Prader-Willi syndrome is a genetic disorder due to absence of the action of genes on the long arm of the paternal chromosome 15, the result of paternal deletion, maternal uniparental disomy of chromosome 15 or methylation-induced imprinting errors in the paternal genes. The prevalence of this condition is approximately 1 in 12,000 to 1 in 15,000. Major features include infantile hypotonia, hyperphagia and food-seeking behaviors leading to obesity, cognitive/behavior difficulties, short stature and hypogonadism. The latter indicate hypothalamic-pituitary dysfunction with documented growth hormone deficiency and hypogonadotropism. GH is approved for use in Prader-Willi syndrome with or without GH deficiency, and several studies, as detailed in the paper by Coupaye et al, document not only improvements in height, but also in body composition, including a decrease in percentage of body fat and an increase in percent of muscle mass, with improvement in muscle function. Early initiation of treatment appears to result in significant improvements in all the physical (but not behavioral) parameters.
Coupaye and colleagues now show in their study that the metabolic improvements induced by GH therapy in childhood or adolescence persist into adulthood, several years after GH treatment was discontinued. This is an important finding as it suggests that GH treatment, started at a mean age of 11.8 years and continued for an average of approximately 4 years, imparts a favorable "metabolic memory"with benefits not only in BMI and percent fat mass, but also in improved insulin sensitivity (reduced HOMA-IR), lower basal insulin and lower HbA1c whether the patients did or did not have type 2 diabetes. However, as a group, the GH-treated patients were not restored to normal as mean BMI remained 32.4, consistent with a definition of "obesity"compared with "morbid obesity" (BMI 41.2) in the controls. Further, the percentage of body fat remained elevated in the treated group, though less so than in the untreated group.
This raises several questions. First, would the improvement have been greater if GH therapy had been continued after full growth had been reached? Second, would the improvements be even better if GH had been started earlier, such as at a mean age of 13 months and continued at least until epiphyseal fusion, or later as is done for adults with GH deficiency? No doubt that these questions are on the minds of investigators working with patients who have Prader-Willi syndrome, and results will appear in the future.
Finally, the researchers highlight the important, but frequently forgotten, fact that GH, so named because of its important effects in promoting linear growth, has profoundly important and persistent metabolic benefits in promoting increase in muscle mass and decrease in fat mass through its anabolic effects on proteins and catabolic effects on inducing lipolysis in fat tissue, functions which, to a large degree, also mandate the use of GH therapy in adults with GH deficiency whose growth has been completed.
Mark A. Sperling, MD
Endocrine Today Editorial Board member
Division of Endocrinology
Children's Hospital, University of Pittsburgh
Disclosures: Sperling reports no relevant financial disclosures.