ID 2140 -
Izoflawony sojowe
PL: Izoflawony sojowe
EN: Soy Isoflavones
Pdf: soy isoflavones
1. Charakterystyka żywności / składnika
The food constituent that is the subject of the health claims is soy isoflavones.
Soy isoflavones constitute a wide range of compounds of plant origin, which mainly comprise genistein, daidzein and glycitein, among others (Ma et al., 2008a, 2008b). Soy isoflavones can be consumed as isolated soybean protein, as whole-soybean foods, or as supplements containing extracts, pure compounds or mixtures (Cassidy et al., 2006).
The Panel considers that the food constituent, soy isoflavones, which is the subject of the health claims, is sufficiently characterised.
2.2. Ograniczenie objawów naczyniopochodnych związanych z menopauzą (np. uderzenia gorąca, zlewne poty) (ID 1654, 1704, 2140, 3093, 3154, 3590)
The claimed effect which is eligible for further assessment relates to the reduction of vasomotor symptoms associated with menopause. The proposed target population is peri- and post-menopausal women.
Changes in vasomotor symptoms associated with menopause such as frequency and severity of hot flushes and night sweats can be assessed using questionnaires.
The Panel considers that reduction of vasomotor symptoms associated with menopause is a beneficial physiological effect.
2.3. Ograniczenie objawów naczyniopochodnych związanych z menopauzą (np. uderzenia gorąca, zlewne poty) (ID 1654, 2140, 3154, 3590, 1704b, 3093b)
The claimed effects are “menopause”, “menopause/skin and hair health during menopause/cholesterol management”, “soy contains the phytoestrogens isoflavones that can function as either an estrogen agonist or antagonist”, “act as phytoestrogens”, “helps to keep healthy thermoregulation during climacterium”, and “helps to alleviate the symptoms of menopause”. The Panel assumes that the target population is post-menopausal women.
In the context of the proposed wordings and the clarifications provided by Member States, the Panel assumes that the claimed effects refer to the reduction of vasomotor symptoms associated with menopause. Changes in vasomotor symptoms associated with menopause such as frequency and severity of hot flushes and night sweats can be assessed using questionnaires.
The Panel considers that reduction of vasomotor symptoms associated with menopause is a beneficial physiological effect.
3.2. Ograniczenie objawów naczyniopochodnych związanych z menopauzą (np. uderzenia gorąca, zlewne poty) (ID 1654, 1704, 2140, 3093, 3154, 3590)
In a previous assessment of this claim (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2011), 12 RCTs (Albertazzi et al., 2005; Cheng et al., 2007; Crisafulli et al., 2004; D'Anna et al., 2007; Faure et al., 2002; Han et al., 2002; Khaodhiar et al., 2008; Knight et al., 2001; Kotsopoulos et al., 2000; Nahas et al., 2007; St Germain et al., 2001; Upmalis et al., 2000) were evaluated for the scientific substantiation of the claim. RCTs evaluating outcomes other than vasomotor symptoms, assessing the effect of foods other than soy isoflavones, or RCTs for which confounding could not be excluded or which showed considerable limitations in methodology or reporting, or meta-analyses which included these studies, were not considered pertinent to the evaluation of the claim.
In the framework of further assessment, 23 references, two of which (Basaria et al., 2009; Lethaby et al., 2007) had already been considered in the Panel’s previous opinion, were provided as well as a range of comments on the Panel’s earlier assessment. The Panel notes that reasons for reaching the conclusions in its earlier assessment have been described in its previous opinion (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2011).
This evaluation combines the scientific references provided in the previous submission and the additional references subsequently submitted for further assessment for this claim on soy isoflavones and reduction of vasomotor symptoms associated with menopause.
Among the 21 additional references provided in the framework of further assessment which have not yet been considered by the Panel was a report on an outcome of a symposium of the North American Menopause Society (The North American Menopause Society, 2011) and two narrative reviews (Kurzer, 2008; Messina and Hughes, 2003) which did not provide any original data for the scientific substantiation of the claim. Two meta-analyses were provided as conference proceedings in abstract form only (Kurzer et al., 2009; Taku et al., 2010c), one human intervention study was not randomised (Battaglia et al., 2009), one study was a single arm uncontrolled study (Chedraui et al., 2011) and one was an open label study (Cancelo Hidalgo and Castelo Branco, 2011). In one RCT, no results were presented in relation to frequency or severity of vasomotor symptoms, but only for the somatic subscale of the Menopause Rating Scale, which not only comprises hot flushes, but also heart discomfort, sleeping problems and muscle and joint problems (Carmignani et al., 2010). One study reported on the number of subjects experiencing an increased or decreased severity, or an increased frequency, of hot flushes in the intervention and control group without presenting a statistical analysis (Pop et al., 2008). In another study (Hachul et al., 2011), differences in the baseline frequency of hot flushes between groups were not taken into account in the analysis, and in
another RCT (Levis et al., 2011) results with respect to the effect of isoflavones on frequency of hot flushes were insufficiently reported. The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claim.
