Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

Sustained benefits of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome are dose-dependent

BACKGROUND: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a growth hormone (GH) deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While recent studies have demonstrated short-term benefits of treatment with GH, a critical question is whether beneficial changes persist or wane with prolonged therapy, and whether these effects on body composition are dose-dependent as seen in adult GH deficiency. OBJECTIVES AND METHODS: After 24 months of GH theapy at a dose of 1 mg/m2/day ("standard dose"), the effects of 12 additional months of GH treatment at varying doses (0.3-1.5 mg/m2/day) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual X-ray absorptiometry (DXA). Indirect calorimetry was used to determine REE and to calculate respiratory quotient (RQ). RESULTS: During months 24-36 of GH therapy, further changes in body composition (decrease in fat mass, and increase in lean body mass), growth velocity, and REE occurred with standard and higher-dose GH therapy (1.5 mg/m2/day), but not with lower dose GH (0.3 mg/m2/day). Prior improvements in BMD, and strength and agility, which occurred during the initial 24 months, were sustained during the additional 12 months (to 36 months) regardless of dose. CONCLUSIONS: Salutary and sustained GH-induced changes in growth, body composition, and physical function in children with PWS require GH doses of >0.3 mg/m2/day. Conversely, BMD increased during the additional 12 months of therapy regardless of GH dose. Lower doses of GH, effective in improving body composition in adults with GHD, do not appear to be effective in children with PWS.     

Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome

BACKGROUND: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a growth hormone (GH)-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. Although recent studies have demonstrated short-term benefits of treatment with GH, a critical question is whether beneficial changes persist or wane with prolonged therapy. OBJECTIVES AND METHODS: Effects of 24 months of GH treatment (1 mg/m(2)/d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure, and fat utilization were assessed in 35 children with PWS. Percent body fat, lean muscle mass, and bone mineral density were measured by dual-energy x-ray absorptiometry. Indirect calorimetry was used to determine resting energy expenditure and to calculate the respiratory quotient. RESULTS: Compared with baseline evaluations, increased height velocity (SD score -1.1 +/- 2.5 to 2.2 +/- 2.3; P <. 001), reduced percent body fat (46.4% +/- 8.4% to 40.3% +/- 10.0%, P <.001), and improved respiratory muscle function and physical strength and agility (sit-ups, weight-lifts, running speed, and broad jump; P <.01) were observed after 24 months of GH treatment. A decline in respiratory quotient (0.81 +/- 0.07 to 0.75 +/- 0.06; P <. 01) and a trend toward increased resting energy expenditure were also observed. Changes in response to GH occurred predominantly during the initial 12 months of GH therapy. CONCLUSIONS: Children with PWS had sustained increases in lean body mass, decreases in percent body fat, improvements in physical strength and agility, and increased fat oxidation after 24 months of GH therapy. However, between 12 and 24 months, the growth rate slowed. Consequently, encouraging initial results require even more prolonged study to draw conclusions regarding the long-term value of GH therapy in changing body composition in children with PWS.     

Endocrine problems in children with Prader-Willi syndrome: special review on associated genetic aspects and early growth hormone treatment

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder characterized by hypothalamic-pituitary dysfunction. The main clinical features include neonatal hypotonia, distinctive facial features, overall developmental delay, and poor growth in infancy, followed by overeating with severe obesity, short stature, and hypogonadism later in development. This paper reviews recent updates regarding the genetic aspects of this disorder. Three mechanisms (paternal deletion, maternal disomy, and deficient imprinting) are recognized. Maternal disomy can arise because of 4 possible mechanisms: trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and postfertilization mitotic nondisjunction (Mit). Recently, TR/GC caused by nondisjunction at maternal meiosis 1 has been identified increasingly, as a result of advanced maternal childbearing age in Korea. We verified that the d3 allele increases the responsiveness of the growth hormone (GH) receptor to endogenous GH. This paper also provides an overview of endocrine dysfunctions in children with PWS, including GH deficiency, obesity, sexual development, hypothyroidism, and adrenal insufficiency, as well as the effects of GH treatment. GH treatment coupled with a strictly controlled diet during early childhood may help to reduce obesity, improve neurodevelopment, and increase muscle mass. A more active approach to correct these hormone deficiencies would benefit patients with PWS.     

