Peptides associated with hyperphagia in adults with Prader–Willi syndrome before and during GH treatment

Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which--if left untreated--leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment.CONCLUSION: Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS.     

Growth hormone treatment improves body composition in adults with Prader-Willi syndrome

OBJECTIVE: Low growth hormone (GH) secretion and hypogonadism are common in patients with Prader-Willi syndrome (PWS). In this study we present the effects of GH treatment on body composition and metabolism in adults with PWS. PATIENTS AND MEASUREMENTS: Nineteen patients with clinical PWS were recruited, 13 had PWS genotype. They were randomised to treatment with placebo or GH (Genotropin, Pharmacia Corporation, Sweden) 0.8 IU (0.2 mg) daily for 1 month and then 1.6 IU (0.5 mg) daily for 5 months. Thereafter patients received open label treatment so that all had 12 months of active GH treatment. Doses were individually titrated to keep serum IGF-I within the normal range for age. Body composition using dual energy X-ray absorptiometry (DXA), metabolic and endocrinological parameters, including oral glucose tolerance test (OGTT), were studied every 6 months. Seventeen patients, nine men and eight women, 17-32 years of age, with a mean body mass index (BMI) of 35 +/- 3.2 kg/m2 completed the study. RESULTS: Compared to placebo, GH treatment increased IGF-I (P < 0.01) levels and decreased body fat (P = 0.04). When all patients recieved GH treatment a mean reduction in body fat of 2.5% (P < 0.01) concomitant with a mean increase in lean body mass of 2.2 kg (P < 0.05) was seen. Significant changes in body composition were only seen in the patients with the PWS genotype. Lipid profiles were normal in most patients before treatment and did not change. OGTT was impaired in five patients at 12 months, but two of these patients increased in fat mass. Insulin levels were unchanged. According to homeostasis model assessment (HOMA), insulin resistance did not change. Side-effects attributed to water retention occurred in three patients, one of whom had to be given increased diuretic therapy. CONCLUSION: This study shows beneficial effects of GH treatment on body composition in adult PWS patients without significant side-effects. Consequently, further studies are encouraged.     

Sleep-related breathing disorders in prepubertal children with Prader-Willi syndrome and effects of growth hormone treatment

CONTEXT: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited. OBJECTIVE: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children. DESIGN: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them. PATIENTS: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1-7.2) yr and body mass index of +1.0 sd score (-0.1-1.7). INTERVENTION: Intervention included treatment with GH 1 mg/m2.d. RESULTS: Apnea hypopnea index (AHI) was 5.1 per hour (2.8-8.7) (normal 0-1 per hour). Of these, 2.8 per hour (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = -0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6-7.9) at baseline to 4.0 (2.7-6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography. CONCLUSIONS: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered.     

Serum adiponectin levels in adults with Prader-Willi syndrome are independent of anthropometrical parameters and do not change with GH treatment

OBJECTIVE: Obesity and growth hormone (GH) deficiency are common in Prader-Willi syndrome (PWS) and these patients are at risk of metabolic diseases in adult life and of reduced life span. Low adiponectin values are associated with obesity and the metabolic syndrome. We therefore found it of interest to measure adiponectin levels in PWS. PATIENTS AND METHODS: 17 adults, nine men and eight women, 17 to 32 years of age, with a mean body mass index (BMI) of 35+/-3.2 kg/m2 participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin) for six months, and subsequently all received GH for 12 months. At baseline, serum total adiponectin levels in the PWS patients were compared with 25 lean and 34 obese controls. Body composition and various metabolic parameters, including adiponectin, were studied every six months in the PWS group. RESULTS: Serum adiponectin levels in PWS subjects were significantly lower (P<0.001) compared with lean and significantly higher (P<0.001) compared with obese controls. In PWS patients, no correlation was found between adiponectin and anthropometrical parameters or measures of insulin sensitivity (e.g. fasting insulin and insulin sensitivity as estimated by the homeostasis model assessment), or between adiponectin and IGF binding protein-1 or IGF-I. Adiponectin did not change during GH intervention. CONCLUSION: In this study of adults with PWS serum total adiponectin levels were higher than in controls with simple obesity and were independent of anthropometrical parameters. In accordance with this the metabolic syndrome is not necessarily present in all PWS patients. Correction of GH deficiency had no effect on serum adiponectin levels.     