The meta-analysis by Bolaños et al. (2010) included 19 RCTs with a duration of at least 12 weeks in peri-/post-menopausal women with hot flushes attributed to climacterium and without a cancer background, in which soy was provided in supplement form, as soy extract or as pure genistein or daidzein, and investigated the effect on vasomotor symptoms. The Panel notes that this meta-analysis contains studies which did not allow conclusions to be drawn on the scientific substantiation of the claim owing to the following limitations: uncertainty as to whether women were on tamoxifen (Albertazzi et al., 1998), uncertainty as to whether subjects were blinded to the intervention (Colacurci et al., 2004), uncertainty on the amount of isoflavones provided (Murkies et al., 1995), or use of medication throughout the study, such as Cimicifuga racemosa (L.) Nutt., or therapy for thyroid disease, which could have had an impact on the claimed effect, or subjects started taking antibiotics during the study which was one of the exclusion criteria for the study (Lewis et al., 2006). The Panel considers that no conclusions can be drawn from this meta-analysis for the scientific substantiation of the claim.
The meta-analysis by Bolaños-Diaz et al. (2011) was designed as an indirect comparison of two meta-analyses to evaluate the effects of soy extracts vs. HRT on the reduction of hot flushes. The meta-analysis comparing soy isoflavones to placebo considered studies included in the meta-analysis by Bolaños et al. (2010) plus an additional two RCTs. However, RCTs which used soy in the form of a supplement were excluded from the meta-analysis. The Panel notes that this meta-analysis does not contain the totality of studies which could be considered pertinent to the claim, and considers that no conclusions can be drawn from it for the scientific substantiation of the claim.
Therefore, in this combined evaluation the Panel will consider 15 RCTs, of which 12 were already considered in the previous opinion, on the effect of soy isoflavones on vasomotor symptoms, and three in vitro studies related to a possible mechanism by which isoflavones could exert the claimed effect. The characteristics of these 15 RCTs are summarised in Table 3.
Table 3 Study characteristics of human intervention studies which assessed the effect of soy isoflavones on vasomotor symptoms
Author PY Duration Outcome measure
Assessed by IF dose (mg/d)
Randomised (n)
Completers (n)
Attrition rate (%)
Baseline Analysis Power
calculation
Albertazzi 2005 6 we HF frequency HF severity
diaries GCS
90 0
100 (cross- over)
100 99
1 frequency x severity: 7
ITT by LOCF no
Cheng 2007 12 we HF frequency HF severity NS frequency NS severity
diaries self-rating scale diaries self-rating scale
60 0
60 26 25
15 severity: 1.4 on a 5- point scale
completers no
Crisafulli 2004 12 mo HF frequency diaries
54 HRT 0
30 30 30
83 12 4.6 HF/day ITT no
D'Anna 2009 24 mo HF frequency HF severity
diaries self-rating scale
27 0
135 130
119 117
11 4.3 HF/day severity: 2.3 on a 3- point scale
completers yes (post-hoc)
Evans 2011 21 we HF frequency HF severity
diaries diaries/GCS
30 0
42 42
32 36
19 9.5 HF/day severity: 1.9 on a 3- point scale
completers MITT
yes (42 per arm)
Faure 2002 16 we HF frequency diaries 70 0
39 36
33 22
27 10 HF/day PP ITT by LOCF
yes (30 per arm)
Ferrari 2009 12 we HF frequency diaries 80 0
85 95
55 66
32 7.8 HF/day completers yes (86 per arm)
Han 2002 16 we HF severity KI 100 0
41 41
40 40
2 severity: 2.5 on a 3- point scale
ITT by LOCF no
Khaodhiar 2008 13 we HF frequency HF severity
diaries self-rating scale
60 40 0
191 49 48 45
26 8 HF/day severity: 2.1 on a 4- point scale
PP yes (50 per arm)
Knight 2001 12 we HF frequency HF severity
diaries GCS
77 0
12 12
9 11
17 7.5 HF/day ITT no
Kostopoulos 2000 12 we HF severity validated questionnaire
118 0
44 50
34 41
20 severity: 0.8 on a 3- point scale
PP no
Lopes de Sousa
2006 16 we HF frequency HF severity
diaries diaries
120 0
42 42
77 (groups not reported)
8 6.8 HF/day severity: not reported
completers no
Nahas 2007 10 mo HF frequency HF severity
diaries self-rating scale
100 0
40 40
38 38
10 10 HF/day severity: 9 on a 12- point scale
completers no
St Germain 2001 24 we HF frequency HF severity NS frequency NS severity
interviewer administered menopausal index
80 4 0
24 24 21
24 24 20
1 10 VMS/week PP no
Upmalis 2000 12 we HF frequency HF severity NS frequency
diaries self-rating scale diaries
50 0
90 87
59 63
31 9 HF/day severity: 2 on a 3- point scale
PP no
IF = isoflavones HF = hot flushes GCS = Greene Climacteric Scale (vasomotor subscale) ITT = Intention-to-treat KI = Kupperman Index (vasomotor subscale)
LOCF = last observation carried forward MITT = modified intention-to-treat NR = not reported NS = night sweats PP = per protocol
PY = publication year VMS = vasomotor symptoms Completers = analysis carried out in all subjects completing
the study
The Panel notes that most of these RCTs were at high risk of bias due to major methodological weaknesses in the statistical analyses performed (e.g. inadequate handling or no consideration of missing data, repeated measures and/or multiple comparisons not taken into account, analysis of data with a high risk of not being normally distributed by parametric tests without verification of the assumption of the statistical test applied), and/or that data were inadequately reported.
