Hypothalamic syndrome and central sleep apnoea associated with toluene exposure.
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Adolescent↗
Biomedical subjects
C R Edwards
Publications and source records attributed to C R Edwards.
Glycyrrhetinic acid and potentiation of hydrocortisone activity in skin.
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Drug Synergism↗
Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.
11-beta-Hydroxysteroid Dehydrogenases↗
5 alpha-reductase activity in polycystic ovary syndrome.
11 patients with polycystic ovary syndrome (hirsutism and oligomenorrhoea), but with no deficiency of 21-hydroxylase or 3 beta-hydroxysteroid dehydrogenase, had abnormal cortisol metabolism. The high ratio of 5 alpha to 5 beta cortisol metabolites in the urine is consistent with enhanced activity of 5 alpha-reductase. Urinary total cortisol metabolites were higher in patients than controls. Increased 5 alpha-reductase activity in liver and skin enhances hepatic cortisol metabolism at the expense of androgen excess and may be the underlying abnormality in polycystic ovary syndrome.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Diurnal variation of plasma corticosterone in depression.
Hypersecretion of cortisol is associated with depression. Because corticosterone may show greater responsiveness than cortisol to exogenous ACTH in depression and it has behavioural effects in rodents, we determined whether depression is also associated with hypersecretion of corticosterone. Both cortisol and corticosterone were significantly elevated in depression, with greatest differences from control subjects during the afternoon and evening. The ratio of corticosterone/cortisol was constant and similar throughout the day in both depressed patients and controls. We conclude that there is no disproportionate endogenous hypersecretion of corticosterone in depression.
Adolescent↗
Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man.
1. 11-beta-Hydroxysteroid dehydrogenase is an enzyme complex consisting of 11 beta-dehydrogenase and 11-oxoreductase responsible for the interconversion of cortisol to cortisone in man. Inhibition of 11 beta-dehydrogenase (e.g. after liquorice ingestion) results in cortisol acting as a potent mineralocorticoid. We have evaluated the effect of the synthetic liquorice derivative, carbenoxolone, on this enzyme complex. 2. Carbenoxolone given to six volunteers in metabolic balance produced sodium retention with suppression of the renin-angiotensin-aldosterone system. Plasma potassium fell, although there was no kaliuresis. This was associated with inhibition of 11 beta-dehydrogenase (as measured by a rise in the plasma half-life of [11 alpha-3H]cortisol). Unlike liquorice, however, carbenoxolone also inhibited 11-oxoreductase (as measured by the generation of cortisol after oral cortisone acetate). 3. The mineralocorticoid activity of carbenoxolone, like liquorice, is mediated via cortisol by inhibition of 11 beta-dehydrogenase. Carbenoxolone, however, also inhibits 11-oxoreductase activity and this may relate to its effect on renal potassium excretion.
11-beta-Hydroxysteroid Dehydrogenases↗
Epidural peg electrodes for the presurgical evaluation of intractable epilepsy.
A new electrode design for the extradural recording of electrical brain activity is described. Epidural peg electrodes are implantable mushroom-shaped composites of Silastic elastomer and a stainless steel or platinum disc. These electrodes are useful for the preoperative mapping of seizure foci in some patients who have cranial defects or severe muscle artifacts on scalp recordings. They are also used for canvassing wide areas of cortex to determine whether a seizure is focal in origin, arises diffusely from a hemisphere, or has a bilateral origin. Advantages of epidural peg electrodes over screw and other types of epidural electrodes include low risk of infection or hemorrhage and improved patient comfort.
Electrodes, Implanted↗
Autoimmune progesterone dermatitis.
Hypersensitivity to progesterone is rare, but the occurrence of skin rash in the luteal phase of the menstrual cycle or during pregnancy should alert one to this possibility. The diagnosis can be readily confirmed by intradermal testing and is eminently treatable by ovulation suppression.
Adult↗
Renal 11-beta-hydroxysteroid dehydrogenase: a mechanism ensuring mineralocorticoid specificity.
In vitro studies with mineralocorticoid receptors (MR) have shown that they are non-specific and do not distinguish between glucocorticoids (cortisol in man, corticosterone in rodents) and aldosterone. These findings contrast with in vivo aldosterone selectivity. Our studies on the congenital deficiency of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD; which converts cortisol to cortisone or corticosterone to 11-dehydrocorticosterone) and acquired deficiency secondary to liquorice or carbenoxolone indicate that this enzyme plays a crucial role in protecting the MR from glucocorticoid exposure. The localisation of 11 beta-OHSD in both the proximal and distal nephron suggests that it has both an autocrine and a paracrine role. The presence of this protective mechanism in the toad bladder suggests that it is at least 300 million years old.
