Final height after combined growth hormone and gonadotrophin-releasing hormone analogue therapy in short healthy children entering into normally timed puberty.

Abstract

Combined gonadotrophin-releasing hormone analogue and recombinant human growth hormone therapy has been used in an attempt to improve the final height of short non-GH deficient adolescents with normally timed puberty; its use, however, is still controversial as only short-term studies in a very limited number of patients have been undertaken, with either improvement in height prognosis or no beneficial effect on predicted growth. We have treated a group of extremely short healthy children with very low predicted adult heights entering into normally timed puberty with combined therapy, in order to determine whether we could improve their final height above their pretreatment predicted adult height. We treated 10 healthy adolescent short children (7 girls and 3 boys) simultaneously for 30.0 +/- 5.2 months with the GnRH analogue leuprolide acetate (0.3 mg/kg im every 28 days) and with rhGH (0.1 U/kg/day, sc, 6 days a week). The mean chronological age of our patients was 11.8 +/- 1.3 years, with a mean bone age of 11.2 +/- 0.9 years, height of 128.9 +/- 7.5 cm (-2.4 +/- 0.4 SD below the mean) and a predicted adult height of 150.7 +/- 9.8 cm; they were all in Tanner stage II-III of puberty. Ten healthy short children (7 girls and 3 boys) in the early stages of puberty with a mean chronological age of 11.4 +/- 1.0 years, a mean bone age of 11.0 +/- 0.8 years, height of 128.9 +/- 7.8 cm (-2.3 +/- 0.4 SD below the mean) and a mean adult predicted height of 151.8 +/- 10.1 cm served as controls and were simultaneously followed without therapy for the same study period. Height and pubertal status were followed every 3 months during combined therapy and until final height of our patients was reached; bone ages were obtained every 6 months. Growth hormone deficiency was ruled out in all our subjects prior to beginning of the study by a normal response to oral clonidine and normal IGF-1 levels. Basal serum testosterone and/or oestradiol levels, as well as LH and FSH following administration of LH-releasing hormone were obtained before treatment and after 6 weeks and 4 months of combined therapy and every 6 months thereafter. Routine biochemistry as well as thyroid function tests were obtained at each visit. Combined treatment resulted in an interruption of pubertal development with a suppression of gonadal steroids and of the LH response to LH-releasing hormone. Growth velocity decreased from 6.5 +/- 1.6 cm/year before treatment to 5.5 +/- 1.5 cm/year and 3.9 +/- 1.3 cm/year during the first and second year of treatment (P < 0.02 and P < 0.05, respectively) resulting in a height Z score reduction, declining from -2.4 +/- 04 to -2.6 +/- 0.7 SD. Bone age maturation declined averaging 0.75 bone age year/year of treatment but height SDS for bone age declined from -1.7 +/- 0.7 to -2.2 +/- 0.5 at the end of the second year of therapy with no improvement in predicted adult height (150.7 +/- 9.8 cm before and 150.0 +/- 8.0 after 2 years of therapy). After discontinuing treatment growth velocity did not improve and bone maturation advanced more rapidly (averaging 2.0 +/- 0.4 year/year of follow up) and the mean final height of our patients was 151 +/- 2.4 cm (-2.6 +/- 0.6 SD below the mean) which was not greater than the mean pretreatment predicted adult height and well below their target height; these results were also similar to those of the control population in whom the predicted adult height at the beginning of the study and after 2 years of follow up, was not different from their final height and well below their target height. We conclude that combined rhGH and GnRH analogue therapy in short adolescents with normally timed puberty does not contribute to increase their final height above their pretreatment predicted adult height; we can therefore not recommend this form of therapy for this group of patients given the poor results obtained, as well as the cost of these medications and the