Carbohydrate metabolism during long-term growth hormone treatment in children with short stature born small for gestational age.

OBJECTIVE: To assess possible side-effects of long-term continuous growth hormone (GH) treatment on carbohydrate (CH) metabolism in children with short stature born small for gestational age. DESIGN: In a prospective, randomised double-blind, dose-response multicentre trial, the effect of GH treatment on CH metabolism was evaluated, comparing two GH dosages [3 vs. 6 IU/(m(2) body surface.day)]. PATIENTS: Seventy-eight children with short stature (height SD-score < - 1.88) born small for gestational age (birth length SD-score < - 1.88) being all prepubertal with a mean (SD) chronological age of 7.3 (2.2) years before start of treatment. MEASUREMENTS: Glucose and insulin concentrations during oral glucose tolerance tests (OGTTs) and glycosylated haemoglobin (HbA(1c)) were measured before and during 6 years of GH treatment. RESULTS: Before treatment, the glucose response to oral glucose after 120 min was in six of the 78 children (8%) above 7.8 mmol/l but below 11.1 mmol/l, indicating impaired glucose tolerance (IGT), whereas after 6 years of GH treatment, IGT was found in 4% of the children. None of the children developed diabetes mellitus. Mean fasting glucose levels had increased significantly by 0.5 mmol/l after 1 year of GH treatment, without a further increase thereafter. The 2-h area under the curve adjusted for fasting levels (AUCab) for glucose and the HbA(1c) levels were lower after 6 years of GH treatment compared to baseline. During GH treatment, all HbA(1c) levels were in the normal range. In contrast to the effects on glucose levels, GH treatment induced considerably higher fasting insulin levels and glucose-stimulated insulin levels. The increase in AUCab for insulin occurred particularly during the first year of treatment, whereas the fasting insulin levels showed a further increase from one to six years. As a result, the 30- and 120-min ratios of insulin to glucose were higher during GH treatment compared to the start of treatment. The children who remained prepubertal during the entire study period showed similar patterns in glucose and insulin levels compared to the children who entered puberty. None of the observed changes were different between the GH dosage groups. CONCLUSIONS: Continuous GH treatment during 6 years in children with short stature born small for gestational age has no adverse effects on glucose levels, even with dosages up to 6 IU/(m(2) d). However, as has been reported in other patient groups, GH treatment induces higher fasting insulin levels and glucose-stimulated insulin levels, indicating relative insulin resistance. Since the consequences of long-term hyperinsulinism during childhood are unknown, careful follow-up of these GH-treated children born small for gestational age is required.

Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial.

The growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy Dutch children and in the range of their target height SD score. Only in children who remained prepubertal during the study period was the 5-yr increase in height SD score (HSDS) for chronological age significantly higher in the study group receiving 6 compared to 3 IU GH/m2 x day. Remarkably, the 5-yr increment in HSDS for chronological age was not related to spontaneous GH secretion, maximum GH levels after provocation, or baseline insulin-like growth factor I levels. GH treatment was associated with an acceleration of bone maturation regardless of the GH dose given. The HSDS for bone age and predicted adult height increased significantly. GH treatment was well tolerated. In conclusion, our 5-yr data show that long term continuous GH treatment at a dose of 3 or 6 IU/m2 x day in short children born SGA results in a normalization of height during childhood followed by growth along the target height percentile.

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group.

BACKGROUND AND OBJECTIVE: Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature. DESIGN: We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7). RESULTS: In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION: rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.

Effects of two years of methionyl growth hormone therapy in two dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. (Dutch Growth Hormone Working Group).

Thirty short, slowly growing children with normal plasma growth hormone response to standard provocation tests were randomly assigned to a group (n = 20) undergoing therapy with methionyl growth hormone, 2 IU/m2 subcutaneously once daily, (group 1) or a control group (n = 10, group 2). The mean (+/- SD) height velocity increment in group 1 was 3.0 +/- 1.9 cm/yr in the first year, compared with -0.2 +/- 0.7 cm/yr in group 2. Of the 18 children who completed the first year of treatment, 12 had a height velocity increment of more than 2 cm/yr and 11 of them continued treatment for a second year (group 1A). The remaining six children also reached height velocities greater than the mean for bone age, but because of a low height velocity increment they were termed nonresponders and their growth hormone dosage was increased to 4 IU/m2/day (group 1B). Of the 10 children in the control group, seven received authentic biosynthetic growth hormone in the second year of the study (group 2); the remaining three received no therapy (group 3). The mean height velocities (measured in centimeters per year) before and during the first and second years of therapy were 3.6, 7.6, and 6.1 in group 1A; 5.7, 6.9, and 7.3 in group 1B; 4.2, 4.0, and 6.7 in group 2; and 5.0, 4.9, and 5.2 in group 3. The effect of doubling the dosage was a further increase of 1.9 cm/yr. Bone age advance paralleled growth acceleration, resulting in an unchanged height standard deviation score for bone age and ambiguous results on final height prediction. Growth hormone therapy in such short children appears to be safe and efficacious in increasing growth velocity for 2 years, but its efficacy in terms of increasing final height is uncertain.

A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group.

Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group (n = 20) undergoing treatment with methionyl GH (somatrem), 2 IU per m2 body surface s.c. daily, or a control group (n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity (r = -0.8) and the short-term height velocity increment (r = 0.7-0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.