11-beta-Hydroxysteroid Dehydrogenases↗
11 beta-hydroxysteroid dehydrogenase bioactivity and messenger RNA expression in rat forebrain: localization in hypothalamus, hippocampus, and cortex.
In peripheral aldosterone target sites (e.g., kidney), 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes corticosterone to inactive 11-dehydrocorticosterone and thus protects mineralocorticoid receptors from exposure to corticosterone in vivo. We have investigated whether 11 beta-OHSD could account for the site-specific differences in corticosteroid receptor sensitivity to corticosterone in rat brain. Enzyme activity, estimated as the percentage conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in the presence of NADP+ (200 microM), was: hippocampus, 55.8 +/- 2.7%; cortex, 52 +/- 3.1%; pituitary; 40 +/- 2%, hypothalamus, 26.1 +/- 1.2%; brain stem, 21.4 +/- 1.7%; and spinal cord, 12.3 +/- 1.8%. Northern blots, using [32P]dCTP-labeled probes from an 11 beta-OHSD cDNA clone derived from rat liver, showed expression of a single mRNA species in all brain areas, of identical size to 11 beta-OHSD mRNA in liver and kidney. Highest expression was found in hippocampus and cortex. In situ hybridization, using [35S]UTP-labeled cRNA probes, localized high mRNA expression to cerebral cortex (particularly parietal cortex, layer IV), hippocampus (highest in CA3), hypothalamic medial preoptic area and arcuate nuclei and anterior pituitary. In conclusion, there is localized 11 beta-OHSD mRNA expression and enzyme bioactivity in rat brain. The distribution of 11 beta-OHSD corresponds to areas of reduced glucocorticoid or mineralocorticoid receptor affinity for corticosterone. Therefore, 11 beta-OHSD may regulate the access of corticosterone to cerebral mineralocorticoid and/or glucocorticoid receptors and thus modulate corticosteroid effects on brain function.
11-beta-Hydroxysteroid Dehydrogenases↗
Systemic capillary leak syndrome.
Systemic capillary leak syndrome is a rare condition characterized by unexplained episodic capillary hyperpermeability. A shift of fluid and protein from the intravascular to the interstitial space results in hypovolaemia. Attacks vary in frequency, severity and duration and can be fatal, although they often remit spontaneously. During acute episodes there is a pathognomonic elevated haematocrit and reduced serum albumin, frequently associated with a monoclonal gammopathy. Treatment has been largely empirical but there are anecdotal reports of beneficial therapy. We describe a further case which highlights the typical clinical presentation, course and investigate findings and review the other cases described.
Blood Volume↗
The specificity of the human mineralocorticoid receptor: clinical clues to a biological conundrum.
Data from in vitro studies show that the mineralocorticoid receptor has an equal affinity for cortisol and aldosterone. This contrasts with the well known selectivity of aldosterone for binding to tissues such as the kidney despite the much higher circulating levels of glucocorticoids. This paper puts forward the hypothesis that the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) is responsible for determining this selectivity. Congenital or acquired deficiency of this enzyme results in a failure of the normal protective mechanism by which cortisol is converted to cortisone or corticosterone to 11-dehydrocorticosterone. As a result the receptor is exposed to cortisol or corticosterone in high concentration which results in sodium retention and potassium loss. In contrast the hippocampal type 1 receptor is associated with much lower 11 beta-OHSD activity and is thus not aldosterone-selective.
11-beta-Hydroxysteroid Dehydrogenases↗
The adrenal gland and progesterone stimulates testicular steroidogenesis in the rat in vivo.
Administration of pharmacological doses of glucocorticoid to male rats in vivo suppresses adrenal steroidogenesis and inhibits testicular steroidogenesis by inhibiting the anterior pituitary secretion of LH. In contrast, administration of ACTH to these pharmacologically-suppressed rats stimulates the adrenal secretion of progesterone and testicular steroidogenesis. The mechanism by which ACTH increases testicular steroidogenesis is dependent on the presence of the adrenal gland and is reproduced by the administration of progesterone. The conclusion from these data is that the adrenal gland has an important role in generating external signals that modulate the hypothalamic-pituitary-gonadal axis in male rats. The adrenal secretion of glucocorticoid acts as a negative signal to testicular steroidogenesis whereas progesterone acts as a positive signal. The adrenal secretion of progesterone and its conversion to testosterone by steroidogenic enzymes in the cytoplasm of the Leydig cell may provide an alternative pathway for testosterone biosynthesis and may account for the increased plasma testosterone levels during the acute phase of stress and mating.
Adrenalectomy↗
Adrenalectomy does not influence basal secretion of testosterone in rat in vivo.