The majority of the studies were conducted as parallel studies, except one (Albertazzi et al., 2005) which was of cross-over design. Isoflavones were consumed as pure genistein (Albertazzi et al., 2005; Crisafulli et al., 2004; D'Anna et al., 2009; Evans et al., 2011), as daidzein-rich isoflavone aglycones from soy germ (Khaodhiar et al., 2008), in soy extracts (Faure et al., 2002; Ferrari, 2009; Lopes de Sousa et al., 2006; Nahas et al., 2007; Upmalis et al., 2000), in soy powder (Knight et al., 2001; Kotsopoulos et al., 2000), in (isolated) soy protein (Han et al., 2002; St Germain et al., 2001), and in a soy bean drink (Cheng et al., 2007).
The Panel notes that group analyses, which were not pre-planned, were performed in two studies (Albertazzi et al., 2005; Khaodhiar et al., 2008), and considers that no conclusions can be drawn from these secondary analyses for the scientific substantiation of the claim. Therefore, only primary analyses of these studies are taken into account for this assessment.
In the majority of the studies, data analyses were carried out in the PP or completers population only, except in six RCTs in which data were analysed in the intention-to-treat (ITT) or MITT population (Albertazzi et al., 2005; Crisafulli et al., 2004; Evans et al., 2011; Faure et al., 2002; Han et al., 2002; Knight et al., 2001). In three of these studies, the last observation was carried forward (LOCF) to impute missing data (Albertazzi et al., 2005; Faure et al., 2002; Han et al., 2002), while in the remaining three studies the method for imputing missing data was not specified.
Ten RCTs investigated the effect of soy isoflavones on both frequency and severity of hot flushes (Albertazzi et al., 2005; Cheng et al., 2007; D'Anna et al., 2009; Evans et al., 2011; Khaodhiar et al., 2008; Knight et al., 2001; Lopes de Sousa et al., 2006; Nahas et al., 2007; St Germain et al., 2001; Upmalis et al., 2000), three investigated frequency only (Crisafulli et al., 2004; Faure et al., 2002; Ferrari, 2009) and two severity only (Han et al., 2002; Kotsopoulos et al., 2000). Three of these studies also investigated the effect of soy isoflavones on night sweats (Cheng et al., 2007; St Germain et al., 2001; Upmalis et al., 2000). In all of these studies, subjects in the intervention and control groups were not different at baseline with regard to the frequency and/or severity of hot flushes and/or night sweats.
In 12 out of 13 studies which investigated the effect of soy isoflavones on the frequency of hot flushes, frequency of hot flushes was self-assessed in symptom diaries, in which the daily symptoms were noted, while in the remaining study by St Germain et al. (2001) this outcome was assessed by an interviewer-administered menopausal index. In the 12 studies which investigated the effect of soy isoflavones on severity of hot flushes, severity of hot flushes was assessed by self-rating scales in five studies (Cheng et al., 2007; D'Anna et al., 2009; Khaodhiar et al., 2008; Nahas et al., 2007; Upmalis et al., 2000), by the vasomotor sub-scale of the Greene Climacteric Scale in three studies (Albertazzi et al., 2005; Evans et al., 2011; Knight et al., 2001), by the vasomotor symptom score of the Kupperman Index in one study (Han et al., 2002), by an interviewer-administered menopausal index in one study (St Germain et al., 2001), by a validated questionnaire in a further study (Kotsopoulos et al., 2000) and by diaries in two other studies (Evans et al., 2011; Lopes de Sousa et al., 2006). In the three of the aforementioned studies investigating night sweats, one study (Upmalis et al., 2000) assessed the frequency of night sweats only, while St Germain et al. (2001) and Cheng et al. (2007) assessed both frequency and severity of night sweats.
Five (Crisafulli et al., 2004; D'Anna et al., 2009; Evans et al., 2011; Ferrari, 2009; Nahas et al., 2007) of the 13 RCTs which investigated the effect of soy isoflavones on frequency of hot flushes reported a statistically significant effect of soy isoflavones on this outcome. These five studies together considered 575 subjects for data analysis (30-119 subjects per group) and provided 27 to 100 mg soy isoflavones per day for 3-24 months. Power calculations were performed in three of
these studies (D'Anna et al., 2009; Evans et al., 2011; Ferrari, 2009), which were reported to be powered to detect a difference of two hot flushes per day between groups (Ferrari, 2009), or a 20 to 35 % difference in change from baseline between groups (D'Anna et al., 2009; Evans et al., 2011). Conversely, six studies (Albertazzi et al., 2005; Khaodhiar et al., 2008; Knight et al., 2001; Lopes de Sousa et al., 2006; St Germain et al., 2001; Upmalis et al., 2000) which considered 623 subjects for data analysis (12-100 subjects per group/period) and provided 40 to 120 mg of soy isoflavones per day for six weeks to six months did not report an effect of soy isoflavones on the frequency of hot flushes, while one study (Cheng et al., 2007) did not report results of this outcome. Power calculations were performed in one of these studies (Khaodhiar et al., 2008), which was reported to have been powered to detect a difference in change from baseline of 1.2 hot flushes per day between groups. In one study (Faure et al., 2002) in 75 subjects, in which 70 mg/day soy isoflavones were administered for 16 weeks and which was powered to detect a difference of three hot flushes per day between groups, the PP and ITT analyses led to inconsistent results with respect to an effect of soy isoflavones on hot flush frequency. The Panel notes that the studies by Knight et al. (2001) and St. Germain et al. (2001) might have been underpowered to detect a statistically significant effect of soy isoflavones on frequency of hot flushes.
