Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature

Context: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. Objectives: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. Design: Randomized three-arm open-label comparator. Setting: Outpatient clinical research. Patients: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]. Intervention: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months. Outcomes: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. Results: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8)cm(P<.0006, analysis of covariance). Height SDS was: AI,-1.73 (0.12); GH,-1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved,∼97.6%] was: AI,-1.4 (0.1); GH,-1.4 (0.2); AI/GH,-1.0 (0.1) (P=.06). Absolute height change was: AI,+18.2 (1.6) cm; GH,+20.6 (1.5) cm; AI/GH,+22.5 (1.4) cm (P=.01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. Conclusions: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more thanGHand AI alone treated for 24-36 months with a strong safety profile.