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   

A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-I without significant deterioration in glucose tolerance

OBJECTIVE: Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF-I response. DESIGN: The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF-I, and in patients with sub-normal serum IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week. PATIENTS: Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21-28). MEASUREMENTS: Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured. Directly after the 24-h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP-1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bio-impedance analysis (BIA) and quality of life was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS: After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median -2.9%; range -1.0-(-6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = -0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy. CONCLUSIONS: In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP-1 suggest that serum IGFBP-1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF-I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.     

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 replacement on physical performance and body composition in GH deficient adults

OBJECTIVES: Adults with GH deficiency complain frequently of low energy levels resulting in a low perceived quality of life. Body composition is altered, with increased fat mass and decreased lean body mass, and muscle strength is reduced. The aims of this study were to determine the effects of GH replacement on physical performance and body composition in GH deficient (GHD) adults. STUDY DESIGN: The study consisted of a 6-month randomised, double-blind, placebo controlled study of the administration of GH (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17F), mean age 39.8 years (range 21.1-59.9), on conventional replacement therapy as required. METHODS: Maximum aerobic capacity was measured using an incremental walking test to volitional exhaustion on a motorized treadmill. Quadriceps muscle strength was assessed by measuring maximum voluntary contractions and body composition by dual energy X-ray absorptiometry (DEXA). RESULTS: There were no statistically significant changes in quadriceps muscle strength between the GH and placebo groups. In both groups, there was a significant increase in quadriceps muscle strength compared to baseline during the double-blind period (GH group: P = 0.016; placebo group: P = 0.048). Compared to baseline, muscle strength was further improved in the GH treatment group after 12 months of treatment (P = 0.007). No further improvement was noted in the placebo group after 6 months on open GH treatment. In the placebo group, maximum aerobic capacity decreased during the placebo period (P = 0.017). No significant change was observed in the GH group. During open GH treatment the previously placebo treated group had a significant increase of maximum aerobic capacity (P < 0.049) whereas no significant improvement could be seen in the GH group. In the GH group there was a significant increase in lean body mass (P = 0.001) and a significant decrease in fat mass (P < 0.001). No statistically significant changes were noted in the placebo group: the differences in these changes between treatment groups were statistically significant (lean body mass: P = 0.009; fat mass: P < 0.001). The changes in body composition in the GH group during the 6 month placebo-controlled period were maintained during continued open treatment. Similar changes in body composition to those observed in the GH group during the 6 month placebo-controlled period were also seen in the placebo group once the patients received GH treatment. CONCLUSIONS: Our data show that GH replacement in GH deficient adults is associated with favourable changes in body composition, which could be important in the long term health outcome and physical activity of GH deficient patients. Our data support the concept that GH therapy alone, in the absence of some form of exercise programme, may increase the amount of lean tissue but not the quality or functional capacity of this tissue and it may be that training, in addition to GH therapy, may be necessary to significantly increase physical performance in these patients. We suggest that future trials with GH therapy and general approaches to the treatment of GH deficiency should include a planned activity programme as an approach to health improvement in these patients.     

Lack of reduction in body fat after treatment with insulin-like growth factor-I in two children with growth hormone gene deletions

Two patients with growth hormone (GH) gene deletions were treated with recombinant insulin-like growth factor-I (IGF-I) (80-240 (microg/kg/day) and the effects on bone mass and body composition were compared to administration of GH (0.075 U/kg/day) to 8 patients with idiopathic GH deficiency. Bone mass and body composition were measured by dual photon X-ray absorptiometry (DEXA ) before and 3 and 6 months after treatment with GH or IGF-I. Similar increases in growth velocities were observed after GH and IGF-I treatment. Treatment with GH resulted in prompt and significant reduction in body fat percentage (basal, 3 and 6 months: 22+/-10, 17+/-9, and 16+/-9%) whereas body fat percentage remained unchanged after IGF-I therapy (basal, 3 and 6 months: 49, 52 and 48% in patient 1 and 45, 42 and 43% in patient 2, respectively). Fat percentage remained elevated after 18 months of IGF-I treatment in patients 1 (51%) and 2 (44%), respectively. Lean mass and bone mineral content increased with GH and IGF-I therapies. We conclude that reduction of body fat measured by DEXA, observed after administration of GH but not after IGF-I treatment in these children with GH deficiency, suggests that the GH effect on body fat mass is not mediated by circulating IGF-I.     

