High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature

Abstract

Background: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3-9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost-benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period.

Aims: To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset.

Methods: Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4-8 years for girls or 4-10 years for boys, GH concentration >10 micro g/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment).

Results: In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls.

Conclusions: High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS.

Figure 1

Height SDS for chronological age during five years of study in GH treated children compared to controls. Bars represent the 95% confidence intervals of the means.

Figure 2

Bone age during five years of study in GH treated children compared to controls. Bars represent the 95% confidence intervals of the means.

Figure 3

Cumulative proportion of GH treated and control children in puberty since start of study, adjusted for age at randomisation and sex.