Aromatase Inhibitor Effectiveness on Height Augmentation: Optimizing Letrozole Therapy for Height Gain in Short-Statured Boys

Abstract Background Aromatase inhibitors (AIs) such as letrozole (Lz) have proposed to increase final adult height by delaying epiphyseal closure through reducing estrogen synthesis, but optimal timing for initiation and duration of treatment remains unclear. Objective To evaluate the effect of Lz, with or without recombinant human growth hormone (rhGH), on final adult height (FAH) and to identify treatment duration and bone age thresholds that maximize clinical responsiveness. Methods A retrospective cohort study of 40 boys with bone age of 12–16 years with the diagnosis of idiopathic short stature (ISS) or growth hormone deficiency (GHD) and no prior history of growth-modulating therapy followed to their FAH. They have been treated with Lz (2.5 mg/day) for 1 to 2.5 years. Nine received Lz as monotherapy and 31 received Lz + rhGH. Results Both letrozole monotherapy and combination therapy demonstrated significant increases in FAH versus predicted adult height (PAH) with the height augmentation of 2.30 ± 1.24 cm and 4.40 ± 2.51 cm, respectively (p < 0.001). In the Lz + rhGH group, height augmentation positively correlated with treatment duration up to a 21-month breakpoint (ρ = 0.703, p < 0.001), while beyond that point, the effectiveness decreased significantly. Notably, height augmentation negatively correlated with baseline bone age (ρ = − 0.367, p = 0.0425). Patients treated at or below a bone age of 14.5 years gained 5.15 cm compared to 2.58 cm in older boys (p = 0.018). Conclusions Administering Lz with GH after a bone age of 14.5 years showed a significant decrease in height augmentation. Moreover, extending Lz therapy up to 21 months enhances this gain, while benefits appear to decrease significantly beyond that point. Early initiation and careful optimization of treatment duration maximize efficacy and minimize the risk of overtreatment and adverse effects.