Abstract
BACKGROUND: There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14. RESULTS: Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P < 0.00001; I(2) = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P = 0.0001; I(2) = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P < 0.00001; I(2) = 69%) and counts of different types of follicles. In addition, it elevates the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P < 0.00001; I(2) = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P < 0.00001; I(2) = 80%) expression, while reducing FSH expression (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P < 0.00001; I(2) = 90%). Subgroup analysis indicates that the source of EVs, animal species, modeling method, administration route, and test timepoint affected efficacy. Trial sequential analysis showed that there was sufficient evidence to confirm the effects of stem cell-derived EVs on birth counts, ovarian weights, and follicle counts. However, the impact of stem cell-derived EVs on pregnancy rates needs to be further demonstrated through more animal experimental evidence. CONCLUSIONS: Stem cell-derived EVs demonstrate safety and efficacy in treating POF animal models, with potential improvements in fertility outcomes. TRIAL REGISTRATION: PROSPERO registration number: CRD42024509699.