Five (Cheng et al., 2007; D'Anna et al., 2009; Han et al., 2002; Nahas et al., 2007; Upmalis et al., 2000) of the 12 RCTs which investigated the effect of soy isoflavones on severity of hot flushes reported a statistically significant effect of soy isoflavones on this outcome. In these studies a total of 567 subjects were considered for data analysis (25-119 per group) and provided 27 to 100 mg soy isoflavones per day for 3-24 months. Conversely, seven studies (Albertazzi et al., 2005; Evans et al., 2011; Khaodhiar et al., 2008; Knight et al., 2001; Kotsopoulos et al., 2000; Lopes de Sousa et al., 2006; St Germain et al., 2001) did not report an effect of soy isoflavones on the severity of hot flushes. In these studies, 668 subjects entered data analysis (12-100 subjects per group/period) and provided 40 to 120 mg of soy isoflavones per day for six weeks to six months. Only one study (Khaodhiar et al., 2008) presented power calculations for this outcome and was reported to have been powered to detect a three unit difference in hot flush scores between groups. The Panel notes that the studies by Knight et al. (2001) and St. Germain et al. (2001) might have been underpowered to detect a statistically significant effect of soy isoflavones on the severity of hot flushes.
None of the three RCTs (Cheng et al., 2007; St Germain et al., 2001; Upmalis et al., 2000) investigating the effect of soy isoflavones on frequency or severity of night sweats reported a statistically significant difference between groups. Although both frequency and severity of night sweats were assessed in the study by Cheng et al. (2007), results for severity of night sweats only were reported in the paper.
The Panel notes that the human intervention studies provided are inconsistent with respect to an effect of soy isoflavones on frequency and/or severity of hot flushes, and that none of the RCTs which investigated night sweats showed an effect on night sweats.
With regard to the mechanism by which soy isoflavones could exert the claimed effect, it has been proposed that soy isoflavones could have a weak oestrogenic effect on ERβ. This was investigated in the three in vitro studies (Choi et al., 2008; Harris et al., 2005; Kuiper et al., 1997) provided, which assessed the affinity of isoflavones to ERα and ERβ and their half maximal inhibitory concentration (IC50) and their half maximal effective concentration (EC50), and reported that isoflavones had a greater potency to bind to ERβ than to ERα in vitro.
It was proposed in the information provided that ERβ could play a role in body temperature control through which soy isoflavones could be involved in the regulation of vasomotor stability.
The Panel notes that currently there is no consensus on the physiological pathways involved in the occurrence of hot flushes (Andrikoula and Prelevic, 2009; Stearns et al., 2002), and considers that the evidence provided for a possible mechanism by which soy isoflavones could exert an effect on vasomotor symptoms is weak.
In weighing the evidence, the Panel took into account that the evidence provided by 15 human intervention studies is inconsistent with respect to an effect of soy isoflavones on reduction of vasomotor symptoms. The Panel also took into account that most of these studies were at high risk of bias, that the inconsistent results could not be explained by dose, sample size, study duration, or baseline frequency or severity of vasomotor symptoms, and that the evidence of the proposed mechanism of action is weak.
The Panel concludes that the evidence provided is insufficient to establish a cause and effect relationship between the consumption of soy isoflavones and reduction of vasomotor symptoms associated with menopause.
3.3. Ograniczenie objawów naczyniopochodnych związanych z menopauzą (np. uderzenia gorąca, zlewne poty) (ID 1654, 2140, 3154, 3590, 1704b, 3093b)
Among the references provided for the scientific substantiation of the claim were narrative reviews which were either unrelated to the claimed effect or did not contain any original data which could be used for the scientific substantiation of the claim. A number of human, animal and in vitro studies were unrelated to the claimed effect. These references included studies on the effect of soy isoflavones on blood lipid concentrations, severity of asthma, DNA damage, mood, cognitive function, bone loss, bone fractures, cancer incidence, LDL peroxidation, weight loss, inflammation, cardiovascular disease risk and endothelial function. Some human intervention studies used food constituents other than soy isoflavones (e.g. red clover isoflavones) or a combination of soy isoflavones with other constituents (Brzezinski et al., 1997; Campagnoli et al., 2005). Three publications were available only in the form of a brief communication (Jou et al., 2005; Ricciotti et al., 2005) or an abstract (Imhof et al., 2008) which did not provide sufficient information with regard to the study design and the statistical analysis for a full scientific evaluation. One prospective cohort study (Nagata et al., 2001) and two cross-sectional studies (Nagata et al., 1999; Somekawa et al., 2001) which investigated the association of consumption of soy isoflavones and soy products with vasomotor symptoms associated with menopause were provided. The Panel notes that these studies were not sufficiently controlled for other dietary factors or medication use both of which could have an effect on vasomotor symptoms. The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claim.
Two meta-analyses (Howes et al., 2006; Nelson et al., 2006), six systematic reviews (Howes et al., 2006; Huntley and Ernst, 2004; Kronenberg and Fugh-Berman, 2002; Lethaby et al., 2007; Nelson et al., 2006; Tempfer et al., 2007) and 39 human intervention studies which addressed the effect of soy isoflavone consumption on vasomotor symptoms associated with menopause were provided either separately in the consolidated list or in the systematic reviews/meta-analyses provided.