Endocrine and metabolic aspects of adult Prader-Willi syndrome with special emphasis on the effect of growth hormone treatment.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features. Excessive eating causes progressive obesity with increased cardiovascular morbidity and mortality. In the PWS genotype loss of one or more normally active paternal genes in region q11-13 on chromosome 15 is seen. It is supposed that the genetic alteration leads to dysfunction of several hypothalamic centres and growth hormone (GH) deficiency (GHD) is common. PWS is well described in children, in whom GH treatment improves body composition, linear growth, physical strength and agility. Few studies have focused on adults. We examined a cohort of 19 young adults with clinical PWS (13 with positive genotype) and mean BMI of 35 kg/m2. At baseline the activity of the GH-insulin-like growth factor-I (IGF-I) system was impaired with low GH values, low total IGF-I and in relation to the obesity low levels of free IGF-I and non-suppressed IGF-binding-protein-1 (IGFBP-1). 2/3 were hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and nine patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. Seven patients had a moderate dyslipidemia. The 13 patients with the PWS genotype were shorter and had significantly lower IGF-I. Seventeen (9 men and 8 women), subsequently completed a 12 months GH treatment trial, and GH had beneficial effects on body composition without significant adverse effects. The effects were more pronounced in the patients with the PWS genotype. Analysis of peptides involved in appetite regulation showed that leptin levels were high reflecting obesity and as a consequence NPY levels were low. In relation to the patients obesity circulating oxytocin levels were abnormally low and ghrelin levels abnormally high. Thus, oxytocin and ghrelin might be involved in the hyperphagia. NPY, leptin and ghrelin did not change during GH treatment.In conclusion this pilot study showed that adults with PWS have a partial GH deficiency, and GH treatment has beneficial effects on body composition in adult PWS without significant side-effects. Larger and longer term studies on the effect of GH replacement in adult PWS are encouraged.     

The growth hormone-insulin-like growth factor axis in adult patients with Prader Willi syndrome.

OBJECTIVE: Prader Willi syndrome (PWS) is a genetic disorder characterised by short stature, extreme obesity, body composition abnormalities and behavioural problems. Hypothalamic dysfunction with low growth hormone (GH) secretion and low levels of GH-related growth factors is common. However, the interpretation is difficult because of the concomitant obesity, which in itself has important effects on the GH-IGF-I-system. We therefore analysed free and total IGF-I, total IGF-II and their binding proteins in obese PWS adults before and during 12 months GH treatment. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-2.3 kg/m(2) participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin, Pharmacia) 0.8 IU (0.26 mg) for one month, and then 1.6 IU (0.53 mg) for 5 months. Subsequently GH doses were individually titrated to normal levels for age. Overnight fasting levels of free and total IGF-I, total IGF-II, GH-binding protein (GHBP) and IGF-binding proteins (IGFBP)-1, -2 and -3 were measured by RIA at baseline and after 6 and 12 months GH treatment. Mean levels+/-SEM of free IGF-I were 1.02+/-0.12 microg/L as compared to a reference value of 0.95+/-0.15 microg/L, while mean total IGF-I was 128+/-15 microg/L (212+/-14 microg/L) and total IGF-II was 704+/-45 microg/L (825+/-34 microg/L). Mean IGFBP-2 158+/-24 microg/L (764+/-72 microg/L) and GHBP 2.65 nmol/L (1.71+/-0.3 1nmol/L). IGFBP-1 and IGFBP-3 levels were normal. Both free and total IGF-I increased significantly during GH treatment, while IGF- and GH-binding proteins as well as total IGF-II remained unchanged. CONCLUSION: Low total IGF-I and, in relation to the obesity, low free IGF-I, low total IGF-II and non-suppressed IGFBP-1 are consistent with the concept that PWS patients have a partial GH deficiency, which can be corrected by GH replacement.     

