003eData are weighted mean differences (95% confidence intervals) using the generic inverse variance method modelled by random effects meta-analyses for summary effects of soy isoflavones on measures of estrogenicity. To allow the pooled effect estimates for each end point to be displayed on the same axis, mean differences were transformed to standardized mean differences (SMDs). Pseudo-95% confidence intervals for each transformed SMD were derived directly from the original mean difference and 95% confidence intervals. Between-study heterogeneity was assessed by the Cochran Q statistic, where P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.100 is considered statistically significant, and quantified by the I\u003csup\u003e2\u003c/sup\u003e statistic, where I\u003csup\u003e2\u003c/sup\u003e≥50% is considered evidence of substantial heterogeneity.\u003c/p\u003e\n\u003cp\u003eThe effects of total soy isoflavones are denoted by the effect estimates as diamonds. The effects of individual isoflavone sources are denoted by the effect estimates as squares.\u003c/p\u003e\n\u003cp\u003eThe Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as \"High\" certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; FSH, follicle stimulating hormone; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; MD, mean difference; N, number; SMD, standardized mean difference\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Since all included trials were randomized controlled trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded or upgraded based on pre-specified criteria. Criteria for downgrades included risk of bias (ROB) (downgraded if the majority of trials were considered to be at high ROB); inconsistency (downgraded if there was substantial unexplained heterogeneity [I\u003csup\u003e2\u003c/sup\u003e ≥ 50%, P\u003csub\u003eQ \u003c/sub\u003e\u0026lt; 0.10]; indirectness (downgraded if there were factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results); imprecision (downgraded if the 95% confidence interval crossed the minimally important difference [MID] for harm set at 0.30 for ET, 3.8 for VMI, 7.4 for FSH and 5.2 for estradiol based on 10% of the baseline mean of 3.0mm, 37.6, 7.4IU/L, and 5.2pmol/L, respectively), and publication bias (downgraded if there is evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (P\u0026lt;0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis). Criteria for upgrades included a significant dose-response gradient.\u003c/p\u003e","description":"","filename":"F2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3857624/v1/18d88c8c273a043cd4335c97.jpg"},{"id":56658817,"identity":"d068cc11-083a-40cb-83e3-64710b97b357","added_by":"auto","created_at":"2024-05-17 10:49:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2246371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3857624/v1/0452f8d8-5d7f-4bf7-aac5-f18ed5f77d7a.pdf"},{"id":50795082,"identity":"f26bf992-1f84-42d8-93e3-67bceceb2c09","added_by":"auto","created_at":"2024-02-07 11:48:32","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":33180,"visible":true,"origin":"","legend":"","description":"","filename":"Viscardietal.PRISMAChecklistJan32024.docx","url":"https://assets-eu.researchsquare.com/files/rs-3857624/v1/e5ed604f2b3cab48300c32ee.docx"},{"id":50795085,"identity":"27b70d48-d7e5-4416-857c-34784c584ec2","added_by":"auto","created_at":"2024-02-07 11:48:33","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":7910175,"visible":true,"origin":"","legend":"","description":"","filename":"Viscardietal.SupplementalMaterialsDec192023.docx","url":"https://assets-eu.researchsquare.com/files/rs-3857624/v1/cae136b258ec5717522ca030.docx"}],"financialInterests":"Competing interest reported. AZ is a part-time research associate at INQUIS Clinical Research Ltd, a contract research organization, and has received consulting fees from Glycemic Index Foundation. \nTAK has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. He has received funding from the Toronto 3D Knowledge Synthesis and Clinical Trials foundation.\nMM was employed by the Soy Nutrition Institute Global, an organization that receives funding from the United Soybean Board (USB) and from members involved in the soy industry.\nCWCK has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate \u0026 Lyle, Unilever and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation.\nDJAJ has received research grants from Saskatchewan \u0026 Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg's Company, Canada, Quaker Oats, Canada, Procter \u0026 Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut \u0026 Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker's panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan \u0026 Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter \u0026 Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael's Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael's Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan.\nJLS has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund which has received donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and vegan grants through the Karuna Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate \u0026 Lyle, Inquis Clinical Research, Ingredion, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. \nLC has received research support from Protein Industries Canada (a Government of Canada Global Innovation Clusters).\nGV, SB, AA, SY, SBM, and AS have no conflicts of interest to disclose.","formattedTitle":"Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDespite dietary recommendations to consume more plant foods for public and planetary health(\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and their components, especially soy isoflavones, are a barrier to their intake. The negative views of soy, including a worsening of the prognosis of women with estrogen-sensitive breast cancer(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), are predominately driven by the results of animal studies(\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). These studies have limited implications for human health, in part due to differences in metabolism of soy isoflavones between rodents and humans(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In contrast, human studies indicate soy has cardioprotective effects including health claims for soy and cholesterol and coronary heart disease risk reduction(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). There is also evidence that isoflavones reduce risk of breast(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and prostate(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) cancer, improve bone health(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and memory(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), and alleviate menopausal symptoms(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). This issue is thus particularly relevant to women in which cardiovascular disease (CVD), the leading cause of death in both women and globally(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), is underrecognized and undertreated(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and up to 80% experience moderate-to-severe vasomotor symptoms and seek an alternative to hormone replacement therapy (HRT), which has been associated with elevated cancer risk(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEven with the known benefits, there is still public concern about the estrogenicity of soy foods and isoflavones. Although isoflavones are commonly classified as phytoestrogens, they differ from the hormone estrogen at both the molecular and clinical level. For example, isoflavones preferentially bind to estrogen receptor (ER)β in comparison with ERα, whereas estrogen binds with equal affinity to these receptors(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). These receptors have different tissue distributions and when bound by ligands result in different and sometimes opposite physiological effects(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In general, activation of ERα and ERβ is seen as exerting proliferative and anti-proliferative effects, respectively(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Their preferential binding provides a conceptual basis for classifying isoflavones as selective estrogen receptor modulators (SERMs)(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven that consumption of soy foods is extremely low in North America with only 3\u0026ndash;4% reporting consumption of a soy-containing product on any given day(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), yet both dietary guidance and cardiovascular clinical practice guidelines on nutrition therapy recommend to consume more plant foods(\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) including soy foods, there is a public health need to better understand and characterize soy isoflavones. Addressing public concerns over the estrogenicity of soy foods will also support addressing the gender gap in CVD as this concern is of particular relevance to menopausal women given the increase in CVD risk and vasomotor symptoms, which increased soy consumption may alleviate. We therefore undertook a systematic review and meta-analysis of randomized controlled trials in postmenopausal women to determine the effect of soy isoflavones on four measures of estrogenicity: endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and circulating estradiol.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eWe followed the Cochrane Handbook for Systematic Reviews of Interventions (version 6.3)(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) for the conduct of our systematic review and meta-analysis and reported our results following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-Equity) guidelines(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The study protocol was registered on PROSPERO (CRD42023439239).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData sources and search strategy\u003c/h2\u003e \u003cp\u003eWe systematically searched MEDLINE, Embase and the Cochrane Central Register of Controlled Studies from inception through July 20th, 2023. \u003cb\u003eSupplemental Tables\u0026nbsp;1\u0026ndash;2\u003c/b\u003e show the search strategy based on the PICOTS framework without language restrictions. Validated filters from the Cochrane Handbook for Systematic Reviews of Interventions were applied to limit the database search to controlled studies(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Manual searches of the reference lists of included studies complemented the systematic search.