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We evaluated the effect of six-month treatment with growth hormone (GH) or low-dose oxandrolone in a group of boys with constitutional growth delay (CGD). Sixteen boys were randomly assigned to two treatment groups. Group 1 received GH (0.6 U/kg/week sc 5-6 times/week) and Group 2 received oxandrolone (0.07 mg/kg po). The boys of the two groups were closely matched for age (13.7 +/- 0.5 and 12.8 +/- 0.4 years) (mean +/- SE), chronologic age/bone age ratio (1.15 +/- 0.04 and 1.16 +/- 0.02), height standard deviation score (SDS; -2.7 +/- 0.4 and -2.5 +/- 0.3) and pretreatment height velocity (HV) (3.7 +/- 0.8 and 4.0 +/- 0.4 cm/year). Other known causes of short stature were excluded in all subjects, and none had taken long-term medication prior to the study. After 6 months of treatment HV increased to 7.5 +/- 0.4 and to 8.1 +/- 0.5 cm/year in group 1 and 2, respectively. Plasma IGF-I concentrations rose significantly after treatment in both groups. Predicted adult height was not significantly affected by either GH or oxandrolone treatment. We conclude that a short-term course of low-dose oxandrolone is as effective as GH to accelerate growth in boys with CGD. Low-dose oxandrolone represents an effective, cheap, and convenient therapeutic approach in boys with CGD.

Six male prepubertal children with constitutional growth delay (CGD), and a subnormal growth hormone (GH) response to insulin hypoglycemia, and four normal prepubertal children were given in different occasions 1 microgram/Kg iv synthetic hpGRF-40 or a single oral dose of 0.15 mg/m2 clonidine (Clon), an effective growth hormone (GH) secretagogue. In the normal children brisk and clear-cut GH rises were detected in plasma after hpGRF-40 (peak GH levels at 15-30 min) or clonidine (peak GH levels 60-90 min). In CGD children hpGRF-40 induced a biphasic response, e.g. a slight increase in plasma GH at 15 min followed by a delayed and erratic GH rise occurring 45-120 min post-injection. Also the GH response to Clon was sluggish and delayed and peak plasma GH levels were attained only 90-180 min post-drug administration. These data indicate that the CGD children of our study have a defect in the pituitary GH reserve.

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH-releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11.0-17.1 years were given oxandrolone 0.1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1-40, 1 microgram/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously-released neurohormone.

34 pubertal children with constitutional growth delay (CGD) were treated with clonidine orally twice a day. In 25 of the children the height velocity rose on clonidine treatment, and in 21 of them by more than 2 cm/yr during the first 6 months of treatment (mean [SD] growth increment 4.4 [0.5] cm/yr). Of the 22 who were treated for 12 months the increment in height velocity was maintained in 13 (3.4[0.4] cm/yr). Withdrawal of clonidine for 6 months did not stop the stimulatory effect of the drug on linear growth in 6 children, but in the other 8 children height velocities fell to pretreatment levels or below. In a few children reinstitution of clonidine for 2-4 months resulted in a new increment in height velocity. A high height standard deviation score and low growth velocity before treatment were predictive of a good growth response to clonidine. Clonidine did not induce noticeable side-effects. It may be a useful form of therapy for children with CGD.

The effect of one of the new human pancreatic growth hormone releasing factors (hpGRFs) was assessed in children or young adults with different forms of growth retardation or endocrine-metabolic diseases. Intravenously administered synthetic hpGRF-40 (1 microgram/kg) induced a clear-cut and prompt rise in plasma growth hormone (GH) levels in 8 normal prepubertal children and a definite GH rise in 11 out of 14 children with isolated GH deficiency (IGHD) and one child with the Silver-Russel syndrome. In two out of three subjects with craniopharyngioma hpGRF-40 did not induce any plasma GH increase. In seven out of ten children with constitutional growth delay (CGD), hpGRF-40 induced a biphasic GH response, with a prompt small GH increment followed by a second, more consistent rise. Both in children with IGHD and with CGD the rise in plasma GH following hpGRF-40 was markedly lower than in controls. In children with CGD the GH response to hpGRF-40 was defective, despite the fact that in most of them the GH response to standard pharmacological stimuli was normal according to generally accepted criteria. hpGRF induced a small but sustained plasma GH rise in four hypothyroid subjects, while in three out of four children with idiopathic obesity the GH response to hpGRF was strikingly reduced. These data demonstrate that hpGRF is a potent stimulus of GH release in normal prepubertal children and a physiological means of investigating GH function in diseases associated with growth impairment.

