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SUMMARY
Adrenocortical suppression tests, based on the fall in urinary 17-hydroxy-corticosteroid excretion during the oral administration of dexamethasone, were found to be of value in the diagnosis of Cushing's syndrome, but less useful in differentiating bilateral adrenal hyperplasia from adrenal tumour. Such tests have the disadvantage of requiring accurate urine collections and of taking several days to perform. A test is described, based on the decrease in plasma cortisol concentration during i.v. infusion of dexamethasone at a rate of 1 mg./hr. The results obtained in 12 patients with Cushing's syndrome and bilateral adrenal hyperplasia differed from those found in control subjects in that there was a delay between the start of the infusion and the fall of plasma cortisol, and the rate of fall was less rapid. The values found after 180 min., expressed either as μg./100 ml. or as a percentage of the resting level, differed significantly (P < 0·001) in the two groups. The test proved valuable as an aid to the diagnosis of Cushing's syndrome, was easy to perform, and could be completed in 3 hr.
In some patients with Cushing's syndrome, the administration of synthetic glucocorticoids appeared to result in an increased urinary steroid excretion. A transient increase in plasma cortisol levels was also observed in some of these patients during the early period of dexamethasone infusion. It is thought that this finding reflects an alteration in steroid metabolism induced by dexamethasone and fluorocortisol.
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Search for other papers by V. H. T. JAMES in
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SUMMARY
The adrenocortical response to stress as shown by an increase of the plasma cortisol concentration during insulin-induced hypoglycaemia has been studied. The response was found to depend upon the degree and duration of the hypoglycaemia and upon the integrity of the entire hypothalamo-pituitary-adrenal axis. Thus, there was no response in subjects in whom the blood sugar did not fall below 40 mg./100 ml., nor in patients with severe hypothalamic or pituitary disorders.
The test was quick and simple to perform and did not require admission to hospital; it would seem to be of considerable value in the investigation of patients with suspected endocrine disease.
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Search for other papers by V. H. T. JAMES in
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SUMMARY
The effect of methandienone administration on urinary steroid excretion has been studied in subjects with normal pituitary-adrenal function and in patients with various endocrine diseases.
In the control subjects, a marked suppression of urinary 17-KS and 17-OHCS excretion occurred, which persisted throughout even prolonged periods of methandienone administration. Upon cessation of methandienone treatment a prompt rise in urinary steroid excretion occurred, on occasions to levels slightly higher than those seen before treatment.
Similar results were obtained in subjects with acromegaly and Cushing's syndrome, but in patients with anorexia nervosa and a low basal steroid excretion, the suppressive effect of methandienone was less marked.
During treatment with methandienone, pituitary response to metopirone was depressed, but adrenal response to corticotrophin was unaltered.
It was concluded that methandienone diminishes the rate of production of adrenocortical steroid by inhibiting corticotrophin production or release. Unlike the inhibition observed during treatment with glucocorticoids, it was not associated with atrophy of the adrenal glands.
Search for other papers by J. W. H. DOAR in
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Search for other papers by P. J. WEBB in
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SUMMARY
The use of the resting plasma cortisol level, the diurnal plasma cortisol rhythm and plasma cortisol response to a maximal adrenocorticotrophic hormone (ACTH) infusion or insulin-induced hypoglycaemia as indirect tests of hypothalamo—pituitary—adrenocortical function was examined in a group of 27 patients with pituitary disease. While the first three tests provided similar information about hypothalamo—pituitary—adrenocortical function, the plasma cortisol response to insulin-induced hypoglycaemia did not provide further clinically useful information. Difficulties in interpretation of dynamic tests of hypothalamo—pituitary—adrenocortical function are discussed.
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Search for other papers by F. C. GREENWOOD in
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SUMMARY
The plasma sugar, 11-hydroxycorticosteroid, and growth hormone responses to insulin have been studied in patients with Cushing's disease. They showed an impaired or absent plasma 11-hydroxycorticosteroid and growth hormone rise during the test, as compared with control subjects, despite the injection of amounts of insulin which produced a similar degree of hypoglycaemia. This test proved of value in differentiating between these patients and those with 'simple ' obesity since the latter usually showed a normal growth hormone and adrenal response provided an adequate amount of insulin was administered.
The patients with Cushing's disease also had an impaired adrenal response to pyrogen and to dexamethasone administration and failed to show a normal plasma 11-hydroxycorticosteroid circadian rhythm. Their response to corticotrophin, lysine vasopressin, and metyrapone, however, was normal or enhanced. It is suggested that these findings imply an abnormality of hypothalamic or cerebral control and not a primary defect of pituitary function as proposed originally by Harvey Cushing.
The growth hormone response to insulin remained impaired in four out of six patients totally adrenalectomized for Cushing's disease but was normal in three patients adrenalectomized for other reasons. It is suggested that the defect which impairs the adrenal response to insulin may, on occasions, also impair the mechanism normally operative for growth hormone secretion.
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Search for other papers by V. WYNN in
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Impaired oral (OGTT) and i.v. glucose tolerance (IVGTT) has been found in some women receiving oral contraceptives (Wynn & Doar, 1966). The precise cause is not known but it has been suggested that elevated plasma growth hormone (GH) levels may be responsible (Spellacy, Carlson & Schade, 1967). Striking increases of OGTT and IVGTT blood pyruvate levels have also been found during oral contraceptive therapy (Wynn & Doar, 1966). The present study was undertaken to investigate the acute effects of GH on carbohydrate and intermediary metabolism.
Two IVGTT's were carried out by methods previously described (Wynn & Doar, 1966) in 12 normal ambulatory subjects (aged 20–49), six of whom were women. The first test served as a control. The second test was carried out 120 min. after i.v. administration of 5 mg. human GH (HGH, MRC R. 10 Batch). Blood samples were analysed for plasma glucose (Cramp, 1967), non-esterified fatty acid
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Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2 tm1a/tm1a ) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2 tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2 tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.