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003eWe included randomized controlled feeding trials in postmenopausal women of all health backgrounds, with intervention periods\u0026thinsp;\u0026ge;\u0026thinsp;3 months. We included studies that investigated the effect of isoflavones from soy (as either supplements or foods) compared with a suitable non-isoflavone-containing control (such as placebo capsules or soy protein nearly devoid of isoflavones) on measures of estrogenicity. We excluded studies of interventions containing no isoflavones or isoflavones from non-soy sources. In reports containing more than one eligible trial comparison, we included all available trial comparisons.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and quality assessment\u003c/h2\u003e \u003cp\u003eAt least two independent reviewers (GV, SB, AA) extracted relevant data from eligible studies. Relevant information included the number of participants, age, health status, years since last menses, study design, level of feeding control, intervention type, isoflavone dose, comparator, follow-up duration, energy balance, energy control, funding source, and outcome data. Authors were contacted for missing outcome data when it was indicated that relevant outcomes were measured but not reported. In the absence of numerical values for outcomes and inability to obtain the original data from authors, values were extracted from figures using Plot Digitizer where available(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIncluded studies were assessed for risk of bias independently by at least two independent reviewers (GV, SB, AA) with the Cochrane Risk of Bias V.2.0 tool(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Assessment was done across six domains of bias (randomization process, risk of bias arising from period or carryover effects (crossover studies only), deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported results). The tool provides a judgment of \u0026lsquo;low risk of bias\u0026rsquo;, \u0026lsquo;some concerns\u0026rsquo; or \u0026lsquo;high risk of bias\u0026rsquo; for each domain based on responses to signaling questions. An overall risk of bias was determined based on judgments from each domain. We resolved discrepancies in data extraction and risk of bias by consensus and review by the senior author (LC).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcomes included 4 measures of estrogenicity: ET, VMI, FSH and levels of estradiol. Mean differences (MDs) between the intervention and control arm and respective standard errors were extracted for each trial. If these were not provided, they were derived from available data using published formulas(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Mean pairwise difference in change-from-baseline values were preferred over end values. When median data was provided, they were converted to mean data with corresponding variances using methods developed by McGrath et al.(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). When no variance data was available, the standard deviation of the MDs was borrowed from a trial similar in size, participants, and nature of intervention.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData synthesis and analysis\u003c/h2\u003e \u003cp\u003eWe used STATA software, version 18.0 (StataCorp, College Station, TX, USA) for all analyses. The principal effect measures were the mean pair-wise differences in change from baseline (or alternatively, end differences) between the intervention arm providing the soy isoflavones and the comparator/control arm in each trial comparison (significance at P\u003csub\u003eMD\u003c/sub\u003e\u0026lt;0.05). Results are reported as MDs with 95% confidence intervals (95% CI). Data were analyzed using the generic inverse variance method with DerSimonian and Laird random-effects model(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). A fixed effects model was used when the number of trial comparisons was \u0026lt;\u0026thinsp;5(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Paired analyses were applied to all crossover trials with the use of a within-individual correlation coefficient between treatment of 0.5 as described by Elbourne et al.(\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). To mitigate a unit-of-analysis error, when arms of trials with multiple intervention or control arms were used more than once, the corresponding sample size was divided by the number of times it was used for calculation of the standard error(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Each pairwise trial comparison was considered a separate trial for the purpose of this analysis.\u003c/p\u003e \u003cp\u003eHeterogeneity was assessed using the Cochran Q statistic and quantified using the I\u003csup\u003e2\u003c/sup\u003e statistic(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). We considered an I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;50% and P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.10 as evidence of substantial heterogeneity(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Sources of heterogeneity were explored by sensitivity and subgroup analyses. We conducted sensitivity analyses by influence analysis in which each trial was systematically removed from the meta-analysis with recalculation of the summary effect estimate. A trial whose removal explained the heterogeneity or changed the significance, direction, or magnitude (by more than the minimally important difference (MID) for harm set at 0.30 for ET, 3.8 for VMI, 7.4 for FSH and 5.2 for estradiol based on 10% of the baseline mean of 3.0mm, 37.6, 7.4IU/L, and 5.2pmol/L, respectively) of the effect was considered an influential trial. To determine whether the overall results were robust to the use of different correlation coefficients in crossover trials, we also conducted sensitivity analyses using correlation coefficients of 0.25 and 0.75. We also performed sensitivity analyses using fixed effects model. If\u0026thinsp;\u0026ge;\u0026thinsp;10 trials were available(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e), we conduced subgroup analyses to explore sources of heterogeneity using meta-regression (P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.05). \u003cem\u003eA priori\u003c/em\u003e subgroup analyses were conducted by age, participant health status, baseline outcome level, years since last menses, isoflavone dose, intervention type, comparator, follow-up duration, study design, energy balance of the intervention relative to the basal diet (neutral, positive, negative), level of energy control relative to the comparator (substitution, addition, subtraction, ad libitum), feeding control (dietary advice, supplemented, metabolic), funding and risk of bias. Post-hoc subgroup analyses were conducted by type of mean difference (change from baseline or end differences), baseline BMI, comparator by presence of soy protein and by continent where the study was conducted. Meta-regression analyses were used to assess the significance of each subgroup categorically and when possible, continuously.\u003c/p\u003e \u003cp\u003eIf\u0026thinsp;\u0026ge;\u0026thinsp;6 trial comparisons are available(\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), dose-response analyses were performed using meta-regression to assess linear (by generalized least squares trend estimation models) and non-linear spline curve modelling (by the MKSPLINE procedure with 3 knots(\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e)) dose-response gradients (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eIf\u0026thinsp;\u0026ge;\u0026thinsp;10 trials were available(\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e), we assessed publication bias by inspection of contour enhanced funnel plots and formal testing with the Egger\u0026rsquo;s and Begg\u0026rsquo;s tests (P\u0026thinsp;\u0026lt;\u0026thinsp;0.10)(\u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). If there was evidence of publication bias, we adjusted for funnel plot asymmetry by imputing the missing trial data using the Duval and Tweedie trim-and-fill method and assessed for small study effects(\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCertainty of the evidence\u003c/h2\u003e \u003cp\u003eThe certainty of the evidence was assessed using the GRADE approach(\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e) and software (GRADEpro V.3.2(\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e). Evidence was rated as high, moderate, low, or very low certainty. The included randomized trials were initially rated as high certainty by default and then downgraded or upgraded based on pre-specified criteria. Reasons for downgrading the evidence included risk of bias (Cochrane Risk of Bias V.2.0 tool(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)), inconsistency (substantial unexplained interstudy heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;50%, P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.10), indirectness (absence or presence of factors limiting the generalizability of results), imprecision (95% CI for pooled effect estimates cross the MID for harm), and publication bias (significant evidence of small study effects). The reason for upgrading the evidence was presence of a significant dose-response gradient(\u003cspan additionalcitationids=\"CR57 CR58 CR59 CR60 CR61 CR62\" citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e). The importance of the magnitude of the pooled estimates was assessed using our prespecified MIDs and the effect size categories according GRADE guidance(\u003cspan additionalcitationids=\"CR65 CR66\" citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e) as follows: large effect (\u0026ge;\u0026thinsp;5x MID); moderate effect (\u0026ge;\u0026thinsp;2x MID); small important effect (\u0026ge;\u0026thinsp;1x MID); and trivial/unimportant effect (\u0026lt;\u0026thinsp;1 MID).