Height, muscle, fat and bone response to growth hormone in short children with very low birth weight born appropriate for gestational age and small for gestational age.

Growth hormone (GH) treatment is approved for short children born SGA but not for AGA. Our aim was to study the effect of GH in short VLBW SGA and AGA children. The study group comprised 44 prepubertal short children with a birth weight <1,500 g: 27 AGA (12 females) and 17 SGA (6 females). Mean values at GH start were (AGA, SGA): age 6.94, 7.14 years, height standard deviation score (SDS) -3.33, -3.33, and GH dose (mean ± SD) 54 ± 12, 51 ± 11 µg/kg/day. Arm and calf cross-sectional muscle area using peripheral quantitative computer tomography, body composition data using dual-energy X-ray absorptiometry and body impedance assessment, maximal isometric grip force and skin fold thickness, IGF-1 and IGFBP-3 were measured at the start and after 12 months of GH. At GH start, both groups had similar characteristics with low height, weight, height velocity, muscle mass, bone thickness and content. The first year of GH treatment led to changes in muscle area SDS (AGA, SGA) -2.23 to -0.73 (p = 0.0010), -3.18 to -1.17 (p = 0.060) (AGA vs. SGA p = 0.61), fat area SDS -1.06 to -1.83 (p = 0.054), -0.62 to -1.75 (p = 0.12) (AGA vs. SGA p = 0.65) and height velocity SDS -0.0015 to 4.2 (p < 0.0001), -0.18 to 3.3 (p < 0.0001) (AGA vs. SGA p = 0.36). Growth, muscle and fat mass are similarly impaired in short prepubertal AGA and SGA VLBW children. The children born AGA show a similar or better response to GH compared to those born SGA. These results reveal the arbitrary nature of using the criterion 'SGA' for eligibility to GH treatment in children born with a birth weight <1,500 g.

Berndt C ，Schweizer R ，Ranke MB ，Binder G ，Martin DD ... -  《-》

Muscle function improves during growth hormone therapy in short children born small for gestational age: results of a peripheral quantitative computed tomography study on body composition.

Schweizer R ，Martin DD ，Schönau E ，Ranke MB ... -  《-》

Short children with low birth weight born either small for gestational age or average for gestational age show similar growth response and changes in insulin-like growth factor-1 to growth hormone treatment during the first prepubertal year.

Growth hormone (GH) is an accepted treatment for short children born small for gestational age (SGA). The aim of this analysis was to compare the growth response to GH in children with low birth weight born SGA or appropriate for gestational age (AGA). This retrospective observational study is from one center. Of all the children with a birth weight <2,500 g treated, 50 were primarily diagnosed as having growth hormone deficiency ([A] SGA, n = 26; [B] AGA, n = 24) and 138 were originally diagnosed SGA or AGA (reclassified: [C] SGA, n = 102; [D] AGA, n = 36). [Median; A, B, C, D]: at an age of 4.9, 5.2, 5.8, 5.8 years, a height of -2.9, -2.4, -2.8, -2.9 SDS and a GH dose of 27, 28, 41, 39 μg/kg/day, the children grew 0.9, 0.9, 0.8, 0.9 SDS in height, respectively. Insulin-like growth factor-1 (IGF-1) at GH start was, respectively, -2.1, -2.2, -0.4, -0.9 SDS and rose to (delta IGF-1) 1.8, 2.0, 1.7, 1.5 SDS during the first year on GH. All differences were not significant. We show for the first time that short stature children with low birth weight born AGA experience the same increase in height and IGFs to GH treatment as those born SGA irrespective of actual GH secretory status.

Ranke MB ，Martin DD ，Ehehalt S ，Schwarze CP ，Serra F ，Wollmann HA ，Schweizer R ... -  《-》

IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age.

A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters. Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.

Ranke MB ，Traunecker R ，Martin DD ，Schweizer R ，Schwarze CP ，Wollmann HA ，Binder G ... -  《hormone research》

Final height data, body composition and glucose metabolism in growth hormone-treated short children born small for gestational age.

Low birth weight has been associated with impaired insulin sensitivity, type 2 diabetes mellitus, hypertension and cardiovascular disease in later life. GH therapy is known to increase fasting and postprandial insulin levels. For this reason concern has been expressed regarding the possible detrimental effects of GH therapy in children born small for gestational age (SGA). To assess the effects of GH therapy on body composition, carbohydrate metabolism and final height in short SGA children, 165 prepubertal short children born SGA were enrolled in either a multicentre, double-blind, randomized, dose-response GH trial (n = 75) or in a GH controlled trial (n = 90). The inclusion criteria were: (1) birth length standard deviation score (SDS) below -2; (2) age 3-8 years; (3) height SDS below -2. The children's mean (SD) age was 7.3 (2.1) years (GH dose-response trial) and 6.0 (1.5) years (GH controlled trial), birth length SDS was -3.6 and height SDS was -3.0 (0.7). In the GH dose-response trial, children were randomly assigned to either 1 mg GH/m(2) per day (group A, n = 41) or 2 mg GH/m(2) per day (group B, n = 38) ( approximately 0.033 or 0.067 mg/kg per day, respectively). In the GH controlled trial, children were randomly assigned to 1 mg GH/m(2) per day (n = 60) or served as controls (n = 30). Subjects underwent standard oral glucose tolerance tests and measurement of body mass index, systolic and diastolic blood pressure and serum lipids at baseline and after 1 and 6 years of GH therapy and again 6 months after discontinuation of GH. Body composition was measured by dual energy x-ray absorptiometry at baseline and again after 3 years in the GH controlled trial. Mean (SD) final height SDS was not significantly different between the two GH dosage groups: -1.2 (0.7) in group A and -0.8 (0.7) in group B. At the start of GH therapy, 8% of children had impaired glucose tolerance (IGT). Systolic blood pressure was significantly higher in comparison with healthy peers. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels after 1 and 6 years, regardless of GH dosage. After 6 years, 4% of children had IGT. Six months after discontinuation of GH, glucose levels remained normal, whereas fasting and glucose-stimulated insulin returned to levels comparable to those of healthy peers. None of the children developed diabetes. During 6 years of GH therapy both systolic and diastolic blood pressure decreased significantly and remained so after discontinuation of GH therapy. At baseline all children had reduced bone mineral content and lean body mass. Fat mass was not significantly lower than normal. Treatment with 1 mg GH/m(2) per day resulted in a significant increase in (and normalization of) bone mineral content and lean body mass in comparison with untreated short SGA controls. Fat mass decreased during the first year of GH but returned to values comparable to those at baseline in the following 2 years of GH therapy. We found that long-term, continuous GH therapy in short children born SGA leads to a normalization of height during childhood and to a normal final height in most children, regardless of GH dosage. Only very short or relatively older children may need a dosage of 2 mg GH/m(2) per day. Long-term GH therapy had no adverse effects on glucose levels and serum lipids and had a positive effect on blood pressure, even with GH dosages of up to 2 mg/m(2) per day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH serum insulin levels returned to normal age-reference levels. Short SGA children have a reduction in bone mineral content and lean body mass when compared with healthy controls, which significantly improved (normalized) with GH therapy at a dose of 1 mg/m(2) per day.

Hokken-Koelega AC ，van Pareren Y ，Sas T ，Arends N ... -  《hormone research》