Kamp et al report on the experience of their multicenter European randomized trial of high dose (0.07mg/kg/week) recombinant growth hormone (GH) in prepubertal idiopathic short stature (ISS) children with baseline heights less than - 2SDS. Forty children (ages 4 –10 years) were recruited and 12 completed 4 years of study while 8 completed 5 years of treatment. Inclusion criteria, in addition to pre-pubertal status and age <8 years for girls and < 10 years for boys, were normal responses to GH stimulation testing (GH >10µg/l). Subjects were measured and Tanner staging  performed every three months;  bone age determinations were made yearly. During the first year of treatment all subjects randomized to GH treatment participated in a “GH responsiveness” study where GH was administered at two different doses for three months each, separated by three-month washout periods. High dose GH treatment was continued until the first signs of puberty.

In the second and subsequent years of treatment, height SDS for chronological age increased significantly and there was a significant difference in bone age advancement compared to controls. Indeed, height SDS for bone age was not different between the two groups at five years. Eighty-five percent (11/13) of boys in the high dose GH group entered puberty at a median age of 12.2 years during the study, compared with 54% (7/13) of controls at a median age of 13.9 years. Similar findings for girls included 50% (2/4) of treated children entering puberty at a median age of 10.2 years versus 20% (1/5) of controls at a median age of 9.9 years. The age and sex adjusted relative risk of entering puberty earlier was 4.7.

The authors conclude that there is no evidence that young children with ISS benefit from high dose GH in the pre-pubertal period. They point out that their study differs from previous studies in that they sought to treat younger pre-pubertal children with ISS for a longer period of time with high dose GH, and that they discontinued GH at the onset of puberty so as to separate the influence of GH from that of sex steroids in pubertal growth. They are critical of other studies that did not include randomized ISS control groups, but used reference data for pubertal onset and GH dose.

Kamp GA, et al.  Arch Dis Child 2002;87:215-220.

Editor’s Comment:  This is an interesting and well-conceived study. The use of high dose GH in ISS remains controversial, and well-controlled studies using different GH doses in different age groups are important aids in helping the endocrinologist decide whom to treat and for how long. The data from this manuscript suggest that early high dose GH treatment may improve height SDS for CA, but that there may be a price to pay in final height gain by entering puberty earlier. We await the data on final heights of the subjects in this study.

In an accompanying “Commentary”, Clayton¹ summarizes and reiterates previous data which demonstrate that the response to GH in ISS, whether short, mid- or long-term is variable, that overall reported gains in final heights range from 3 – 9 cm in various studies, and that pre-pubertal improvements in growth velocity are dose dependent. He reemphasizes the importance of matched contemporaneous control groups and the current lack of information regarding the dose response for GH in conditions where it is currently being used.

William L. Clarke, MD

Reference

1. Clayton PE.  Arch Dis Child 2002;87:219-220.