Pyridostigmine enhances, but does not normalise, the GH response to GH-releasing hormone in obese subjects

Abstract

Obese patients are characterised by several neuroendocrine abnormalities, including characteristically a decrease in growth hormone responsiveness to GH-releasing hormone. In normal subjects, the GH response to GHRH is enhanced by the acetylcholinesterase inhibitor, pyridostigmine. We have studied the effect of this drug on GH secretion in gross obesity. Twelve obese patients were studied (mean weight 156% of ideal) and compared with a group of 8 normal volunteers. Each subject was initially studied on two occasions, in random order, with GHRH (1-29) NH2 100 \g=m\g iv alone and following pretreatment with pyridostigmine 120 mg orally one hour prior to GHRH. In obese patients, the GH response to GHRH was significantly blunted when compared to controls (GH peak: 20 \ m=+-\4 vs 44 \m=+-\16 \g=m\g/l ; mean \ m=+-\ sem). After pyridostigmine, the response to GHRH was enhanced in the obese subjects, but remained significantly reduced compared to non-obese subjects treated with GHRH and pyridostigmine (GH peak: 30 \ m=+-\5 vs 77 \ m=+-\20 \g=m\g/l ,respectively). In 6 subjects, higher doses of GHRH or pyridostigmine did not further increase GH responsiveness in obese patients. Our results suggest that obese patients have a disturbed cholinergic control of GH release, probably resulting from increased somatostatinergic tone. This disturbed regulation may be responsible, at least in part, for the blunted GH responses to provocative stimuli.Obese patients have blunted growth hormone re¬ sponses to a wide variety of stimuli (1-8). It has also been shown that these patients have decreased GH responses to GH-releasing hormone (9-14). This could be due to reduced pituitary sensitivity to GHRH, excess of hypothalamic somatostatin, or a chronic state of GHRH deficiency. Several lines of evidence point to a role for somatostatin in the de¬ creased GH release found in obesity. Obese pa¬ tients have blunted thyroid stimulating hormone response to TSH-releasing hormone (15), which might also reflect an increase in somatostatinergic tone. Furthermore, genetically-obese rats have in¬ creased hypothalamic somatostatin content (16) and increased hypothalamic somatostatin release in vitro (17). However, there is little direct evidence in the human.Pyridostigmine is a drug which activates cholinergic receptors by decreasing the activity of acetylcholinesterase, and enhances GH responsiveness to ; this is considered to occur via the inhibition of hypothalamic somatostatin (22). Recent studies have suggested that pyridostigmine may increase the GH response to GHRH in obesity, but only single doses of the drug were used, which did not take into account the increased body weight of the obese group compared to the controls (23,24).In order to investigate whether hypothalamic so¬ matostatin activity is increased in obesity, we have therefore studied the effect of several doses of py¬ ridostigmine on the GH response to GHRH in obese patients.

Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing’s disease: Comparison with GH-releasing peptide-6 (GHRP-6) and GHRH

“…Moreover, our data confirms two recent reports showing that the GH response to ghrelin is decreased in patients with CD [30,31]. Obesity is associated with blunted GH responses to ghrelin, GHRP-6 and GHRH [32][33][34]. A decreased GH response to ghrelin was previously found in obese [30] and overweight [31] hypercortisolemic patients compared to lean normal subjects.…”

Pyridostigmine Enhances Even if it Does Not Normalize the Growth Hormone Responses to Growth Hormone-Releasing Hormone in Patients with Cushing’s Disease

“…Unfortu nately, in this previous study, no details about the GH data from each single patient were given [20], In contrast with previously reported results [20], in all the patients studied the GH response to GHRH was enhanced by PD pretreatment; moreover, in some of them this effect was of relevant magnitude. Possible explanations of this dis crepancy between the two studies are the small number of patients studied and the heterogeneity of patients with Cushing's disease concerning clinical features with po tential influences on GH secretory capacity: age [21], body weight [22], basal blood glucose [23] and cortisol levels [4], This clinical heterogeneity may also account for the variability of the effect of PD on the GH response to GHRH in the patients of our study. Therefore, our findings suggest that in patients with Cushing's disease there may be a glucocorticoid-mediated decrease in cen tral cholinergic tone which in turn may cause an increase in hypothalamic somatostatinergic tone.…”

Acipimox enhances spontaneous growth hormone secretion in obese women

“…hyposomatotropism; growth hormone kinetics; somatotroph cell function; free fatty acid SPONTANEOUS PULSATILE growth hormone (GH) release (36,49) and GH secretion in response to various provocative exogenous stimuli (1,7,14) are markedly blunted in obese patients. The mechanism underlying this neuroendocrine feature of obese humans remains elusive.…”