Discussion:
To the best of our knowledge this is the first meta-analysis which
reported the effect of soy products based on soy isoflavones and the
combination of soy isoflavones plus soy protein on serum CRP levels
among postmenopausal women.
Our systematic review contains 23 articles studying the effects of soy
isoflavones and soy isoflavones plus soy protein on serum CRP
concentration. Meta-analysis contains 19 articles with 33 datasets and
its results indicated that soy isoflavones and soy isoflavones plus soy
protein could not change CRP concentration among postmenopausal women.
Our meta-analysis results confirm the result of a meta-analysis in year
2011(37) which reported the effect of
overall soy products, furthermore; this results revealed that new
published papers with longer treatment duration, using higher dose of
soy isoflavones or soy protein, and more sample size could not change
non-significant effect of soy products on serum CRP levels in previous
article.
There was no significant change in serum levels of CRP in subgroup
analysis based on dose, age, intervention duration, baseline CRP level,
sample size, region, quality assessment, publication year, and health
status. Dose response analysis revealed no association of higher dose of
soy isoflavones with isoflavones effect on CRP levels.
Review articles revealed that some nutrients might change inflammatory
mediators (56,
57). Evidence from in vitro
(58) and animal studies
(59) have indicated that soy products can
reduce the activity of nuclear factor-kB as cytokine-induced signal
transduction thereby decreases the concentration of pro-inflammatory
cytokine. Furthermore, new evidence suggested that IL-6 by activating
nuclear factor-kB is able to induce hs-CRP expression
(60). Therefore, in participants with
health condition which enhances IL-6 levels, soy products by inhibition
of IL-6 effect on nuclear factor-kB and CRP expression can reduce CRP
levels, but this results were not confirm in our meta-analysis.
Regardless of subgroup analysis, one of the main reasons for
non-significant effect of soy isoflavones or the combination of soy
isoflavones and soy protein on serum CRP levels might be due to
different ability of participants in the metabolization of isoflavones
to equol (61). Equol is an isoflavandiol
estrogen produced from daidzein by bacterial flora in the intestines
(61). Although equal has the superior
antioxidant activity in compared with other isoflavones, most people do
not have ability to produce equol. In western countries 20-25% of
papulation have the capacity to produce equol and in Asian countries
about 60% of populations produce equol
(62). The result of univariate
meta-regression analysis showed there is a significant association
between region and soy isoflavones effect on serum CRP levels.
In a study by Acharjee et al., (25)
revealed that taking soy products causes no significant changes in blood
CRP levels among equol non-producers women, but equol-producers
indicated significant reduction. Most articles in our meta-analysis did
not report any information regarding equol production in participants
and we could not perform subgroup analysis based on equol non-producers
and equol-producers.
According to scientific proposal, soy products might be more effective
among Asian papulation, but our analysis revealed non-significant
changes in CRP levels in subgroup analysis based on region. One possible
reason for this result might be participants age in this meta-analysis.
Subjects in our article were postmenopausal women and intestinal
microflora changes during aging might be a reason for low amount of
equal production in intestine, therefore; soy isoflavones fail to exert
anti-inflammatory effects. (63)
There was a considerable heterogeneity between included studies even in
most subgroup analysis. The probable reasons might be related to
discrepancies in the ability of study papulation in metabolization and
absorption of isoflavones, participants’ intestinal flora, dietary habit
and genetic background of the participants.
Our systematic review and meta-analysis has several limitations. First
of all, most articles did not have any information related to equal
production among participants, therefore; we did not assess whether
equal production could change non-significant effect of soy products on
CRP to significant effect among elderly subjects. Secondly,
participants’ dietary habit was not reported in any article. Since
dietary habit might change intestinal flora, neglecting confounding
effect of dietary habit is an important issue. Thirdly, most articles
did not have any information regarding drugs used by participants.
Fourthly, trials included in this meta-analysis had small or moderate
sample size. Small sample size does not have enough statistical power to
detect a significant effect in trials and in the meta-analysis. Fifthly,
even though changes in fat mass are very important factor in
inflammatory mediators levels, most RCTs did not report any information
related to body composition changes. Sixthly, we did not include
non-English articles.
Our meta-analysis had a number of strengths in comparison with previous
meta-analysis. First of all, the large number of studies were included
in meta-analysis, therefore; we could conduct subgroup analysis based on
dose, age, intervention duration, baseline CRP level, sample size,
region, BMI, quality assessment, and publication year. Secondly, we
included RCTs which used only soy products in form of supplements or
natural soy products and we excluded studies with other food supplements
beside soy products. Thirdly, our meta-analysis included 19 trials from
different countries; therefore, we might limit the differences in habits
and lifestyles in this analysis. Fourthly, we reported the effect of soy
isoflavones or the combination of soy isoflavones and soy protein
separately with sufficient effect sizes. Fifthly, we did not any
limitation on publication time. Finally, Egger’s test revealed no
evidence of significant publication bias.
In conclusion according to our results, published RCTs did not provide
strong evidence regarding decreasing effect of soy isoflavones or the
combination of soy isoflavones plus soy protein on CRP concentration
among postmenopausal women. Future studies should report soy effect
among equal producers and non-producers and assess gut microbial
composition; furthermore, confounding effect of diet should be adjusted.