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Search for other papers by J. M. BASSETT in
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SUMMARY
Some metabolic effects of cortisol were investigated in non-pregnant ewes fed either ad lib. or on a restricted ration.
Cortisol (25 mg./day) administered for a period of 21 days stimulated the voluntary food intake of fat ewes offered food ad lib. Higher levels of cortisol (50 and 75 mg./day) administered for similar periods subsequently had little additional effect on voluntary food intake, but an even greater cortisol dose (150 mg./day) resulted in a marked decline in voluntary food intake. Ewes fed a constant restricted ration did not refuse food at any time during cortisol administration.
Urinary nitrogen excretion was increased during cortisol administration but sequential increases in the cortisol dose failed to increase urinary nitrogen excretion proportionately above the level attained during administration of 25 mg. cortisol/day.
The blood glucose level was elevated progressively as the level of cortisol administered was increased. Similarly, tolerance for a glucose load was impaired progressively.
Only very small changes in blood ketones and plasma free fatty acid levels were observed during cortisol administration.
The changes in blood glucose during cortisol administration cannot be accounted for by changes in gluconeogenesis, and it is suggested that they reflect a progressive impairment of glucose utilization relative to the blood glucose level, though not a reduction in total glucose utilization.
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SUMMARY
The metabolism of [4-14C]cortisol in a patient with Cushing's syndrome has been studied by the isolation, identification and measurement of the specific radioactivities of the major metabolites.
The results show that the metabolism of cortisol was not abnormal in the aspects studied. The biological half-lives of cortisol and of the tetrahydrocorticosteroid metabolites were found to be normal. Data obtained on excretion rates of metabolites indicated that the metabolic pathways of cortisol were normal. There was no evidence for an increased conversion of cortisol to 6β-hydroxycortisol when the excretion of the latter was expressed as a fraction of the cortisol production.
The overall pattern was one of an abnormally high secretion of cortisol by the adrenals, resulting in a proportionally high excretion of tetrahydrocortisone, tetrahydrocortisols, cortolones, cortols, 11-oxygenated 17-oxosteroids, 6β-hydroxycortisol, cortisone and cortisol. Apart from an increased ratio of 11β-hydroxy-metabolites to 11-oxo-metabolites, each metabolite, expressed as a fraction of the cortisol secreted, was excreted in a normal proportion.
Hence, in spite of the grossly elevated cortisol secretion rate, the major pathways available for cortisol metabolism were not overloaded and there was no evidence of increased metabolism via minor pathways.
Evidence for an increased secretion of corticosterone by the adrenals was obtained by the isolation of abnormal amounts of tetrahydrocorticosterone.
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Institute of Obstetrics and Gynaecology, Queen Charlotte's Hospital, Goldhawk Road, London, W6 OXG
(Received 4 September 1974)
It is well established that the rise in total plasma cortisol which follows the administration of corticotrophin (ACTH) or tetracosactrin is greater in late pregnancy than in non-pregnant women (Jailer, Christy, Longson, Wallace & Gordon, 1959; Campbell, Bain, Dewhurst & Fotherby, 1970; Johnstone & Campbell, 1974). However, it is not clear whether this can be completely explained by the increased corticosteroidbinding globulin levels in pregnancy (Doe, Fernandez & Seal, 1964; De Moor, Steeno, Brosens & Hendrikx, 1966) or whether there is a true rise in tissue exposure to unbound cortisol. In non-pregnant subjects, 1·0 mg depot tetracosactrin (Ciba) appears to give a maximal adrenal stimulus, at least over the first 4 h (Besser, Butler & Plumpton, 1967; Nelson, Neill, Montgomery, Mackay, Sheridan & Weaver, 1968), and we have described the total 11-hydroxycorticosteroid patterns
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Abstract
Cortisol inhibits growth hormone (GH) release in short-term culture and is stimulatory in long-term cultures of rat and human pituitary cells. This study sought to determine the in vitro effects of cortisol on GH release and the signal transduction pathways mediating the effects of cortisol on GH release from cultured ovine somatotrophs. Pituitary cells were dispersed with collagenase and placed in culture medium for 4 days. The data indicate that cortisol inhibited growth hormone-releasing hormone (GHRH)-stimulated GH release by at least 2 h. In short-term culture GHRH-, forskolin- and dibutyryl cyclic AMP-stimulated GH release were inhibited by cortisol, suggesting an effect distal to the membrane and involving a protein kinase A (PKA)-dependent pathway. GH release initiated by KCl was inhibited by cortisol, but GH release caused by the calcium ionophore A23187 was unaffected. This suggests a possible action of cortisol on the calcium channels. The inhibition by cortisol of the calcium-dependent secretion of GH release appeared to play a smaller role in mediating cortisol inhibition of GH release than that seen with PKA. Attempts to overcome cortisol inhibition of GH release using puromycin, arachidonic acid or pertussis toxin were unsuccessful. Since cortisol inhibition of GH release does not occur via the mechanisms found in other cell types, cortisol inhibition of pituitary cell secretions appears to be cell-specific rather than utilizing a single inhibitory mechanism. The majority of cortisol actions on the somatotroph appear to act at a site distal to the production of cyclic AMP. In contrast to man and the rat, the sheep somatotroph does not appear to increase GH release when treated with cortisol for 24 h, perhaps related to the lack of effect of cortisol on somatotroph content of GH.
