ID 3093 - 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.

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.

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