Growth hormone (GH) secretion, either spontaneous or evoked by provocative stimuli, is markedly blunted in
obesity. In fact obese patients display, compared to normal weight subjects, a reduced half-life, frequency of secretory episodes and daily production rate of the
hormone. Furthermore, in these patients GH secretion is impaired in response to all traditional pharmacological stimuli acting at the hypothalamus (
insulin-induced hypoglycaemia,
arginine,
galanin,
L-dopa,
clonidine, acute
glucocorticoid administration) and to direct somatotrope stimulation by exogenous
growth hormone releasing hormone (GHRH). Compounds thought to inhibit hypothalamic
somatostatin (SRIH) release (
pyridostigmine,
arginine,
galanin,
atenolol) consistently improve, though do not normalize, the
somatotropin response to GHRH in
obesity. The synthetic
growth hormone releasing
peptides (GHRPs)
GHRP-6 and
hexarelin elicit in obese patients GH responses greater than those evoked by GHRH, but still lower than those observed in lean subjects. The combined administration of GHRH and
GHRP-6 represents the most powerful GH releasing stimulus known in
obesity, but once again it is less effective in these patients than in lean subjects. As for the peripheral limb of the GH-
insulin-like growth factor I (
IGF-I) axis, high free
IGF-I, low
IGF-binding proteins 1 (IGFBP-1) and 2 (IGFBP-2), normal or high
IGFBP-3 and increased
GH binding protein (GHBP) circulating levels have been described in
obesity. Recent evidence suggests that
leptin, the product of adipocyte specific ob gene, exerts a stimulating effect on GH release in rodents; should the same hold true in man, the coexistence of high
leptin and low GH serum levels in human
obesity would fit in well with the concept of a
leptin resistance in this condition. Concerning the influence of metabolic and nutritional factors, an impaired
somatotropin response to hypoglycaemia and a failure of
glucose load to inhibit spontaneous and stimulated GH release are well documented in obese patients; furthermore, drugs able to block lipolysis and thus to lower serum
free fatty acids (
NEFA) significantly improve
somatotropin secretion in
obesity.
Caloric restriction and
weight loss are followed by the restoration of a normal spontaneous and stimulated GH release. On the whole, hypothalamic, pituitary and peripheral factors appear to be involved in the GH hyposecretion of
obesity. A SRIH hypertone, a GHRH deficiency or a functional failure of the somatotrope have been proposed as contributing factors. A lack of the putative endogenous
ligand for GHRP receptors is another challenging 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 spite of this, treatment with biosynthetic GH has been shown to improve the body composition and the metabolic efficacy of lean body mass in obese patients undergoing therapeutic severe
caloric restriction. GH and conceivably GHRPs might therefore have a place in the
therapy of
obesity.