Evaluation of the growth-hormone-releasing hormone test in short normal and growth-hormone-deficient children

Growth-hormone-releasing hormone (GHRH) tests were performed once [GHRH(1-29)NH2, 1 microgram/kg] or on 2 consecutive days [GHRH(1-44)NH2, 1 and 2 microgram/kg administered in random order] in 27 children with idiopathic, isolated growth hormone (GH)-deficiency and in 49 short normal children, all clinically prepubertal. No differences in GH release were found between the tests performed on the 1st and 2nd day or according to GHRH dose or sex, both in GH-deficient and control children. 80% of GH-deficient and 87% of control children responded (GH peak greater than 10 ng/ml) to GHRH(1-29)NH2, and 65% of GH-deficient and all control children to GHRH(1-44)NH2. No differences in GH release were found between GH-deficient GHRH responders and control children. 17% of GH-deficient and 10% of control children responded only to one of the two tests performed on 2 consecutive days; the lack of responsiveness was unrelated to GHRH dose and sequence of GHRH administration (1st or 2nd day). The GHRH test does not seem to be a reproducible test for the evaluation of GH release, nor is it useful to differentiate GH-deficient GHRH responders from short normal children.     

Calcitonin increases peripheral plasma somatostatin-like immunoreactivity levels in humans

Even though the inhibitory effects of CT on both hormone secretion and gastrointestinal functions have been well established, the exact mechanism of action still remains unclear. Since the effects of CT can be reproduced by somatostatin, we studied in man the effect of SCT on peripheral plasma SLI levels. Immediately after the onset of CT infusion SLI rose from its mean basal value of 45 +/- 5.5 pg/ml to a peak value of 91 +/- 11 pg/ml (p less than 0.005). SLI levels were still significantly elevated at 30 (p less than 0.05), 45 (p less than 0.05), 90 (p less than 0.005) and 120 min (p less than 0.02). Our results, in good agreement with the previous report by Chiba et al. on isolated perfused rat stomach, suggest that CT effects may, at least in part, be mediated by endogenous somatostatin release.     

Pancreatic somatostatin-like immunoreactivity suppresses gastric acid secretion in rats.

Somatostatin-like immunoreactivity (SLI) was extracted from the canine pancreas and purified by ion exchange, affinity chromatography and gel filtration. The 1600 dalton fraction, which is physicochemically similar to synthetic somatostatin was infused into the peripheral circulation of anesthetized rats and its effect upon gastric acid secretion was compared with that of synthetic somatostatin. Both synthetic somatostatin and pancreatic SLI in a dose of 7–8 μg/kg/h suppressed pentagastrin-stimulated gastric acid secretion. It is concluded that the highly purified 1600 dalton fraction of canine pancreatic SLI, like synthetic somatostatin, can exert biological activity upon the stomach of rats.     

Plasma somatostatin-like immunoreactivity responses to a mixed meal and the heterogeneity in healthy and non-insulin-dependent (NIDDM) diabetics

Peripheral plasma somatostatin-like immunoreactivity (SLI) was estimated in non-extracted plasma using a specific somatostatin-14 (SS-14) antiserum. The basal plasma SLI level in healthy subjects (n = 18) was 43 +/- 2.9 pg/ml (mean +/- SE) and rose significantly to 8.3 +/- 2.7, 7.3 +/- 1.1 and 5.8 +/- 2.1 pg/ml above the mean basal level 20, 30, and 40 min after a mixed meal, respectively (P less than 0.05). Basal plasma SLI levels in diet (n = 8), sulfonyl urea (n = 8), and insulin groups (n = 8) of non-insulin-dependent maturity onset diabetics (NIDDM) were 50 +/- 1.6, 59 +/- 4.5, and 74 +/- 5.8 pg/ml, respectively. The basal levels for patients with NIDDM were significantly higher than those for healthy subjects (P less than 0.05). No significant increases in plasma SLI were observed after a mixed meal in any group of NIDDM subjects. Elevated plasma SLI levels are considered to be closely related to the severity of the diabetes. The ratios of SS-14 and SS-28 to the total amount of basal plasma SLI were analyzed using high pressure liquid chromatography (HPLC). The ratio of SS-14 to the total SLI was 71-80% in healthy subjects. The ratio of SS-28 to the total SLI increased from 26-30% in the diet group to 50-55% in the group on insulin. These findings suggest a possible pathophysiological role for gastrointestinal somatostatin in NIDDM.     

Tissue and serum somatostatin-like immunoreactivity in lean and obese Zucker rats

Tissue and serum somatostatin levels were measured in genetically lean and obese Zucker rats. Immunoreactive somatostatin content was decreased in three central nervous system regions (hypothalamus, septum and preoptic area and thalamus) of obese rats but was increased in cerebral cortex. No differences were observed in antral or colonic somatostatin content but obese animals had significantly elevated pancreatic levels. Portal vein somatostatin-like immunoreactivity in contrast was significantly lower in obese rats. The widespread alterations in tissue and serum somatostatin-like immunoreactivity suggest either a diffuse abnormality of somatostatin physiology or a response to a generalised feature of the obese hyperinsulinaemic state.     