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSearch results\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the flow of the literature review. We retrieved 5,858 reports from databases and manual searches, 5,636 of which were excluded based on the title or abstract. Of the 224 reports reviewed in full text, 40 reports of randomized trials (52 trial comparisons, N\u0026thinsp;=\u0026thinsp;3,285) met the eligibility criteria(\u003cspan additionalcitationids=\"CR69 CR70 CR71 CR72 CR73 CR74 CR75 CR76 CR77 CR78 CR79 CR80 CR81 CR82 CR83 CR84 CR85 CR86 CR87 CR88 CR89 CR90 CR91 CR92 CR93 CR94 CR95 CR96 CR97 CR98 CR99 CR100 CR101 CR102 CR103 CR104 CR105 CR106\" citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTrial characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cb\u003eSupplemental Table\u0026nbsp;3\u003c/b\u003e show the trial characteristics. Trial sizes ranged from a median of 50 participants (range 18\u0026ndash;245) for FSH to 65 (27\u0026ndash;389) for ET. Participants were postmenopausal women with a median age of 54 (\u003cspan additionalcitationids=\"CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e) years for VMI, FSH and estradiol to 55 (\u003cspan additionalcitationids=\"CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72 CR73\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e) years for ET, without diagnosed chronic disease, except for one trial of participants with a history of breast cancer and one with insulin resistance. Years since last menses ranged from a median 5 (\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) years for trials of FSH and estradiol to a median of 7 (\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) years for trials of ET. Most trials were performed in North America (29\u0026ndash;38%) and Europe (10\u0026ndash;43%) and were parallel in design (ranging from 75 to 93% in trials of VMI and ET, respectively). Feeding control was mostly supplemented (88\u0026ndash;100%). The median dose of isoflavones ranged from 66mg (36\u0026ndash;154) in trials of ET to 77mg (40\u0026ndash;600) in trials of FSH. The intervention duration ranged from a median of 13 weeks (\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72 CR73 CR74 CR75 CR76 CR77 CR78 CR79 CR80 CR81 CR82 CR83 CR84 CR85 CR86 CR87 CR88 CR89 CR90 CR91 CR92 CR93 CR94 CR95 CR96 CR97 CR98 CR99 CR100 CR101 CR102 CR103\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e) in trials of FSH to 24 weeks (12\u0026ndash;156) for ET. Most trials were funded by agency sources (government, not-for-profit health agency, or university sources) (19\u0026ndash;43%), followed by both agency and industry sources (7\u0026ndash;39%). The comparators included placebo capsules of casein (2%), lactose (7%) and dextrin (%), soy protein nearly devoid of isoflavones (4%), starch (5%), casein-based foods/beverages (10%), usual diet (5%), non-soy-based foods/beverages (2%), soy protein-based foods/beverages nearly devoid of isoflavones (8%), and milk protein-based foods/beverages (8%). Of comparators, most did not include soy protein (88%) whereas a few included soy protein nearly devoid of isoflavones (12%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of characteristics of included trial comparisons assessing the effect of soy isoflavones on outcome measures of estrogenicity*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrial characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrial thickness\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVaginal maturation index\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFollicle-stimulating hormone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEstradiol\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTrial comparisons (No)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy size (median No (range) of participants)\u003c/b\u003e \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (27\u0026ndash;389)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (18\u0026ndash;142)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (18\u0026ndash;245)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56 (18\u0026ndash;245)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years; median (range))\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (49\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (49\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (48\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (48\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHealth status (%; absence of disease: insulin resistance: history breast cancer)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93:0:7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100:0:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97:0:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94:3:3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears since menopause (years; median (range))\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (2\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (2\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (2\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eContinent (No of comparisons, and by country)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNorth America\u0026thinsp;=\u0026thinsp;4 (USA\u0026thinsp;=\u0026thinsp;4); South America\u0026thinsp;=\u0026thinsp;3 (Brazil\u0026thinsp;=\u0026thinsp;3); South Asia\u0026thinsp;=\u0026thinsp;1 (India\u0026thinsp;=\u0026thinsp;1);\u0026nbsp;Europe\u0026thinsp;=\u0026thinsp;6 (Finland\u0026thinsp;=\u0026thinsp;1; Italy\u0026thinsp;=\u0026thinsp;4; Sweden\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNorth America\u0026thinsp;=\u0026thinsp;3 (USA\u0026thinsp;=\u0026thinsp;3); South America\u0026thinsp;=\u0026thinsp;2 (Brazil\u0026thinsp;=\u0026thinsp;2); South Asia\u0026thinsp;=\u0026thinsp;1 (India\u0026thinsp;=\u0026thinsp;1); Oceania\u0026thinsp;=\u0026thinsp;1 (Australia\u0026thinsp;=\u0026thinsp;1); Europe\u0026thinsp;=\u0026thinsp;1 (Italy\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorth America\u0026thinsp;=\u0026thinsp;12 (USA\u0026thinsp;=\u0026thinsp;12); South America\u0026thinsp;=\u0026thinsp;5 (Brazil\u0026thinsp;=\u0026thinsp;4; Chile\u0026thinsp;=\u0026thinsp;1); East Asia\u0026thinsp;=\u0026thinsp;4 (China\u0026thinsp;=\u0026thinsp;2; Japan\u0026thinsp;=\u0026thinsp;1; South Korean\u0026thinsp;=\u0026thinsp;1); South Asia\u0026thinsp;=\u0026thinsp;4 (India\u0026thinsp;=\u0026thinsp;4); Oceania\u0026thinsp;=\u0026thinsp;3 (Australia\u0026thinsp;=\u0026thinsp;3); Europe\u0026thinsp;=\u0026thinsp;3 (Finland\u0026thinsp;=\u0026thinsp;1; Italy\u0026thinsp;=\u0026thinsp;1; Sweden\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNorth America\u0026thinsp;=\u0026thinsp;11 (USA\u0026thinsp;=\u0026thinsp;11); South America\u0026thinsp;=\u0026thinsp;5 (Brazil\u0026thinsp;=\u0026thinsp;4; Chile\u0026thinsp;=\u0026thinsp;1); East Asia\u0026thinsp;=\u0026thinsp;9 (China\u0026thinsp;=\u0026thinsp;4; Japan\u0026thinsp;=\u0026thinsp;4; South Korean\u0026thinsp;=\u0026thinsp;1); South Asia\u0026thinsp;=\u0026thinsp;2 (India\u0026thinsp;=\u0026thinsp;2); Europe\u0026thinsp;=\u0026thinsp;4 (Finland\u0026thinsp;=\u0026thinsp;1; Italy\u0026thinsp;=\u0026thinsp;1; Spain\u0026thinsp;=\u0026thinsp;1; Sweden\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy design (%; crossover: parallel)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7:93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25:75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13:87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13:87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFeeding control (%; supplemented: ad libitum)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93:7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88:12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDose of isoflavones (mg; median (range))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (36\u0026ndash;154)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (47\u0026ndash;200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (40\u0026ndash;600)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e75 (40\u0026ndash;200)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up duration (median No (range) of weeks)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (12\u0026ndash;156)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (12\u0026ndash;104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (12\u0026ndash;104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (12\u0026ndash;104)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFunding sources (%; A: I: A, I: NR)\u003c/b\u003e\u003csup\u003e\u003cb\u003ef\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43:36:7:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38:25:37:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19:23:32:26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29:16:39:16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComparator (No of comparisons)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUsual diet\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003ePlacebo capsule\u0026thinsp;=\u0026thinsp;4;\u003c/p\u003e \u003cp\u003eLactose capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eSoy protein capsule without isoflavone\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eCalcium supplement\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003cp\u003eSoy protein-based food/beverage without isoflavone\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eMilk protein-based food/beverage\u0026thinsp;=\u0026thinsp;3;\u003c/p\u003e \u003cp\u003eOatmeal beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUsual diet\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003ePlacebo capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eLactose capsule\u0026thinsp;=\u0026thinsp;1; Calcium supplement\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eWheat flour-based food/beverage\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eSoy protein-based food/beverage without isoflavone\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eMilk protein-based food/beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCasein protein-based food/beverage\u0026thinsp;=\u0026thinsp;6;\u003c/p\u003e \u003cp\u003eCasein capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003ePlacebo capsule\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003cp\u003eLactose capsule\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eSoy protein capsule without isoflavone\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eDextrin capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eWheat flour-based food/beverage\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eStarch capsule\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eNon-soy-based food/beverage\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eSoy protein-based food/beverage without isoflavone\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eMilk protein-based food/beverage\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eOatmeal beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUsual diet\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eCasein protein-based food/beverage\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eCasein capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003ePlacebo capsule\u0026thinsp;=\u0026thinsp;11;\u003c/p\u003e \u003cp\u003eLactose capsule\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eSoy protein capsule without isoflavones\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eDextrin capsule\u0026thinsp;=\u0026thinsp;4;\u003c/p\u003e \u003cp\u003eStarch capsule\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eNon-soy-based food/beverage\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eNo