Two of the studies provided were open-label, one-arm, uncontrolled human interventions in 190 (Albert et al., 2002) and 169 (Drews et al., 2007) post-menopausal women, respectively. The Panel considers that no conclusions can be drawn from these uncontrolled studies for the scientific substantiation of the claim. Some RCTs included women with a diagnosis of breast cancer and/or on tamoxifen therapy (MacGregor et al., 2005; Nikander et al., 2003; Petri Nahas et al., 2004; Quella et al., 2000; Secreto et al., 2004; Van Patten et al., 2002). In one study, tamoxifen use was not an exclusion criterion, and the number of women recruited who were on tamoxifen (if any) was not reported (Albertazzi et al., 1998). The Panel notes that no evidence has been provided that women with breast cancer and/or on tamoxifen therapy are representative of the target population with respect to the frequency and/or severity of hot flushes and night sweats, or that results obtained in women with breast cancer and/or on tamoxifen therapy can be extrapolated to menopausal women in the general population. In one study, hormone replacement therapy (HRT), which could have an impact on the claimed effect, was started by some of the subjects during the study (Burke et al., 2003) and in one study (Penotti et al., 2003) the use of HRT or other medication was not reported to be an exclusion criterion, and the number of women (if any) recruited who were on HRT or on other medication which could have an effect on vasomotor symptoms was not reported. In another study (Lewis et al., 2006), some of the subjects took, throughout the study, medication such as Cimicifuga racemosa (L.) Nutt. or therapy for thyroid disease, which could have had an impact on the claimed effect, or during the study started antibiotic therapy which had been defined as an exclusion criterion for the study. In three of the studies (Colacurci et al., 2004; Washburn et al., 1999; Welty et al., 2007a) subjects were not appropriately blinded to the intervention (i.e. the effects of soy isoflavones in various forms were compared to no treatment, or the control and intervention were not consumed at the same daily frequency). The Panel notes that successful blinding of subjects is particularly important to evaluate self-reported health outcomes, such as frequency and severity of hot flushes, for which a high placebo effect can be expected. The description of the methods used for statistical analyses was not provided in two studies (Caserta et al., 2005; Uesugi et al., 2004), one study did not report on the amount of isoflavones used (Murkies et al., 1995), two studies did not report on vasomotor symptoms specifically but on scores for menopausal symptoms combined using the Kupperman Index (Sammartino et al., 2003), or on general quality of life questionnaires (Kok et al., 2005), and one study used the Menopause-Specific Quality of Life Questionnaire, which only provides information about the occurrence and degree of bother caused by menopausal symptoms, including vasomotor symptoms, but not on their frequency or severity (Basaria et al., 2009). In one cross-over study only within-treatment, but no between-treatment, comparisons were reported (Dalais et al., 1998), in one study randomisation did not take into account the pre-planned sub-group analysis of equol and non-equol producing subjects, and no overall results were reported (Jou et al., 2008), and in a further study in which the presence of menopausal symptoms was not an inclusion criterion, no information was provided on whether subjects were comparable at baseline with regard to menopausal symptoms, and whether the use of HRT or other medication, which could have had an impact on the claimed effect, was an exclusion criterion for the study (Scambia et al., 2000). In two small sample size studies (Balk et al., 2002; Duffy et al., 2003) the presence of menopausal symptoms was not an inclusion criterion, and the sample size of women experiencing menopausal symptoms in these studies might have been insufficient to detect a statistically significant difference between the intervention and the control, and in one study (Kaari et al., 2006) the effect of soy isoflavones was compared to oestrogen therapy but lacked a negative control. The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claim.
In the meta-analysis by Howes et al. (2006), four electronic databases were searched (time span of search not reported) for parallel design RCTs of at least four weeks which compared an isoflavone intervention to a non-isoflavone, non-oestrogenic control, and reported the frequency and variance of hot flushes. Twelve studies on soy isoflavones met the inclusion criteria (Albertazzi et al., 1998; Burke et al., 2003; Colacurci et al., 2004; Faure et al., 2002; Han et al., 2002; Knight et al., 2001; Murkies et al., 1995; Penotti et al., 2003; Scambia et al., 2000; St Germain et al., 2001; Upmalis et al., 2000; Van Patten et al., 2002). The Panel notes that study quality was not assessed in this meta-analysis and that some of the studies included did not allow conclusions to be drawn on the effects of isoflavones on the frequency of hot flushes owing to the following limitations: inclusion of women with breast cancer on tamoxifen (Van Patten et al., 2002), uncertainty as to whether women were on tamoxifen (Albertazzi et al., 1998), uncertainty as to whether subjects were blinded to the intervention (Colacurci et al., 2004), uncertainty on the amount of isoflavones provided (Murkies et al., 1995), and uncertainty as to comparability at baseline in the study groups (Scambia et al., 2000). The Panel considers that no conclusions can be drawn from these studies, and thus from the meta-analysis for the scientific substantiation of the claim.
In the meta-analysis by Nelson et al. (2006), several databases were searched up to October 2005 for RCTs in English on the effect of non-hormonal therapies on the frequency and severity of hot flushes. In addition, systematic reviews were hand searched. Eleven trials on soy isoflavone extracts met the inclusion criteria. Trials were included if they measured frequency or severity of hot flushes. Six (Crisafulli et al., 2004; Faure et al., 2002; Penotti et al., 2003; Quella et al., 2000; Scambia et al., 2000; Upmalis et al., 2000) out of the 11 trials provided data for a meta-analysis. The Panel notes that this meta-analysis included a study in patients with breast cancer on tamoxifen medication (Quella et al., 2000), as well as a trial considered by the authors as being of poor quality (Scambia et al., 2000). Results were reported overall and excluding either the study in breast cancer patients or the poor quality trial, but not excluding both. The Panel considers that no conclusions can be drawn from this meta-analysis for the scientific substantiation of the claim.
