Growth hormone in obesity

Growth hormone (GH) secretion, either spontaneous or evoked by provocative stimuli, is markedly blunted in obesity. in fact obese patients display, co mpared to normal weight subjects, a reduced half-life, frequency of secreto ry episodes and daily production rate of the hormone. Furthermore, in these patients GH secretion is impaired in response to all traditional pharmacol ogical stimuli acting at the hypothalamus (insulin-induced hypoglycaemia, a rginine, galanin, L-dopa, clonidine, acute glucocorticoid administration) a nd to direct somatotrope stimulation by exogenous growth hormone releasing hormone (GHRH). Compounds thought to inhibit hypothalamic somatostatin (SRI H) release (pyridostigmine, arginine, galanin, atenolol) consistently impro ve, though do not normalize, the somatotropin response to GHRH in obesity. The synthetic growth hormone releasing peptides (GHRPs) GHRP-6 and hexareli n elicit in obese patients GH responses greater than those evoked by GHRH, but still lower than those observed in lean subjects. The combined administ ration of GHRH and GHRP-6 represents the most powerful On releasing stimulu s known in obesity, but once again it is less effective in these patients t han in lean subjects. As for the peripheral limb of the GH-insulin-like gro wth factor I (IGF-I) axis, high free IGF-I, low IGF-binding proteins 1 (IGF BP-1) and 2 (IGFBP-2), normal or high IGFBPS-3 and increased GH binding pro tein (GHBP) circulating levels have been described in obesity. Recent evide nce suggests that leptin, the product of adipocyte specific ob gene, exerts a stimulating effect on On release in rodents; should the same hold true i n man, the coexistence of high leptin and row GH serum levels in human obes ity would fit in well with the concept of a leptin resistance in this condi tion. Concerning the influence of metabolic and nutritional factors, an imp aired somatotropin response to hypoglycaemia and a failure of glucose load to inhibit spontaneous and stimulated On release are well documented in obe se patients; furthermore, drugs able to block lipolysis and thus to lower s erum free fatty acids (NEFA) significantly improve somatotropin secretion i n obesity. Caloric restriction and weight loss are followed by the restorat ion of a normal spontaneous and stimulated GH release. On the whole, hypoth alamic, pituitary and peripheral factors appear to be involved in the GH hy posecretion of obesity. A SRIH hypertone, a GHRH deficiency or a functional failure of the somatotrope have been proposed as contributing factors. A l ack of the putative endogenous ligand for GHRP receptors is another challen ging hypothesis. On the peripheral side, the elevated plasma levels of NEFA and free IGF-I may play a major role. Whatever the cause, the defect of GH secretion in obesity appears to be of secondary, probably adaptive, nature since it is completely reversed by the normalization of body weight. In sp ite of this, treatment with biosynthetic GH has been shown to improve the b ody composition and the metabolic efficacy of lean body mass in obese patie nts undergoing therapeutic severe caloric restriction. On and conceivably G HRPs might therefore have a place in the therapy of obesity.