Effects of combined training during GnRHa therapy on pubertal biomarkers and executive-function outcomes in girls with central precocious puberty and overweight or obesity: an exploratory secondary analysis of a randomized controlled trial

This exploratory secondary analysis examined whether combined aerobic and resistance training was associated with puberty-related endocrine biomarkers and executive-function outcomes in girls with central precocious puberty (CPP) and overweight or obesity receiving gonadotropin-releasing hormone agonist (GnRHa) therapy. Data were obtained from a two-arm randomized controlled trial with a separately recruited non-randomized reference group. Thirty-six girls with CPP and overweight or obesity were randomized to combined training plus ongoing GnRHa therapy (CPPT; n = 18) or GnRHa therapy alone (CPP; n = 18). Fifteen age-matched prepubertal girls with overweight or obesity without CPP formed the reference group (CO). CPPT completed three supervised 60-min sessions weekly for 12 weeks, followed by 4 weeks of detraining. Outcomes were assessed at baseline, week 12, and week 16. Kisspeptin, leptin, and estradiol were treated as exploratory endocrine outcomes, and executive-function measures as a separate exploratory outcome family. All randomized participants were analyzed using linear mixed models with all available observations. Holm adjustment was applied across the three endocrine Group × Time interaction tests and the Benjamini–Hochberg false discovery rate (FDR) procedure across the executive-function interaction tests. Time-specific CPPT–CPP contrasts were Bonferroni-adjusted. After Holm adjustment, the Group × Time interactions remained statistically significant for kisspeptin (F[2, 32.67] = 4.03; adjusted P =0.027), leptin (F[2, 32.61] = 6.52; adjusted P =0.008), and estradiol (F[2, 32.46] = 8.78; adjusted P =0.003). Compared with CPP, CPPT had lower kisspeptin concentrations at week 12 (mean difference, − 4.93 pg/mL; 95% CI, − 7.50 to − 2.36; P =0.001) and week 16 (− 3.70 pg/mL; 95% CI, − 6.57 to − 0.82; P =0.041). Leptin and estradiol concentrations were also lower in CPPT at weeks 12 and 16. None of the executive-function interactions remained statistically significant after FDR correction, and no time-specific CPPT–CPP executive-function contrast was significant. Exploratory analyses indicated lower kisspeptin, leptin, and estradiol concentrations when combined training was added to GnRHa therapy, with differences remaining at week 16 after 4 weeks of detraining. These hypothesis-generating findings require confirmation in larger, prospectively registered trials. Iranian Registry of Clinical Trials, IRCT20210525051396N1. Retrospectively registered on 12 November 2021.