Comparative Efficacy of GnRHa Monotherapy vs Combination Therapy for Central Precocious Puberty

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 This work aims to synthesize evidence comparing the effects of GnRHa monotherapy and combination therapies on height-related outcomes in children with CPP. Methods Data sources included PubMed, EMBASE, Cochrane Library, Wanfang Data, and CNKI through December 31, 2024. Study selection included randomized controlled trials (RCTs) and cohort studies involving children aged 12 years or younger with CPP or early puberty, reporting height-related outcomes and a follow-up of 6 months or more. Data were pooled using common- or random-effects models and reported as mean differences (MDs) with 95% 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. Results A total of 70 studies (30 RCTs and 40 cohort studies; 5266 children) were included. Growth hormone (GH) combination therapy significantly improved PAH change (MD, 3.48 cm; 95% CI, 2.98-3.98) and GV (MD, 1.82 cm/y; 95% CI, 1.32-2.31) in RCTs, and height gain (MD, 3.81 cm; 95% CI, 2.77-4.84) and PAH change (MD, 3.06 cm; 95% CI, 2.26-3.86) 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. Conclusion 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.