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The alterations in GH secretory pattern seen in both obesity and starvation underiine the importance of nutritional conditions in GH secretion. Computer-assisted (deconvolution) analysis shows that the half-hfe of endogenous GH is significantly less in obese than in normal weight subjects. Furthermore, obese men had significantly fewer GH secretory bursts. Whereas GH secretion is enhanced during fasting, in obese individuals, spontaneous GH secretion is attenuated and the GH response to all tested stimuli (hypoglycemia, L-dopa, glucagon, exercise, clonidine and the secretagogues (GHRH and arginine) is significantly decreased. The fact that both exogenous GHRH- and GHRP-6-induced GH secretion are attenuated in obese volunteers eliminates a secretory deficit of either endogenous GHRH or the endogenous ligand for the GHRP-6-receptor as causative factors. This condition is reversed by weight loss or fasting.
The reason for the blunted GH response in obesity is unclear. Some data suggest that an enhanced somatostatinergic tone is the mechanism behind altered somatotrophic function in obesity. Others suggest that a chronic increase in somatostatin might lead to reduced function of somatotroph cells. Data published by Cordido showed that the combination of GHRH and GHRP-6 in obese subjects led to an increase in GH secretion, which did not differ greatly from that observed in normal subjects. Surprisingly, the combined administration of GHRP-6 plus GHRH seems to act independently of the somatostatinergic tone as the effects of the combined administration of GHRP-6 and GHRH are not further affected by pretreatment with pyridostigmine. These scientists also reported that the somatotrope cell in obesity has a considerable GH secretory capacity and that somatotrophs do not atrophy in the obese. Another interesting study suggested that free fatty acids were involved in the disrupted GH secretion of obesity. A study investigated the effects of 25 mg MK 677 daily for 8 weeks in 24 obese men.
The IGF-1 levels increased approximately 40% as well as the IGFBP-3 levels, which were also significantly increased. Fat-free mass increased significantly, whereas total and visceral fat were not significantly changed. Interestingly, GH levels were increased by MK-677 treatment throughout the 8-week study period, even though the GH response to MK-677 was lower at 2 and 8 weeks compared to the initial response. The scientists speculate that the observation period was too short or the dose too low to appreciate changes in visceral fat. Furthermore no women were included into the study. Johansson described that in obese males, GH treatment reduces the visceral fat mass over a 9 month period. As obesity is an important risk factor in hypertension, diabetes and cardiovascular disease, the results of long-term studies investigating the effects of GH secretagogues on body composition may provide important information on possible therapeutic applications in other pathologic states as well. In the acute phase of critical illness the response of the somatotropic axis is characterized by an increase of the total amount of GH released. The interpulse concentrations of GH are relatively high whereas the serum concentrations of IGF-1 are low. These changes are probably explained by a state of GH resistance, which may be related to a decreased GH receptor expression.
Whereas IGFBP-3 decreases, IGFBP-1 remains in normal or slightly elevated concentrations. In prolonged critical illness GH secretion is characterized by a reduced pulse amplitude, elevated interpulse levels and the number of pulses is high. This condition is also associated with low levels of IGF-1,IGFBP-3 and acid-labile subunit. Growth hormone binding protein (GHBP) has been found to be low in critically ill patients; GHBP is positively regulated by GH. Several studies have demonstrated that there are short-term benefits in nitrogen balance following the administration of pharmacological doses of GH to patients in an increased catabolic state. Vara-Torbeck and colleagues investigated the effects of GH treatment (2.6 mg daily) in 180 patients undergoing cholecystectomy in a placebo-controlled study. The results suggest that there is a reduction in hospital stay and infection rate in the treatment group compared to those receiving placebo. Nevertheless, due to the state of GH resistance it is anticipated that ongoing trials with exogenous GH may be unable to demonstrate major benefit in the acute phase of illness. Recently a large multicenter study of GH treatment in intensive care unit patients was discontinued due to an increase in mortality of GH treated patients.