Supplementary Material for: Gonadotropin-Releasing Hormone Agonists During Gonadal Chemotherapy for the Effect on Pregnancy Outcome and Ovarian Function in Premenopausal Patients With Breast Cancer: A Systematic Review and Meta-Analysis

Objectives：To evaluate the effects of gonadotropin-releasing hormone agonists (GnRHa) on pregnancy outcomes, ovarian function failure (POF), menstrual recovery, disease-free survival (DFS), and adverse events in premenopausal breast cancer patients during gonadal chemotherapy. Methods：We systematically searched PubMed, Cochrane Library and Embase databases. The trials were eligible if they included premenopausal breast cancer patients treated chemotherapy alone or with concurrent GnRHa, and reported ovarian function recovery data. Heterogeneity for the eligible data was assessed and a pooled risk ratio (RR) with 95% confidence interval (CI) was calculated. A meta-analysis was conducted using a fixed-effects model. Results：Fifteen randomized controlled trials were included in this analysis. The results indicated that GnRHa combined with chemotherapy significantly increased pregnancy rates compared with chemotherapy alone (RR=1.76; 95% CI:1.16-2.67), and decreased rates of POF (RR=0.42; 95% CI: 0.35-0.51). For secondary endpoints, the GnRHa group improved menstrual recovery rates (RR=1.20; 95% CI: 1.11-1.30), and decreased the rate of amenorrhea 1-2 years after chemotherapy (RR=0.50; 95% CI: 0.40-0.63). Furthermore, the 5-year DFS and OS rate were significantly improved in the GnRHa group. Conclusion：For premenopausal breast cancer patients receiving gonadal toxic chemotherapy, adjuvant chemotherapy with GnRHa can better protect the ovarian function of patients, reduce the rate of premature ovarian failure and amenorrhea, and improve the pregnancy rate, menstrual recovery rate, disease-free survival rate and overall survival rate of patients.