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

Abstract

Highlights What are the main findings? In this single-arm retrospective study, combined letrozole and growth hormone therapy was associated with a mean gain of 6.58 ± 3.46 cm in final adult height relative to baseline predicted adult height in late-pubertal males with BA 15 –< 18 years and open knee physes (p < 0.001). The observed height gain diminished with advancing baseline bone age; the largest gain (10.04 ± 4.66 cm) was seen in the BA 15 –< 16 subgroup, where final height exceeded mid-parental height. What are the implications of the main findings? Knee epiphyseal patency may serve as an indicator of residual growth potential in adolescents with advanced wrist bone age, potentially broadening the therapeutic window for aromatase inhibitor plus GH therapy beyond conventional age thresholds. These preliminary findings suggest that baseline skeletal maturity, particularly knee physeal status, should be considered when individualizing treatment decisions; however, prospective controlled studies are needed to confirm these observations. Abstract 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.