Effects of growth hormone treatment in adults with Prader–Willi syndrome

ObjectiveSince limited data exist on adults with Prader–Willi syndrome (PWS) and growth hormone (GH) treatment, we report our experience on the effects of treatment for one year on body composition, physical activity, strength and energy expenditure, diet, general chemistry and endocrine data with quality of life measures.DesignWe studied 11 adults with PWS (6F:5M; average age = 32 yrs) over a 2 year period with GH treatment during the first year only. Electrolytes, IGF-I, glucose, thyroid, insulin, lipids, body composition, physical activity and strength, diet, energy expenditure and quality of life data were collected and analyzed statistically using linear modeling at baseline, at 12 months following GH therapy and at 24 months after treatment cessation for 12 months.ResultsTotal lean muscle mass was significantly increased (p < 0.05) during GH treatment along with moderate-vigorous physical activity and plasma IGF-I and HDL levels, but returned to near baseline after treatment. Percent body fat decreased during the 12 months of GH treatment but increased after treatment.ConclusionsPreviously reported beneficial effects of GH treatment in children with PWS were found in our adults regarding body composition, physical activity and plasma HDL and IGF-I levels. Several beneficial effects diminished to near baseline after cessation of GH treatment for 12 months supporting the continuation of treatment in PWS into adulthood and possibly adults not previously treated during childhood.     

Adiponectin levels in prepubertal children with Prader-Willi syndrome before and during growth hormone therapy

CONTEXT: Children with Prader-Willi syndrome (PWS) may have obesity and an abnormal body composition with a high body fat percentage, even if they have a normal body weight. Adiponectin has been inversely related to obesity and insulin resistance. OBJECTIVE: The objective of the study was to evaluate in prepubertal PWS children the following: 1) adiponectin levels, body composition, carbohydrate metabolism, and triglyceride levels; 2) associations between adiponectin and body composition, carbohydrate metabolism, and triglycerides; and 3) effects of GH treatment on these outcome measures. PATIENTS: Twenty prepubertal PWS children participated in the study. INTERVENTION: The subjects were randomized into a GH treatment group (n=10, 1 mg/m2.d) and a non-GH-treated control group (n=10). MAIN OUTCOME MEASURES: At baseline, after 1 and 2 yr of GH treatment, fasting levels of adiponectin, glucose, insulin, and triglycerides were assessed. Body composition and fat distribution were measured by dual energy x-ray absorptiometry. RESULTS: PWS children had significantly higher median (interquartile range) adiponectin levels [17.1 mg/liter (13.9-23.2)] than healthy sex- and age-matched controls [11.8 mg/liter (9.7-12.5), P<0.005]. Body fat percentage was significantly higher than 0 sd score [1.8 sd score (1.5-2.1), P<0.001]. Adiponectin levels were inversely related to triglyceride levels (r=-0.52, P=0.03). There was a tendency to an inverse relation with body fat percentage and body mass index, but no correlation with fasting insulin or glucose levels, the insulin to glucose ratio, or homeostasis model assessment index. During GH treatment, adiponectin levels increased significantly and did not change in randomized controls. CONCLUSION: Adiponectin levels were increased, and inversely associated with triglyceride levels, in prepubertal, not overweight PWS children, although they had a relatively high body fat percentage. During GH treatment, adiponectin levels further increased, whereas no change was found in the controls, which is reassuring with respect to the development of insulin resistance during GH treatment.     

Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study

Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition.     

Growth hormone treatment of adults with Prader-Willi syndrome and growth hormone deficiency improves lean body mass, fractional body fat, and serum triiodothyronine without glucose impairment: results from the United States multicenter trial

CONTEXT: GH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies. OBJECTIVES: Our objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults. DESIGN: We conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods. Setting: The study was conducted at outpatient treatment facilities at four U.S. academic medical centers. PATIENTS: Lean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations. INTERVENTION: Human recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated. MAIN OUTCOMES MEASURES: Lean body mass and percent fat were measured by dual-energy x-ray absorptiometry. RESULTS: Lean body mass increased from 42.65 +/- 2.25 (se) to 45.47 +/- 2.31 kg (P < or = 0.0001), and percent fat decreased from 42.84 +/- 1.12 to 39.95 +/- 1.34% (P = 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6-12 months of GH. Mean fasting glucose of 85.3 +/- 3.4 mg/dl, hemoglobin A1c of 5.5 +/- 0.2%, fasting insulin of 5.3 +/- 0.6 microU/ml, area under the curve for insulin of 60.4 +/- 7.5 microU/ml, and homeostasis model assessment of insulin resistance of 1.1 +/- 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T(3) increased 26.7% from 127.0 +/- 7.8 to 150.5 +/- 7.8 ng/dl (P = 0.021) with normalization in all subjects, including six (20%) with baseline T(3) values at least 2 sd below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients). CONCLUSIONS: This multicenter study demonstrates that GH improves body composition, normalizes T(3), and is well tolerated without glucose impairment in PWS genotype adults.     

Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment

BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited. OBJECTIVE: To evaluate thyroid function in children with PWS, before and during GH treatment. DESIGN/PATIENTS: At baseline, serum levels of T4, free T4 (fT4), T3, reverse T3 (rT3) and TSH were assessed in 75 PWS children. After 1 year, assessments were repeated in 57 of the them. These children participated in a randomized study with two groups: group A (n = 34) treated with 1 mg GH/m(2)/day and group B (n = 23) as controls. RESULTS: Median age (interquartile range, IQR) of the total group at baseline was 4.7 (2.7-7.6) years. Median (IQR) TSH level was -0.1 SDS (-0.5 to 0.5), T4 level -0.6 SDS (-1.7 to 0.0) and fT4 level -0.8 SDS (-1.3 to -0.3), the latter two being significantly lower than 0 SDS. T3 level, at 0.3 SDS (-0.3 to 0.9), was significantly higher than 0 SDS. After 1 year of GH treatment, fT4 decreased significantly from -0.8 SDS (-1.5 to -0.2) to -1.4 SDS (-1.6 to -0.7), compared to no change in untreated PWS children. However, T3 did not change, at 0.3 SDS (-0.1 to 0.8). CONCLUSIONS: We found normal fT4 levels in most PWS children. During GH treatment, fT4 decreased significantly to low-normal levels. TSH levels remained normal. T3 levels were relatively high or normal, both before and during GH treatment, indicating that PWS children have increased T4 to T3 conversion.     

Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study

Prader-Willi syndrome (PWS) is characterized by short stature, muscular hypotonia, cognitive dysfunction, and hyperphagia usually leading to severe obesity. Patients with PWS share similarities with growth hormone deficiency (GHD). Few studies have dealt with growth hormone (GH) treatment in PWS adults. The purpose of the Scandinavian study was to evaluate the effects of GH on body composition, lipid and glucose metabolism, physical performance and safety parameters in adults with PWS. Twenty-five women and 21 men with PWS were randomized to treatment with GH or placebo during 1?year followed by 2?years of open labeled GH treatment. At baseline 1/3 had normal BMI, six patients severe GHD, ten impaired glucose tolerance and seven diabetes. At 1?year insulin-like growth factor I (IGF-I) SDS had increased by 1.51 (P?相似文献   

The influence of growth hormone (GH) therapy on cardiac performance in patients with childhood onset GH deficiency.

OBJECTIVE: There is accumulating evidence that growth hormone (GH) plays an important role in the maintenance of normal cardiac growth and function. Abnormalities in left ventricular diastolic function and impairment of systolic function have also been reported in patients with GHD. In this study, we investigated the effects of 12 months GH replacement therapy on cardiac functional indices measured by echocardiography, the ECG stress test and SPECT imaging. DESIGN: Sixteen patients with childhood onset GHD (age 42.3+/-13.1 years, 10 males) were investigated before, and after, 12 months of GH treatment at a dosage of 0.02 IU/kg/day (7 microg/kg/day). The GH administration resulted in serum IGF-I levels within the normal range in all the patients. The following investigations were performed initially and after 12 months: electrocardiography, systolic and diastolic blood pressure, heart rate measurement, a complete Doppler-echocardiographic examination, treadmill exercise test and Technetium-99m sestamibi single-photon emission computer tomography (SPECT) imaging at rest and after exercise. RESULTS: Echocardiography showed improvement in left ventricular systolic function after GH treatment. End-systolic volume fell from 29.9+/-12.4 to 24.4+/-6.9 ml (p<0.05) and the ejection fraction increased from 56.2+/-7.2% to 63.2+/-6,1% (p<0.01). Left ventricular diameter and wall thickness did not change after GH treatment, although systolic increase in interventricular septum thickness (IVS%) and systolic increase in posterior wall thickness (PWT%) increased significantly (IVS% 52.2+/-31.9% vs. 67.3+/-30.4% and PWT% 48.7+/-20.2% vs. 58.0+/-17.7%, p<0.01, p<0.01, respectively). Contractile function, measured at midwall level, improved as left ventricular midwall fractional shortening (MWS) increased (16.11+/-6.55 vs. 23.30+/-5.89 %, p<0.01) and stress-corrected MWS increased between the examinations performed before and after 12 months of GH treatment (90.97+/-36.66 vs. 133.10+/-32.84 %, p<0.01). Diastolic function did not change, as assessed by early diastolic flow (E), diastolic flow secondary to atrial contraction (A), or the E/A ratio. The LV-mass index did not change significantly after GH treatment (78.4+/-22.1 vs. 81.9+/-21.1g/m(2)). After 12 months of GH treatment the myocardial performance index (MPI) decreased significantly from 0.483+/-0.146 at baseline to 0.410+/-0.086 at the end of the study (p<0.05). There was a trend towards an increase in exercise duration and capacity after GH treatment but the differences did not reach levels of statistical significance. SPECT imaging basally and after 12 months showed normal myocardial perfusion at rest and after exercise in all the patients. In conclusion, GH replacement therapy in adults with GHD demonstrated the beneficial effects on cardiac functions.     

