Effects of Progesterone on Preclinical Animal Models of Traumatic Brain Injury: Systematic Review and Meta-analysis

Since the publication of two phase III clinical trials not supporting the use of progesterone in patients with traumatic brain injury (TBI), several possible explanations have been postulated, including limitations in the analysis of results from preclinical evidence. Therefore, to address this question, a systematic review and meta-analysis was performed to evaluate the effects of progesterone as a neuroprotective agent in preclinical animal models of TBI. A total of 48 studies were included for review: 29 evaluated brain edema, 21 evaluated lesion size, and 0 studies reported the survival rate. In the meta-analysis, it was found that progesterone reduced brain edema (effect size - 1.73 [- 2.02, - 1.44], p < 0.0001) and lesion volume (effect size - 0.40 [- 0.65, - 0.14], p = 0.002). Lack of details in the studies hindered the assessment of risk of bias (through the SYRCLE tool). A funnel plot asymmetry was detected, suggesting a possible publication bias. In conclusion, preclinical studies show that progesterone has an anti-edema effect in animal models of TBI, decreasing lesion volume or increasing remaining tissue. However, more studies are needed using assessing methods with lower risk of histological artifacts.