From the remaining human intervention studies provided, either separately in the consolidated list or in the systematic reviews, seven investigated the effect of soy isoflavones on both frequency and severity of hot flushes (Albertazzi et al., 2005; D'Anna et al., 2007; Khaodhiar et al., 2008; Knight et al., 2001; Nahas et al., 2007; St Germain et al., 2001; Upmalis et al., 2000), two investigated frequency only (Crisafulli et al., 2004; Faure et al., 2002) and three severity only (Cheng et al., 2007; Han et al., 2002; Kotsopoulos et al., 2000). Three of these studies also investigated the effect of soy isoflavones on night sweats (Cheng et al., 2007; St Germain et al., 2001; Upmalis et al., 2000). In all of these studies, subjects in the intervention and control groups within these studies were not different at baseline with regard to the frequency and/or severity of hot flushes and/or night sweats.
In eight out of nine studies which investigated the effect of soy isoflavones on the frequency of hot flushes, frequency of hot flushes was self-assessed in symptom diaries or cards, in which the daily symptoms were noted, while in the remaining study by St Germain et al. (2001) this outcome was assessed by an interviewer-administered menopausal index. In the 10 studies which investigated the effect of soy isoflavones on severity of hot flushes, severity of hot flushes was assessed by self-rating scales in five studies (Cheng et al., 2007; D'Anna et al., 2007; Khaodhiar et al., 2008; Nahas et al., 2007; Upmalis et al., 2000), by the vasomotor sub-scale of the Greene Climacteric Scale in two studies (Albertazzi et al., 2005; Knight et al., 2001), by the vasomotor symptom score of the Kupperman Index in one study (Han et al., 2002), by an interviewer-administered menopausal index in one study (St Germain et al., 2001), and by a validated questionnaire in the remaining study (Kotsopoulos et al., 2000). In the three of the aforementioned studies which investigated night sweats, one study (Cheng et al., 2007) assessed the severity of night sweats only, one study (Upmalis et al., 2000) assessed the frequency of night sweats only, while St Germain et al. (2001) assessed both of these measures of night sweats.
In the double-blind, randomised cross-over study by Albertazzi et al. (2005), 100 post-menopausal women (44-65 years) were allocated to consume daily 90 mg genistein and placebo for six weeks each without a wash-out period in between; the cross-over design had not been pre-planned. Subjects had a mean hot flush score (frequency x severity) of 7 at baseline, but the study also included subjects who were not experiencing any symptoms. The primary endpoint of the study was markers of bone turnover. One subject dropped out in the placebo group. Statistical analysis was adjusted for sequence and time to exclude a carry-over and a period effect. Frequency and severity of hot flushes were not significantly different between the genistein and the placebo periods. Subjects with a hot flush score >9 were analysed in a post-hoc analysis (n=41). The Panel notes that this sub-group analysis was not pre-planned, and considers that no conclusions can be drawn from the sub-group analysis for the scientific substantiation of the claim. The Panel also notes that not all subjects included in the study were experiencing vasomotor symptoms, and that the overall results of this study do not show an effect of genistein on the frequency or severity of hot flushes.
In the double-blind, randomised, placebo-controlled study by Khaodhiar et al. (2008) 191 post-menopausal women (aged 38-60 years) experiencing at least four hot flushes (mean frequency: approx. 8, mean severity approx. 2.1 on a 4-point scale) per day were randomised to consume daily either 40 mg daidzein-rich isoflavone aglycones (DRI) (n=48 analysed), 60 mg DRI (n=49 analysed) or placebo (n=45 analysed) in capsule form for 13 weeks. It was calculated that 50 women per group would be needed to detect with an 80 % power an average difference between groups of 1.2 hot flushes per day and a hot flush score (frequency x severity) of three units per day with a 0.58 SD and a p-value <0.05. Forty-nine subjects did not complete the study (group not reported) and were not taken into account in the analysis. Hot flush frequency and severity was not significantly different between the 40 mg or 60 mg DRI groups compared to placebo at any time point (4, 8 and 12 weeks). In a post-hoc analysis, data from week 12 from both DRI groups were pooled together and compared to placebo. The Panel notes that the data pooling was not pre-planned, and considers that no conclusions can be drawn from this post-hoc analysis for the scientific substantiation of the claim. The Panel also notes the high drop-out rate, that missing data were not taken into account in the analysis, and that the primary analysis of this study does not show an effect of daidzein-rich isoflavone aglycones on the frequency or severity of hot flushes.
In the double-blind, randomised, placebo-controlled trial by Kotsopoulos et al. (2000), 94 post-menopausal women (mean age 59.5 years) of whom 80 % were experiencing menopausal symptoms (not different between groups, mean symptom score approx. 0.8 on a 3-point scale) were randomised to consume either 118 mg isoflavones in soy powder (n=44) or casein powder (n=50) twice daily in sachet form taken in the form of beverages for 12 weeks. Nineteen subjects withdrew from the study (10 in the soy and 9 in the placebo group), and a further two in the soy group were not taken into account in the analysis (n=32 analysed in the soy group and n=41 analysed in the placebo group). No statistically significant differences were observed between the intervention and control group with respect to vasomotor symptom scores at 12 weeks. No other time points were measured. The Panel notes that missing data were not taken into account in the analysis and that this study does not show an effect of soy isoflavones on the severity of hot flushes.
