Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation

We recently reported that treatment with a pharmacologic dose of recombinant human growth hormone (GH) resulted in a significant loss of body fat and gain in lean tissue in HIV-infected patients with syndromes of fat accumulation. However, insulin-mediated glucose disposal decreased transiently after one month of GH therapy. The present paper focuses on the changes of hepatic carbohydrate and fat metabolism associated with GH treatment in the same subjects. We assessed hepatic insulin sensitivity under both fasting and hyperinsulinemic-euglycemic clamp conditions prior to and after one and six months of GH treatment (3 mg/day) in five patients using stable isotope tracer techniques. Indirect calorimetry, and measurements of lipid concentrations. Fasting endogenous glucose production (EGP) increased significantly at one month (12.0 +/- 0.7 to 14.9 +/- 0.9 micromol/kg/min, P < 0.03), and the increase was sustained at six months of GH treatment (14.0 +/- 1.1 micromol/kg/min, NS). This increase in EGP was driven in part by increased glucogenesis (GNG) (3.5 +/- 0.9 to 5.2 +/- 0.9 and 5.8 +/-1.2 micromol/kg/min, n = 4, P < 0.01 and P < 0.01 at one and six months, respectively); small changes in hepatic glycogenolysis also contributed. Sustained increases in lipolysis and progressive decreases in hepatic fractional de novo lipogenesis (DNL) and triglyceride concentrations occurred with GH treatment. These changes were accompanied by an improved lipid profile with a significant increase in HDL cholesterol and significant decreases in total and LDL cholesterol and triglyceride levels, the latter consistent with the decrease in hepatic DNL. During a hyperinsulinemic-euglycemic glucose clamp, EGP and GNG were markedly suppressed compared to the corresponding time points under fasting conditions, albeit less so when measured after one month of GH treatment. Thus, in HIV-infected patients with abnormal fat distribution, pharmacologic doses of GH improved the overall lipid profile, but worsened glucose homeostasis under both fasting and hyperinsulinemic conditions. The combined implications of these positive and negative metabolic effects for cardiovascular disease risk remain unknown.     

Effects of growth hormone on glucose and fat metabolism in human subjects.

This article focuses on in vivo data from tests performed in normal subjects and in patients who had abnormal growth hormone (GH) status. Experimental data in human subjects demonstrate that GH acutely inhibits glucose disposal in skeletal muscle. At the same time GH stimulates the turnover and oxidation of free fatty acid (FFA), and experimental evidence suggests a causal link between elevated FFA levels and insulin resistance in skeletal muscle. Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance, but it is recommended that overdosing be avoided and glycemic control be monitored.     

The effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats

ObjectiveTo study the effect of polyethylene glycol recombinant human growth hormone on growth and glucose metabolism in hypophysectomized rats, and compare the effect of treatment between recombinant human growth hormone (rhGH) and polyethylene glycol rhGH (PEG-rhGH).MethodsHypophysectomy was performed in juvenile rats to build the animal model of GH deficiency. The hypophysectomized animals were randomly assigned into three groups and treated with saline (negative control, n = 20), rhGH (n = 20) and PEG-rhGH (n = 20). A sham operation was performed to set up the normal control (n = 20). Body weight, body length and tail length were recorded every 2 days for a 14-day treatment and bone growth was measured at the end of therapy. Glucose infusion rate (GIR) determined by euglycemic hyperinsulinemic clamp was used to evaluate insulin sensitivity after GH treatment. We also examined plasma glucose and serum insulin levelsResultsCompared with the negative control, the body weight, body length, tail length and bone growth increased significantly in hypophesectomized rats treated by GH (P < 0.01). Although the weight gain in the first 10 days was higher in the PEG-rhGH group than in the rhGH group (P < 0.05), the growth promoting effect was similar between rhGH and PEG-rhGH (P > 0.05). Neither rhGH nor PEG-rhGH impaired glucose tolerance of rats after hypophesectomy. Compared with negative controls, according to decreased serum insulin, reduced insulin expression in pancreatic cells and increased GIR in the clamp, both rhGH and PEG-rhGH groups had improved insulin sensitivity within 14 days (P < 0.01). However, with prolonged treatment, the GIR in the rhGH-treated rats decreased significantly (P < 0.05); while PEG-rhGH did not interfere with GIR, even after a doubled dose (P > 0.05).ConclusionsPEG-rhGH had the same linear growth promoting efficacy as unmodified rhGH. The short-term GH replacement could improve insulin sensitivity in hypophysectomized rats, especially after PEGylation.     

