Three-monthly gonadotropin-releasing hormone agonist for ovarian function suppression in premenopausal breast cancer: a systematic review and meta-analysis

PURPOSE: Ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) improves outcomes in premenopausal women with hormone receptor-positive (HR +) breast cancer (BC), most commonly using monthly administration. The potential equivalence of 3-monthly (3 M) versus monthly (1 M) schedules has been suggested but remains uncertain. METHODS: We performed a systematic review and meta-analysis of interventional studies comparing 3 M and 1 M GnRHa regimens in premenopausal women with HR + BC receiving endocrine therapy. Outcomes included ovarian escape (OE), mean estradiol (E2) levels, disease-free survival (DFS), progression-free survival (PFS), and adverse events. Subgroup analyses were performed by estradiol assay type, and a sensitivity analysis restricted to RCTs. RESULTS: Fifteen studies comprising 4,324 patients were included, of whom 2,098 (48%) received a 3 M regimen. The pooled OE was 10% and showed no significant difference between schedules (RR 0.86; 95% CI 0.60-1.22; p = 0.39). Ultrasensitive assays yielded higher OE detection (31%) without inter-regimen differences (RR 0.90; 95% CI 0.38-2.14). Mean E2 concentrations at 12 weeks were similar (MD 1.36 pg/mL; 95% CI -3.66 to 6.38), with consistent findings in RCT-only analyses (MD -1.77 pg/mL; 95% CI -5.71 to 2.17). DFS (RR 1.02; 95% CI 0.67-1.56) and PFS (RR 0.86; 95% CI 0.72-1.04) were also comparable. No clinically relevant differences were observed in reported safety outcomes. CONCLUSION: 3 M GnRHa achieved OFS efficacy comparable to 1 M regimens, with no meaningful differences in survival or safety. The findings support 3 M GnRHa as a valid and practical alternative for OFS in appropriately selected premenopausal women with HR + BC.