New perspectives on the treatment of growth hormone deficiency

In the last few years the therapeutic management of GHD children has been improved by the recent synthesis of GH by DNA recombinant technique (rGH). rGH made it possible to overcome the problems of availability and purity of extractive GH, obtaining the same results (in growth velocity) without any information as regards late side effects of such a treatment. GHRH therapy in GHD patients of hypothalamic origin is still on trial and a lot of aspects are to be pointed out (indications to treatment, schedule and route of administration, cost/benefit ration, side effects).     

Growth hormone secretory pattern in non-obese children and adolescents with Prader-Willi syndrome

The aetiology of impaired growth hormone (GH) secretion in Prader-Willi syndrome (PWS) remains controversial due to the common occurrence of obesity. To further clarify whether suboptimal GH secretion in PWS is an artefact of excess weight, we evaluated both GH immunological activity and GH bioactivity after arginine administration in 23 non-obese PWS patients [seven females, aged 6.9 +/- 0.9 years, body mass index (BMI) SDS 0.63 +/- 0.26], in comparison with a control group of 32 healthy subjects, matched for age, gender and BMI (10 females, aged 7.9 +/- 0.3 years, BMI SDS 0.21 +/- 0.20). Serum GH concentration was measured with a time-resolved immunofluorometric assay (IFMA), while GH bioactivity was evaluated by the Nb2 cell bioassay. Serum IGF-I concentrations were measured by double-antibody RIA. GH mean peak after pharmacological stimulation was significantly lower in PWS individuals compared with controls when measured either by IFMA (6.05 +/- 1.23 microg/L vs. 23.7 +/- 1.06 microg/L, p < 0.0001) or by Nb2 (6.87 +/- 0.55 microg/L vs. 12.88 +/- 0.19 microg/L, p < 0.0001). Analysis of integrated GH secretion (AUC) confirmed that the PWS group differed significantly from the control subjects (387.9 +/- 76.1 microg/L/h vs. 1498.1 +/- 56.2 microg/L/h, p < 0.0001); the same result was obtained when the GH rise after arginine administration was expressed as nAUC (278.2 +/- 53.3 microg/L/h vs. 1443.6 +/- 52.5 microg/L/h, p < 0.0001). PWS patients had an IGF-I SDS significantly lower than those found in control subjects (p < 0.0001). Subnormal IGF-I values were present in 19 PWS individuals (82.6%) and two healthy controls (6.2%). These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurs in PWS.     

Body composition in Prader-Willi syndrome compared with nonsyndromal obesity: Relationship to physical activity and growth hormone function.

OBJECTIVE: To study the relationship of fat mass, extracellular-to-intracellular-water ratio, and bone mineral density with growth hormone function and physical activity in Prader-Willi syndrome. STUDY DESIGN: There were 17 patients with PWS (10 women, ages 7.5-19.8 years) and 17 obese control patients, matched for gender and bone age. FM and extracellular-to-intracellular-water ratio were measured by bromide-deuterium dilution, BMD by dual-energy x-ray absorptiometry, GH function by fasted serum insulin-like growth factor-I concentration, and physical activity by doubly-labeled water in combination with basal metabolic rate by a ventilated hood. RESULTS: The PWS group had a similar fat mass, but a lower fat-free mass, whereas the extracellular-to-intracellular-water ratio was higher compared with the control group (0.87 +/- 0.07 l/l and 0.80 +/- 0.06 l/l, respectively [P <.01]). Fat mass was inversely related with PA in the PWS group, whereas IGF-I was positively correlated with FFM, ICW, and BMD of the limbs. BMD tended to be lower in patients with PWS. CONCLUSIONS: In children and adolescents with PWS, adiposity is associated with a reduced fat-free mass and extracellular-to-intracellular-water ratio is increased. Both findings are related to GH function and physical activity. BMD, especially in the limbs, tends to be reduced in patients with PWS and is related to GH function.     