Effects of growth hormone on body composition and bone metabolism

Physiologic effects of growth hormone (GH) extend beyond the stimulation of linear growth during childhood and adolescence. These effects include building and sustaining lean body mass, facilitating the utilization of fat mass for energy needs, and maintaining bone mineral density. These nongrowth effects of GH appear to be important throughout life. Children and adults with severe GHD demonstrate marked reductions in lean body mass, increases in percent body fat, and subnormal bone mineral density. Replacement of GH attenuates these abnormalities, though it remains unknown whether it does so completely. Children with body composition abnormalities resembling the GHD state (e.g., Prader-Willi syndrome) also appear to respond fovorably to administration of GH treatment, and demonstrate concomitant improvements in strength and agility. Long-term body composition benefits of GH supplementation in these and other non-GHD individuals remain unproven.     

A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation

OBJECTIVE: To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation. DESIGN AND METHODS: Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters. RESULTS: TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose. CONCLUSIONS: TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.     

Synergistic effects of testosterone and growth hormone on protein metabolism and body composition in prepubertal boys

During human puberty there is a substantial increase in growth hormone (GH) and sex steroidal hormone concentrations, as well as in GH production rates and insulin-like growth factor-I (IGF-I) These studies were designed to investigate some of the interactions of testosterone (T) and GH in the metabolic changes of puberty. Ten boys with severe GH deficiency (GHD) were studied (mean age, 12.5 +/- 0.5 years) using stable isotope infusions, indirect calorimetry, and body composition analysis. After the baseline study, they received 2 doses of T enanthate (50 to 75 mg, intramuscular [IM]), and they were studied again 4 weeks later. The boys were then begun on daily subcutaneous (SC) GH (0.3 mg/kg/wk), while T therapy was continued for another 4 weeks and the studies repeated a third time. The treatment order was randomized. Protein oxidation rates decreased after T alone (-28%, P <.01), decreasing further after combined T/GH treatment (-36% v baseline, P <.01). The nonoxidative leucine disposal (NOLD), a measure of whole body protein synthesis, increased significantly after combined T/GH regardless of treatment order. The combination of T/GH also resulted in greater changes in body composition than T alone, with comparable decreases in %FM and corresponding increases in fat free mass (FFM). Measures of carbohydrate (CHO) metabolism, including glucose production and oxidation rates, were unaffected by either T or T/GH combination. Plasma IGF-I concentrations increased after T treatment and even more after T/GH combination, regardless of the treatment order. In conclusion GH and T are synergistic on whole body protein anabolism and body composition in males, even at a young age, but the positive effects of T on protein anabolism and body composition appear to need a basal amount of GH for those effects to be observed. GH and T both potentiate the development of the full body composition and metabolic changes of puberty.     

Effects of recombinant growth hormone on visceral fat accumulation: pilot study in human immunodeficiency virus-infected adolescents

