FINAL HEIGHT AFTER COMBINED GROWTH-HORMONE AND GONADOTROPIN-RELEASING-HORMONE ANALOG THERAPY IN SHORT HEALTHY-CHILDREN ENTERING INTO NORMALLY TIMED PUBERTY

OBJECTIVE Combined gonadotrophin-releasing hormone analogue and recomb inant human growth hormone therapy has been used in an attempt to impr ove the final height of short non-GH deficient adolescents with normal ly timed puberty; its use, however, is still controversial as only sho rt-term studies in a very limited number of patients have been underta ken, with either improvement in height prognosis or no beneficial effe ct on predicted growth. We have treated a group of extremely short hea lthy children with very low predicted adult heights entering into norm ally timed puberty with combined therapy, in order to determine whethe r we could improve their final height above their pretreatment predict ed adult height. PATIENTS We treated 10 healthy adolescent short child ren (7 girls and 3 boys) simultaneously for 30.0 +/- 5.2 months with t he GnRH analogue leuprolide acetate (0.3 mg/kg im every 28 days) and w ith 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, heig ht of 128.9 +/- 7.8 cm(-2.3 +/- 0.4 SD below the mean) and a mean adul t predicted height of 151.8;+/- 10.1 cm served as controls and were si multaneously followed without therapy for the same study period. MEASU REMENTS 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 nor mal response to oral clonidine and normal IGF-1 levels. Basal serum te stosterone and/or oestradiol levels, as well as LH and FSH following a dministration of LH-releasing hormone were obtained before treatment a nd after 6 weeks and 4 months of combined therapy and every 6 months t hereafter. Routine biochemistry as well as thyroid function tests were obtained at each visit. RESULTS Combined treatment resulted in an int erruption of pubertal development with a suppression of gonadal steroi ds and of the LH response to LH-releasing hormone. Growth velocity dec reased from 6.5 +/- 1.6 cm/year before treatment to 5.5 +/- 1.5 cm/yea r and 3.9 +/- 1.3 cm/year during the first and second year of treatmen t (P< 0.02 and P< 0.05, respectively) resulting in a height Z score re duction, declining from -2.4 +/- 04 to -2.6 +/- 0.7 SD. Bone age matur ation declined averaging 0.75 bone age year/year of treatment but heig ht SDS for bone age declined from - 1.7 +/- 0.7 to - 2.2 +/- 0.5 at th e end of the second year of therapy with no improvement in predicted a dult height (150.7 +/- 9.8cm before and 150.0 +/- 8.0 after 2 years of therapy). After discontinuing treatment growth velocity did not impro ve and bone maturation advanced more rapidly (averaging 2.0 +/- 0.4 ye ar/year of follow up) and the mean final height of our patients was 15 1 +/- 2.4cm (-2.6 +/- 0.6 SD below the mean) which was not greater tha n the mean pretreatment predicted adult height and well below their ta rget height; these results were also similar to those of the control p opulation in whom the predicted adult height at the beginning of the s tudy and after 2 years of follow up, was not different from their fina l height and well below their target height. CONCLUSIONS We conclude t hat combined rhGH and GnRH analogue therapy in short adolescents with normally timed puberty does not contribute to increase their final hei ght above their pretreatment predicted adult height; we can therefore not recommend this form of therapy for this group of patients given th e poor results obtained, as well as the cost of these medications and the difficulty in administering them.