Dose-, IGF-I- and sex-dependent changes in lipid profile and body composition during GH replacement therapy in adult onset GH deficiency

OBJECTIVE: Patients with GH deficiency of adult onset (GHDA) exhibit dyslipidaemia and increased cardiovascular morbidity. GH replacement potently reduces body fat and serum lipids in GHDA. In recent years, lower GH doses have been introduced. The purpose of this analysis was to explore the response relationship between GH doses, lipids and body composition. DESIGN: Two consecutive, randomized 12-month GH replacement studies covering placebo and three different doses of GH (0.5, 1.0 and 1.7 IU/m(2) per day). Low and intermediate doses were IGF-I titrated. PATIENTS: Fifty-eight patients with severe GHDA, not previously treated with GH and stably substituted for other endocrine deficiencies, were included in the study. METHODS: Serum lipoproteins, serum IGF-I and body composition analysis by dual energy X-ray absorptiometry (DXA) were used. RESULTS: Fifty-seven percent of patients exhibited low density lipoprotein (LDL) cholesterol levels above 4.16 mmol/l, corresponding to the American Heart Association threshold of 160 mg/dl. GH treatment resulted in significant decreases in total and LDL cholesterol, with no significant change in high density lipoprotein cholesterol or triglycerides. The low dose induced no significant changes in lipid levels, whereas the medium dose reduced LDL cholesterol and the high dose decreased both LDL and total cholesterol. The effects depended significantly on the GH dose and the level of IGF-I obtained, but not on gender. GH replacement induced dose-dependent reductions in fat mass and sex-dependent increases in lean mass. CONCLUSIONS: GH given for 1 year at a dosage between 0.5 and 1.7 IU/m(2) per day reduced fat mass in a dose-dependent manner, increased lean body mass and lowered total and LDL cholesterol in patients with severe GHDA. Low dose GH treatment with normal IGF-I levels induced smaller changes compared with high dose therapy, and may need a longer treatment time.     

Growth hormone induced lipolysis during short- and long-term administration in adult Prader–Willi patients

Prader-Willi syndrome (PWS) is a complex genetic disease, clinically characterised by short stature, abnormal body composition, with more body fat than lean body mass, hyperphagia and obesity. Partial growth hormone (GH) deficiency is common, and GH treatment to PWS children and adults has shown beneficial effects on body composition. In this study, we have evaluated indices of GH's lipolytic effect in 6 PWS adults analysing glycerol, lactate and glucose in dialysate from microdialysis in subcutaneous abdominal adipose tissue. The patients were four men and two women, 19-37 years old; all hypogonadal. BMI was 24.2-49.1, mean 35.9 kg/m(2). All had normal serum insulin levels. They received GH therapy (Genotropin Pfizer) during 12 months and doses were individually titrated to normal serum IGF-I for age. Immediately before treatment start and at 12 months, 30-36 h after the last GH injection, sampling of dialysate was carried out at night (11 p.m. to 7 a.m.), as well as after intravenously injection of a standardised GH dose (0.8 mg). At baseline individual mean night time glycerol and lactate were similar to levels in adults without PWS (160.7-278.1 micromol/L and 0.80-3.99 mmol/L, respectively), and did not change with 12 months GH treatment. Glucose levels were normal, except in a patient with diabetes, and did not change during the study. Compared to baseline the immediate effect of GH injection resulted in a significant increase in glycerol levels after 12 months. In conclusion, night time lipolytic response in this small group of PWS adults seemed normal and did not change after 12 months GH treatment. On the other hand short-term GH induced lipolysis increased, indicating normal lipolytic response in PWS.     

Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease

Although a specific GH deficiency (GHD) syndrome in the adult and the response to GH replacement therapy are well recognized, there are few data available on the effect of GH replacement therapy in elderly GH-deficient patients. We studied the effect of GH therapy on body composition and bone mineral density measured by dual energy x-ray absorptiometry, markers for bone metabolism, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in 31 patients (6 women and 25 men; aged 60-79 yr; mean, 68 yr) with multiple pituitary hormone deficiencies. The GH response to arginine or insulin was below 3 microg/L (9 mU/L) in all subjects. They were randomized to GH (Humatrope, Eli Lilly & Co.) or placebo for 6 months, followed by 12 months of open treatment. The dose was 0.05 IU/kg x week for 1 month, and after that it was 0.1 IU/kg x week divided into daily sc injections (0.75-1.25 IU/day). There were no changes in any of the measured variables during placebo treatment. GH treatment normalized serum IGF-I in a majority of the patients and increased IGFBP-3 and -5 as well as IGFBP-4 and IGF-II to values within normal range. Lean body mass was increased, and the increase at 6 and 12 months correlated with the increase in IGF-I (r = 0.46; P = 0.010 and r = 0.54, respectively; P = 0.003). GH treatment caused a modest, but highly significant, reduction of total body fat. Mean bone mineral density was not different from that in healthy subjects of the same age and did not change during the observation period. Markers for bone formation (bone-specific alkaline phosphatase activity, osteocalcin, and procollagen I carboxyl-terminal peptide in serum) increased within the normal range, and levels were sustained throughout the study. The bone resorption marker (pyridinoline in urine) was significantly elevated for 12 months. Side-effects were mild, mostly attributed to fluid retention. In two patients with normal glucose tolerance at the start of the study, pathological glucose tolerance occurred in one patient and was impaired in one. In conclusion, elderly patients with GHD respond to replacement therapy in a similar manner as younger subjects, with an improvement in body composition and an increase in markers for bone metabolism. Side-effects are few, and elderly GHD patients can be offered treatment. As long-term risks are unknown, GH doses should be titrated to keep IGF-I within the age-related physiological range.     

Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults

OBJECTIVES: To study the effects on body composition after 1 month's administration of supraphysiological doses of growth hormone (GH) in healthy, active young adults with normal GH-IGF-I axis. SUBJECTS AND METHODS: Thirty healthy, physically active volunteers (15 men and 15 women), mean age 25.9 years (range 18-35), participated in this study, designed as a randomized, double-blind, placebo-controlled, parallel study with three groups (n = 10: five men and five women in each group). The groups comprised the following: placebo (P), GH 0.1 IU/kg/day [0.033 mg/kg/day] (GH 0.1) and GH 0.2 IU/kg/day [0.067 mg/kg/day] (GH 0.2). RESULTS: In the pooled group with active GH treatment (n = 20) the results showed significant increases: IGF-I increased by 134% (baseline vs. after 1 month), body weight by 2.7%, fat free mass by 5.3%, total body water by 6.5% and extracellular water (ECW) by 9.6%. Body fat decreased significantly by 6.6%. No significant change in intracellular water was detected. The observed increase in fat free mass by 5.3% was explained by the ECW increase, indicating limited anabolic effects of the supraphysiological GH doses. Changes were noticeable in both genders, although more prominent in the male subjects. Fluid retention symptoms occurred in the majority of individuals. CONCLUSIONS: This is, to our knowledge, the first placebo-controlled trial to show the effects of supraphysiological GH doses on body composition and IGF-I levels in physically active and healthy individuals of both genders; the results indicate limited anabolic effects of GH with these supraphysiological doses. The role of GH as an effective anabolic doping agent is questioned.     

Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement

OBJECTIVE: Adult growth hormone deficiency (AGHD) is characterized by abnormalities in body composition and a poor perceived quality of life (QoL). Weight-based high-dose growth hormone replacement (GHR) results in improvements in body composition and QoL in AGHD. However, a high patient percentage reported side-effects on high-dose GHR resulting in a high rate of patient withdrawal from growth hormone (GH) treatment. High-dose GH therapy also leads to supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations that have been associated with breast and prostate cancer, raising major concerns over the use of such high-dose GH regimen in AGHD. The aim of this study was to assess the effects of low-dose growth hormone replacement (GHR) on body composition and QoL as early as 1 and 3 months. STUDY DESIGN: A prospective, open treatment design study to determine the early effects of low-dose GH administration on body composition and QoL. GH was initiated at a daily dose of 0.4-0.5 IU, and titrated up to achieve and maintain IGF-I standard deviation score (IGF-I SDS) between the median and upper end of the age-related reference range. PATIENTS: Forty-six, post-pituitary surgery, severe AGHD patients (22 women), defined as peak GH response < 9 mU/l to provocative testing. The mean age was 50.4 years (range 26-72). Forty-three patients required additional pituitary replacement hormones following pituitary surgery and were on optimal doses at recruitment. MEASUREMENTS: Body composition and QoL were assessed prior to GHR and subsequently at 1 and 3 months after initiating GHR. Body mass index (BMI) and waist hip ratio (WHR) were calculated from measurements of height, weight, and waist and hip circumference, respectively. Bioelectrical impedance analysis (BIA) was used to determine body fat and lean body mass. QoL was assessed using the disease-specific 'QoL-assessment of growth hormone deficiency in adults (QoL-AGHDA)' questionnaire. Serum IGF-I was measured at each visit to assess the adequacy of GHR. RESULTS: IGF-I and IGF-I SDS increased significantly at 1 and 3 months (P < 0.001) after commencing GHR. The increase in IGF-I (P < 0.05) and IGF-I SDS (P < 0.01) was significant between 1 and 3 months in the absence of any significant increase in GH dose (P = ns) during this period. Eighty-five per cent of patients achieved IGF-I SDS levels between median and upper end of the age-related reference range after 3 months of GHR, and no side-effects were reported during this period. There was a significant reduction in body fat percentage (BFP) from 36.1 +/- 9.1% at baseline to 34.9 +/- 9.3% (P < 0.01) at 1 month and 34.1 +/- 9.2% (P < 0.001) at 3 months. Body fat mass (BFM) reduced from 32.8 +/- 13.6 kg at baseline to 31.9 +/- 13.9 kg at 1 month (P < 0.05) and 31.1 +/- 13.6 kg at 3 months (P < 0.001). These changes in BFP and BFM occurred in the absence of any significant change in BMI and WHR (P = ns). Lean body mass (LBM) was 55.9 +/- 11.1 kg at baseline and increased to 57.1 +/- 11.3 kg after 1 month (P < 0.01) and to 57.6 +/- 11.5 kg (P < 0.001) after 3 months of GHR. Significant improvement was observed in the perceived QoL with the AGHD assessment scores reducing from 13.3 +/- 6.4 to 11.5 +/- 6.6 within 1 month (P < 0.01) and 10.0 +/- 6.6 at 3 months (P < 0.001). There was no significant correlation between improvement in QoL and changes in body fat percentage (r = 0.01 at 1 month and r = 0.12 at 3 months, P = ns) or IGF-I levels (r = 0.04 and r = 0.003, P = ns at 1 and 3 months, respectively). The improvement in body composition and QoL was significant between 1 and 3 months. CONCLUSIONS: Low-dose GHR improves body composition and QoL as early as 1 month after commencement and the beneficial effects continue at 3 months. Most importantly, these changes occur in the absence of side-effects. We therefore suggest the use of low-dose GH therapy, maintaining IGF-I between the median and upper end of the age-related reference range, for the treatment of AGHD.     

Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults--an 18-month randomised, placebo-controlled, double blinded trial

OBJECTIVE: To evaluate the effect of physiological adult growth hormone (GH) replacement on bones. DESIGN: Thirty-six prospective severely growth hormone-deficient (GHD) adults (22 females and 14 males) were randomised to either 18 months of GH (0.03 mU/kg/day) or placebo treatment. METHODS: Bone mineral density and content (BMD, BMC) and body composition were evaluated by dual energy X-ray absorptiometry at baseline and after 6, 12 and 18 months. Serum concentrations of insulin-like growth factor-I (IGF-I), IGF binding protein 3, osteocalcin, carboxyterminal propeptide of type I collagen, carboxyterminal crosslink telopeptide of type I collagen, amino-terminal propeptide of type III procollagen and urine pyridinolin and deoxypyridinolin were determined. RESULTS: IGF-I levels increased from 63.2 microg/l (+/-10.1) to 193.6 (+/- 25.8) microg/l (mean (+/-s.e.)) (P<0.001 compared with placebo). Markers of bone turnover increased significantly from 142% to 227% of baseline values (all P<0.001 compared with placebo). Body composition changes were an increase of lean body mass and a decrease of fat mass resulting in a reduction of percentage body fat of +/- 1.8 (+/- 3.8) in the GH-treated group vs an increase of 1.0 (+/-2.9)) in the placebo-treated group (P=0.002). CONCLUSIONS: No significant difference in BMD or BMC between the GH and placebo groups was found after 18 months. At several sites the variances of changes from baseline were significantly greater in the GH than in the placebo group, indicating an impact of the treatment. From baseline to 6 months an insignificant reduction of total BMD was seen while an increase of BMD was found from 6 to 18 months in the GH group compared with the placebo group.This placebo-controlled trial confirmed the longer term open studies on the effect on bones in patients with GHD, with an initial overrepresentation of bone resorption followed by an increase in BMD which at 18 months had reached baseline level.     

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.     

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.     

Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults

GH deficiency (GHD) in adulthood is accompanied by physical and psychological impairments. One hundred fifteen patients (67 male, 48 female) with pronounced GHD were enrolled in a randomized, double-blind, placebo-controlled study with objectives that included effects on body composition, cardiac structure, and function and safety of replacement therapy with recombinant human GH (Saizen). Sixty patients (31 male, 29 female) received GH at a dose of 0.005-0.010 mg/kg.d, and 55 patients (36 male, 19 female) received placebo for 6 months. Assessment of body composition by dual-energy x-ray absorptiometry demonstrated a treatment difference in lean body mass increase of 2.1 kg (between-group comparison, P < 0.0001), which was significantly greater among males than females (P < 0.0001) [males: GH, +3.13 kg (2.42, 3.84); placebo, +0.11 kg (-0.60, 0.82); and females: GH, +0.64 kg (-0.15, 1.44); placebo: -0.90 kg (-2.20, 0.39)] [mean change 0-6 months (95% confidence limits)] and was associated with IGF-I changes. The decrease in fat mass of 2.8 kg (between-group comparison, P < 0.0001) noted by DEXA was also evident from bioelectric impedance and anthropometric measurements. Echocardiography showed comparable improvement in left ventricular systolic function after GH treatment in both genders. End-systolic volume decreased by 4.3 +/- 10.5 ml (from 35.8 +/- 17.6 ml; between-group comparison, P = 0.035) and ejection fraction increased by 5.1 +/- 10.0% (from 55.0 +/- 11.2%; between-group comparison, P = 0.048), approaching normalcy. Diastolic function did not change as assessed by isovolumic relaxation time, early diastolic flow, diastolic flow secondary to atrial contraction, or ratio of peak mitral early diastolic and atrial contraction velocity. GH treatment was well tolerated, with adverse events primarily related to effects on fluid balance. No apparent relationship between IGF-I levels and the occurrence or severity of adverse events was identified. In conclusion, GH replacement therapy in adults with GHD demonstrated beneficial effects on lean body mass composition that was more pronounced in males than females. In contrast, cardiac function improvement appears to benefit both genders equally.     

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.     

Growth hormone binding protein correlates strongly with leptin and percentage body fat in GH-deficient adults, is increased by GH replacement but does not predict IGF-I response.