CONTEXT: Recombinant human GH (rhGH) reduces excess accumulation of intraabdominal adipose tissue (IAT) in lipodystrophic HIV-infected adults, whereas data in pediatric patients are lacking. OBJECTIVE: The objective of this study was to assess the efficacy of rhGH treatment on lipodystrophy in HIV-infected adolescents. DESIGN: The study is a prospective, 24-wk open-label study of rhGH. SETTING: The study was conducted at a referral center for pediatric HIV infection. PATIENTS AND OTHER PARTICIPANTS: Eight HIV-infected adolescents (ages, 13.7-18.5 yr), with abnormal IAT accumulation (>41 cm(2) at L4-magnetic resonance imaging) and 97 healthy controls (HC) (ages, 9.5-19.9 yr) were enrolled. INTERVENTION: rhGH was given by sc injection at a daily dose of 0.028 mg/kg. MAIN OUTCOME MEASURES: The main outcome was change in IAT at L4-magnetic resonance imaging. Body composition by dual-energy x-ray absorptiometry, glucose and lipid metabolism, and IGF-I changes were also evaluated. RESULTS: All patients completed the study period; none of them showed adverse event, and no change in the daily dose of rhGH was required. The treatment was associated with a mean height increase of 2.4 cm. From baseline to wk 24, IAT area decreased significantly by a median of 34.5% (-19.2 to -70%). Fat mass decreased significantly in patients, compared with HC, with a median loss of total, trunk, and arm and leg fat mass of 10.4, 10.9, 12.7, and 5.4%, respectively. Total, arm, and leg lean masses increased significantly, compared with HC. IGF-I increased significantly, but supraphysiological values of mild degree (2-23% over the upper normal limit) were detected in only nine of 24 samples. No significant effects on glucose metabolism, triglyceride, and cholesterol levels were observed. CONCLUSIONS: Our data showed that rhGH 0.028 mg/kg daily for 24 wk in HIV-infected adolescents reduces IAT, trunk, and also limb fat and increases lean mass. Overall, short-term rhGH is well tolerated and is not associated with a worsening of glucose and lipid metabolism.     

The circulating molecular weight forms of infused recombinant insulin-like growth factor-I and effects on glucose and fat metabolism in lambs

Summary We have investigated the relationship between the plasma distribution of infused recominant insulin-like growth factor-I across the insulin-like growth factor binding proteins and the resultant effects on glucose and fat metabolism. The studies were performed in 24-h fasted ram lambs which received primed constant infusions of ³H labelled glucose tracer. When isotopic equilibrium had been reached, the animals received 90-min infusions of human insulin-like growth factor-I at various doses (2.5, 20, 40 and 120 g· kg^–1·h^–1, n=3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40 g·kg^–1·h^–1 (from 185±14 g/l to 442±41 g/l, p<0.05) and 120g·kg^–1h^–1 (from 181±2 g/l to 953±39 g/1, p<0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable (<15 g/l) at the end of the 2.5 and 20 g·kg^–1·h^–1 doses, but were significantly elevated at the end of the 40 and 120 g·kg^–1·h^–1 infusions (to 71±14 g/l, p<0.05 and 176±55 g/l, p<0.01 respectively). The infused insulin-like growth factor-I associated primarily with 35–60 kilodalton binding proteins. Glucose kinetics were significantly altered only by the highest dose infusion, during which there was a fall in plasma glucose concentration from 3.5±0.2 mmol/l to 1.9±0.2 mmol/l (p<0.05). This was due to a 51% increase in the rate of glucose clearance. There was no significant change in the rate of glucose production. The plasma concentrations of glycerol and non-esterified fatty acid were not changed by any of the doses infused. We conclude that the hypoglycaemic action of infused recombinant insulin-like growth factor-I relates to a marked elevation of free insulin-like growth factor-I in the plasma, but that a threshold concentration of free insulin-like growth factor-I must be exceeded before this action is observed. The hypoglycaemic action of recominant insulin-like growth factor-I results primarily from an increase in glucose clearance while glucose metabolism was more sensitive than fat metabolism to infused recominant insulin-like growth factor-I. Both these actions contrast with those of insulin, and suggest that the acute metabolic effects of recombinant insulin-like growth factor-I are not mediated simply by cross-reaction with insulin receptors.     

