Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature

Abstract

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 than GH and AI alone treated for 24-36 months with a strong safety profile.

Figures

Figure 1.

Changes in mean (SE) height SDS (top panel) and bone age (bottom panel) over 24 months in the groups treated with AIs, GH, and AI/GH. *, P < .0012 (top panel); and **, P = .002 (bottom panel) represent the probability of difference in mean changes between groups for all parameters (ANCOVA). n = 76 (baseline), 72 (12 months), and 65 (24 months).

Figure 2.

Top panel shows mean (SE) differences in near-final height (cm) (n = 71) in the AI, GH, and AI/GH groups regardless of length of treatment (n = 21, 25, and 25, respectively) (P < .001 within groups; *, P = .19 among groups). Bottom panel shows net gain in height (cm) in the same three groups (*, P = .01 among groups; **, P = .002 between AI and AI/GH groups). Average height and net gain in height of young men of similar ages with height SDS −2.0 are shown for comparison on the far right bars (CDC data).

Figure 3.

Changes in FFM (top panel) and percentage fat mass (%FM) (bottom panel) over 24 months in the AI, GH, and AI/GH groups by DXA [mean (SE)]. FFM, P < .001 within each group; *, P = .015 among groups; %FM, P = .50. AI, 0.0012; GH, < .0001; AI/GH, **, P = .003 among groups. n = 76 (baseline), 72 (12 months), 63 (24 months).

Figure 4.

Changes in mean (SE) concentrations of T (top panel), estradiol (middle panel), and IGF-1 (bottom panel) in the AI, GH, and AI/GH groups (*, P < .0001 among groups for T and IGF-1; **, P < .001 for estradiol). n = 76 (baseline), 72 (12 months), 65 (24 months).