4. Discussion
Our study aims to investigate the efficacy and safety, as well as the
influencing factor of phytoestrogens in alleviating depression among
postmenopausal women. The results indicated that phytoestrogens have a
positive significant effect at reducing depression among postmenopausal
women, and would be more effective when using high dosages (High Dose:
dose>100mg). Lephart et al44 has
published research in 2005 on the mechanism of phytoestrogen action,
which investigated the levels of brain Bcl-2-associated death protein (a
proapoptotic member of Bcl-2 protein family) and neuron-specific β-III
tubulin (an early marker of neuronal differentiation/survival) in rats,
suggesting that soy isoflavones can potentially ameliorate anxiety and
quicken recovery from trauma. Therefore, based on animal trials, the
effectiveness of phytoestrogens has scientifically been proved and they
can be used to relieve mental disorders.
The
effects of the
isoflavone
group were better than the lignans group. Among
them,
the red clover isoflavones indicated the best effectiveness among all
included phytoestrogens (SMD=-1.05; 95% [CI]=-1.45 to -0.65). As
one study found in legumes, red clover isoflavone through estrogen
receptor (ER) binding and activation of ER-dependent gene
transcription,
which has a relatively high binding affinity for the ER-α and ER-β,
isoflavones demonstrate up to ~1600 times lower affinity
for ER-α45. This may explain the significant effect of
isoflavones.
High doses (dose>100mg/day) of isoflavone phytoestrogens
are more effective than low doses. The reason why isoflavone at the
higher dose effectively alleviated menopausal symptoms in the current
study may be because the isoflavones were completely presented in the
aglycone form, which is absorbed faster and in greater amounts than the
glucoside form46. Other studies reported excellent
tolerance for the use of soy isoflavones to extract in the daily dose
from 40 to 50mg47,48. However, the alarm raised by the
Italian study that showed an increase in endometrial hyperplasia after a
5-year intake of 150 mg/day of isoflavones33.
Therefore, to identify the best dose to use, which could better
alleviate the symptoms of depression in postmenopausal women, we look
forward to more primary studies on phytoestrogens in the future.
The postmenopausal women in Europe had the best depressive remission
among the five continents. As the dietary habits of the women in various
countries are different, such as the preferable diet of having soy
products in Japan and Korea may cause an effect on the results of the
phytoestrogens49.
Additionally, considering the ethnic diversity in different regions,
more experiments are needed to explore the specific conclusions.
106 participants have reported 17 different adverse reactions in five of
the ten included studies with 379 participants. Mild intensity abdominal
pain is the predominant AE of phytoestrogens in postmenopausal women
with depression. However, concerning the adverse events searched in the
included studies, due to the sporadic nature of reported by various
groups, it was not possible to determine the association of these events
with the use of phytoestrogens.
Although
this systematic review and meta-analysis found that phytoestrogens were
effective in postmenopausal women, our outcomes need to be treated with
caution due to several
limitations.
Firstly, the number of studies included in this meta-analysis was not
very many that some subgroup analyses could only be combined with two or
three studies. Besides, though all the studies we included were RCTs,
there was the weakness of methodologies in several studies, such as
inadequate treatment allocation, small sample size, and unclear blinding
method. Secondly, the sensitivity
and specificity of various measurements are all different, and there is
no utilized gold-standard diagnostic for depression. Hence, we hope that
specific depression scales can be unified in the evaluating methods in
future clinical research. Thirdly, even we used subgroup analysis to
explore the sources of heterogeneity, but the results still showed high
heterogeneity. Therefore, more caution is needed in the promotion of the
results50.
There
still needs to be more clinical trials on different phytoestrogens, to
identify the most appropriate dosage, duration, and other treatment
applications to relieve menopausal depression as much as possible.