Combined Letrozole and Growth Hormone Therapy in Late-Pubertal Males with Advanced Bone Age and Open Knee Physes

Background/Objectives: The therapeutic window for growth hormone (GH) therapy in late-pubertal males with advanced bone age (BA ≥ 15 years) is generally considered closed. Yet, open knee physes may indicate residual growth potential. This single-arm retrospective study evaluated the efficacy and safety of letrozole combined with GH in Chinese males with short stature, advanced BA (15 -< 18 years), and open knee physes. Methods: We included 139 male adolescents stratified by baseline BA: 15 ≤ BA < 16 (n = 24), 16 ≤ BA < 17 (n = 31), and 17 ≤ BA < 18 (n = 84). All received subcutaneous GH (0.05-0.07 mg/kg/day) and oral letrozole (2.5 mg/day). The primary outcome was the change in final adult height (FAH) from baseline predicted adult height (PAH). Longitudinal changes in height velocity and height SDS-BA were also assessed. Results: Among 75 patients who reached FAH, combination therapy was associated with a mean gain of 6.58 ± 3.46 cm over baseline PAH (p < 0.001). The gain was inversely correlated with baseline BA; the largest gain occurred in the 15 ≤ BA < 16 subgroup (10.04 ± 4.66 cm), significantly exceeding gains in the 16 ≤ BA < 17 (6.30 ± 3.01 cm) and 17 ≤ BA < 18 (5.70 ± 2.52 cm) subgroups (p < 0.001). In the youngest subgroup, FAH exceeded mid-parental height. The safety profile was acceptable; acne was the most common adverse event (46.76%), and no severe metabolic or endocrine disorders were observed. Conclusions: Letrozole plus GH therapy may be associated with improved FAH in late-pubertal males with advanced BA and open knee physes, with gains varying by baseline skeletal maturity and being numerically greatest in those with BA 15 -< 16 years. Knee epiphyseal status may be a useful consideration when individualizing therapy in this population.