In a double-blind, randomised, controlled, multicentre study, 75 post-menopausal women (mean age: 53 years) with at least seven hot flushes (including night sweats) per day (mean frequency: 10) during a 2-week pre-study period were allocated to consume daily for 16 weeks either 70 mg soy isoflavones in the form of a soy extract (n=39) or placebo (n=36, microcrystalline cellulose and magnesium stearate) (Faure et al., 2002). A sample size of 30 subjects per arm was required to detect, with 90 % power, a difference of three hot flushes per 24 hours, assuming an SD of 3.8 with a p<0.05. The primary endpoint of the study was the number of daily moderate to severe hot flushes (including night sweats) in each month of treatment. Six subjects dropped out in the soy group, and 14 in the placebo group. Data analysis was reported to have been performed per protocol, and as “last observation carried forward”. The Panel notes that carrying forward the last observation is not an appropriate
method of taking into account missing data. Per protocol/completer analysis did not show a statistically significant difference between the soy and placebo groups in numbers of moderate to severe hot flushes. The Panel notes the high drop-out rate, and that the primary analysis of this study does not show an effect of soy isoflavones on the frequency of hot flushes.
In the double-blind, placebo-controlled intervention by St Germain et al. (2001), 69 peri-menopausal women (aged 42-62 years) who were experiencing at least 10 vasomotor symptoms per week (mean frequency and severity not reported) received either isolated soy protein containing 80.4 mg/day isoflavone aglycone components (ISP+, n=24), 4.4 mg/day isoflavone aglycone components (ISP-, n=24) or control (whey protein, n=21) in the form of muffins and soy or placebo powder as meal replacements for 24 weeks in four different cohorts in which the interventions were equally represented. One control subject was not included in the analysis. No statistically significant effect of soy isoflavones on the reduction of frequency or severity of hot flushes and night sweats between groups was found at any time point (12 and 24 weeks). The Panel notes the lack of power calculations, and that this study does not show an effect of soy isoflavones on the frequency or severity of hot flushes or night sweats.
In the double-blind, randomised, placebo-controlled trial by Knight et al. (2001), 24 post-menopausal women (40-65 years) with at least three hot flushes (mean frequency: approx. 7.5, mean severity not reported) per day were randomised to receive either 134.4 mg soy isoflavones (containing 77.4 mg of aglycones) in 60 g soy powder (n=12) or casein powder (n=12) once daily in sachet form (to be consumed as beverages) for 12 weeks. Three women in the intervention group and one in the placebo group withdrew from the study. Analyses were reported to have been performed in the intention-to-treat population. No statistically significant differences were found between the soy and the placebo groups with regard to frequency and severity of hot flushes at 12 weeks. No other time points were measured. The Panel notes that no power calculations were performed, and that this study does not show an effect of soy isoflavones on the frequency or severity of hot flushes.
In the double-blind, randomised, controlled, multicentre (15 centres) trial by Upmalis et al. (2000), 177 post-menopausal women with at least five hot flushes per day (mean frequency: 9, mean severity: 2 on a 3-point scale) were randomised to receive daily either 50 mg of soy isoflavones in a soy extract in tablet form (n=89) or placebo (not specified, n=86) for 12 weeks. The primary endpoint for efficacy was reported to be the reduction of frequency and severity of hot flushes. Data from 59 subjects in the intervention group and 63 in the placebo group were evaluated for hot flushes and night sweats. There was a statistically significant reduction in severity of hot flushes per week between the soy and the placebo group at week 12 (approx. -27 % vs. -19 %, p=0.01). There was a statistically significant reduction in the frequency of hot flushes and episodes of night sweats (as assessed by awakenings during the night) between the soy and the placebo group at week six (approx. -27 % vs. -12 %, p=0.02 for hot flushes; approx. -60 % vs. -25 % p<0.04 for night sweats), while this difference was not significant at week 12. The Panel notes that missing data were not taken into account in the analysis, and that this study shows an effect of soy isoflavones on the severity of hot flushes, but that soy isoflavones did not have a sustained effect on the frequency of hot flushes and episodes of night sweats. The Panel notes that the results of this study are inconsistent with respect to the effect of soy isoflavones in soy protein on vasomotor symptoms.
In a sub-study of a double-blind, randomised, controlled bone loss trial, D'Anna et al. (2007) analysed 247 (of 389) post-menopausal women (mean age: approx. 53 years) experiencing hot flushes (mean frequency: approx. 4, mean severity: approx. 2.3 on a 3-point scale) who consumed either 27 mg per day of genistein (n=125) or placebo (n=122) for 12 months. It was calculated that at least 97 subjects per group were needed to detect, with an 80 % power in two-sided tests, a difference of 20 % between groups with a p<0.05. Ten subjects dropped out in the genistein group and eight in the placebo group, and were not taken into account in the data analysis (n=115 analysed in the genistein group and n=114 analysed in the placebo group). A statistically significant difference was observed between the
genistein and the placebo groups in the frequency of hot flushes per day at 1 month (mean change -1.1 vs. 0.2, p<0.001), at 3 months (mean change -1.8 vs. 0.5, p<0.001), at 6 months (mean change -2.0 vs. 0.5, p<0.001) and at 12 months (mean change -2.5 vs. 0; p<0.001), and in severity scores at 1 month (mean change -0.3 vs. 0.1, p=0.005), at 3 months (mean change -0.6 vs. 0.1, p<0.001), at 6 months (mean change -0.7 vs. 0, p<0.001) and at 12 months (mean change -0.9 vs. -0.1; p<0.001). The Panel notes that the study was a sub-analysis of a bone study, and that missing data were not taken into account in the analysis. The Panel also notes that this study shows an effect of genistein on the frequency and severity of hot flushes.