capsule\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eSoy protein-based food/beverage without isoflavone\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eMilk protein-based food/beverage\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eOatmeal beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSoy protein containing comparator (%; non-soy protein-containing: soy protein-containing\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75:25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90:10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntervention (No of interventions)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIsoflavone capsule\u0026thinsp;=\u0026thinsp;9;\u003c/p\u003e \u003cp\u003eSoy protein-based beverage/food\u0026thinsp;=\u0026thinsp;4;\u003c/p\u003e \u003cp\u003eIsoflavone containing beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIsoflavone capsule\u0026thinsp;=\u0026thinsp;2;\u003c/p\u003e \u003cp\u003eSoy protein powder\u0026thinsp;=\u0026thinsp;1; Soy protein-based beverage/food\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIsoflavone capsule\u0026thinsp;=\u0026thinsp;19;\u003c/p\u003e \u003cp\u003eSoy protein powder\u0026thinsp;=\u0026thinsp;1;\u003c/p\u003e \u003cp\u003eSoy protein-based beverage/food\u0026thinsp;=\u0026thinsp;9;\u003c/p\u003e \u003cp\u003eIsoflavone containing beverage\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eisoflavone capsule\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003cp\u003eSoy protein-based beverage/food\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003cp\u003eisoflavone containing beverage\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSetting (%; outpatient: inpatient)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100:0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline BMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e; \u003cb\u003emedian (range))\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.3 (24.9\u0026ndash;29.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.8 (25.2\u0026ndash;29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.6 (22.6\u0026ndash;29.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.2 (21.1\u0026ndash;29.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline outcome (median (range))\u003c/b\u003e \u003csup\u003e\u003cb\u003eb,c\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1 (2.2\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.8 (27.4\u0026ndash;49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76.0 (40.7\u0026ndash;108.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44.2 (12.8\u0026ndash;133.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEnergy balance (%; neutral: positive: negative)\u003c/b\u003e\u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64:36:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25:75:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65:35:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77:23:0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEnergy control (%; substitution: addition: subtraction)\u003c/b\u003e\u003csup\u003e\u003cb\u003ee\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86:14:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50:50:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84:13:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90:10:0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType MD (%; CFB: ED)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93:7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94:6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90:10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eA, agency; BMI, body mass index; CFB, change from baseline; ED, end difference; I, industry; MD, mean difference\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eAll numbers with the exception of baseline values were rounded to the nearest whole number to improve readability.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eAll sample sizes reflect participants included in the data analysed.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e Not all trials reported baseline values. Baseline values were not reported for: age (n\u0026thinsp;=\u0026thinsp;6), years since menopause (n\u0026thinsp;=\u0026thinsp;17), and baseline BMI (n\u0026thinsp;=\u0026thinsp;8)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ec\u003c/sup\u003e Not all trials reported baseline outcome measures. Baseline outcome measures were not reported for: vaginal maturation index (n\u0026thinsp;=\u0026thinsp;1).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ed\u003c/sup\u003e Neutral energy balance refers to the maintenance of usual energy intake. Positive energy balance refers to a greater than normal energy intake. Negative energy balance refers to a deficit in normal energy intake.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ee\u003c/sup\u003e Energy control refers to the energy intake of the intervention group compared to the control group where substitution refers to energy matched between intervention and comparator, addition refers to excess energy between intervention and comparator, and subtraction refers to deficit in energy between intervention and comparator.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ef\u003c/sup\u003e Agency funding is that from government, university, or not-for-profit sources. The majority of industry funding is that from trade organisations that obtain revenue from the sale of products.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;1\u0026ndash;2\u003c/b\u003e show a summary of the ROB assessments. Across outcomes, most trials were assessed as having low ROB in the randomization (86\u0026ndash;97%), missing (63\u0026ndash;87%), measurements (100%), and selection (71\u0026ndash;88%) domains, and some concerns in the deviations (35\u0026ndash;42%) domain. Fewer trials were assessed as having high ROB ranging from 3% in the randomization and measurements domains, to 16\u0026ndash;38% in the deviations domain, and 13\u0026ndash;38% in the missing domain. Most trials were judged overall as low (32\u0026ndash;39%) or some (25\u0026ndash;48%) concerns, with fewer as high ROB (19\u0026ndash;38%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcomes\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cb\u003eSupplemental Figs.\u0026nbsp;3\u0026ndash;6\u003c/b\u003e present the effect of soy isoflavones on ET, VMI, FSH and estradiol. Isoflavones had no statistically significant effects on any of the measures of estrogenicity; ET (14 trials; MD: -0.22mm; 95% CI: -0.45 to 0.01mm, P\u003csub\u003eMD\u003c/sub\u003e=0.059; substantial heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;69.3%, P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.001), VMI (8 trials; MD: 2.31; 95% CI: -2.14 to 6.75, P\u003csub\u003eMD\u003c/sub\u003e=0.310; no substantial heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;1.3%, P\u003csub\u003eQ\u003c/sub\u003e=0.420), FSH (31 trials; MD: -0.02IU/L; 95% CI: -2.39 to 2.35IU/L, P\u003csub\u003eMD\u003c/sub\u003e=0.987; substantial heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;51.9%, P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.001), and estradiol (31 trials; MD: 1.61pmol/L; 95% CI: -1.17 to 4.38pmol/L, P\u003csub\u003eMD\u003c/sub\u003e=0.256; no substantial heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;23.5%, P\u003csub\u003eQ\u003c/sub\u003e=0.121).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events and acceptability\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Table\u0026nbsp;4\u003c/b\u003e presents the data reported in 5 trials on acceptability and 18 trials on adverse events. All trials reported data descriptively except for one trial. Of the 5 trials reporting acceptability, women in the intervention groups mainly reported a dislike for taste or volume of food, with Knight et al. 2001(\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e) reporting a tendency to dislike the taste of the soy isoflavone beverage compared to control (P\u0026thinsp;=\u0026thinsp;0.07). Among the 18 trials reporting adverse events, gastrointestinal upset was the most common reported symptom, where it was experienced to a similar extent in both those in the intervention and control groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;7\u0026ndash;10\u003c/b\u003e present the individual trial influence analyses for each outcome. Removal of either Atteritano et al. 2007(\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e), Kenny et al. 2009 (control\u0026thinsp;+\u0026thinsp;isoflavone)(\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e), Nahas et al. 2007(\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e), or Upmalis et al. 2000(\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e) resulted in a gain of significance for a decrease in ET. Removal of either Jassi et al. 2010(\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e) or Kim et al. 2013(\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e) provided a partial explanation of the evidence of substantial heterogeneity for FSH.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSupplemental Table\u0026nbsp;5\u003c/b\u003e shows sensitivity analyses for the different correlation coefficients (0.25 and 0.75) used in paired analyses of crossover trials for each outcome. The use of these different correlation coefficients did not alter the direction, magnitude, or significance of the effect or evidence for heterogeneity.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;11\u0026ndash;14\u003c/b\u003e present the sensitivity analyses where fixed effects models were used. The use of a fixed effects model resulted in isoflavones showing a significant reduction on ET (14 trials; MD: -0.12mm; 95% CI: -0.24 to -0.01mm, P\u003csub\u003eMD\u003c/sub\u003e=0.032; substantial heterogeneity, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;69.34%, P\u003csub\u003eQ\u003c/sub\u003e\u0026lt;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analyses\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;15\u0026ndash;23\u003c/b\u003e present the subgroup analyses and continuous meta regression analyses for the effect of isoflavones on ET, FSH and estradiol as there were \u0026ge;\u0026thinsp;10 trial comparisons. There was significant effect modification by years since menopause (trials with median\u0026thinsp;\u0026lt;\u0026thinsp;5 years tending towards a reduction, while trials with a median\u0026thinsp;\u0026ge;\u0026thinsp;5 years tending towards an increase in FSH), continent (with neither continental subgroup showing statistical significance) and intervention type and energy control, however the latter 2 were driven by 1 trial in which soy protein powder showed a greater reduction than other trials examining FSH. In continuous subgroup analyses, follow-up duration was significant (β\u0026thinsp;=\u0026thinsp;0.09 [0.00\u0026ndash;0.18], P\u0026thinsp;=\u0026thinsp;0.044). These subgroups partially explained evidence of substantial heterogeneity for FSH (residual I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;25\u0026ndash;48%). There was also significant effect modification by comparator for estradiol, however this was driven by 1 trial where the comparator was soy protein capsules without isoflavones that showed an increase in estradiol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eDose response analyses\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;24\u0026ndash;27\u003c/b\u003e present linear and non-linear dose-response analyses. There was no dose response for the effect of isoflavones on any measure of estrogenicity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSmall-study effects\u003c/h2\u003e \u003cp\u003e \u003cb\u003eSupplemental Figs.