We evaluated the effect of chronic clonidine administration on 24-h integrated GH secretion (IC-GH) in eight children (six boys and two girls; age, 6.0-13.0 yr) with constitutional growth delay (CGD). Clonidine was given orally in a daily dose of 0.1 mg/m2 at bedtime for 6 months; 24-h secretion studies were performed before and after 2 months of treatment. Clonidine caused a significant augmentation (P less than 0.02) of mean IC-GH from 2.6 +/- 0.4 (+/- SE) to 4.6 +/- 0.6 micrograms/L. The increase in IC-GH was mainly the result of increased GH pulse amplitude, which rose from 12.3 +/- 1.3 to 18.2 +/- 2.1 micrograms/L (P less than 0.01). The mean GH pulse amplitude was significantly higher (P less than 0.02) during sleep (15.9 +/- 2.4 micrograms/L) than during the awake hours (8.4 +/- 1.5 micrograms/L) before treatment. During clonidine treatment the mean GH pulse amplitude during the awake hours (15.0 +/- 3.8 micrograms/L) was similar to that during sleep (20.3 +/- 3.1 micrograms/L). GH pulse frequency was not altered by treatment during either the awake or sleep hours. The mean insulin-like growth factor I levels after 2 (1400 +/- 300 U/L) and 6 (1760 +/- 430 U/L) months of treatment were significantly higher (P less than 0.02 and P less than 0.05, respectively) than the pretreatment value (920 +/- 240 U/L). After 2 months of clonidine treatment, growth velocity increased from 3.1 +/- 0.5 to 10.2 +/- 1.0 cm/yr (P less than 0.001), and after 6 months of treatment is was still significantly higher (7.0 +/- 0.7 cm/yr; P less than 0.02) than that before treatment. These results confirm the ability of clonidine to accelerate growth in children with CGD and indicate that clonidine is capable of increasing IC-GH levels. They also reinforce the view that many children with CGD have decreased endogenous GH secretion.

We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 micrograms/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 micrograms/kg/h of Gal infusion (13.3 +/- 1.7 ng/mL; mean +/- SEM) was higher (p less than 0.02) than in NS children (8.5 +/- 0.8 ng/mL). When the dose of Gal was increased to 15 micrograms/kg/h the mean plasma GH peak in CGD children (18.5 +/- 3.5 ng/mL) was still higher than in the NS group (13.2 +/- 2.9 ng/mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 micrograms/kg/h of Gal (3.8 +/- 0.7 and 3.9 +/- 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p less than 0.0002) or NS children (p less than 0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 +/- 3.0 ng/mL) was higher than that observed after either dose of Gal used (p less than 0.001 and p less than 0.05 with 8 and 15 micrograms/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 +/- 2.6 and 4.1 +/- 1.2 ng/mL, respectively) was not significantly different from that observed after either dose of Gal.(ABSTRACT TRUNCATED AT 250 WORDS)

4 children with isolated growth hormone deficiency (IGHD) and 4 with constitutional growth delay (CGD) were treated with clonidine, 0.1 mg/m2 daily, for 60 days. In 2 children with IGHD and all 4 with CGD, basal growth hormone (GH) and somatomedin-C levels were increased, pituitary GH response to challenges with a synthetic pancreatic GH releasing factor and clonidine was enhanced, and linear growth was stimulated.