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  • Author: M O Savage x
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P. J. Trainer, J. M. W. Kirk, M. O. Savage, A. B. Grossman and G. M. Besser


The GH response to insulin-induced hypoglycaemia and growth hormone-releasing hormone (GHRH) has been shown to be impaired in subjects with Cushing's syndrome and in healthy volunteers given oral glucocorticoids. Pyridostigmine is an anticholinesterase that stimulates GH secretion, probably by inhibition of hypothalamic somatostatin secretion. This work was designed to study the site of action of glucocorticoids in inhibiting the secretion of GH.

Eight healthy male volunteers were studied on three occasions in random order. They took 2 mg oral dexamethasone or placebo at precisely 6-hourly intervals for 48 h before receiving 120 mg oral pyridostigmine or placebo, followed 60 min later by GHRH (100 μg) i.v. Samples for measuring GH were obtained at 15 min intervals for 2 h.

The 'area under the curve' (AUC) for each of the treatments was significantly different: dexamethasone–pyridostigmine–GHRH (mean ± s.e.m., 1938 ± 631 mU/min per 1), dexamethasone–placebo–GHRH (634 ±211) and placebo–placebo–GHRH (4267 ± 1183) (P<0·02, Wilcoxon test).

In conclusion, dexamethasone given for 48 h significantly inhibited the AUC for GH following treatment with GHRH. However, pretreatment with pyridostigmine significantly reversed the inhibition although this was still partial. Our data suggested that this short-term suppressive effect of dexamethasone was independent of GHRH, and most probably relates to stimulation of the release of somatostatin.

Journal of Endocrinology (1992) 134, 513–517

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A. Blacklay, A. Grossman, R. J. M. Ross, M. O. Savage, P. S. W. Davies, P. N. Plowman, D. H. Coy and G. M. Besser


A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1–29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1–29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1–29)NH2 in all the children, and in five the peak serum GH response was > 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GH RH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.

J. Endocr. (1986) 108, 25–29

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M Maamra, A Milward, H Zarkesh Esfahani, L P Abbott, L A Metherell, M O Savage, A J L Clark and R J M Ross

Growth hormone insensitivity syndrome (GHIS) has been reported in a family homozygous for a point mutation in the GH receptor (GHR) that activates an intronic pseudoexon. The resultant GHR (GHR1–656) includes a 36 amino-acids insertion after residue 207, in the region known to be important for homodimerization of GHR. We have examined the functional consequences of such an insertion in mammalian cells transfected with the wild type (GHRwt) and mutated GHR (GHR1–656). Radio-ligand binding and flow cytometry analysis showed that GHR1–656 is poorly expressed at the cell surface compared with GHRwt. Total membrane binding and Western blot analysis showed no such difference in the level of total cellular GHR expressed for GHR1–656 vs GHRwt. Immunofluorescence showed GHR1–656 to have different cellular distribution to the wild type receptor (GHRwt), with the mutated GHR being mainly perinuclear and less vesicular than GHRwt. Western blot analysis showed GH-induced phosphorylation of Jak2 and Stat5 for both GHR1–656 and GHRwt, although reduced Stat5 activity was detected with GHR1–656, consistent with lower levels of expression of GHR1–656 than GHRwt at the cell surface. In conclusion, we report that GHIS, due to a 36 amino-acids insertion in the extracellular domain of GHR, is likely to be explained by a trafficking defect rather than by a signalling defect of GHR.

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J. M. P. Holly, C. P. Smith, D. B. Dunger, J. A. Edge, R. A. Biddlecombe, A. J. K. Williams, R. Howell, T. Chard, M. O. Savage, L. H. Rees and J. A. H. Wass


We have looked at the relationship between fasting levels of insulin and a small insulin-like growth factor (IGF)-binding protein (IBP-1) in a cross-sectional study of 116 normal subjects aged 5–48 years. The relationship between IBP-1 and insulin was also examined within individual normal children in over-night profiles of IBP-1 and insulin obtained from two children at each stage of puberty (Tanner stages 1–5). In the cross-sectional study high levels of IBP-1 were found in early childhood and these fell throughout puberty as fasting levels of insulin rose. Multiple regression analysis revealed that both these changes were predominantly due to pubertal development rather than to age. After the age of 16 IBP-1 levels remained low despite fasting insulin levels returning to prepubertal levels. A strong negative correlation was obtained between IBP-1 and insulin in children of 5–16 years (r = −0·63; n = 60; P <0·001), no such relationship being found after the age of 16. In the second study, IBP-1 underwent a marked circadian variation in all cases and an inverse correlation with insulin, measured at the same time, was obtained at pubertal stages 1 to 4, but not at stage 5 (pooled data stages 1–4, r = −0·69; n = 53; P <0·001). We have demonstrated that a potential inhibitor of IGF-activity is inversely related to insulin throughout the period of active GH-related growth and that this relationship weakens after puberty.

Journal of Endocrinology (1989) 121, 383–387