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Department of Chemical Pathology, St. Bartholomew's Hospital, London, EC1A 7BE
(Received 17 January 1975)
CONTENTS
PAGE
Glossary of abbreviations 143
Introduction 143
Classification 144
Evidence for the secretion of hormones by non-endocrine tumours 145
Incidence 147
Processes of formation and release of ectopic hormones 149
Ectopic hormone secretion 151
(1) Adrenocorticotrophin/lipotrophic hormone/melanocyte-stimulating hormone 151
(2) Non-metastatic hypercalcaemia 155
(3) Antidiuretic hormone, oxytocin, neurophysin 157
(4) Gonadotrophins 159
(5) Human placental lactogen 159
(6) Growth hormone 159
(7) Insulin 160
(8) Calcitonin 162
(9) Thyroid-stimulating hormone 162
(10) Prolactin 162
(11) Erythropoietin 163
(12) Gut hormones 163
(13) Hypophosphataemic osteomalacia 163
(14) Multiple ectopic hormone secretion 163
Ectopic hormones as tumour-indexing substances 164
Postulated mechanisms of ectopic hormone secretion 165
Conclusions 167
References 167
GLOSSARY OF ABBREVIATIONS
ACTH Adrenocorticotrophin
ADH Antidiuretic hormone
APUD Amine precursor uptake and decarboxylation
AVP Arginine vasopressin
CLIP Corticotrophin-like intermediate lobe peptide
5-HT Serotonin
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SUMMARY
The half-life of plasma cortisol in the rhesus monkey (M. mulatta), determined by two methods, was about 130 min and longer than that in man; it was unaffected by administration of dexamethasone. Dexamethasone (5 mg, i.v.) immediately inhibited the secretion of ACTH from the monkey pituitary. The plasma half-life of NH2-terminal immunoreactive ACTH was found to be about 55 min which was much longer than the biological half-life. The adrenal synthesis of cortisol was inhibited by metyrapone which caused a prompt increase in the plasma concentration of ACTH and 11-deoxycortisol. The hypothalamicpituitary-adrenal system of the rhesus monkey sedated with phencyclidine hydrochloride responded rapidly to alteration in the level of steroids in the circulation.
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SUMMARY
The pars intermedia of the rat pituitary contains a peptide resembling the 18–39 portion of adrenocorticotrophic hormone (ACTH), which has been termed 'corticotrophin-like intermediate lobe peptide' (CLIP). It can be detected by its cross-reaction with an antiserum directed against the CO2H-terminal portion of the ACTH molecule; it has an amino acid composition identical to the 18–39 portion of human ACTH, except for one less glycine and an extra valine residue, and it is rapidly released from neurointermediate lobes maintained in organ culture. The pars intermedia also contains a peptide with an amino acid composition and biological potency identical to that of melanocyte-stimulating hormone (α-MSH) isolated from other mammals, and which accounts for the bulk of melanocyte-stimulating activity in the pituitary. Rat ACTH resembles human ACTH in amino acid composition, except for an extra valine and one less glycine residue. On the basis of these data it is proposed that ACTH is the precursor of α-MSH and CLIP, which are both present in the cells of the pars intermedia.
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A chromatographic procedure has been developed for the characterization of ACTH- and lipotrophin- (LPH) related peptides in human plasma under acid-dissociating conditions to minimize artifacts of protein binding. The recovery and sensitivity of this method permits identification of ACTH at normal physiological levels in the circulation. Plasma profiles obtained from normal subjects and patients with pituitary dependent Cushing's disease, Addison's disease and Nelson's syndrome showed only one significant peak of ACTH activity eluting in the position of purified native human 1–39 ACTH. However, the plasma profiles obtained from all the patients with the ectopic ACTH syndrome demonstrated a second peak of immunoreactive larger-molecular-weight ACTH and in some plasma samples this was the only form of ACTH observed. This larger-molecular-weight ACTH eluted midway between the void volume and 1–39 ACTH and co-eluted with a protein marker of molecular weight 22 000.