Growth hormone (GH) substitution for one year normalizes elevated GH-binding protein levels in GH-deficient adults secondary to a reduction in body fat. A placebo-controlled trial.

The high affinity growth hormone binding protein (GHBP) in human serum derives from the extracellular domain of the GH receptor. It is well known that fat mass correlates positively to GHBP levels, but it is uncertain whether GH secretory status influences GHBP levels. Since body composition is known to change during GH substitution in adult GHD patients, we determined the relation between GHBP and body composition during GH substitution in GHD adults. Twenty-five GHD adults aged 45.0 +/- 1.8 years, were examined before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. A group of 27 healthy age- and gender-matched normal-weight adults provided reference data. The participants underwent anthropometric measurements [body mass index (BMI), waist/hip ratio (W/H)], computer-tomography (CT-scan) of femoral and abdominal regions, dual-energy X-ray absorptiometry (DEXA-scan), and bioimpedance (BIA), as well as blood sampling. At baseline, the GHBP levels were increased compared to controls (1.63 +/- 0.14 nmol/l vs 1.12 +/- 0.1 nmol/l, P = 0.01). During 12 months of GH substitution, GHBP levels decreased to the levels of the control subjects. GHBP correlated positively to indices of adiposity in GHD patients at baseline: intra-abdominal fat (r = 0.54, P = 0.005), subcutaneous abdominal fat (r = 0.59, P < 0.002), body fat (BIA) (r= 0.41, P= 0.044), BMI (r= 0.58, P = 0.002), and total body fat (DEXA scan) (r= 0.61, P < 0.001). After 12 months of GH substitution, different estimates of body fat were significantly decreased in the GH treated group, but the positive relationship between GHBP and these estimates of body fat was maintained. In multiple linear regression analyses, fasting insulin levels were also a significant determinant of GHBP levels. We conclude that GHBP levels are increased in GHD patients and decrease to normal levels during 12 months of GH substitution. Furthermore, GHBP is predominantly correlated to indices of adiposity also in GHD patients.     

The effects of growth hormone replacement therapy on overnight metabolic fuels in hypopituitary patients