\u0026nbsp;28\u0026ndash;30\u003c/b\u003e present the contour-enhanced funnel plots and publication bias assessments for all outcomes with \u0026ge;\u0026thinsp;10 trials available. There was no evidence of funnel plot asymmetry for any outcome. Note that publication bias was not assessed for VMI as \u0026lt;\u0026thinsp;10 trial comparisons were available (n\u0026thinsp;=\u0026thinsp;8).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eGRADE assessment\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cb\u003eSupplemental Table\u0026nbsp;6\u003c/b\u003e present the GRADE assessments. The certainty of evidence for the effect of isoflavones was moderate for ET (no effect), owing to a downgrade for inconsistency due to unexplained heterogeneity, moderate for VMI (no effect) owing to a downgrade for imprecision, and high for FSH (no effect) and estradiol (no effect).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis systematic review and meta-analysis included 40 trials (52 trial comparisons) involving 3,285 postmenopausal women, who were predominantly middle aged, without diagnosed chronic disease and a median 5\u0026ndash;6 years since last menses. We showed that consumption of soy isoflavones does not affect 4 measures of estrogenicity. These measures were chosen because they are known to be affected by the hormone estrogen and were evaluated in many trials involving isoflavones. The median intervention duration ranged from 13 (FSH) to 24 weeks (ET, estradiol). The lack of estrogenic effect was robust to sensitivity and subgroup analyses. The median dose of isoflavones ranged from 66mg/d (range 36-154mg) in trials of ET to 77mg/d (40-600mg) in trials of FSH.\u003c/p\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eFindings in the context of literature\u003c/h2\u003e \u003cp\u003eThe lack of estrogenic effect on ET in the current analysis is consistent with a 2016 systematic review and meta-analysis of trials\u0026thinsp;\u0026ge;\u0026thinsp;3 months(\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e), which examined the effects of isoflavones from red clover and soy, in peri- and postmenopausal women. They found there was no significant change in ET when all women were included in the analysis (23 trials, 2,167 participants, standardized mean difference (SMD): -0.05, 95% CI: -0.23 to 0.13, P\u0026thinsp;=\u0026thinsp;0.60). However, a daily dose of more than 54mg decreased ET by 0.26mm (10 trials, 984 participants, SMD: -0.26, 95% CI: -0.45 to -0.07, P\u0026thinsp;=\u0026thinsp;0.007). This finding suggests that higher isoflavone doses, by reducing ET, could potentially reduce risk of developing endometrial cancer, a suggestion for which there is some epidemiological support(\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e). Additionally, Li et al. 2010(\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e) found that when trials were stratified according to study location, isoflavone supplementation significantly decreased ET by 0.23mm in North American trials (N\u0026thinsp;=\u0026thinsp;7, 726 participants, SMD: -0.23, 95% CI: -0.44 to -0.01, P\u0026thinsp;=\u0026thinsp;0.04), but tended to increase ET in Asian trials (N\u0026thinsp;=\u0026thinsp;3, 128 participants, SMD: 0.23; 95% CI: -0.04 to 0.50, P\u0026thinsp;=\u0026thinsp;0.10). The non-significant increase in ET observed in Asian trials, albeit based on only 3, may result from ethnic differences in isoflavone metabolism wherein Asians are more likely to host intestinal bacteria that convert daidzein into equol(\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e), which has a much higher receptor binding affinity for both ERs than its parent isoflavone daidzein(\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e). However, observational studies involving Asians show soy or isoflavone intake is associated with a decreased risk of endometrial cancer(\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e). Our analyses did not demonstrate effect modification on ET by continent, where the lack of effect was consistent across trials from varying continents.\u003c/p\u003e \u003cp\u003eThe lack of effect on circulating estradiol and FSH levels is consistent with the findings of a 2009 systematic review and meta-analysis of trials\u0026thinsp;\u0026ge;\u0026thinsp;4 weeks(\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e). In their meta-analysis, neither soy nor isoflavone consumption affected estradiol, estrone, FSH or luteinizing hormone levels in pre- (6\u0026ndash;11 trials per comparison) or postmenopausal (21 trials per comparison) women. No previously published meta-analysis has explored the effects of isoflavones on VMI. Although only 8 trials examined this endpoint, the lack of effect is consistent with the results of the other 3 measures of estrogenicity considered in the current analysis.\u003c/p\u003e \u003cp\u003eThe lack of estrogenic effects of isoflavones on ET, VMI, FSH and estradiol in the current analysis, does not rule out these soybean constituents from exerting estrogen-like effects on other tissues and measures or endpoints. As noted previously, isoflavones are classified as SERMs. By definition, SERMs have tissue-specific effects. For example, tamoxifen exerts an anti-estrogenic effect on breast tissue, but an estrogenic effect on endometrial tissue(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Therefore, the current analysis does not undermine findings that isoflavones alleviate menopausal symptoms(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), reduce bone loss(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and improve memory(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) in postmenopausal women; effects thought to result from the interaction between isoflavones and ERs. Similarly, they do not rule out isoflavones from exerting estrogenic effects on breast tissue, although substantial clinical evidence indicates this is not the case(\u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). Nor do they rule out isoflavones from having anti-estrogenic effects. In premenopausal women, genistein (a soybean isoflavone accounting for approximately 50% of total isoflavone content of the soybean(\u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e)) has demonstrated inhibitory effects on endometrial hyperplasia, a precancerous condition indicated by an irregular thickening of the endometrial wall(\u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e). Furthermore, soy isoflavones have been shown to reduce the risk of breast cancer recurrence in postmenopausal women with estrogen-dependent cancer taking anastrozole, an estrogen-lowering therapy(\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e). However, the findings of the current systematic review and meta-analysis serve to illustrate that isoflavones differ clinically from the hormone estrogen. This difference is evident when comparing the effect of soy isoflavones to that of HRTs (\u003cb\u003eSupplemental Table\u0026nbsp;7\u003c/b\u003e). In systematic reviews and meta-analyses of the effect of HRTs on measures of estrogenicity, they demonstrate increases in ET, VMI and estradiol and reductions in FSH, which contrast with the lack of effects of isoflavones observed in the present analysis. Furthermore, these differences were also observed in a head-to-head comparison between HRT with soy isoflavones(\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e). This differentiation is important because safety concerns raised about isoflavones are based on their similarity to estrogen.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eImplications\u003c/h2\u003e \u003cp\u003e Although most trials in the present analysis provided isoflavones as capsules, the results of these trials did not differ from those trials in which isoflavones were provided as soy protein-based beverages or foods (approximately 30%). Furthermore, mean isoflavone intake in the included trials (median 66-77mg/d) was higher than the typical isoflavone intake among older Japanese women (30-50mg/d)(\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e) and the typical amount associated with a range of beneficial effects in observational studies where a systematic review and meta-analysis demonstrated each 10 mg/d increment of soy isoflavones intake was significantly associated with a 4% lower risk of overall cancer incidence(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The intake of soy isoflavones per capita in the United States(\u003cspan additionalcitationids=\"CR122\" citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e) and Europe(\u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e) is no more than 6 mg/d and most likely fewer than 3 mg. Traditional Asian soy foods (e.g., tofu, miso, soymilk) contain approximately 3.5 mg isoflavones/g protein, thus a typical serving of tofu or soymilk which provides\u0026thinsp;~\u0026thinsp;8g protein may contain\u0026thinsp;~\u0026thinsp;28mg soy isoflavones, while foods made from soybeans using concentrated sources of soy protein such as soy protein isolates or soy protein concentrates, where as much as 90% of isoflavone content can be lost during the processing of soybeans, may contain lower concentrations of isoflavones. Thus, given the intake of soy foods is extremely low, our results may help to allay safety concerns about soy foods and isoflavones and support consumption of soy foods as high-quality plant protein foods with low environmental impact and cost. These data support the translation of dietary guidance and cardiovascular dietary guidelines for sustainable plant-based dietary patterns(\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The results of these data also support addressing the gender gap in CVD as this concern is of particular relevance to menopausal women given the fact that as the leading cause of death in women(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) which is underrecognized and undertreated(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), encouraging an increased intake of soy foods can reduce cardiovascular risk, as evident in health claims(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The current findings are also particularly relevant to menopausal women since soy foods have been shown to alleviate menopausal symptoms and up to 80% experience moderate-to-severe vasomotor symptoms, diminishing quality of life, and seek an alternative to hormone replacement therapy (HRT) due to its association with elevated cancer risk(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe strengths of the analyses include a comprehensive identification of all eligible studies resulting from a rigorous search and selection strategy; inclusion of primarily high quality trials providing the highest protection against bias; use of intention to treat data, when available, providing more conservative pooled estimates(\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e), and using the GRADE approach to assess the overall certainty of evidence.