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International audience; Context: Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic growth 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 μg/kg/day) or a standard dose (43 μg/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 HOMA (-38.9 %) after two years of individualized GH treatment in comparison to standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (∆) height SDS correlated with ∆insulin-like growth factor I (IGF-I), ∆leptin and ∆body composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [∆lean body mass (LBM) SDS and ∆IGF-I SDS] clustered together and correlated strongly with ∆height SDS and GH dose, whereas lipolytic variables [∆fat mass SDS and ∆leptin] were clustered separate from the anabolic. Regression analysis showed GH dose-dependency in ISS, and to a lesser degree in GHD, for ∆LBM SDS and ∆height SDS, but not for changes in fat mass. 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.

The regulation of growth, body composition and bone mineralisation during childhood and adolescence is a complex and multifactorial process. Growth hormone (GH) is essential for normal growth; in addition, it influences bone mineralisation and body composition in both children and adults. Leptin is a hormone secreted by adipose tissue which is involved in the regulation of both appetite and energy expenditure. Furthermore, it may also play an important role in hypothalamic-pituitary functions, such as the regulation of GH secretion. Thus, measurements of body composition have become important in clinical endocrinology and endocrine research in order to assess the metabolic effects of hormones and nutritional status on skeletal, adipose and lean tissues. Aim: The general aim of the thesis was to study the relationships among GH secretion, leptin concentration and body composition measured by dual energy X-ray absorptiometry (DXA) and bioelectric impedance (BIA). Furthermore, to evaluate the effect of GH treatment and discontinuation of GH treatment on body composition. Additionally, the aim was to evaluate two different methods for body composition measurements. Results: The main findings from the four papers that form the basis of this thesis are outlined below. Paper I: Seventy-one children were investigated. They were healthy and had different GH secretory capacities before the planned start of GH treatment. Relationships between GH secretion, leptin concentration and body composition, measured by DXA, were studied. A strong positive correlation between leptin levels and body fat, a significant negative correlation between leptin levels and GH secretion, and a significant negative correlation between body fat and GH secretion were found.Paper II: Changes in body composition in relation to changes in leptin concentration were studied during the first year of GH therapy in 33 prepubertal children. Height increased from -2.33 to -1.73 SDS. After 1 year of GH treatment, total body fat decreased by 3%, lean tissue mass increased by 2.9% and total bone mineral density (BMD) increased significantly. Total body BMD SDS was not increased significantly compared with reference values. Serum leptin levels decreased and there was a correlation between the change in body fat and the change in serum leptin levels during the 1 year of GH treatment.Paper III: Forty adolescents treated with GH for more than 3 years and 16 matched controls were studied. The consequences of discontinuing GH treatment on bone mineralisation were examined over a period of 2 years. There were no differences between GH-deficient, GH-sufficient and control subjects either at baseline or after 2 years in bone mineral content (BMC) and BMD measurements. However, biochemical bone markers decreased over the 2 years in the GH treated cohort.Paper IV: Fat-free mass, body fat mass and percentage fat were measured in 61 healthy children to determine the level of agreement between body composition measurements by DXA and single and multifrequency bioelectrical impedance spectroscopy. The estimates were highly correlated between the methods. However, a Bland-Altman comparison showed wide limits of agreement between the methods.Conclusions: The study support the existing evidence for a close correlation between leptin and body fat. Furthermore, the study demonstrate correlations between leptin, body fat and GH secretion. Specific regional fat depots have different relationships with leptin and markers of GH secretion. Leptin may be involved in the hypothalamic regulation of GH secretion. GH treatment affects body composition and bone mineralisation. The present swedish treatment of GH-deficient children to final height results in a normal BMD. Furthermore, DXA and bioelectric impedance methods should not be used interchangeably to measure body composition in children.