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A Randomized Controlled Trial of Three Years Growth Hormone and Gonadotropin-Releasing Hormone Agonist Treatment in Children with Idiopathic Short Stature and Intrauterine Growth Retardation¹

Department of Pediatrics, Leiden University Medical Center (G.A.K., W.O., J.M.W.), Sophia Children’s Hospital Rotterdam, subdivision Endocrinology (D.M.), Catharina Hospital Eindhoven (J.J.J.W.), University Medical Center Utrecht (M.J., L.V.-W.), Free University Hospital Amsterdam (H.A.D.-v.d.W.), Department of Clinical Chemistry, and Leiden University Medical Center (M.F.), The Netherlands

Address correspondence and requests for reprints to: Prof. Dr. J. M. Wit, Department of Pediatrics, LUMC J6-204, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: JMWit{at}lumc.nl

Abstract

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period.

Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2–3; boys, G2–3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m² · day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively.

During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) ‘yr’/yr vs. 1.15 (0.37) ‘yr’/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment.

Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m² seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children.

We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

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