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A sensitive extracted radioimmunoassay for methionine enkephalin (met-enkephalin) has been developed which allows measurement of its concentration in human plasma and cerebrospinal fluid (CSF). The first evidence for the existence of met-enkephalin in the circulation of man is described and its presence in CSF confirmed. The susceptibility of the methionine residue in met-enkephalin to undergo oxidation to the methionine sulphoxide analogue was utilized. All extracted samples were oxidized by hydrogen peroxide before assay and this allowed measurement of total met-enkephalin. The assay had unique specificity with no cross-reaction with leucine enkephalin, purified human β-endorphin or β-lipotrophin (β-LPH). A purification method for radio-iodinated enkephalin has been developed with octadecasilyl-silica (ODS-silica) (10 μm) yielding a high-affinity monoiodinated tracer stable on storage for up to 3 months at 4 °C. A method to extract met-enkephalin from acidified plasma or CSF has been developed with larger particle size ODS-silica (35–70 μm) suitable for extracting repeated samples. Met-enkephalin immunoreactivity was detectable in plasma of all subjects tested and ranged from 14 to 140 pg/ml. In CSF, however, the range was 5–29 pg/ml. Met-enkephalin immunoreactivity was not generated by incubating exogenous or endogenous β-LPH and β-endorphin in plasma or CSF. Two hypopituitary subjects and one dexamethasone-suppressed subject, all with undetectable immunoreactive plasma adrenocorticotrophic hormone and NH2- and CO2H-terminal β-LPH, had measurable met-enkephalin in their plasma suggesting met-enkephalin was not of pituitary origin nor a breakdown product of secreted β-LPH or β-endorphin.
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Levels of endogenous somatostatin, gastric inhibitory polypeptide (GIP), glucagon and insulin were measured during gastric (abomasal) emptying in the conscious calf. Isotonic NaHCO3 infused into the duodenum increased rates of emptying of a saline test meal and of gastric acid secretion, but had no effect on basal levels of blood glucose, somatostatin, GIP, insulin or glucagon. By contrast, intraduodenal infusion of 60 mm-HCl caused complete inhibition of gastric emptying, reduction of acid secretion, and an immediate increase in plasma somatostatin from 121·3 ± 9·4 (s.e.m.) to 286·3 ± 16·3 pg/ml (P <0·01) but levels of GIP, insulin, glucagon and glucose were unaltered. Intravenous injection of somatostatin (0·5 μg/kg) suppressed the antral electromyographic recording and gastric efflux so long as plasma somatostatin levels remained above approx. 200 pg/ml. This suggests that somatostatin can be released by intraduodenal acidification and that it inhibits gastric function by an endocrine effect. Since somatostatin retards gastric emptying it may therefore have an indirect role in nutrient homeostasis by limiting discharge of gastric chyme to the duodenum.
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Differences in foetal and adult adrenal function may be due to qualitative as well as quantitative changes in the pituitary corticotrophic stimulus. Pituitary glands from adult and foetal sheep were freshly dissected and stored at −70 °C until extracted at pH 1·5. The extracts were subjected to chromatography on Sephadex G-100 superfine and fractions were assayed by multiple radioimmunoassays directed against the NH2- and CO2H-terminal sequences of ACTH and lipotrophin (LPH). Peaks corresponding to β-melanocyte-stimulating hormone (β-MSH), β-LPH, γ-LPH, β-endorphin and ACTH were identified, with little or no evidence for the presence of α-MSH and corticotrophin-like intermediate lobe peptide. Three peaks of large molecular weight material, A. B and C, were identified and their relative proportions shown to be considerably greater in the foetus than in the adult. The immunoassay profile of peaks A and B suggested that they were 'stem hormones' which could give rise to a family of biologically active peptides. Since the 'family tree' which they engender varies according to the stage of development, it is proposed that the changes in the 'trophic family' may explain the different adrenal responses of the foetal and adult sheep.
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SUMMARY
The cytochemical (redox) bioassay for LH has been compared with established LH assays. Measurements made by redox bioassays were considerably lower than those made by radioimmunoassay in human female plasma samples obtained at mid-cycle. There was no apparent relationship between measurements on incubation media from cultures of sheep pituitary glands made by redox bioassay and the ovarian ascorbic acid depletion (OAAD) assay. After polyacrylamide gel electrophoresis of a crude extract of a human pituitary gland, redox LH measurements were lower than those of the OAAD assay and radioimmunoassay in the cathodal segments of the gel. By contrast, there was reasonable agreement between LH measurements made by radioimmunoassay and redox assay in cathodal fractions from gel electrophoresis of a purified pituitary LH preparation. Follicle-stimulating hormone, and the α- and β-subunits of LH depressed the response of intact LH in the redox assay; this might explain the relatively low levels of LH measured by redox assay in some of the experiments described. Which type of assay best reflects the biological activity of LH in man remains to be determined.