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

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Molecular Medicine

Sammanfattning: Prader Willi Syndrome (PWS) is a complex genetic disorder characterized by muscular hypotonia, hyperphagia, obesity and behavioural problems. Partial growth hormone (GH) deficiency and hypogonadism are common. Results of several GH treatment studies in children with PWS have shown improvements not only in growth, but also in body composition, physical strength and agility. The partial GH deficiency seen in PWS might render these patients at risk of metabolic diseases in adult life and of reduced life span. The non-growth effects of GH treatment in PWS children have directed the interest towards the PWS adults in preventing the long-term consequences of GH deficiency. Until recently, neither the endocrine and metabolic consequences of the syndrome in adult patients, nor the potential effects of GH treatment have been known in detail. Aims: To study endocrine, metabolic and psycho-social functions, in adult PWS patients and the impact of GH treatment on these parameters. Patients and methods: We examined a cohort of 19 adult patients with clinical PWS (13 with PWS genotype) of which 17 (9 men and 8 women) with a mean age of 25 years and a mean BMI of 35 k g/M 2, subsequently completed a 12 months GH treatment trial. Results and discussion: At baseline all but three patients were obese despite a strict diet. Waist/hip ratio was increased in all women, and the mean percentage body fat was high in both genders. 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). Approximately two thirds were biochemically hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and 9 patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. A moderate dyslipidemia was seen in seven patients. The 13 patients with genetically confirmed diagnosis were shorter and had significantly lower IGF-I. GH treatment showed beneficial effects on body composition with reduction in body fat and increase in lean body mass following 6 and 12 months of therapy with doses, that normalized total IGF-I levels. The effects were more pronounced in the patients with the PWS genotype. Carbohydrate and lipid metabolism was not significantly affected by GH treatment. The aetiology of hyperphagia in PWS is not known. Examination of peptides involved in appetite regulation, showed that leptin levels were high reflecting obesity, and as a consequence NPY levels were low. In view of the adiposity of the patients circulating oxytocin levels were abnormally low and circulating ghrelin levels abnormally high. Therefore oxytocin as well as ghrelin might be involved in the hyperphagia. The peptides involved in appetite regulation did not change during GH treatment. Psychological evaluation revealed positive effects on intellectual speed and flexibility, reaction time and motor speed. When GH was discontinued significant impairments in physical and social function as well as in the over-all functioning were seen, as judged from questionnaires to relatives and caretakers. Conclusion: GH treatment might offer an opportunity to reduce some of the adverse consequences of the PWS syndrome. It should be remembered, however, that dysfunction of the GH-IGF-I axis and the potential effects hereof are only minor parts of the clinical syndrome. Larger and longer term studies on the effect of GH replacement in adult PWS patients should be carried out.

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