Growth hormone improves body composition and motor development in infants with Prader-Willi syndrome after six months

BACKGROUND: Infants with Prader-Willi syndrome (PWS) show abnormalities of body composition. Children with PWS treated with growth hormone (GH) demonstrate improved body composition and motor skills. OBJECTIVE: To assess body composition and motor changes in infants with PWS following 6 months GH therapy. METHODS: Twenty-five infants with PWS (mean age 15.5 mo) underwent dual energy X-ray absorptiometry (DEXA) assessment of body composition, and motor assessment with the Toddler Infant Motor Evaluation (TIME). Patients were then randomized to treatment (Genotropin, 1 mg/m2/day) or control, with reassessment at 6 months. RESULTS: GH treatment significantly increased lean body mass (6.4 +/- 2.4 kg to 8.9 +/- 2.7 kg) and decreased body fat (27.6 +/- 9.9% to 22.4 +/- 10.3%). Age equivalent motor scores improved 4 months in the treated group vs 2 months in controls (p < 0.01). CONCLUSIONS: Infants with PWS show significant body composition and motor development improvement following 6 months GH therapy. We are investigating whether this improvement leads to long-term reductions in obesity.     

Effects of 5 years growth hormone treatment in patients with Prader-Willi syndrome

BACKGROUND: Short-term studies showed favorable effects of growth hormone (GH) treatment in patients with Prader-Willi syndrome (PWS). AIMS: To evaluate the long-term effects of GH therapy in patients with PWS retrospectively. PATIENTS AND METHODS: Effects of GH treatment (0.5 IU/kg/w s.c.) for a period of 1 to 5 years were assessed for 37 Japanese patients with PWS aged 3-(9/12) to 21-(3/12) years. Height and weight were expressed as standard deviation scores (SDSs) of Japanese PWS patients. Height velocity, final height, body mass index (BMI) and Rohrer index were also evaluated. RESULTS: After 1 year of treatment, the mean height velocity improved significantly from 4.32 to 8.69 cm per year (p < 00001). After 5 years of treatment, mean height SDS increased from -0.99 to +0.88 (p = 0.003). Mean final height of treated patients was 158.0 cm in males and 147.7 cm in females. Mean Rohrer index improved from 182 to 164 (p < 0.0001) after 1 year of treatment and stayed stable thereafter. CONCLUSIONS: Long-term treatment with GH in patients with PWS improved height velocity, height SDS, final height, and the degree of obesity. These data encourage the long-term use of GH in these patients.     

Death in two female Prader-Willi syndrome patients during the early phase of growth hormone treatment

Reports on sudden death in Prader-Willi syndrome (PWS) patients after the start of growth hormone (GH) treatment have been published recently. We observed a 4.7-y-old girl who showed a continuous increase in pulmonary artery pressure and died of cardiorespiratory failure 7 wk after GH therapy had been initiated, and a 9.3-y-old girl with additional trisomy 21 who died during a minor respiratory infection 6 mo after GH had been started. Both patients were overweight (weight for height 127% and 224%, respectively). GH-induced fluid retention may have occurred in the younger girl. In contrast to the reported cases, our PWS patients were female. CONCLUSION: Our cases illustrate the difficulty of differentiation between possible GH side effects and the natural course of disease, in particular with respect to obesity-related comorbidity and mortality.     

Growth hormone therapy for Prader-Willi syndrome: a critical appraisal

Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction resulting in obesity, hypotonia, hypogonadism, and behavioral abnormalities. Clinical features of PWS resemble those of GH deficiency (decreased total lean body mass, IGF-I levels, and poor linear growth). Marked reductions in muscle mass are associated with diminished strength, physical function, and energy expenditure. Lifelong morbidities of PWS include osteoporosis, type 2 diabetes mellitus, respiratory disorders, and cardiorespiratory failure related to obesity and hypotonia. Recent studies show that GH therapy improves linear growth, final height, physical strength, and agility in patients with PWS. Some effects of GH therapy wane with time, however, and strategies for treating adults with PWS remain uncertain. In addition, deaths in markedly obese, GH-treated children with PWS have been reported, and a possible contribution of GH to these events has not yet been definitively excluded. Consequently, critical evaluation should continue of the long-term benefits, risks, and costs of GH therapy for patients with PWS.     

A comprehensive team approach to the management of patients with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder characterized by extreme obesity accompanied by other, multisystem clinical manifestations encompassing both physical and behavioral/cognitive abnormalities. The multi-dimensional problems of patients with PWS cannot be treated with a single intervention and benefit from a team approach to management to optimize outcomes. Childhood stature below target height and reduced final height are some defining characteristics of PWS, and compelling evidence from growth hormone (GH) treatment trials suggests that hypothalamic GH deficiency exists. Treatment with GH has been shown to increase height velocity in children with PWS, decrease weight-for-height index values and body fat mass, and have a positive effect on lean body mass during at least the first year of therapy. In addition to medical concerns, the behavioral manifestations, including an uncorrectable deficit in appetite control, and cognitive limitations associated with PWS, require long-term multidisciplinary management.     