Presence of somatostatin-like immunoreactivity in rat pancreatic juice: a physiological phenomenon

These studies were performed to assess the effects of various exocrine pancreatic stimuli on somatostatin-like immunoreactivity (SLI) secretion in pure rat pancreatic juice. Ingestion of a meal and subcutaneous injections of caerulein (CA), secretin (SE), and their combination (CA + SE) were compared. Basal fasting SLI output over 5 1/2 h averaged 13.7 ng/30 min; the response to feeding resulted in decreased SLI outputs from 9.7 to 1.7 ng/30 min, a reduction of 81%. SLI secretion following CA, SE, and CA + SE was similar to that obtained following feeding but the reductions of 29, 32, and 39% were less marked and of shorter duration. A return to basal SLI levels was observed only 2 1/2 h following CA administration. Increases in pancreatic volume and protein outputs following CA, SE, and CA + SE were comparable to the feeding response although less pronounced. These data indicate that SLI secretion in pure pancreatic juice can be modulated by two peptides and feeding and that its release is reduced when compared with increases in pancreatic volume and protein secretion. The observation that the peptide's response in terms of SLI output as well as protein and volume were in the same range, although less sustained than the response to a meal, indicates that all stimuli used induced a physiological response of the pancreas.     

Reduced somatostatin-like immunoreactivity in the brain of dogs with an Eck fistula

Somatostatin-like immunoreactivity (SLI) in the brains of Eck fistula dogs, prepared as an experimental model of hepatic encephalopathy, was measured to investigate the pathogenesis of hepatic encephalopathy. The values were studied in comparison with the concentrations of amino acids where the imbalance was suggested to cause hepatic encephalopathy. SLI levels in the parietal and temporal cortex of Eck fistula dogs were 76.0 +/- 12.0 (mean +/- S.E.M., fmol/mg wet wt.) and 113.4 +/- 23.7, and those of controls were 144.0 +/- 11.8 and 186.9 +/- 19.2, respectively, the differences being statistically significant (P less than 0.005, P less than 0.05). No significant difference in gel filtration profiles of SLI in extracts from parietal and temporal cortex was observed between Eck fistula dogs and controls. Tyrosine and phenylalanine, which are suggested to be precursors of false neurotransmitters, were significantly increased in the parietal cortex of the Eck fistula dogs, and phenylalanine was significantly increased in the temporal cortex of these dogs. There was a significant negative correlation between SLI and phenylalanine concentrations in the parietal and temporal cortex (r = -0.7171, P less than 0.01). These results suggest that the reduced SLI may be one of the factors which cause the neuropsychiatric disturbances in hepatic encephalopathy.     

Characterization of the somatostatin-like immunoreactivity extracted from an adrenal medullary tumour

Significant amounts of somatostatin-like immunoreactivity (SLI) were detected in the extract of a human catecholamine-secreting adrenal medullary tumour. After salt fractionation and reconstitution the major portion of SLI was purified by gel filtration and two HPLC steps; in all three systems it eluted in the position of somatostatin-14. The purified somatostatin-like peptide inhibited, in a dose-related manner, growth hormone release from stimulated perfused rat anterior pituitary cells in vitro. Amino acid analysis showed the purified peptide to have an identical composition to somatostatin found in other species.     

Growth hormone response to a bolus injection of 1-44 growth-hormone-releasing hormone in very short children with intrauterine onset of growth failure

The release of growth hormone (GH) during the 120 min following a bolus venous injection of 1-44 GH-releasing hormone (GHRH) 2 micrograms/kg was studied in 52 prepubertal children aged 8.4 +/- 2.1 years, having a nonfamilial growth deficiency of prenatal onset (-3.26 +/- 1.13 SDS at birth, -3.22 +/- 0.88 SDS at the time of study) and a normal response to conventional GH stimulation tests. GH release reached a peak level of 96.1 +/- 60.2 microU/ml, being significantly higher than that found in 68 non-GH-deficient very short children whose growth failure had a postnatal onset, and not significantly correlated with the response to conventional tests. 26 of the 52 intrauterine growth retardation (IUGR) patients were re-tested with GHRH in similar conditions after 6-12 months of daily subcutaneous injections of GH and 2 days without. They reached at the second test a peak plasma GH level of 91.7 +/- 56.1 microU/ml, not different from their response to the first test. These data could be taken into consideration for long-term studies of the clinical effects of GH in IUGR children with persisting severe growth deficiency.     

