Effect of Growth Hormone Dose on Bone Maturation and Puberty in Children with Idiopathic Short Stature

Abstract

Context: GH at 0.22 mg/kg⅐wk has been shown to have no effect on pubertal onset or pace, whereas GH at 0.5 mg/kg⅐wk has been shown to advance pubertal onset and bone maturation.Objectives: Our objectives were to determine whether 0.37 mg/kg⅐wk GH advanced pubertal onset, pace, or bone maturation relative to 0.24 mg/kg⅐wk GH; whether 0.37 mg/kg⅐wk GH led to pubertal onset at an inappropriately early age; and whether age at start of GH therapy influenced pubertal onset. Design:We conducted a randomized, open-label study to final height. Patients:We studied children with idiopathic short stature.Intervention: Patients were treated with 0.24 mg/kg⅐wk, 0.24 increasing to 0.37 mg/kg⅐wk, or 0.37 mg/kg⅐wk. Main Outcome Measures:We assessed age at pubertal onset and rates of bone maturation, Tanner stage development, and increase in testicular volume (boys only).Results: For the primary comparison between the 0.24 and 0.37 mg/kg⅐wk dose groups, median ages of pubertal onset (in years) were similar (13.7 vs. 13.5 for boys and 11.7 vs. 11.4 for girls) and were greater than those for the general population for each sex. Age at start of GH therapy did not appear to influence pubertal onset for either sex. Rates of pubertal pace and bone maturation were not significantly different between the 0.24 and 0.37 mg/kg⅐wk dose groups for either sex.Conclusion: GH at 0.37 mg/kg⅐wk does not appear to accelerate pubertal onset, pace, or bone maturation compared with GH at 0.24 mg/kg⅐wk in patients with idiopathic short stature. From a clinical standpoint, our results suggest that the approved dose range of up to 0.37 mg/kg⅐wk GH does not lead to pubertal onset at an inappropriately early age. between GH activity and pubertal timing. Before GH treatment became available, marked delays in pubertal onset were observed in children with isolated GH deficiency (1). Additionally, pubertal delays of 3-7 yr are observed in children with GH insensitivity (2).Randomized controlled studies of recombinant human GH (somatropin) treatment of patients with idiopathic short stature (ISS) have yielded differing results regarding the influence of GH on pubertal onset, pubertal pace, and bone maturation. Although Leschek et al. (3) demonstrated no effect on pubertal onset or pace in boys who began low-dose (0.22 mg/kg⅐wk) GH at a mean age of 12 yr, Kamp et al. (4) demonstrated acceleration of pubertal onset and bone maturation by approximately 1 yr in boys and girls who began high-dose (0.5 mg/kg⅐wk) GH at a mean age of 8 yr. These results suggest that the influence of GH on pubertal timing and bone maturation may be dose-dependent. Thus, based on the current literature, decisions regarding GH dosing are limited by uncertainty as to which doses between 0.22 and 0.5 mg/kg⅐wk might accelerate puberty and bone maturation in patients with ISS.We tested the influence of GH dose on pubertal onset, pubertal pace, and bone maturation during a randomized, open-label study to final height in patients with ISS (mean age, 9.8 yr) randomized to one of three GH dose...

A Randomised Study of the Effect of Two Doses of Biosynthetic Human Growth Hormone on Final Height of Children with Familial Short Stature

“…A more detailed approach assessing usage and proxy measures such as repeated measurements of serum insulin-like growth factor 1 concentrations may have allowed us to formally exclude this as a factor that may have influenced our results. Finally, our study did not suggest any significant effect of therapy on pubertal tempo, suggesting that this was not the explanation for the lack of efficacy of the higher dose, confirming other reports using similar dosing schedules [21]. …”

Does Growth Hormone Treatment Influence Pubertal Development in Short Children?

“…Crowe et al [15] conducted a direct comparison of two GH doses [240 or 370 µg/kg/week (34 or 53 µg/kg/day)] as part of a randomized, European, multicenter study. They studied bone age maturation and puberty in 239 children (158 boys) who were all prepubertal at the start of GH treatment.…”

“…The randomized controlled studies available so far suggest that GH treatment of children with short stature from prepuberty until near adult height at the doses 0.22 mg/kg/week (31 µg/kg/day) [13], 0.24–0.37 mg/kg/week (34–53 µg/kg/day) [15] or 0.23–0.46 mg/kg/week (33–67 µg/kg/day) (present results) does not influence the age of initiation of puberty, the age of menarche or accelerate pubertal pace. However, a word of caution is appropriate.…”

Hormonal Treatment of Idiopathic Short Stature

“…Results so far are somewhat contradictory. Among the population treated at the higher dose of 0.37 mg/kg in the study by Wit et al [32, 36], there was no evidence of accelerated pubertal or skeletal maturation. By contrast, Kamp et al [37] reported accelerated pubertal development and skeletal maturation at a 30% greater GH dose.…”