We have studied the effect of adrenalectomy on the testicular secretion of testosterone in the rat. In the acute period following adrenalectomy plasma testosterone levels were reduced but this was no different from those levels in appropriate sham-operated controls. This reduction in plasma testosterone levels is probably a result of direct effects of anaesthesia and surgical stress. Whilst studies on the late effect of adrenalectomy avoided this problem, plasma testosterone levels were normal in both adrenalectomised and sham-operated animals. Resetting of anterior pituitary-gonadal relationships may mask the absence of any contribution made by the adrenal gland to testicular steroidogenesis. In contrast to previous data we were unable to demonstrate that adrenalectomy influenced the secretion of testosterone in the male rat.
Adrenalectomy↗
The kidney is the major site of cortisone production in man.
The major site of cortisol metabolism in man has been thought to be the liver. Studies in patients with either congenital or acquired deficiency of 11 beta-hydroxysteroid dehydrogenase (an enzyme responsible for the interconversion of cortisol to cortisone) suggested that the kidney was an important site of cortisone production. In 88 patients with proven renal disease but normal liver function, arbitrarily divided into four groups on the basis of plasma creatinine, 0900 h plasma cortisone was significantly reduced in all groups when compared with 47 controls (e.g. 21 +/- 3 nmol/l (mean +/- SEM) in patients with plasma creatinine greater than 0.45 mmol/l vs 62 +/- 3 nmol/l in controls, P less than 0.001). 0900 h plasma cortisol was not significantly different. There was an inverse correlation between plasma creatinine and plasma cortisone (r = -0.55, p less than 0.01). Four anephric patients had a 0900 h plasma cortisone level of 6 +/- 1 nmol/l. We conclude that the kidney is a major site for the conversion of cortisol to cortisone and hence cortisone production in man. The relevance of this to the pathophysiology of salt and water metabolism in renal disease remains to be elucidated.
Adult↗
The effect of testosterone replacement on plasma lipids and apolipoproteins.
Ten men with Klinefelter's syndrome were studied to assess the effect of testosterone replacement on plasma lipids and apolipoproteins. Measurements taken before the insertion of a testosterone ester implant were compared with those obtained 1 week and 4 weeks later. Mean plasma testosterone, androstenedione, total cholesterol and calculated LDL-cholesterol increased significantly after 1 and 4 weeks. No significant changes were seen in total plasma concentrations of HDL-cholesterol, HDL-cholesterol subfractions 2 and 3 or in apoplipoproteins A-I, A-II or B. A significant correlation was seen between total cholesterol and plasma oestradiol concentrations (Rs = 0.61; P less than 0.001). A significant negative correlation was seen between the concentrations of total testosterone and total triglyceride (Rs = -0.56; P less than 0.005) but not with the other lipid parameters. Testosterone replacement is associated with slight but potentially adverse changes in plasma cholesterol levels.
Adult↗
Steroid metabolism determines mineralocorticoid specificity in the toad bladder.
Edwards et al. (C. R. W. Edwards, P. M. Stewart, D. Burt, L. Brett, M. A. McIntyre, W. S. Sutanto, E. R. de Kloet, and C. Monder, Lancet 2: 986-989, 1988) proposed that 11 beta-hydroxysteroid-dehydrogenase (11 beta-OHSD) plays a key role in the kidney by converting glucocorticoids (cortisol or corticosterone), which display a high affinity for type 1 mineralocorticoid receptors, into their inactive metabolites (cortisone or 11-dehydroxy-corticosterone), thus preventing their illicit occupation of the receptor in the target cell for aldosterone. We have tested this hypothesis in the urinary bladder of Bufo marinus by measuring the sodium transport responses to aldosterone and corticosterone. Aldosterone (10 nM) on the serosal side elicited a quarter of the maximal increase in sodium transport. At the same concentration, corticosterone (10 nM, serosal side) was ineffective. Adding corticosterone (10 nM) on the mucosal side elicited a response equivalent to that of aldosterone, suggesting that corticosterone was inactivated in the serosal or underlying tissue of the toad bladder. Carbenoxolone (10 microM, serosal side), a potent inhibitor of 11 beta-OHSD, did not modify the base-line sodium transport. However, in the presence of carbenoxolone (10 microM, serosal side, 2 h pretreatment) corticosterone (10 nM, serosal side) became as potent as aldosterone in eliciting the mineralocorticoid response. Our data are consistent with the idea that corticosterone is converted into an inactive metabolite in the mucosal and/or submucosal tissue of the toad bladder. These studies are consistent with our concept that 11 beta-OHSD is crucial in protecting the nonspecific mineralocorticoid receptor from glucocorticoid.
11-beta-Hydroxysteroid Dehydrogenases↗
Normal growth hormone response to the 75 g oral glucose tolerance test measured by immunoradiometric assay.
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Administration, Oral↗