Journal of Endocrinology (1994) 141, 517–525
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SUMMARY
A method is described for determining the degree of binding by plasma proteins of cortisol by a technique of pressure ultrafiltration at 37° after addition of radioactively labelled cortisol.
In normal subjects, the mean concentration of transcortin binding sites was 5·82 × 10−7 moles/l. and the apparent association constant at 37° was 4·27 × 107 l./mole. Evidence of increased protein binding of cortisol was obtained in oestrogen-treated subjects and in women in the last 3 months of pregnancy. In the latter subjects normal levels of non-protein bound cortisol were found. The mean level of non-protein bound cortisol in eight men treated with stilboestrol was increased, but normal levels were present in four of these subjects.
The protein binding of cortisol in three patients with Cushing's syndrome and in three patients with Addison's disease was normal. Thirty-five% of cortisol in adrenal venous plasma was in the unbound state.
Increased levels of plasma 17-hydroxycorticosteroids (17-OHCS) were found in patients in stressful situations (post-operative states, infections and burns). There was no evidence of increased protein binding of cortisol.
Patients at death had increased levels of plasma 17-OHCS including three patients who had been on long-term steroid therapy. There was no evidence of increased protein binding of cortisol. On the contrary, there was some evidence of a decrease in transcortin binding sites.
It is concluded that stressful situations in man, regardless of the outcome, are associated with increased plasma levels of biologically active cortisol.
Search for other papers by E. A. ESPINER in
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SUMMARY
Measurements of urinary free cortisol were made in convalescent subjects and in patients with established Cushing's syndrome and the results compared with those in acutely ill patients, in pregnancy and in surgical patients. Cortisol was measured in urine after paper chromatography, each measurement being corrected for losses according to the recovery of added internal standard (tritiated cortisol). In a number of cases, the diurnal rhythm of cortisol excretion was also examined and the results related to plasma 11-hydroxycorticosteroid levels and measurements of renal function.
The mean 24 hr. urinary cortisol excretion in 13 convalescent subjects was 74μg. (range 35–98 μg./24 hr.) and all showed a well-marked diurnal rhythm. Patients with Cushing's syndrome excreted more than normal amounts of cortisol, even when plasma 11-hydroxycorticosteroids were in the normal range; there was a marked reversal in the diurnal rhythm of cortisol excretion. In 13 acutely ill medical patients with pyrexia, four only showed unequivocal increases in cortisol excretion although there was frequently an upset in the diurnal rhythm. The duration of the illness, rather than the severity, appeared to be an important factor so far as the response of the adrenals was concerned. A consistent increase in cortisol excretion was found in pregnancy but there was no significant difference between the day and night excretion of cortisol. The response to the stress of surgical trauma was largely dependent upon the severity of the operative procedure. The importance of emotional stress immediately before operation was shown in 4 out of 14 patients.