The effects of growth hormone on protein metabolism in adult growth hormone deficient patients

OBJECTIVE Growth hormone treatment given to adult growth hormone deficient patients leads to an increase in lean body mass by an unknown mechanism. The aim of this study was to investigate the actions of growth hormone treatment on protein metabolism in adult growth hormone deficient patients. DESIGN Double-blind, placebo controlled trial of recombinant human growth hormone (0 018 U/kg/day for 1 month followed by 0.036 U/kg/day for 1 month) with isotopic whole body protein turnover studies at 0 and 2 months. PATIENTS Eighteen adult growth hormone deficient patients (nine male, nine female of mean age 46.6 (range 30–56). MEASUREMENTS Whole body isotopic leucine turnover using L-1-¹³C-leucine measuring leucine R a (a measure of protein degradation), non-oxidative leucine R d (a measure of protein synthesis) and leucine oxidation rate. RESULTS Lean body mass (P<0.02), circulating insulinlike growth factor I (P<0 01) and insulin (P<0.02) were significantly increased at 2 months in the treatment group but there was no change in the placebo group. When expressed in relation to body weight, leucine fia and non-oxidative leucine fid increased (P<0.01) and leucine oxidation decreased (P<0.02) after 2 months growth hormone treatment. When expressed in relation to lean body mass non-oxidative leucine R d increased (P<0.02) and leucine oxidation decreased (P<0.02) but there was no significant change in leucine R a after 2 months growth hormone treatment. In the placebo group there were no significant changes in leucine metabolism expressed as lean body mass or body weight after 2 months. changes in leucine metabolism expressed as lean body mass or body weight after 2 months. CONCLUSION These results indicate that the increase in lean body mass resulting from growth hormone treatment in adult growth hormone deficient patients is due to an increase in protein synthesis.     

Monoclonal antibody enhancement of the effects of human growth hormone on growth and body composition in mice

Dwarf mice were treated for 10 days with phosphate-buffered saline (PBS), human growth hormone (hGH) or hGH with monoclonal antibody EB1 (hGH/MAB-EB1); for each treatment there were three groups which received 50, 75 or 100% of the amount of food eaten when available ad libitum. The PBS control groups lost more or gained less weight than equivalent groups receiving hGH alone, and mice given hGH/MAB-EB1 showed a greater weight gain than those in comparable groups receiving hGH alone. When weight gain or loss was expressed as g/g food eaten, groups treated with hGH gained more or lost less than the PBS groups. Similarly, weight gain/g food was significantly greater in hGH/MAB-EB1 animals than in the comparable groups given hGH alone. A similar pattern of response was observed for increases in tail length and uptake of 35SO42- into costal cartilage in vivo. For mice given hGH alone, fat content was decreased compared with that in the equivalent group given PBS, and mice treated with hGH/MAB-EB1 had less fat than the equivalent group given hGH alone. Administration of hGH alone caused a concomitant increase in protein content and body weight such that, compared with mice given PBS, there was no significant increase in protein as a proportion of body weight. However, hGH/MAB-EB1 caused an increase in whole body protein which was significantly greater than that for the equivalent group given hGH alone, when expressed as per cent body weight. Monoclonal antibody EB1 has been shown to enhance the actions of hGH on growth and body composition in Snell dwarf mice and to increase food conversion efficiency.     

The effects of body fat distribution on glucose tolerance in overweight subjects: glucose intolerance and insulin resistance induced by intra-abdominal fat accumulation]

To evaluate the pathophysiological significance of intra-abdominal fat accumulation in Japanese subjects with mild to moderate overweight, 107 subjects (56 men and 51 women, aged 16-68 years) with body mass index (BMI, kg/m2) of 17-39 (mean +/- SD, 25 +/- 4.3) were evaluated. Subjects with disorders which affect glucose metabolism, such as thyroid, adrenal, liver, and kidney diseases, were excluded. A 75 g oral glucose tolerance test (OGTT) was performed in all subjects, and venous samples were obtained before 15, 30, 60, 90 and 120 min after the glucose load for plasma glucose (PG), immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) measurements. In 72 of the subjects, plasma free fatty acid (FFA) level at fasting was also determined. The degree of visceral fat accumulation was evaluated using a CT-scan by the method reported by Fujioka et al. (Metabolism, 36: 54-59, 1987), and intra-abdominal fat area/subcutaneous fat area (V/S ratio) was obtained. V/S ratio and BMI correlated positively in subjects with BMI less than 25 (17 men and 16 women, aged 28-62 years) but they did not correlate at all with each other in those with BMI greater than or equal to 25 (39 men and 35 women, aged 16-68 years). Based on this finding, the possible adverse effects of increased intra-abdominal fat on glucose metabolism were investigated in the subjects with BMI greater than or equal to 25. For this purpose, the correlation of V/S ratio with fasting PG (FPG), fasting IRI (FIRI), fasting CPR (FCPR), FPG/FIRI, FFA, or PG area (sigma PG) and sigma PG/sigma IRI at OGTT was analyzed. V/S ratio positively correlated with FPG, sigma PG, FPG/FIRI and sigma PG/sigma IRI but not with FFA. The correlation between V/S ratio and FIRI or FCPR was significant in the subjects with V/S ratio greater than or equal to 0.8 in men and greater than or equal to 0.4 in women. In sharp contrast to V/S ratio, BMI did not correlate at all with any of these metabolic indices. We conclude that in Japanese subjects with mild overweight to moderate obesity, intra-abdominal fat accumulation, but not the increase in the degree of obesity, accompanies worsening of glucose tolerance. Because PG elevation relative to IRI secretion is progressively greater with increasing V/S ratio, it is suggested that the deleterious effects of intra-abdominal fat accumulation can be attributed to increased insulin resistance.     

