Protein markers predict body composition during growth hormone treatment in short prepubertal children.

OBJECTIVE: A high-throughput pharmaco-proteomic approach has previously been successfully used to identify lipoprotein biomarkers related to changes in longitudinal growth and bone mass in response to growth hormone (GH) treatment. The aim of this study was to identify protein markers involved in the diverse anabolic and lipolytic remodelling of body composition during GH treatment. DESIGN, PATIENTS AND MEASUREMENTS: The study population consisted of 128 prepubertal children receiving GH treatment. Thirty-nine were short as a result of GH deficiency, and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after 1 year of GH treatment were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Body composition was analysed by dual-energy X-ray absorptiometry (DXA), reliably estimating muscle mass from appendicular (arms and legs) lean soft tissue mass (LST). DXA was also used to estimate appendicular bone mineral content (BMC) and fat mass for the total body. RESULTS: Specific protein expression patterns associated with GH response in different body compartments were identified. Among identified proteins, different isoforms of nutrition markers such as apolipoproteins (Apo) were recognized: Apo C-I, Apo A-II, serum amyloid A4 (SAA4) and transthyretin (TTR). In addition, unidentified peaks were associated with GH effects on specific body compartments. CONCLUSIONS: Our results suggest that unique protein markers are associated with remodelling of different body compartments during GH treatment, which in the future might be useful to optimize GH treatment not only with regard to longitudinal growth.

Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency.

OBJECTIVE: Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period. DESIGN: Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17-100 µg/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental height(SDS) , children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n = 28) or an unchanged individualized dose (UID, n = 37) for 2 years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 µg/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX. RESULTS: We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55·1%), lean soft tissue (-27·8%) and bone mineral content (-31·3%) in RID compared with UID (all P < 0·05), but no differences compared with FIX. CONCLUSIONS: Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired height(SDS) is achieved to avoid overtreatment in terms of metabolic outcome.

Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children.

BACKGROUND: In addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. HYPOTHESIS: There are different dose-dependent thresholds for metabolic effects in response to GH treatment. METHOD: A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17-100 µg/kg/day (n=87) and (b) fixed GH dose of 43 µg/kg/day (n=41). The individualized GH dose group was used for finding dose-response effects, where the effective GH dose (ED 50%) required to achieve 50% Δ effect was calculated with piecewise linear regressions. RESULTS: Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(±24.4) µg/kg/day for Δ left ventricular diastolic diameter (cm), 39(±24.5) µg/kg/day for Δ alkaline phosphatase (µkat/L), 47(±43.5) µg/kg/day for Δ lean soft tissue (SDS), 48(±35.7) µg/kg/day for Δ insulin (mU/L), 51(±47.6) µg/kg/day for Δ height (SDS), and 57(±52.7) µg/kg/day for Δ insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose-response effect for Δ fat mass (SDS) or Δ leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial. CONCLUSIONS: Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.

Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency.

CONTEXT: Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses. DESIGN: Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day). OBJECTIVE: To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. HYPOTHESIS: Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. RESULTS: We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM. CONCLUSIONS: Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children.

Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period. Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period. Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non-GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 µg/kg/d (GHFIX)]. Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUID and GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose. Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was -0.75 ± 1.0 at 3 months (P = 0.003) and -0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02). Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

Combined treatment with testosterone (T) and ethinylestradiol (EE2) in constitutionally tall boys: is treatment with T plus EE2 more effective in reducing final height in tall boys than T alone?

Estrogens have been shown to rapidly inhibit longitudinal growth in tall boys. To antagonize the initial growth accelerating effect of T, 41 boys with an initial height prediction in excess of 203 cm were treated prospectively with either T enanthate (TE) 250 mg/wk im in combination with ethinylestradiol (EE2) 0.1 mg/d taken orally for the first 5.8 +/- 0.47 wk (mean +/- SE) of treatment (group 1, n = 20) or with TE alone (group 2, n = 21). Patients were randomized to one or the other treatment regimen. Mean (+/-SE) predicted adult height was 206.8 +/- 0.7 cm in group 1 and 206.4 +/- 0.8 cm in group 2. Total duration of treatment was 16.1 +/- 0.8 months and 14.0 +/- 1.2 months in group 1 and 2, respectively (NS). EE2-induced side effects in group 1 (gynecomastia) were limited and fully reversible. No negative long-term sequelae were found at final height with respect to hypothalamic-pituitary-gonadal axis activity and to testis volumes. Although there was a tendency to a lower initial growth velocity measured by knemometry in group 1 (0.30 +/- 0.05 vs. 0.38 +/- 0.05 mm/wk, NS), final height did not differ in both study groups (195.0 +/- 0.8 cm in group 1, 194.6 +/- 0.8 cm in group 2). Similarly, height reduction (initial predicted adult height minus final height) was not significantly different between the two groups (12.0 +/- 0.9 cm in group 1, 11.7 +/- 0.9 cm in group 2). In conclusion, the addition of EE2 during the initial treatment phase to high-dose T in tall boys has no significant effect on height reduction. The results of this clinical trial suggest that the initial growth inhibiting effect of EE2 on the epiphyseal growth plates is overridden by the long-term administration of high dose TE.

Protein profiling identified dissociations between growth hormone-mediated longitudinal growth and bone mineralization in short prepubertal children.

Growth hormone (GH) promotes longitudinal growth and bone mineralization. In this study, a proteomic approach was used to analyze the association between serum protein expression pattern and height-adjusted bone mineralization in short prepubertal children receiving GH treatment. Patterns of protein expression were compared with those associated with longitudinal bone growth. Specific protein expression patterns associated with changes in height-adjusted bone mineralization in response to GH treatment were identified. Out of the 37 peaks found in significant regression models, 27 were uniquely present in models correlated with changes in bone mineralization and 7 peaks were uniquely present in models correlated with changes in height. The peaks identified corresponded to apolipoproteins, transthyretin, serum amyloid A4 and hemoglobin beta. We conclude that a proteomic approach could be used to identify specific protein expression patterns associated with bone mineralization in response to GH treatment and that height-adjusted bone mineralization and longitudinal bone growth are regulated partly by the same and partly by different mechanisms. Protein isoforms with different post-translational modifications might be of importance in the regulation of these processes. However, further validation is needed to assess the clinical significance of the results.