Short-Term Growth Hormone Treatment in Girls With Turner Syndrome Decreases Fat Mass and Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Claus Højbjerg Gravholt, MD, PhD*; Rune Weis Naeraa, MD*‡; Kim Brixen, MD, PhD§; Knud William Kastrup, MD¶; Leif Mosekilde, MD, DrMedSci§; Jens Otto Lunde Jørgensen, MD, DrMedSci*; and Jens Sandahl Christiansen, MD, DrMedSci* ABSTRACT. Background. Most girls with Turner syn- drome (TS) receive growth hormone (GH) treatment dur- ing childhood and adolescence, but controlled data on the effects on body composition and glucose metabolism are lacking. Objective. To study the effects of GH treatment on insulin sensitivity, glucose metabolism, bone turnover, and body composition. Methods. A randomized, placebo-controlled, cross- over study was conducted with girls with TS. All girls with TS were treated with GH 0.1 IU/kg/d subcutane- ously at bedtime or with placebo for 2 months and stud- ied at the end of each period. Control subjects were studied once without treatment. Twelve girls with TS, aged 9.5 to 14.8 years (median: 12.9 years) and 16 age- matched control subjects (10.3–16.0 years; median: 12.1 years) were studied. Twenty-four-hour sampling of blood was performed; GH, insulin-like growth factor I (IGF-I), IGF binding proteins (IGFBPs), insulin, glucose, and lipolytic and gluconeogenic precursors were assayed, followed by an oral glucose tolerance test. Body compo- sition was evaluated by dual-energy x-ray absorptiom- etry scanning and body mass index (BMI). Fasting bone markers were measured. Results. Height was reduced in TS as compared with control subjects. In the placebo situation, 24-hour inte- grated GH as well as IGF-I was significantly reduced in girls with TS compared with control subjects. Control- ling for differences in lean body mass (LBM; or fat mass [FM]) and sexual development did not explain the dif- ference in 24-hour integrated GH. Differences in sexual development, BMI, FM, insulin sensitivity, and IGFBP-3 could explain the difference in IGF-I between TS and control subjects. Carbohydrate metabolism in TS was comparable with control subjects. GH treatment induced insulin resistance, with increments in fasting glucose and insulin, as well as 24-hour insulin. Circulating levels of lipid and gluconeogenic substrates were comparable in TS and control subjects and unchanged in response to treatment. Bone markers increased in response to GH. Total FM was increased in girls with TS, accounted for by an increased FM in the arms and trunk, whereas LBM was decreased. Especially LBM in the legs was decreased. Overall, bone mineral content was diminished. Treat- ment with GH reduced FM in TS, especially in the arms and legs, and likewise increased total LBM, primarily in the trunk. Conclusion. This study documented evidence of im- paired GH secretion and action, disproportionate body composition, but a normal carbohydrate metabolism in girls with TS. Short-term GH administration was associ- ated with favorable changes in body composition but also with relative impairment of glucose tolerance and insulin sensitivity. We recommend that glucose metabo- lism be monitored carefully during long-term GH treat- ment in these patients. Pediatrics 2002;110:889 – 896; growth hormone treatment; glucose metabolism, insulin sensitivity, DXA scan, body composition, IGF-I, body mass index. ABBREVIATIONS. TS, Turner syndrome; GH, growth hormone; BMI, body mass index; OGTT, oral glucose tolerance test; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor bind- ing protein; FFA, free fatty acid; DXA, dual-energy x-ray absorp- tiometry; BMC, bone mineral content; LBM, lean body mass; FM, fat mass; HOMA, Homeostasis Model Assessment; ISI comp , com- posite whole-body insulin sensitivity index; CV, coefficient of variation; RIA, radioimmunoassay; PTH, parathyroid hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; AUC, area under the curve; BMD, bone mineral density. T urner syndrome (TS) is an approved indication for growth hormone (GH) treatment in many countries. Numerous studies have docu- mented the growth-promoting effect of GH treat- ment in these patients, and final height can be sig- nificantly increased and perhaps even normalized with GH. 1,2 Many safety aspects of GH therapy, however, have never been studied in detail. Thus, data from controlled studies on the effects on body composition, substrate metabolism, and glucose ho- meostasis during GH therapy are lacking. We there- fore conducted a double-blind, placebo-controlled, crossover study in TS on the effect of GH on insulin sensitivity, glucose tolerance, bone turnover, and body composition. From the *Medical Department M (Endocrinology and Diabetes) and Med- ical Research Laboratories, Aarhus Kommunehospital, Aarhus University Hospital, Aarhus, Denmark; ‡Pediatric Department, Skejby Sygehus, Århus University Hospital, Aarhus, Denmark; §Department of Endocrinology C, Aarhus Amtssygehus, Aarhus University Hospital, Aarhus, Denmark; De- partment of Endocrinology M, Odense University Hospital, Odense, Den- mark; and Pediatric Department, Copenhagen County Hospital, Glostrup, Denmark. Drs Gravholt and Naeraa contributed equally to this work. Received for publication Oct 1, 2001; accepted Apr 10, 2002. Reprint requests to (C.H.G.) Medical Department M (Endocrinology and Diabetes), Århus Kommunehospital, DK-8000 Aarhus C, Denmark. E-mail: ch.gravholt@dadlnet.dk PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- emy of Pediatrics. PEDIATRICS Vol. 110 No. 5 November 2002 889