Different growth hormone sensitivity of target tissues and growth hormone response to glucose in HIV-infected patients with and without lipodystrophy

Growth hormone (GH)-secretion in HIV-lipodystrophy is impaired; however, GH-sensitivity of GH-target tissues remains to be evaluated. We measured overnight fasting concentrations of GH-sensitive insulin-like growth-factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) including GH binding protein (GHBP), a marker of GH-receptor sensitivity, in antiretroviral treated HIV-infected patients with (LIPO) and without lipodystrophy (NONLIPO) and antiretroviral naive HIV-infected patients (NAIVE). Three h GH-suppression tests using oral glucose were undertaken to determine dynamics of GH-secretion. IGF-I and IGFBP-3 were increased in LIPO compared with NONLIPO (p <0.05), but did not differ significantly between NONLIPO and NAIVE. Area under the curve of GH (AUC-GH) during the GH-suppression test was decreased in LIPO compared with NONLIPO (p <0.05). Ratio of limb to trunk fat, which was decreased in LIPO compared to NONLIPO and NAIVE (p <0.001), correlated positively with AUC-GH and rebound-GH (p <0.05). All groups displayed suppression of GH during the suppression test (p <0.05) and all groups, except LIPO, displayed a rebound of GH (p <0.05), which probably is explained by persistently increased plasma glucose in LIPO compared with NONLIPO and NAIVE (p <0.01). GHBP was inversely correlated with AUC-GH (p <0.01). Our data suggest that GH-target tissues in LIPO are at least as GH-sensitive as in HIV-infected patients without lipodystrophy.     

Effects of growth hormone secretion on body composition in patients with Crohn's disease