OBJECTIVE: Hypopituitary adults on conventional replacement have low concentrations of metabolic fuels throughout the night, possibly related to GH deficiency or to decreased cortisol levels overnight. We investigated whether GH replacement corrects the overnight fuel deficiency. DESIGN: We measured circulating levels of metabolic fuels: glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) and insulin concentrations over 24 h (from 0730 h to 0700 h) in hypopituitary adults before and after GH treatment in a randomized double-blind placebo-controlled trial of 3 months' duration. PATIENTS: Thirteen hypopituitary patients, 8 women and 5 men, were studied. RESULTS: Six patients (4 women and 2 men) received GH and 7 patients (4 women and 3 men) were allocated to receive placebo. There was no difference in fasting (0730 h), area under the curve (AUC) between 2400 h and 0700 h (overnight) and AUC over 24 h for plasma glucose, 3-OHB, glycerol and insulin concentrations as a result of GH treatment. Fasting and overnight AUC for NEFA were significantly higher on GH treatment ((mean +/- SEM) 243 +/- 29 vs. 446 +/- 90 micromol/l, P = 0.03, 1522 +/- 208 vs. 2167 +/- 123 micromol/l H, P = 0.046, respectively), but AUC over 24 h was not affected significantly. No significant changes in any fuel were seen in the placebo group. The changes in fasting, overnight and 24 h AUC for glucose, 3-OHB, glycerol and insulin levels with GH and with placebo for 3 months were similar. The changes in fasting and overnight AUC for NEFA before and after 3 months were significantly different in the group treated with GH vs. the group treated with placebo (median (lower-upper quartile) 104 (90-276) vs. -89 (-98 to 26) micromol/l, P = 0.002; 633 (263-967) vs. -895 (-1379 to -494) micromol/l h, P = 0.002, respectively), but the changes in 24-h AUC for NEFA were not significant between the two groups. CONCLUSIONS: GH replacement in hypopituitary adults increases fasting and overnight (between 2400 h and 0700 h) non-esterified fatty acid concentrations, consistent with the known lipolytic effect of GH. GH did not influence the concentrations of other metabolic fuels or insulin.     

Conditional cardiovascular response to growth hormone therapy in adult patients with Prader-Willi syndrome

CONTEXT: In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function when compared with controls. OBJECTIVES: The objective of the study was to evaluate the cardiovascular response to GH therapy in adult PWS patients. STUDY PARTICIPANTS: Thirteen obese PWS adults (seven males and six females, aged 26.9+/-1.2 yr, body mass index 46.3+/-1.6 kg/m2) participated in the study. METHODS: Determination of IGF-I, metabolic parameters, echocardiography, and cardioscintigraphy with dobutamine stimulation was made during 12 months GH therapy, with results analyzed by repeated-measures ANOVA. RESULTS: GH therapy increased IGF-I (P<0.0001); decreased C-reactive protein levels (P<0.05); and improved lean mass (P<0.001), fat mass (P<0.05), and visceral fat (P<0.001). Echocardiography showed that 6- and 12-month GH therapy increased left ventricle mass in 76 and in 61% of patients, respectively (P<0.05), did not change diastolic function, and slightly decreased the left ventricle ejection fraction (LVEF) (P=0.054). Cardioscintigraphy documented stable values of LVEF throughout the study, whereas right ventricle ejection fraction decreased significantly (P<0.05) being normally responsive to dobutamine infusion. A positive association between IGF-I z-scores and LVEF occurred at the 6- and 12-month follow-up (P<0.05). CONCLUSIONS: In PWS, GH therapy increased cardiac mass devoid of diastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular function during GH therapy suggest the need for appropriate cardiac and hormonal monitoring in the therapeutic strategy for Prader-Willi syndrome.     

Leptin response to insulin in humans is related to the lipolytic state of abdominal subcutaneous fat.

Insulin-induced leptinemia in humans appears to be blunted by insulin resistance. We therefore examined the relationship between insulin action and plasma leptin by monitoring regional and whole body lipolysis and plasma leptin levels in 15 premenopausal women (body fat range, 14-59%) during a two-stage euglycemic clamp (insulin was infused 90 min each at 6-10 and 12-20 mU/m2 x min). Microdialysis probes were placed in abdominal and femoral sc adipose tissue. Subjects were given a primed, constant infusion of a stable isotope tracer (2H5-glycerol), and plasma glycerol isotope enrichments were analyzed by mass spectrometry to determine glycerol kinetics. Although there was no mean change in plasma leptin during the clamp (baseline, 16.6 +/- 4.5 ng/mL; final, 16.3 +/- 4.3 ng/mL), there was large interindividual variability in the changes in plasma leptin (range, -18% to +19%). Changes in plasma leptin during the clamp stages were correlated with abdominal dialysate glycerol concentrations (r = -0.44; P < 0.05), but not femoral dialysate glycerol concentrations (r = -0.15), the rate of appearance of glycerol in plasma (r = 0.005), or plasma insulin levels (r = 0.16). The results suggest that insulin-induced changes in plasma leptin are more related to the lipolytic state (i.e. low leptin response when lipolysis is high) of abdominal sc adipose tissue than that of other fat depots.     

