Stem cell therapy for premature ovarian insufficiency: a systematic review and meta-analysis of animal and clinical studies.

Abstract

The aim of this systematic review and meta-analysis is to evaluate the efficacy of stem cell therapy in mouse models of POI and patients with POI. The PubMed, Web of Science, and Embase databases were searched from inception to February 2022 for relevant animal and clinical studies. The reference lists of the included reviews were manually searched to identify additional eligible studies. Data were independently extracted by two investigators, and disagreements were resolved by discussion. SYRCLE's risk of bias tool and the MINORS tool were used to assess the quality of animal and clinical studies by two independent investigators. All statistical analyses were conducted using Review Manager 5.3 software. A total of twenty animal studies and six clinical studies were included in this meta-analysis. In animal studies, the results showed that stem cells could improve hormone levels, follicle count, estrous cycle and pregnancy outcome. For hormone levels, stem cells increased serum E2 and AMH levels and decreased serum FSH and LH levels compared with the control group (serum E2 level: SMD: 5.05, 95% CI 4.21-5.90, P < 0.00001; serum AMH level: SMD: 4.42, 95% CI 3.06-5.79, P < 0.00001; serum FSH level: SMD: -3.79, 95% CI -4.87 to - 2.70, P < 0.00001; serum LH level: SMD: -1.31, 95% CI -1.65 to -0.96, P < 0.00001). All follicle counts, except for the antral follicle count, were significantly changed compared with the control group. (primordial follicle count: SMD: 4.61, 95% CI 3.65-5.56, P < 0.00001; primary follicle count: SMD: 3.35, 95% CI 1.08-5.63, P = 0.004; secondary follicle count: SMD: 3.23, 95% CI 1.92-4.55, P < 0.00001; total follicle count: SMD: 4.84, 95% CI 2.86-6.83, P < 0.00001; oocyte count: SMD: 7.56, 95% CI 5.92-9.20, P < 0.00001; atretic follicle count: SMD: -1.79, 95% CI -2.59 to -1.00, P < 0.00001). For the estrous cycle, stem cell therapy increased the number of estrous cycles (WMD: 2.72, 95% CI 2.07-3.37, P < 0.00001) and decreased the duration of the estrous cycle (WMD: -1.26, 95% CI -1.84 to -0.69, P < 0.0001) compared with the control group. For pregnancy outcomes, stem cell therapy increased the fertility rate (RR: 3.00, 95% CI 1.74-5.17, P < 0.0001) and litter size (WMD: 3.82, 95% CI 0.36-7.28, P = 0.03) compared with the control group. In animal studies, the asymmetric funnel plot of serum E2 and FSH levels indicated the possibility of publication bias. Unpublished and negative studies may be the source of publication bias. In clinical studies, the results showed that stem cell therapy could decrease serum FSH level (MD: -30.32, 95% CI -59.03 to -1.01, P = 0.04) and increase AFC (MD: 1.07, 95% CI 0.70-1.43, P < 0.00001), pregnancy rate (RD: 0.19, 95% CI 0.04-0.34, P = 0.01) and live birth rate (RD: 0.19, 95% CI 0.07-0.31, P = 0.001) in POI patients. In addition, there was no significant difference in menstrual function regained (RD: 0.22, 95% CI -0.03-0.46, P = 0.09), oocytes retrieved (MD: 1.00, 95% CI -0.64-2.64, P = 0.23) and embryos (MD: 0.80, 95% CI -0.15-1.76, P = 0.10) between different groups. This meta-analysis suggested that stem cell therapy might be effective in POI mouse models and patients and could be considered a potential treatment to restore fertility capability in POI patients.