GH-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor (GHR) and has been shown to be closely related to body fat. This study aimed to examine the inter-relationship between GHBP, leptin and body fat, and to test the hypothesis that GHBP is modified by GH replacement in GH-deficient adults and predicts IGF-I response. Twenty adults, mean age 47 years (range 20-69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. Plasma GHBP and leptin were measured at baseline and 2, 4, 8 and 12 weeks after each treatment. Whole body composition was measured at baseline by dual-energy X-ray absorptiometry (DEXA). There was a strong correlation between baseline leptin and GHBP (r = 0.88, P < 0.0001) and between baseline GHBP and percentage body fat, (r = 0.83, P < 0.0001). Mean GHBP levels were higher on GH compared with placebo, 1.53 +/- 0.28 vs 1.41 +/- 0.25nM, P = 0.049. There was no correlation between baseline IGF-I and GHBP (r = -0.049, P = 0.84), and GHBP did not predict IGF-I response to GH replacement. The close inter-relationship between GHBP, leptin and body fat suggests a possible role for GHBP in the regulation of body composition. GHBP is increased by GH replacement in GH-deficient adults, but does not predict biochemical response to GH replacement.     

Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: a two-year placebo-controlled study

Previous studies have demonstrated beneficial effects of GH replacement, in adults with GH deficiency (GHD), on body composition, physical fitness, and quality of life. These studies, however, concern patients with adult-onset GHD or childhood-onset (CO) patients enrolled several years after withdrawal of initial therapy. So far, the effects of continuation of GH-administration in patients with CO-GHD have not been examined. We studied a group of nineteen young adults (13 males + 6 females; 16-26 yr old; mean age, 20.2 +/- 0.65 yr) with CO-GHD, in a randomized, parallel, double-blind, placebo-controlled trial for 1 yr, followed by an open phase with GH for 1 yr. All patients received GH therapy at the start of study, and trial medication (GH/placebo) was given in a similar dose. Patients randomized to continued GH treatment exhibited no significant changes in any parameters tested, but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems. Discontinuation of GH for 1 yr resulted in a decrease in serum IGF-I, from 422.0 +/- 56.8 to 147.8 +/- 33.4 microg/L, in the placebo group (P = 0.003). After discontinuation of GH for 1 yr, an increase in total body fat (TBF, kg), measured by dual-energy x-ray absorptiometry scan, was seen [placebo: 22.7 +/- 2.7 to 26.5 +/- 2.5 (P = 0.01); GH: 16.2 +/- 2.1 to 17.2 +/- 2.1 (not significant)]. Resumption of GH after placebo was followed by increments in serum IGF-I (microg/L) [from 147.8 +/- 33.4 to 452 +/- 76 (P = 0.001)] and IGF-binding protein 3, as well as in fasting glucose (mmol/L) [4.9 +/- 0.2 vs. 5.3 +/- 0.2 (P = 0.03)]. After resumption of GH lean body mass (kg) increased [52.4 +/- 4.9 vs. 60.7 +/- 5.6 (P = 0.006)]. Likewise, resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio, as assessed by computed tomography [muscle volume (cm2/10 mm): 118.2 +/- 11.7 vs. 130.0 +/- 10.9 (P = 0.002); muscle/fat ratio: 1.33 +/- 0.24 vs. 1.69 +/- 0.36 (P = 0.02)]. In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.     

Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition

OBJECTIVE Studies with GH substitution in GH-deficient (GHD) adults lasting more than 6 months have so far been uncontrolled. End-points such as physical fitness and body composition may be subject to a considerable placebo effect which weakens the validity of open studies. We therefore tested GH (2 IU/m² per day) versus placebo treatment for 12 months. DESIGN Twenty-nine patients (mean age 45.5±2.0 years) with adult-onset GHD were studied in a double-blind, parallel design. Measurements of body composition by means of conventional anthropometry, bioelectrical impedance (BIA), CT scan and DEXA scan, exercise capacity, and isometric muscle strength were performed at baseline and after 12 months treatment. For body composition measurements a control group of 39 healthy, age and sex-matched subjects was included. RESULTS Sum of skinfolds (SKF) at 4 sites decreased significantly after GH treatment. Total body fat (TBF) as assessed by DEXA and BIA was elevated at baseline but normalized after GH. TBF assessed by SKF revealed significantly higher levels compared to DEXA and BIA, although all estimates intercorrelated closely. Visceral and subcutaneous abdominal fat decreased by 25 and 17%, respectively after GH (P<0.01) to levels no longer different from the control group. CT of the mid thigh revealed a significant reduction in fat tissue and a significant increase in muscle volume after GH treatment, both of which resulted in a normalization of the muscle : fat ratio (%) (placebo: 58 : 42 (baseline) vs 58 : 42 (12 months); GH: 66 : 34 (baseline) vs 72 : 28 (12 months) (P=0.002); normal subjects: 67 : 33 (P<0.05 when compared to 12 months placebo data)). Total body resistance and resistance relative to muscle volume decreased significantly after GH treatment suggesting over-hydration as compared to normal subjects. Exercise capacity (kJ) increased significantly after GH treatment (placebo: 54.7±9.8 (baseline) vs 51.6±8.2 (12 months); GH: 64.9±13.3 (baseline) vs 73.5±13.6 (12 months) (P<0.05)). Isometric quadriceps strength increased after GH but no treatment effect could be detected owing to a small increase in the placebo group. Serum IGF-I levels (μg/l) were low baseline and increased markedly after GH treatment to a level exceeding that of normal subjects (270±31 (12 months GH) vs 156±8 (normal subjects (P<0.01)). The levels of serum electrolytes and HbA1c remained unchanged. The number of adverse effects were higher in the GH group after 3 months, but not after 6 and 12 months. CONCLUSIONS (1) The reduction in excess visceral fat during GH substitution is pronounced and sustained; (2) beneficial effects on total body fat, muscle volume and physical fitness can be reproduced during prolonged placebo-controlled conditions; (3) uncontrolled data on muscle strength must be interpreted with caution; (4) a daily GH substitution dose of 2 IU/m² seems too high in many adult patients.     

Low-dose growth hormone inhibits 11 beta-hydroxysteroid dehydrogenase type 1 but has no effect upon fat mass in patients with simple obesity

GH has potent effects on adipocyte biology, stimulating lipolysis but also promoting preadipocyte proliferation. In addition, GH, acting through IGF-I, inhibits 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), which converts the inactive glucocorticoid, cortisone (E), to active cortisol (F) in adipose tissue. Although F is an essential requirement for adipocyte differentiation, it also inhibits preadipocyte proliferation. We hypothesized that inhibition of 11 beta-HSD1 activity in adipose tissue by GH may alter fat tissue mass through changes in local F concentrations. We conducted a randomized, double-blind, placebo-controlled study using low-dose GH (Genotropin 0.4 mg/d) for 8 months in 24 patients with obesity. Although GH treatment significantly raised IGF-I, we were unable to demonstrate significant differences in body composition or metabolic profiles between GH- and placebo-treated groups. In addition, there was no alteration in total fat mass over time in the GH-treated group [total fat mass 41.0 +/- 3.0 vs. 41.3 +/- 3.4 kg (8 months), mean +/- SE, P = ns]. However, in comparison with baseline values, systolic blood pressure increased (119 +/- 3 vs. 130 +/- 4 mm Hg, P < 0.05 vs. baseline) and serum F/E ratio decreased (6.1 +/- 0.5 vs. 3.9 +/- 0.5, P < 0.05 vs. baseline) in the GH-treated group only. Furthermore, although the urinary tetrahydrometabolites of F/E ratio fell in the GH-treated group, it rose in the placebo group (mean ratio change, -0.13 +/- 0.05 vs. +0.09 +/- 0.09, GH vs. placebo, P = 0.07). Treatment with low-dose GH in obesity fails to alter fat mass despite a significant elevation in IGF-I and a shift in the global set point of E to F conversion consistent with inhibition of 11 beta-HSD1.