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.