Acute effects of clonidine and growth-hormone-releasing hormone on growth hormone secretion in patients with hyperthyroidism

Patients with hyperthyroidism have reduced growth hormone (GH) responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of clonidine on GH secretion has been suggested to depend on an enhancement of hypothalamic GH-releasing hormone (GHRH) release. The aim of our study was to evaluate the effects of clonidine and GHRH on GH secretion in patients with hyperthyroidism. Eight hyperthyroid females with recent diagnosis of Graves' disease (age range 20-55 years, body mass index range 19.2-26.2 kg/m2) and 6 healthy female volunteers (age range 22-35 years, body mass index range 19-25 kg/m2) underwent two experimental trials at no less than 7-day intervals: (a) an intravenous infusion of clonidine 150 micrograms in 10 ml of saline, or (b) a bolus intravenous injection of human GHRH (1-29)NH2, 100 micrograms in 1 ml of saline. Hyperthyroid patients showed blunted GH peaks after clonidine (7.1 +/- 1.7 micrograms/l) as compared to normal subjects receiving clonidine (28.5 +/- 4.9 micrograms/l, p less than 0.05). GH peaks after GHRH were also significantly lower in hyperthyroid subjects (8.0 +/- 1.7 micrograms/l) as compared to normal subjects receiving GHRH (27.5 +/- 4.4 micrograms/l, p less than 0.05). No significant differences in the GH values either after clonidine or GHRH were observed in the two groups of subjects examined. Our data demonstrate that the GH responses to clonidine as well as to GHRH in patients with hyperthyroidism are inhibited in a similar fashion with respect to normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of plasma somatostatin-like immunoreactivity to the administration of alloxan in dogs.

The present study was designed to examine the effects of intravenously injected alloxan (75 mg/kg) upon plasma somatostatin-like immunoreactivity (SLI), glucagon (IRG), insulin (IRI) and glucose levels in 6 dogs. Within 2 hours of the injection of alloxan, SLI and IRI levels decreased significantly below their respective baselines, while IRG and plasma glucose concentrations increased. At 8 hours SLI levels had increased significantly by 55 pg/ml, together with a rise in IRI and a decrease in IRG and glucose concentrations. After 24 hours, marked hyperglycemia and hyperglucagonemia had developed whereas SLI levels were not different from preinjection values.     

Immunohistochemical localization of somatostatin-like immunoreactivity in skin lesions from patients with urticaria pigmentosa

Using the indirect immunofluorescence technique of Coons and collaborates, somatostatin-like immunoreactivity was found in skin lesions of patients presented with urticaria pigmentosa. The cytoplasmic immunoreactivity was sometimes of a granular type. In addition, immunofluorescence was also observed in certain surrounding connective tissue elements. No specific staining was seen when supplementing the first antiserum with control serum, nor could any unique specific immunofluorescence by found in the pathological areas (compared with skin of normal healthy volunteers) after incubation with antibodies to substance P, vasoactive intestinal polypeptide or avian pancreatic polypeptide. No thyrotropin releasing hormone or enkephalin immunoreactivity was seen in skin from either the patients or the controls.     

Reduced somatostatin-like immunoreactivity in the brain of LEC rats with hepatic encephalopathy.

Somatostatin-14-like immunoreactivity (S14LI) and somatostatin-28(1-12)-like immunoreactivity (S28(1-12)LI) in the brain of LEC (Long Evans Cinnamon) rats with hepatic encephalopathy were measured. Significant reduction of both S14LI and S28(1-12)LI was observed in the hypothalamus, medulla oblongata, striatum and spinal cord. Both of the immunoreactivities in the hypothalamus of these rats were approx. 50% of those in LEC rats without hepatic encephalopathy. The amounts of reduction of S14LI significantly correlated with those of reduction of S28(1-12)LI. No significant difference in gel chromatographic profiles of S14LI and S28(1-12)LI was observed between LEC rats with and without hepatic encephalopathy. These results suggest that the reduction of somatostatin-like immunoreactivity in LEC rats with hepatic encephalopathy may be caused by a decrease in production of prosomatostatin rather than altered degradation.     

Localization of somatostatin-like immunoreactivity in the Golgi apparatus of central and peripheral neurons

Summary With the indirect immunofluorescence technique of Coons and collaborators somatostatin-like immunoreactivity (SLI) was observed in certain neurons of the central and peripheral nervous system of the rat. In the cell bodies a strong SLI was observed with a distribution resembling that of the Golgi apparatus. In addition a weak SLI was diffusely distributed in the cytoplasm. After photography the sections processed for immunocytochemistry were stained with the thiamine pyrophosphatase technique of Novikoff and Goldfischer. The latter technique is assumed to be a specific marker for the Golgi complex. It was found that the strong SLI and the thiamine pyrophosphatase activity had an identical distribution. Thus, one pool of somatostatin appears to be localized to the Golgi apparatus.This work was supported by grants from the Swedish Medical Research Council (04X-2887, 19X-3412), Magnus Bergvalls Stiftelse, Harald och Greta Jeanssons Stiftelse, and funds from the Karolinska Institute