Biochemical markers of growth hormone (GH) sensitivity in children with idiopathic short stature: individual capacity of IGF-I generation after high-dose GH treatment determines the growth response to GH.
OBJECTIVE
To assess multiple dose-response relationships between three GH doses (1.5, 3.0 and 6.0 IU/m2) and nine different biochemical markers of GH sensitivity in a well-defined group of 17 children with idiopathic short stature (ISS).


METHODS
Serum levels of IGF-I, IGF-II and IGFBP-3, and peripheral markers leptin, C-terminal propeptide of type I collagen (PICP) and N-terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1.5 IU/m2 and GH 3.0 IU/m2. Twelve-week washout periods were applied between the 12-week GH-treatment periods. High-dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6.0 IU/m2. In 18 non-GH-treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12-h day and night periods at start and after 2 weeks GH 1.5, 3.0 and 6.0 IU/m2.


RESULTS
All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF-II at baseline were inversely related to the first-year growth response (r = -0.73, P = 0.001; r = -0.53, P = 0.03; and r = -0.53, P = 0.03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1.5 or 3.0 IU/m2) and second-year growth response were found, but these showed no consistent pattern. However, all changes in IGF-I SDS after GH 6.0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second-year growth response (r = 0.55, P = 0.02; r = 0.81, P = 0.001; and r = 0.86, P < 0.001, respectively). Baseline or GH-stimulated levels of peripheral markers did not correlate with the growth response.


CONCLUSIONS
The individual capacity of IGF-I generation after high-dose GH treatment (6.0 IU/m2) determines the growth response on high-dose GH treatment. Peripheral markers do not seem to play a role in growth prediction of children with ISS.
Department of Pediatrics, Leiden University Medical Center, The Netherlands.
G A
GA
Kamp
A H
AH
Zwinderman
J
J
Van Doorn
W
W
Hackeng
M
M
Frölich
E
E
Schönau
J M
JM
Wit
D015415:Biomarkers / Q000097:blood; D001827:Body Height / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006128:Growth / Q000187:drug effects; D006130:Growth Disorders / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D011379:Prognosis; D016896:Treatment Outcome
D015415:Biomarkers; D018972:Insulin-Like Growth Factor Binding Protein 3; D020738:Leptin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II