Changes in body composition and leptin levels during growth hormone (GH) treatment in short children with various GH secretory capacities

OBJECTIVE: The aim of this study was to follow changes in body composition, estimated by dual-energy X-ray absorptiometry (DXA), in relation to changes in leptin during the first year of GH therapy in order to test the hypothesis that leptin is a metabolic signal involved in the regulation of GH secretion in children. DESIGN AND METHODS: In total, 33 prepubertal children were investigated. Their mean (S.D.) chronological age at the start of GH treatment was 11.5 (1.6) years, and their mean height was -2.33 (0.38) S.D. scores (SDS). GH was administered subcutaneously at a daily dose of 0.1 (n=26) or 0.2 (n=7) IU/kg body weight. Ten children were in the Swedish National Registry for children with GH deficiency, and twenty-three children were involved in trials of GH treatment for idiopathic short stature. Spontaneous 24-h GH secretion was studied in 32 of the children. In the 24-h GH profiles, the maximum level of GH was determined and the secretion rate estimated by deconvolution analysis (GHt). Serum leptin levels were measured at the start of GH treatment and after 10 and 30 days and 3, 6 and 12 months of treatment. Body composition measurements, by DXA, were performed at baseline and 12 months after the onset of GH treatment. RESULTS: After 12 months of GH treatment, mean height increased from -2.33 to -1.73 SDS and total body fat decreased significantly by 3.0 (3.3)%. Serum leptin levels were decreased significantly at all time points studied compared with baseline. There was a significant correlation between the change in total body fat and the change in serum leptin levels during the 12 months of GH treatment, whereas the leptin concentration per unit fat mass did not change. In a multiple stepwise linear regression analysis with 12 month change in leptin levels as the dependent variable, the percentage change in fat over 12 months, the baseline fat mass (%) of body mass and GHt accounted for 24.0%, 11.5% and 12.2% of the variability respectively. CONCLUSIONS: There are significant correlations between changes in leptin and fat and endogenous GH secretion in short children with various GH secretory capacities. Leptin may be the messenger by which the adipose tissue affects hypothalamic regulation of GH secretion.     

Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 microg/kg.d) for 5-7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (-35%; P < 0.001) was still present after intervention but was blunted (-11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population.     

Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults

GH is an important regulator of fat metabolism at rest, but it is not known whether it regulates fat metabolism during exercise. To determine whether physiologic concentrations of GH influence fat metabolism during exercise, we randomized 16 GH-deficient adults, receiving long-term (mean duration, 5 yr) GH replacement, to either continue GH (n = 8) or receive identical placebo (n = 8) for a 3-month period. Metabolic studies, at rest, during and following exhaustive exercise were carried out at baseline and at the end of the 3 months. The rate of appearance of glycerol (glycerol Ra, an index of lipolysis) and free fatty acids (FFA, FFA Ra) and the rate of disappearance of FFA (FFA Rd) in the plasma were measured using infusions of (2)H(5)-glycerol and 1-(13)C-palmitic acid. Changes in body composition were assessed using dual-energy x-ray absorptiometry scanning and anthropometric measurements. In the baseline studies, exercise resulted in an increase in plasma glycerol and FFA concentrations, glycerol Ra, FFA Ra, and FFA Rd (P < 0.001). Three months of GH withdrawal resulted in reductions in plasma glycerol and FFA, glycerol Ra, FFA Ra, and FFA Rd at rest (P < 0.05 vs. baseline) and during exercise (P < 0.05 vs. baseline and vs. GH treated). Lean body mass decreased after 3 months of GH withdrawal, but total body fat, trunk fat, waist circumference, and the sum of skinfold thicknesses increased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). Fasting insulin and homeostasis model assessment of insulin resistance decreased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). In summary, GH withdrawal for 3 months resulted in reductions in release of glycerol and FFA into the circulation and uptake of FFA into the tissues during intense exercise. These changes were accompanied by reduced lean body mass and increased total body and trunk fat. Further studies are required to determine whether reduced mobilization of fat during exercise contributes to reduced exercise capacity and increased body fat in GH-deficient adults.