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The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 beta-HSD2 activity during late gestation when endogenous fetal cortisol levels rise and after exogenous cortisol administration to immature fetuses before the prepartum cortisol surge. Placental 11 beta-HSD2 activity decreased between 128-132 days and term (approximately 145 days of gestation) in association with the normal prepartum increase in fetal plasma cortisol. Raising fetal cortisol levels to prepartum values in the immature fetus at 128--132 days of gestation reduced placental 11 beta-HSD2 activity to term values. In contrast, 11 beta-HSD2 activity in the fetal renal cortex was unaffected by gestational age or cortisol infusion. When all the data were combined, there was an inverse correlation between the log fetal plasma cortisol level at delivery and placental 11 beta-HSD2 activity, expressed both on a weight-specific basis and per mg placental protein. Fetal cortisol therefore appears to be a physiological regulator of placental, but not renal, 11 beta-HSD2 activity in fetal sheep during late gestation. These findings have important implications, not only for glucocorticoid exposure in utero, but also for the local actions of cortisol within the placental tissues that are involved in initiating parturition in the sheep.
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ABSTRACT
Mononuclear cell preparations are capable of metabolizing cortisol to three metabolites which lack the immunosuppressive effect of their precursor. In the present study we noted a linear correlation, up to a point, between glucose concentration and the rate of human mononuclear cell cortisol metabolism in vitro. The mechanism by which glucose exerts its effect was investigated further. We observed that: (1) the effect of glucose on mononuclear cell cortisol metabolism was not influenced by insulin; (2) NADPH and NADH enhanced cortisol metabolism by disrupted cells, irrespective of whether the homogenates were dialysed or not; (3) lactate and ATP inhibited mononuclear cell cortisol metabolism and (4) almost all the glucose used was converted to lactate. It is concluded that mononuclear cell cortisol metabolism can depend on both nucleotides.
J. Endocr. (1986) 109, 181–185
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Subcutaneous injection of cortisol (10 μg/g body wt daily for 5 days) into normal neonatal rats increased the activity of stomach pepsinogen after day 5. l-Thyroxine (T4; 0·2 μg/g body wt daily for 5 days) alone did not affect the activity but it somewhat enhanced the effect of cortisol. Even before day 5, when no effect of cortisol alone was observed, T4 plus cortisol increased pepsinogen activity. In adrenalectomized, thyroidectomized neonatal rats, injection of cortisol alone did not induce enzyme activity but cortisol together with T4 did induce it. Moreover, the increase in pepsinogen activity was depressed in rats thyroidectomized on day 10 but not in those thyroidectomized on day 15. These results suggest that T4 does not have a direct effect on the stomach but plays an important role in making the stomach responsive to glucocorticoids, resulting in increased pepsinogen activity.
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In order to investigate the role of cortisol in the regulation of testicular function, adult male guinea pigs were challenged with ACTH (20 IU), cortisol (8 or 16 mumol), or with ACTH plus dexamethasone (DEX, 2 mumol). The amounts of cortisol, testosterone, progesterone, and androstenedione present in the plasma or secreted by incubated adrenals or testes were determined by radioimmunoassay. The plasma concentrations of LH were determined using a radioimmunoassay for rat LH. ACTH treatment elevated cortisol plasma concentrations to 999% of control values, whereas it reduced testosterone plasma levels to 43% of control values. ACTH treatment did not affect LH plasma levels. A significant negative correlation was found in ACTH-treated animals, when the cortisol and testosterone plasma concentrations in serially taken blood samples (30-240 min after treatment) were compared (rs = -0.90 and rs = -0.99, P < 0.05). In addition to cortisol, ACTH raised progesterone and androstenedione plasma concentrations. If animals were treated with 2 mumol DEX + ACTH, the plasma levels of cortisol and androstenedione but not of progesterone, testosterone or LH were changed. ACTH stimulated the in vitro secretion of cortisol, progesterone and androstenedione by the adrenals but reduced the in vitro release of androstenedione and testosterone by the testes. In summary, treatment of guinea pigs resulted in elevated cortisol and in reduced testosterone plasma concentrations. The mechanism of the cortisol-induced inhibition of testicular function was independent of the LH plasma concentrations. The in vitro experiments indicate that cortisol directly interacts with the Leydig cells, presumably by inhibiting the activity of the testicular 17 alpha-hydroxylase and/or C17,20-lyase. Taking into account the results of comparable investigations in the rat, the inhibition of the testicular 17 alpha-hydroxylase and/or C17,20-lyase takes place if the intracellular cortisol exceeds the capacity of the 11 beta-hydroxysteroid dehydrogenase to inactivate it.
