Metabolic health profile in young adults with Prader-Willi syndrome: results of a 2-year randomized, placebo-controlled, crossover GH trial.

CONTEXT: Patients with Prader-Willi syndrome (PWS) have an increased fat mass and decreased lean body mass. GH-treated young adults with PWS who have attained adult height benefit from continuation of growth hormone (GH) treatment, as GH maintained their improved body composition, whereas fat mass increased during the placebo period. Adults with PWS are predisposed to T2DM and cardiovascular disease. Whether GH affects metabolic health profile of this patient group is unknown. OBJECTIVE: To investigate the effects of GH vs placebo on metabolic health, in young adults with PWS who were GH-treated for many years during childhood and had attained adult height (AH). METHOD: A 2-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and BMI in 27 young adults with PWS. Intervention with GH (0·67 mg/m2 /day) and placebo, both for 1-year duration. RESULTS: Compared to placebo, GH treatment resulted in similar glucose and insulin levels during oral glucose tolerance test. Only fasting glucose and insulin were slightly higher during GH vs placebo (+0·2 mmol/l and +18·4 pmol/l), although both remained within normal ranges in both phases. Blood pressure and lipid profile were similar after GH vs placebo. At baseline (AH) and during GH, no patients had metabolic syndrome, while 1 developed it during placebo treatment. CONCLUSIONS: Growth hormone treatment has no adverse effects on metabolic health profile. Thus, GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment without safety concerns regarding metabolic health.

Effect of cessation of GH treatment on cognition during transition phase in Prader-Willi syndrome: results of a 2-year crossover GH trial.

BACKGROUND: Patients with Prader-Willi syndrome (PWS) have a cognitive impairment. Growth hormone (GH) treatment during childhood improves cognitive functioning, while cognition deteriorates in GH-untreated children with PWS. Cessation of GH treatment at attainment of adult height (AH) might deteriorate their GH-induced improved cognition, while continuation might benefit them. We, therefore, investigated the effects of placebo versus GH administration on cognition in young adults with PWS who were GH-treated for many years during childhood and had attained AH. METHOD: Two-year, randomized, double-blind, placebo-controlled cross-over study in 25 young adults with PWS. Cross-over intervention with placebo and GH (0.67 mg/m2/day), both during 1 year. RESULTS: Total (TIQ), verbal (VIQ) and performance IQ (PIQ) did not deteriorate during 1 year of placebo, compared to GH treatment (p > 0.322). Young adults with a lower TIQ had significantly more loss of TIQ points during placebo versus GH, in particular VIQ decreased more in those with a lower VIQ. The effect of placebo versus GH on TIQ, VIQ and PIQ was not different for gender or genotype. CONCLUSIONS: Compared to GH treatment, 1 year of placebo did not deteriorate cognitive functioning of GH-treated young adults with PWS who have attained AH. However, patients with a lower cognitive functioning had more loss in IQ points during placebo versus GH treatment. The reassuring finding that 1 year of placebo does not deteriorate cognitive functioning does, however, not exclude a gradual deterioration of cognitive functioning on the long term. TRIAL REGISTRATION: ISRCTN24648386 , NTR1038 , Dutch Trial Register, www.trialregister.nl . Registered 16 August 2007.

Dietary Energy Intake, Body Composition and Resting Energy Expenditure in Prepubertal Children with Prader-Willi Syndrome before and during Growth Hormone Treatment: A Randomized Controlled Trial.

BACKGROUND/AIMS: Dietary management is a difficult but key aspect of care in children with Prader-Willi syndrome (PWS). We therefore investigated the effect of growth hormone (GH) treatment on reported energy intake in children with PWS, in relation with body composition, resting energy expenditure (REE) and hormone levels. METHODS: In a randomized controlled GH trial including 47 children with PWS, we assessed 5-day dietary records and dual-energy X-ray absorptiometry for body composition. REE was calculated by Müller's equation, based on fat mass, fat free mass and gender. RESULTS: Baseline energy intake of children with PWS was lower than normal daily energy requirements (p < 0.001), and decreased with age to 50% in prepubertal children. Energy intake in infants [m/f: 11/8; median (interquartile range [IQR]) age 2.7 years (1.5-3.2)] increased after 1 year of GH treatment (p = 0.008); this tended to be higher in the GH group than in the untreated group (p = 0.07). In prepubertal children [m/f: 14/14; median (IQR) age 6.8 years (5.1-8.1)], the increase in energy intake was higher in the GH group, but this was not different compared to the untreated group. REE was not different between the GH group and the untreated group. Increase in energy intake during 2 years of GH treatment was correlated with lower fat percentage standard deviation scores (p = 0.037) and higher adiponectin levels (p = 0.007). CONCLUSION: Our study demonstrates that parents of children with PWS are very well capable of restricting energy intake up to 50% compared to daily energy requirements for age- and sex-matched healthy children. GH treatment was associated with a slight increase in energy intake, but also improved body composition and adiponectin levels, which suggests a protective effect of GH treatment.

Bone mineral density in children and adolescents with Prader-Willi syndrome: a longitudinal study during puberty and 9 years of growth hormone treatment.

CONTEXT: Longitudinal data on bone mineral density (BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. OBJECTIVE: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS. DESIGN AND SETTING: This was a prospective longitudinal study of a Dutch PWS cohort. PARTICIPANTS: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. INTERVENTION: The children received GH treatment, 1 mg/m(2)/day (≅ 0.035 mg/kg/d). MAIN OUTCOME MEASURES: BMDTB, BMDLS, and BMADLS was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. RESULTS: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lower BMADLSSDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. CONCLUSIONS: This long-term GH study demonstrates that BMDTB, BMDLS, and BMADLS remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty.

Eight years of growth hormone treatment in children with Prader-Willi syndrome: maintaining the positive effects.

BACKGROUND: The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition. OBJECTIVES: The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment. SETTING: This was a multicenter prospective cohort study. METHODS: We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat. RESULTS: After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation. CONCLUSION: This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.