\u003c/p\u003e \u003cp\u003eLimitations of the analysis include the evidence indicating serious inconsistency for the effect of isoflavones on ET and serious imprecision in the pooled estimate for VMI where the 95% CIs were wide and could not rule out evidence of effect. Although the present analyses cannot necessarily be extrapolated to tissues and endpoints not examined in the current analysis, they do address the 4 measures of estrogenicity related to endometrial tissues.\u003c/p\u003e \u003cp\u003eWeighing these strengths and limitations, we graded the certainty in the evidence as high for FSH and estradiol and moderate for ET and VMI.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, our synthesis demonstrates that in postmenopausal women, consumption of soy isoflavones results in no effects on 4 measures of estrogenicity, ET, VMI, FSH and estradiol. Certainty in the evidence was high for FSH and estradiol and moderate for ET and VMI. The main sources of uncertainty, inconsistency for ET and imprecision for VMI, should be considered by future large high-quality trials. Therefore, based on the current findings, isoflavones differ from the hormone estrogen and thus, no assumptions about the health effects of soy foods or isoflavones should be based on an understanding of the effects of the hormone estrogen. Addressing public health concerns around soy foods may support their intake as high-quality plant protein foods with low environmental impact and cost, aligning with dietary guidelines.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI, confidence interval; ET, endometrial thickness; ER, estrogen receptor; FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; MD, mean difference; MID, minimally important difference; ROB, risk of bias; SERM, selective estrogen receptor modulator; SMD, standardized mean difference; VMI, vaginal maturation index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are available in the article, additional files, or from the corresponding author upon reasonable request. The study protocol can be accessed on PROSPERO\u0026nbsp;(CRD42023439239).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAZ\u003c/strong\u003e is a part-time research associate at INQUIS Clinical Research Ltd, a contract research organization, and has received consulting fees from Glycemic Index Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTAK\u003c/strong\u003e has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. He has received funding from the Toronto 3D Knowledge Synthesis and Clinical Trials foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMM\u003c/strong\u003e was employed by the Soy Nutrition Institute Global, an organization that receives funding from the United Soybean Board (USB) and from members involved in the soy industry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCWCK\u0026nbsp;\u003c/strong\u003ehas received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate \u0026amp; Lyle, Unilever and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDJAJ\u003c/strong\u003e has received research grants from Saskatchewan \u0026amp; Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg\u0026apos;s Company, Canada, Quaker Oats, Canada, Procter \u0026amp; Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut \u0026amp; Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker\u0026apos;s panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan \u0026amp; Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter \u0026amp; Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael\u0026apos;s Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael\u0026apos;s Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJLS\u003c/strong\u003e has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey \u0026ldquo;Checkoff\u0026rdquo; program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy \u0026ldquo;Checkoff\u0026rdquo; program), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund which has received donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and vegan grants through the Karuna Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestl\u0026eacute;, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate \u0026amp; Lyle, Inquis Clinical Research, Ingredion, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. \u0026nbsp;He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLC\u003c/strong\u003e has received research support from Protein Industries Canada (a Government of Canada Global Innovation Clusters).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGV, SB, AA, SY, SBM, and AS\u003c/strong\u003e have no conflicts of interest to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the United Soybean Board (the United States Department of Agriculture soy check-off program) and the Canadian Institutes of Health Research (funding reference number, 129920) through the Canada-wide Human Nutrition Trialists\u0026apos; Network (NTN). The Diet, Digestive tract, and Disease (3D) Centre, funded through the Canada Foundation for Innovation and the Ministry of Research and Innovation\u0026rsquo;s Ontario Research Fund, provided the infrastructure for the conduct of this work. GV was funded by a CIHR Canada Graduate Scholarship and Toronto 3D Summer Scholarship award. SB was funded by an Undergraduate Student Research Program scholarship. AA was funded by a Charles Hollenburg Summer Scholarship. AZ was funded by a Toronto 3D Postdoctoral Fellowship Award. LC was funded by a Toronto 3D New Investigator Award.\u0026nbsp;None of the sponsors had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. But one of the co-authors, Mark Messina, who was not involved in data collection or analysis, is the Director of Nutrition Science and Research at the Soy Nutrition Institute Global, an organization that receives partial funding from the principal funder, the United Soybean Board (USB).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u003c/strong\u003e LC, AS, MM, CWCK, DJAJ and JLS designed the research (project conception, development of overall research plan, and study oversight). GV, SB, AA and SY conducted the research (hands-on conduct of the experiments and data collection). GV, SB, TAK, and AZ analyzed data or performed statistical analysis. LC wrote the paper. LC had primary responsibility for the final content and takes responsibility for the integrity of the data and the accuracy of the data analysis. All the authors contributed to the critical revision of the manuscript for important intellectual content, read and approved the final manuscript. LC supervised the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHealth Canada. Canada's Food Guide [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://food-guide.canada.ca/en/\u003c/span\u003e\u003cspan address=\"https://food-guide.canada.ca/en/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWillett W, Rockstrom J, Loken B, Springmann M, Lang T, Vermeulen S, et al. Food in the Anthropocene: the EAT-Lancet Commission on healthy diets from sustainable food systems. Lancet. 2019;393(10170):447\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P, Dayan N, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021;37(8):1129\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376\u0026ndash;414.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA et al. /ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor- positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 1998;58(17):3833\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarter MW, Matrone G, Smart WW. Jr. Effect of genistin on reproduction of the mouse. J Nutr. 1955;55(4):639\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarter MW, Smart WW Jr., Matrone G. Estimation of estrogenic activity of genistein obtained from soybean meal. Proc Soc Exp Biol Med. 1953;84(2):506\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng E, Story CD, Yoder L, Hale WH, Burroughs W. Estrogenic activity of isoflavone derivatives extracted and prepared from soybean oil meal. Science. 1953;118(3058):164\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGinsburg J. Tackling environmental endocrine disrupters. Lancet. 1996;347(9014):1501\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu L, House SE, Prior RL, Fang N, Ronis MJ, Clarkson TB, et al. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr. 2006;136(5):1215\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSetchell KD, Brown NM, Zhao X, Lindley SL, Heubi JE, King EC, et al. Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011;94(5):1284\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoukup ST, Helppi J, Muller DR, Zierau O, Watzl B, Vollmer G, et al. Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: a cross-species and sex comparison. Arch Toxicol. 2016;90(6):1335\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHealth Canada. Summary of Health Canada's Assessment of a Health Claim about Soy Protein and Cholesterol Lowering. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.canada.ca/en/health-canada/services/food-nutrition/food-labelling/health-claims/assessments/summary-assessment-health-claim-about-protein-cholesterol-lowering.html\u003c/span\u003e\u003cspan address=\"https://www.canada.ca/en/health-canada/services/food-nutrition/food-labelling/health-claims/assessments/summary-assessment-health-claim-about-protein-cholesterol-lowering.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed December 12, 2023. [December 12, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S, Food. \u0026amp; Drug Administration. Code of Federal Regulations. 21 CFR 101.82 Health claims: Soy protein and risk of coronary heart disease (CHD). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-E/section-101.82\u003c/span\u003e\u003cspan address=\"https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-E/section-101.82\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed December 12, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlanco Mejia S, Messina M, Li SS, Viguiliouk E, Chiavaroli L, Khan TA, et al. A Meta-Analysis of 46 Studies Identified by the FDA Demonstrates that Soy Protein Decreases Circulating LDL and Total Cholesterol Concentrations in Adults. J Nutr. 2019;149(6):968\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang J, Shen H, Mi M, Qin Y. Isoflavone consumption and risk of breast cancer: An updated systematic review with meta-analysis of observational studies. Nutrients. 2023;15(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFan Y, Wang M, Li Z, Jiang H, Shi J, Shi X, et al. Intake of Soy, Soy Isoflavones and Soy Protein and Risk of Cancer Incidence and Mortality. Front Nutr. 2022;9:847421.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanadys W, Baranska A, Blaszczuk A, Polz-Dacewicz M, Drop B, Malm M et al. Effects of soy isoflavones on biochemical markers of bone metabolism in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health. 2021;18(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCui C, Birru RL, Snitz BE, Ihara M, Kakuta C, Lopresti BJ, et al. Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2020;78(2):134\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012;19(7):776\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMensah GA, Fuster V, Murray CJL, Roth GA, Global Burden of Cardiovascular D, Risks C. Global Burden of Cardiovascular Diseases and Risks, 1990\u0026ndash;2022. J Am Coll Cardiol. 2023;82(25):2350\u0026thinsp;\u0026ndash;\u0026thinsp;473.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaas AH, Appelman YE. Gender differences in coronary heart disease. Neth Heart J. 2010;18(12):598\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRyczkowska K, Adach W, Janikowski K, Banach M, Bielecka-Dabrowa A. Menopause and women's cardiovascular health: is it really an obvious relationship? Arch Med Sci. 2023;19(2):458\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85(2):304\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138(3):863\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998;139(10):4252\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParuthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64(1):423\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med. 2008;74(13):1656\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMudryj AN, Aukema HM, Yu N. Intake patterns and dietary associations of soya protein consumption in adults and children in the Canadian Community Health Survey, Cycle 2.2. Br J Nutr. 2015;113(2):299\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 2022 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://training.cochrane.org/handbook/current\u003c/span\u003e\u003cspan address=\"https://training.cochrane.org/handbook/current\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf MI et al. Searching for and selecting studies. Cochrane Handbook for systematic reviews of interventions. 2019:67\u0026ndash;107.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSourceForge. Plot Digitizer 2001 [updated 24-Oct-2015. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://plotdigitizer.sourceforge.net/\u003c/span\u003e\u003cspan address=\"http://plotdigitizer.sourceforge.net/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcGrath S, Zhao X, Steele R, Thombs BD, Benedetti A, Collaboration DSD. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Methods Med Res. 2020;29(9):2520\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTufanaru C, Munn Z, Stephenson M, Aromataris E. Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc. 2015;13(3):196\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol. 2002;31(1):140\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFollmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45(7):769\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalk EM, Earley A, Patel K, Trikalinos TA, Dahabreh IJ. Empirical assessment of within-arm correlation imputation in trials of continuous outcomes. 2012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 2019 [updated July 2019. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.training.cochrane.org/handbook\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCochrane Handbook for Systematic Reviews of Interventions. 2011 [updated March 2011. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.handbook.cochrane.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;21(11):1559\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis: John Wiley \u0026amp; Sons; 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu R, Gartlehner G, Grant M, Shamliyan T, Sedrakyan A, Wilt TJ, et al. Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011;64(11):1187\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New-York: Springer; 2001.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61(10):991\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBegg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994:1088\u0026thinsp;\u0026ndash;\u0026thinsp;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGRADE Handbook. 2013 [updated October 2013. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gdt.gradepro.org/app/handbook/handbook.html\u003c/span\u003e\u003cspan address=\"https://gdt.gradepro.org/app/handbook/handbook.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGRADEpro GDT. GRADEpro Guideline Development Tool [Software] McMaster University2020 [developed by Evidence Prime, Inc.]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gradepro.org/\u003c/span\u003e\u003cspan address=\"https://gradepro.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013;66(2):173\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt GH, Oxman AD, Schunemann HJ. GRADE guidelines-an introduction to the 10th-13th articles in the series. J Clin Epidemiol. 2013;66(2):121\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrunetti M, Shemilt I, Pregno S, Vale L, Oxman AD, Lord J, et al. GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence. J Clin Epidemiol. 2013;66(2):140\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013;66(2):158\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol. 2013;66(2):151\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction\u0026mdash;GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck-Ytter Y, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013;66(7):719\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol. 2020;119:126\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol. 2020;119:126\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSch\u0026uuml;nemann HBJ, Guyatt GOA. GRADE Handbook [Internet]. 2013 [cited 2018 Nov 10]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gdt.gradepro.org/app/handbook/handbook.html\u003c/span\u003e\u003cspan address=\"https://gdt.gradepro.org/app/handbook/handbook.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtteritano M, Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2007;92(8):3068\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas. 2006;54(3):270\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan KK, Soares JM Jr., Haidar MA, de Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99(3):389\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarkness LS, Fiedler K, Sehgal AR, Oravec D, Lerner E. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004;13(9):1000\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang HY, Yang HP, Yang HT, Yang TC, Shieh MJ, Huang SY. One-year soy isoflavone supplementation prevents early postmenopausal bone loss but without a dose-dependent effect. J Nutr Biochem. 2006;17(8):509\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJassi HK, Jain A, Arora S, Chitra R. Effect of soy proteins Vs soy isoflavones on lipid profile in postmenopausal women. Indian J Clin Biochem. 2010;25(2):201\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKenny AM, Mangano KM, Abourizk RH, Bruno RS, Anamani DE, Kleppinger A, et al. Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr. 2009;90(1):234\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause. 2008;15(1):125\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim J, Lee H, Lee O, Lee KH, Lee YB, Young KD, et al. Isoflavone supplementation influenced levels of triglyceride and luteunizing hormone in Korean postmenopausal women. Arch Pharm Res. 2013;36(3):306\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLlaneza P, Gonzalez C, Fernandez-Inarrea J, Alonso A, Diaz-Fernandez MJ, Arnott I, et al. Soy isoflavones, Mediterranean diet, and physical exercise in postmenopausal women with insulin resistance. Menopause. 2010;17(2):372\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMittal N, Hota D, Dutta P, Bhansali A, Suri V, Aggarwal N, et al. Evaluation of effect of isoflavone on thyroid economy \u0026amp; autoimmunity in oophorectomised women: a randomised, double-blind, placebo-controlled trial. Indian J Med Res. 2011;133(6):633\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetri Nahas E, Nahas Neto J, De Luca L, Traiman P, Pontes A, Dalben I. Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy. Maturitas. 2004;48(4):372\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNahas EA, Nahas-Neto J, Orsatti FL, Carvalho EP, Oliveira ML, Dias R. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Maturitas. 2007;58(3):249\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNikander E, Kilkkinen A, Metsa-Heikkila M, Adlercreutz H, Pietinen P, Tiitinen A, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101(6):1213\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNikander E, Rutanen EM, Nieminen P, Wahlstrom T, Ylikorkala O, Tiitinen A. Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal women. Fertil Steril. 2005;83(1):137\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePenotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79(5):1112\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePop EA, Fischer LM, Coan AD, Gitzinger M, Nakamura J, Zeisel SH. Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women: a phase I clinical trial. Menopause. 2008;15(4 Pt 1):684\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRios DR, Rodrigues ET, Cardoso AP, Montes MB, Franceschini SA, Toloi MR. Lack of effects of isoflavones on the lipid profile of Brazilian postmenopausal women. Nutrition. 2008;24(11\u0026ndash;12):1153\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSammartino A, Di Carlo C, Mandato VD, Bifulco G, Di Stefano M, Nappi C. