To Karen K.: Some abstracts on GH treatment (October 2001)

To study the effects of delaying puberty in GH-deficient (GHD) children, we studied 21 GHD (9 boys, 14 girls), treatment-naive, pubertal patients in a prospective, randomized trial. Their chronological age was 14.3 +/- 1.6 yr, and their bone age was 11.3 +/- 1.1 yr (mean +/- SD) at the beginning of the study.
Four patients who developed hypogonadotropic hypogonadism were subsequently excluded from the study. Patients were randomly assigned to receive GH + LH-releasing hormone analog (LHRH-A) (n = 7), or GH alone (n = 10). GH and LHRH-A treatment started simultaneously in each patient. GH (Nutropin) was administered at a dose of 0.1 U/kg x day sc, until patients reached a bone age (BA) of 14 yr in girls and 16 yr in boys, and LHRH-A (Lupron depot) was administered at a dose of 300 microg/ kg every 28 days in during 3 yr. We defined GH deficiency as patients with a growth velocity less than 4 cm/yr, BA delay more than 1 yr in relationship to chronological age, GH response to two stimulation tests less than 7 microg/L, associated with low serum insulin-like growth factor I and insulin-like growth factor binding protein 3 levels. Statistical analysis was performed by ANOVA or Kruskall Wallis when variances were not homogeneous. We observed a significant decrease in the rate of BA maturation in the group treated with GH+LHRH-A (1.5 +/- 0.2 yr) compared with the group treated with GH alone (4.2 +/-0.5 yr) during the 3 years of LHRH-A therapy (P < 0.05). This delay in BA maturation produced a significant gain in final height in the group treated with GH+LHRH-A, which reached - 1.3 +/- 0.5 SD score compared with -2.7 +/- 0.3 SD score (P < 0.05) in the group treated with GH alone. These results indicate that delaying puberty with LHRH-A in GHD children during treatment with GH increases final height.
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OBJECTIVE: 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. PATIENTS: 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.

MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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
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J Clin Endocrinol Metab 1995 Dec;80(12):3596-600
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Adult height in short normal adolescent girls treated with gonadotropin-releasing hormone analog and growth hormone.
Balducci R, Toscano V, Mangiantini A, Municchi G, Vaccaro F, Picone S,
Di Rito A, Boscherini B
Department of Pediatrics, University Tor Vergata, Rome, Italy.

GnRH analog associated with GH therapy has potential importance for treatment of short stature in subjects without GH deficiency and with a normal onset of puberty. We treated 10 girls with familial short stature with the GnRH analog leuprolide (3.75 mg, im, every 25 days) and GH (0.1 IU/kg.day, sc, 6
days/week). The combined therapies were started simultaneously, and the patients were treated for 28.1 +/- 5.4 (range, 24-36) months. At the onset of treatment, chronological age was 11.6 +/- 1.4 yr, bone age was 10.6 +/- 0.9 yr, height was -2.7 +/- 0.7 SD, predicted height (PH; Bayley-Pinneau score) was 143.2 +/- 3 cm. Target height was 147.6 +/- 5.6 cm. Tanner stage was II-III for breast and genitalia. During treatment, puberty was completely suppressed in all patients. Statistical analysis was performed using Student's t test for paired data. After 12 months of treatment, we observed a significant (P < 0.02) improvement of predicted height (146.2 +/- 3.4 cm). This improvement remained significant (147.6 +/- 3.5; P < 0.001) when treatment was withdrawn. At that time, chronological age was 13.9 +/- 1.2 yr, and bone age was 12.4 +/- 0.7 yr. At the present time (3 +/- 0.97 yr after discontinuation), all of the girls have reached a final height of 144.6 +/- 3 cm (range, 140-149.3 cm). The final height is not significantly different compared with the PH at the beginning of treatment or with target height. These data show that in our patients, combined treatment with GnRH analog and GH, despite a significant improvement in PH during therapy and upon its withdrawal, does not result in a significant increase in adult stature.
Larger and perhaps more prolonged studies in patients of both sexes are required to reach definitive conclusions. Nevertheless, the cost of this treatment in terms of both subject compliance and economic cost should be weighed against the small height gain, if any, that may be achieved.