Crohn's disease is a multisystem disorder characterized by chronic intestinal inflammation. Accumulation of mesenteric fat occurs in patients with Crohn's disease, although the mechanisms underlying site-specific changes in adipose deposition are unclear. To investigate whether there are alterations in site-specific adipose deposition in patients with Crohn's disease and to determine hormonal influences that may underlie such changes, we investigated body composition and serum hormone levels in 20 men with Crohn's disease (mean age, 45 +/- 2 yr) and 20 age-, gender-, and body mass index-matched normal controls (mean age, 43 +/- 3 yr). None of the Crohn's patients was receiving glucocorticoid therapy. Subjects underwent hourly GH sampling for 12 h beginning at 2000 h and fasting serum IGF-I and testosterone measurements. Body composition was assessed by quantitative computed tomography of the abdomen and bioelectrical impedance analysis. In the Crohn's disease and control subjects, mean serum GH levels were 1.07 +/- 0.2 and 1.7 +/- 0.2 ng/ml (P = 0.06), serum IGF-I levels were 162.7 +/- 10.5 and 194.8 +/- 15.7 ng/ml (P = 0.1), and serum testosterone levels were 489 +/- 33 and 514 +/- 38 ng/ml (P = NS), respectively. Percentage body fat was significantly higher in the Crohn's patients (21 +/- 0.8% vs. 17.7 +/- 0.9%, respectively; P = 0.013). Intraabdominal fat (IAF) was significantly higher in the Crohn's subjects vs. controls (115 +/- 11 vs. 69 +/- 7 cm(2), respectively; P = 0.001). The ratio of intraabdominal to total body fat was higher in the Crohn's subjects than in the controls (0.4 +/- 0.1 vs. 0.3 +/- 0.1, respectively; P = 0.025). Subcutaneous fat area was similar in the two groups. IAF was higher in Crohn's patients even when controlling for testosterone and mean serum GH. Mean serum GH contributed independently to the differences in IAF (P = 0.001). The ratio of IAF to total body fat remained higher in the Crohn's subjects when controlling for serum testosterone, but was no longer significant in a model that also included IGF-I and mean serum GH. GH levels contributed independently to the differences in the intraabdominal to total body fat ratio (P = 0.02). In the Crohn's patients, serum GH correlated negatively with intraabdominal and total body fat and the ratio of intraabdominal to total body fat. Crohn's disease is associated with an increase in central fat accumulation, with more IAF and a higher ratio of intraabdominal to total body fat compared with controls. Although serum GH levels were similar in the two groups, GH contributed significantly to the abdominal fat measurements. These data show that GH has an important role in modulating visceral fat distribution in patients with Crohn's disease.     

Long-term effect on body composition and metabolic parameters after treatment with recombinant human growth hormone (r-hGH) in HIV-1 infected patients with lipodystrophy

Several studies have shown reduction of visceral adipose tissue (VAT) using recombinant human growth hormone (r-hGH) in HIV-1+ patients, but whether these effects are maintained after the end of treatment is unknown. In a prospective, randomized study we previously studied the effects of r-hGH 4 mg daily vs 3 times/week over 12 weeks, followed by a 2 mg daily maintenance dose for an additional 12 weeks. T1 weighted MRI flash sequences were performed of the face, abdomen and at mid-thigh level (MTF) at baseline, week 12, week 24 and at follow-up.Of 20 subjects who completed the 24-week study, follow-up is available for 16 patients (15 male, mean age 44.8 y, mean duration of HIV infection 13.5 y). After a median time of follow-up of 9 months, VAT remained overall 18% below baseline level (p =0.005). MTF was significantly reduced by 12% compared to its baseline level (p =0.03). Fasting glucose levels significantly improved by 21% compared to baseline (p =0.006). These results suggest that the achieved reduction of VAT using r-hGH in lipodystrophic HIV+ patients is in part maintained after a median follow-up of 9 months.     

Bone density and body composition in children with growth hormone insensitivity syndrome receiving recombinant IGF-I

OBJECTIVE: There are few reports of the metabolic action of insulin-like growth factor 1 (IGF-I) in vivo. Growth hormone insensitivity syndrome is a good model to examine the effects of IGF-I deficiency. This study was designed to assess body composition and bone density in children with growth hormone insensitivity syndrome before and after receiving treatment with recombinant IGF-I. DESIGN: A prospective longitudinal study. PATIENTS: Four prepubertal boys age 6.1-9.8 years with short stature due to growth hormone insensitivity syndrome. MEASUREMENTS: Assessment of body fat by skinfold thickness measurements and dual energy X-ray absorptiometry (DXA) was made during the first 6 months of recombinant IGF-I treatment. Assessment of lumbar spine bone density by DXA was performed prior to IGF-I treatment and during the subsequent five years. RESULTS: Each child showed a significant reduction in fat mass (0.26-1.22 kg) after 6 weeks of IGF-I treatment. Bone density prior to treatment was reduced in comparison to age-matched controls but calculated volumetric bone density was within the normal range. Volumetric bone density progressively improved over the 5-year treatment period. CONCLUSIONS: Children with growth hormone insensitivity syndrome exhibit a metabolic response to IGF-I within 6 weeks analogous to that seen in GH-deficient children receiving GH. Bone density when corrected for body size is within normal limits and demonstrates a response to IGF-I, confirming the anabolic action on bone.