In the randomised, placebo-controlled trial by Han et al. (2002), 82 women (aged 45-55 years) who were experiencing hot flushes (mean severity score approx. 2.5 on a 3-point scale) were assigned to consume daily for four months either 150 mg soy protein and 100 mg soy isoflavones (n=41) or 150 mg soy protein without isoflavones (n=41). One subject in each group dropped out during the study. The vasomotor symptom score of the Kupperman Index significantly decreased in the soy isoflavone group compared to the placebo group (mean change -3.1 vs. -0.1; p<0.01) at four months. The Panel notes the basic statistical analyses performed, and that this study shows an effect of soy isoflavones on the severity of hot flushes.
In the double-blind, randomised, placebo-controlled study by Nahas et al. (2007), 80 post-menopausal women (mean age approx. 55 years) with at least five hot flushes (mean frequency: approx. 10, mean severity: approx. 9 on a 12-point scale) per day were allocated to consume daily either 100 mg of isoflavones in 250 mg standardised soy extract (n=40) or placebo (lactose; n=40) for ten months. Four subjects dropped out during the study (two in the intervention group and two in the placebo group) and were not taken into account in the analysis (n=38 analysed in the soy group and n=38 analysed in the placebo group). At the end of the study, the mean frequency of hot flushes decreased significantly in the soy group as compared to placebo (mean change -6.5 vs. -4.2, p<0.001), as did the hot flush severity scores (mean change -6.5 vs. -2.7, p<0.001). Between-group comparisons for other time points (4 and 7 months) were not reported. The Panel notes that the statistical analysis was not appropriate for the study design, that missing data were not taken into account in the analysis, and that this study shows an effect of soy isoflavones on the frequency and severity of hot flushes.
In the double-blind, placebo-controlled study by Crisafulli et al. (2004), 90 post-menopausal women (47-57 years) experiencing a mean of 4.6 hot flushes per day were randomised to receive either HRT (n=30), 54 mg genistein per day (n=30) or placebo (n=30) for 12 months. The primary endpoint of the study was bone loss. Seven subjects withdrew from taking the intervention or placebo (groups and reasons for withdrawal were not reported) but completed the study and were included in the analysis. Compared to placebo the number of hot flushes decreased significantly after 3 months (-22 %, 95 % -38, -6.2, p<0.01), 6 months (-29 %, 95 % CI -45, -13, p<0.001) and 12 months (-24 %, 95 % CI, -43, -5, p<0.01) of genistein consumption. The Panel notes that the description of the statistical methods used is insufficient, and that this study shows an effect of genistein on the frequency of hot flushes.
In the double-blind, randomised placebo-controlled trial by Cheng et al. (2007), 60 post-menopausal women (49-69 years) with hot flushes and night sweats (mean hot flush and night sweat scores approx. 1.4 on a 5-point scale) were assigned to consume daily either 60 mg isoflavones in a fruit-flavoured drink produced from soy beans (n=26 completers) or a fruit-flavoured oat-meal drink (n=25 completers) for 12 weeks. Both vasomotor symptom frequency and severity were assessed, but results were only reported for severity scores. Data analyses were performed in completers only. At week 12, severity scores for hot flushes were statistically significantly different between the soy and the placebo group (mean change -0.7 vs. +0.1; p<0.01), while no differences were found in the severity scores for night sweats. No other time points were measured. The Panel notes the absence of a placebo effect, that missing data were not taken into account in the analysis, and that this study shows an effect of soy isoflavones on the severity of hot flushes but not on the severity of night sweats.
The Panel notes that from the 12 human intervention studies provided from which conclusions can be drawn for the scientific substantiation of the claim, most of which have some methodological limitations and/or inadequate reporting, five studies (n=498 subjects analysed; range: 25-115 per group) with a duration of 12 weeks to 12 months using doses from 27 mg genistein to 100 mg of total isoflavones showed a statistically significant effect of soy isoflavones on vasomotor symptoms after one month (D'Anna et al., 2007), three months (Cheng et al., 2007; Crisafulli et al., 2004), four months (Han et al., 2002) and 10 months (Nahas et al., 2007), whereas six studies (n=463 subjects analysed, range: 12-99 per group/period) with a duration of six weeks to six months using doses from 40 mg to 118 mg of total isoflavones did not show a statistically significant effect of soy isoflavones on vasomotor symptoms (Albertazzi et al., 2005; Faure et al., 2002; Khaodhiar et al., 2008; Knight et al., 2001; Kotsopoulos et al., 2000; St Germain et al., 2001), and that one study in 122 analysed subjects using a dose of 50 mg isoflavones for four months led to inconsistent results with regard to the effect soy isoflavones on vasomotor symptoms.
In weighing the evidence, the Panel took into account that the evidence provided by 12 human intervention studies is inconsistent with respect to the reduction of vasomotor symptoms, and that the inconsistent results cannot be explained by dose, sample size, study duration, or baseline frequency or severity of vasomotor symptoms.
The Panel concludes that the evidence provided is insufficient to establish a cause and effect relationship between the consumption of soy isoflavones and reduction of vasomotor symptoms associated with menopause.
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