Five-years growth hormone (GH) treatment in adults with Prader-Willi syndrome

AIM: We have previously shown that 1 year of growth hormone (GH) treatment to adults with Prader-Willi syndrome (PWS) has beneficial effects on body composition. The aim of the present observational study was to re-evaluate our cohort, with focus on long-term GH treatment. METHODS: Seven men and seven women, median age 31 years, were available for follow-up for 6 years. Nine were on GH treatment for 5 years. Body composition was measured with Dual Energy X-ray absorptiometry (DXA). RESULTS: In six GH treated patients with genetically verified PWS there was a substantial increase in lean body mass of 5 kg (p = 0.031) and a concomitant, however, non-significant, decrease in body fat of 5% (p = 0.156). The changes in the genetically verified patients without GH treatment were small and unsystematic. No compliance problems were reported. Only one non-GH-treated woman developed overt diabetes. CONCLUSION: Despite inherent behavioural problems it was possible to continue GH injections for 5 years with sustained favourable effects on body composition without clinically, significant side effects.     

MR of the pituitary in patients with Prader-Willi syndrome: Size determination and imaging findings

Prader-Willi syndrome (PWS) is an unusual genetic disorder characterized by short stature, obesity, hypogonadism, hypotonia, cognitive impairment, and dysmorphic facies. There is an interstitial deletion of the proximal long arm of chromosome 15 in about 70% of patients. Some of these clinical features suggest a central hypothalamic/pituitary dysfunction, and recent investigations have demonstrated a marked impairment in spontaneous growth hormone (GH) secretion. We studied 15 GH-deficient PWS patients by magnetic resonance imaging (MRI) to determine whether there was a diminution in the gross morphological size of the anterior pituitary gland, the site of GH synthesis. We also set out to catalog the pertinent imaging findings in this patient population. Our results indicate that this is the first report documenting pituitary size by MRI in PWS patients. No statistically significant difference was found in the height of the anterior pituitary gland in PWS patients compared with either normal children or children with isolated GH deficiency. An interesting imaging finding is that three of 15 patients (20%) demonstrated complete absence of the posterior pituitary bright spot (PPBS), and a fourth patient demonstrated a small PPBS. These observations reflect an objective physiologic disturbance in the hypothalamus. The clinical and radiologic implications of these findings are discussed.     

Growth hormone treatment increases CO2 response, ventilation and central inspiratory drive in children with Prader-Willi syndrome

We studied whether the beneficial effects of growth hormone (GH) treatment on growth and body composition in PWS are accompanied by an improvement in respiratory function. We measured resting ventilation, airway occlusion pressure (P_0.1) and ventilatory response to CO₂ in nine children, aged 7–14 years, before and 6–9 months after the start of GH treatment. During GH treatment, resting ventilation increased by 26%, P_0.1 by 72% and the response to CO₂ by 65% (P < 0.002, <0.04 and <0.02, respectively). This observed increase in ventilatory output was not correlated to changes in body mass index. Conclusion Treatment of children with Prader-Willi syndrome (PWS) seems to have a stimulatory effect on central respiratory structures. The observed increase in ventilation and inspiratory drive may contribute to the improved activity level reported by parents of PWS children during growth hormone therapy. Received: 28 April 1998 / Accepted: 6 April 1999     

Nutrient intake and body composition variables in Prader-Willi syndrome--effect of growth hormone supplementation and genetic subtype

In patients with Prader-Willi syndrome (PWS), limited information exists on the effects of growth hormone (GH) therapy, gender and genetic subtype on nutrient intake and body composition. We therefore compared GH-treated and nontreated patients, taking into account Tanner stage, gender, and genetic form. PATIENTS AND METHODS: In 37 individuals with PWS (20/17 M/F; 21/16 GH+/GH-), dietary intake and body composition (BMI, DEXA) were assessed. RESULTS: Older GH-treated children (Tanner stage 3-4) displayed improved body composition variables (BMI, total and percentage fat mass, truncal fat) (p < 0.05), despite dietary intake similar to non-treated patients; younger children (Tanner stage 1-2) displayed a different pattern, despite greater total caloric and fat intake (p < 0.05) with GH treatment, with only minor differences in body composition. Genetic form and gender had no intrinsic effect on nutrient intake or body composition. CONCLUSION: In 37 patients with PWS, GH treatment selectively affected body composition (BMI, fat mass), and dietary fat intake based on patients' developmental status, while these variables were unaffected by gender or genetic subtype.     

Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome

OBJECTIVES: To determine the effect of growth hormone (GH) on body composition and motor development in infants and toddlers with Prader-Willi syndrome (PWS). STUDY DESIGN: Twenty-nine subjects with PWS (4-37 months of age) were randomized to GH treatment (1mg/m 2 /day) or observation for 12 months. Percent body fat, lean body mass, and bone mineral density were measured by dual x-ray absorptiometry; energy expenditure was measured by deuterium dilution; and motor constructs of mobility (M) and stability (S) were assessed using the Toddler Infant Motor Evaluation (TIME). RESULTS: GH-treated subjects, compared with controls, demonstrated decreased percent body fat (mean, 22.6% +/- 8.9% vs 28.5% +/- 7.9%; P < .001), increased lean body mass (mean, 9.82 +/- 1.9 kg vs 6.3 +/- 1.9 kg; P < .001), and increased height velocity Z scores (mean, 5. 0 +/- 1.8 vs 1.4 +/- 1.0; P < .001). Patients who began GH before 18 months of age showed higher mobility skill acquisition compared with controls within the same age range (mean increase in raw score, 284 +/- 105 vs 206 +/- 63; P < .05). CONCLUSIONS: GH treatment of infants and toddlers with PWS for 12 months significantly improves body composition and when begun before 18 months of age increases mobility skill acquisition. These results suggest that GH therapy instituted early in life may lessen deterioration of body composition in PWS while also accelerating motor development.     

Prader-Willi syndrome: who can have growth hormone?

Growth hormone (GH) is licensed for treatment for Prader-Willi syndrome (PWS) for improvement of body composition,1(-)3 height velocity, mobility, behaviour and quality of life.4 Recent case reports, however, have pointed out the occurrence of sudden death during initiation of GH, mainly during sleep and possibly related to severe obesity and sleep-disordered breathing (SDB).5(-)15 Concerns for an increased mortality in PWS children starting GH therapy led to a call for cessation of its use. Children with PWS are at risk of developing SDB secondary to both deficient autonomic sleep control and upper airway obstruction (UAO). It has been suggested that GH exacerbates pre-existing gas-exchange deficiencies in three ways: (a) by stimulation of adenotonsillar hypertrophy;16 17 (b) by a rise in basal metabolic rate with a resultant rise in oxygen demand;18 and (c) by normalisation of previously decreased hydration with augmentation of volume load.19 Are we withholding GH therapy, a treatment known to be of benefit in PWS, without adequate evidence to justify our actions? We consider it safe to treat severely obese children with GH once SDB is addressed using respiratory support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP). In this paper, we evaluate the current evidence for the use of GH in PWS from a respiratory bias and propose a pathway for the identification and monitoring of these "at risk" patients.     

The effect of growth hormone on sleep-related cardio-respiratory control in Prader-Willi syndrome

Aim: To evaluate the effects of growth hormone (GH) treatment on control of breathing, heart rate and blood pressure during sleep in Prader–Willi Syndrome (PWS). Study design: in a prospective clinical case series study, sixteen consecutive PWS patients (median age 16 months at enrolment) were followed‐up 6 months (2–32 months) after commencing GH treatment. We compared heart rate (HR), Pulse Transit Time (PTT; an index of blood pressure, BP) and ventilatory responses to standard chemostimuli (4% CO₂ and 100% O₂) during quiet sleep prior to and after commencing GH treatment. Results: Growth hormone treatment increased arterial oxygenation during sleep but did not significantly improve breathing stability (apnoea‐hypopnoea index remained unchanged). GH treatment did not alter ventilatory, HR and PTT chemoreceptor‐mediated responsiveness (p = 0.23–0.97) but did significantly improve the coupling between and HR and PTT, indicating that HR and BP rose (or fell) in parallel after but not before GH therapy (p = 0.01). Conclusion: Growth hormone treatment improves arterial oxygenation and cardiovascular function during sleep; these changes are not owing to improved (stronger) chemoreflex‐mediated autonomic drive.