We have found that some children with Down's syndrome (DS) have growth retardation secondary to growth hormone (GH) deficiency. To test the hypothesis that hypothalamic dysfunction is the primary cause for GH deficiency and growth retardation, hypothalamic-pituitary responses of serum GH concentrations to levodopa and clonidine as well as pituitary responses in serum GH concentrations to growth-hormone-releasing hormone (GHRH) were analysed in 14 prepubertal children with DS. Levodopa and clonidine were given, and blood was drawn for determining serum GH levels. Seven prepubertal control children had both levodopa and clonidine tests done. The delta serum GH during levodopa was 5.7 +/- 6.3 ng ml-1 in DS and 13.1 +/- 9.8 ng ml-1 in controls. The delta serum GH during clonidine administration was 3.0 +/- 3.2 ng ml-1 in DS and 17.3 +/- 5.6 ng ml-1 in controls. Children with DS had a significantly lower response to levodopa and clonidine, compared with controls by the Mann-Whitney U-test (P < 0.03 and P < 0.009, respectively). Growth-hormone-releasing hormone was given at 1 microgram kg-1 i.v. bolus and bloods for GH were drawn at-15, 0, 15, 30, 60, 90 and 120 min in 14 subjects with DS and 24 normal controls, both groups prepubertal. The mean delta serum GH concentration in DS was 53.6 +/- 38.3 ng ml-1, and it was 35.6 +/- 25.1 ng ml-1 in controls with P < 0.23 non-significant by the Mann-Whitney U-test. These results indicate that levodopa and clonidine (drugs stimulating hypothalamic GHRH release and secondary pituitary GH release in normal individuals) do not stimulate GH release in DS. Furthermore, normal GH response to GHRH in DS indicates normal pituitary function (normal somatotroph response to GHRH) and supports hypothalamic dysfunction in DS.
Down's syndrome (DS) children have been reported to have severe postnatal growth arrest and microcephaly. To determine if growth hormone (GH) deficiency plays a role in growth retardation in DS, 20 children were studied. The subjects (13 boys, 7 girls) were aged between 15 months and 13'9 years, had a height SDS ranging from -119 to -548, weight SDS ranging from -021 to -4-58, head circumference SDS ranging from -0 40 to -66, and a skeletal age ranging from 0 9 to 4'6 SD below the mean for normal children of same age and sex. GH was evaluated by levodopa (125 mg up to 15 kg, and 250 mg between 15-30 kg), clonidine (015 mg m"^) stimulation tests and hGH secretory patterns by the integrated 24 h. GH concentration (IG-GH) using a constant withdrawal pump with continuous blood collection every 30 min. The serum concentrations were; TSH, 0 7-8 0 mlU mi ' (0 2-5 5); T4, 6 6-14-3 (ig dr' (5-12); T,, 95-254 ng dl' (85-185); LH, <2 0-83 mlU ml' (<3); FSH, <13-7 2 mlUmi' (<3); testosterone, <30 ng dt ' (5-35); estradiol, <5 ng dl"' {<5-25); prolactin, 35-7-2-9 (F: 5-25; m 5-15); and somatomedin-C (Sm-C), 0-14-198 U ml ' (0-08-5-90) (normal values in brackets). Peak serum GH after levodopa and clonidine was found to be below 10 ng ml"' for both stimulatory tests in seven ont of the 20 children studied. Twelve children showed a disparity between levodopa and cionidine testing. Of the 12 children, peak serum GH after levodopa was found to be below 10 ng ml ' in five children; and peak serum GH after clonidine was found to be below 10 ng ml ' in six. One child had a clonidine peak increase in serum GH concentration exactly 10 ng ml ', but had a 12 h IC-GH of 15 ng ml"' (N>3 2). Two children with peak GH after clonidine above 10 ng ml"' had a 24 h IC-GH of 07 and I 3 ng ml"'. A fourth child who had peakGH concentrations above 10 ng mt ' with levodopa and clonidine had a 12 h IC-GH of 05 ng ml '. These data suggest that DS children have marked growth retardation, associated with a reduced serum GH response to levodopa and clonidine stimulation tests, or disparity in responses to the stimulatory tests and low 24 h IC-GH.
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