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol. 2003;17(1):45\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteinberg FM, Murray MJ, Lewis RD, Cramer MA, Amato P, Young RL, et al. Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women. Am J Clin Nutr. 2011;93(2):356\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUesugi T, Toda T, Okuhira T, Chen JT. Evidence of estrogenic effect by the three-month-intervention of isoflavone on vaginal maturation and bone metabolism in early postmenopausal women. Endocr J. 2003;50(5):613\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUpmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7(4):236\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVilla P, Costantini B, Suriano R, Perri C, Macri F, Ricciardi L, et al. The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: relationship with the metabolic status. J Clin Endocrinol Metab. 2009;94(2):552\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu J, Oka J, Higuchi M, Tabata I, Toda T, Fujioka M, et al. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism. 2006;55(4):423\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu J, Oka J, Ezaki J, Ohtomo T, Ueno T, Uchiyama S, et al. Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial. Menopause. 2007;14(5):866\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe YB, Wang ZL, Zhuo SY, Lu W, Liao HF, Verbruggen M, et al. Soy germ isoflavones improve menopausal symptoms but have no effect on blood lipids in early postmenopausal Chinese women: a randomized placebo-controlled trial. Menopause. 2012;19(7):791\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArjmandi BH, Lucas EA, Khalil DA, Devareddy L, Smith BJ, McDonald J, et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J. 2005;4:8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasaria S, Wisniewski A, Dupree K, Bruno T, Song MY, Yao F, et al. Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women. J Endocrinol Invest. 2009;32(2):150\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas. 2010;67(3):262\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiechi LM, Secreto G, Vimercati A, Greco P, Venturelli E, Pansini F, et al. The effects of a soy rich diet on serum lipids: the Menfis randomized trial. Maturitas. 2002;41(2):97\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiechi LM, Putignano G, Guerra V, Schiavelli MP, Cisternino AM, Carriero C. The effect of a soy rich diet on the vaginal epithelium in postmenopause: a randomized double blind trial. Maturitas. 2003;45(4):241\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR, Kurzer MS. Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab. 1999;84(10):3479\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurkies AL, Lombard C, Strauss BJ, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21(3):189\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePersky VW, Turyk ME, Wang L, Freels S, Chatterton R Jr., Barnes S, et al. Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr. 2002;75(1):145\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuaas AM, Kono N, Mack WJ, Hodis HN, Felix JC, Paulson RJ, et al. Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial. Menopause. 2013;20(8):840\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRadhakrishnan G, Rashmi, Agarwal N, Vaid NB. Evaluation of Isoflavone Rich Soy Protein Supplementation for Postmenopausal Therapy. Pak J Nutr. 2009;8(7):1009\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeede HJ, Dalais FS, McGrath BP. Dietary soy containing phytoestrogens does not have detectable estrogenic effects on hepatic protein synthesis in postmenopausal women. Am J Clin Nutr. 2004;79(3):396\u0026ndash;401.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM. Isoflavone treatment for acute menopausal symptoms. Menopause. 2007;14(3 Pt 1):468\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric. 2001;4(1):13\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Yuan F, Gao J, Shan B, Ren Y, Wang H, et al. Oral isoflavone supplementation on endometrial thickness: a meta-analysis of randomized placebo-controlled trials. Oncotarget. 2016;7(14):17369\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi SH, Liu XX, Bai YY, Wang XJ, Sun K, Chen JZ, et al. Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials. Am J Clin Nutr. 2010;91(2):480\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSetchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr. 2010;140(7):1355S\u0026ndash;62S.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang Y, Gong P, Madak-Erdogan Z, Martin T, Jeyakumar M, Carlson K, et al. Mechanisms enforcing the estrogen receptor beta selectivity of botanical estrogens. FASEB J. 2013;27(11):4406\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong XS, Ge J, Chen SW, Xiong YQ, Ma SJ, Chen Q. Association between Dietary Isoflavones in Soy and Legumes and Endometrial Cancer: A Systematic Review and Meta-Analysis. J Acad Nutr Diet. 2018;118(4):637\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHooper L, Ryder JJ, Kurzer MS, Lampe JW, Messina MJ, Phipps WR, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update. 2009;15(4):423\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMessina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst. 1991;83(8):541\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMessina M, Messina V. Increasing use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc. 1991;91(7):836\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;777(1\u0026ndash;2):129\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBitto A, Granese R, Triolo O, Villari D, Maisano D, Giordano D, et al. Genistein aglycone: a new therapeutic approach to reduce endometrial hyperplasia. Phytomedicine. 2010;17(11):844\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010;182(17):1857\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMessina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006;55(1):1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonishi K, Wada K, Yamakawa M, Goto Y, Mizuta F, Koda S, et al. Dietary soy intake is inversely associated with risk of type 2 diabetes in Japanese women but not in men. J Nutr. 2019;149(7):1208\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBai W, Wang C, Ren C. Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr. 2014;65(1):9\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSebastian RS, Wilkinson Enns C, Goldman JD, Martin CL, Steinfeldt LC, Murayi T, et al. A new database facilitates characterization of flavonoid intake, sources, and positive associations with diet among US adults. J Nutr. 2015;145(6):1239\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007;137(5):1244\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZamora-Ros R, Ferrari P, Gonzalez CA, Tjonneland A, Olsen A, Bredsdorff L, et al. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Breast Cancer Res Treat. 2013;139(1):163\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZiauddeen N, Rosi A, Del Rio D, Amoutzopoulos B, Nicholson S, Page P, et al. Dietary intake of (poly)phenols in children and adults: cross-sectional analysis of UK National Diet and Nutrition Survey Rolling Programme (2008\u0026ndash;2014). Eur J Nutr. 2019;58(8):3183\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePorta N, Bonet C, Cobo E. Discordance between reported intention-to-treat and per protocol analyses. J Clin Epidemiol. 2007;60(7):663\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3857624/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3857624/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite dietary recommendations to consume more plant foods for public and planetary health and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and their components, especially isoflavones, are a barrier to their intake. Given the cardioprotective effects and ability to alleviate menopausal symptoms, addressing this issue is particularly relevant to women. We therefore undertook a systematic review and meta-analysis of randomized controlled trials in postmenopausal women to determine the effect of soy isoflavones on measures of estrogenicity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMEDLINE, Embase, and Cochrane Library were searched through July 2023 for randomized controlled trials 3-months investigating soy isoflavones versus non-isoflavone controls in postmenopausal women. The four outcomes included endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and estradiol. Independent authors extracted data and assessed risk of bias. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess certainty of evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included 40 trials (52 trial comparisons, n=3285) assessing the effect of a median daily dose of 75 mg of soy isoflavones in substitution for non-isoflavone control over a median of 24 weeks. Isoflavones had no statistically significant effects on any of the measures of estrogenicity; ET (mean difference, -0.22mm [95% confidence interval, -0.45 to 0.01mm], P\u003csub\u003eMD\u003c/sub\u003e=0.059), VMI (2.31 [-2.14 to 6.75], P\u003csub\u003eMD\u003c/sub\u003e=0.310), FSH (-0.02IU/L [-2.39 to 2.35IU/L], P\u003csub\u003eMD\u003c/sub\u003e=0.987), and estradiol (1.61pmol/L [-1.17 to 4.38pmol/L], P\u003csub\u003eMD\u003c/sub\u003e=0.256). The certainty of evidence was high-to-moderate for all outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCurrent evidence provides a good indication that soy isoflavones do not have an estrogenic effect versus non-isoflavone controls on 4 measures of estrogenicity in postmenopausal women. This synthesis supports the classification of soy isoflavones as selective estrogen receptor modulators and that isoflavones differ clinically from the hormone estrogen where no assumptions about the health effects of soy foods or isoflavones should be based on an understanding of the effects of the hormone estrogen. Addressing public health concerns around soy foods may support their intake as high-quality plant protein foods with low environmental impact and cost, especially relevant for postmenopausal women, and aligning with sustainable dietary patterns and guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration\u003c/strong\u003e: PROSPERO (CRD42023439239)\u003c/p\u003e","manuscriptTitle":"Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-07 11:48:27","doi":"10.21203/rs.3.rs-3857624/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b349225-9937-40a4-80d9-9e2c67e660a6","owner":[],"postedDate":"February 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-17T10:41:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-07 11:48:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3857624","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3857624","identity":"rs-3857624","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}