Comparative Efficacy of GnRHa Monotherapy vs. Combination Therapy for Central Precocious Puberty: A Systematic Review and Meta-Analysis

Abstract Context Central precocious puberty (CPP) can reduce adult height. Studies comparing the efficacy of gonadotropin-releasing hormone analogue (GnRHa) monotherapy with combination therapies show inconsistency. Objective To synthesize evidence comparing the effects of GnRHa monotherapy and combination therapies on height-related outcomes in children with CPP. Data Sources PubMed, EMBASE, Cochrane Library, Wanfang Data, and CNKI through December 31, 2024. Study Selection Randomized controlled trials (RCTs) and cohort studies involving children ≤12 years with CPP or early puberty, reporting height-related outcomes and a ≥ 6-month follow-up. Data Extraction Data were pooled using common- or random-effects models and reported as mean differences (MDs) with 95% confidence intervals (CIs) for primary outcomes, including height gain (adult height minus pretreatment predicted adult height [PAH]), PAH change (posttreatment PAH minus pretreatment PAH), and growth velocity (GV) in children with CPP. Data Synthesis 70 studies (30 RCTs and 40 cohort studies; 5,266 children) were included. Growth hormone (GH) combination therapy significantly improved PAH change (MD, 3.48 cm; 95% CI, 2.98 to 3.98) and GV (MD, 1.82 cm/year; 95% CI, 1.32 to 2.31) in RCTs, and height gain (MD, 3.81 cm; 95% CI, 2.77 to 4.84) and PAH change (MD, 3.06 cm; 95% CI, 2.26 to 3.86) in cohort studies, compared with GnRHa monotherapy. However, high heterogeneity remains across outcomes, even after subgroup analysis of treatment duration and GH dose, which limits the certainty of these findings. Stanozolol, oxandrolone, and estrogen showed improved growth outcomes, although evidence was limited. Longer treatment durations and higher GH doses were associated with greater benefits. Conclusions GH combination therapy enhances growth outcomes in children with CPP compared to GnRHa alone. Stanozolol, oxandrolone, and estrogen show promise but require further research. Personalized combination regimens and additional long-term RCTs are needed, particularly involving male patients and non-GH adjunctive therapies.