20-Dihydroisomers of Cortisol and Cortisone in Human Urine: Excretion Rates under Different Physiological Conditions

Eisenschmid, B.; Heilmann, P.; Oelkers, W.; Rejaibi, R.; Schöneshöfer, M.

doi:10.1515/cclm.1987.25.6.345

Cited by 17 publications

(18 citation statements)

References 19 publications

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“…This may be compatible with the fact that peripheral conversion of cortisol to cortisone in the kidney is inhibited by ACTH and that the marked increase of cortisol/ cortisone ratio is observed in urine and plasma during ACTH infusion but not after hydrocortisone infusion in humans. 18,19 Diederich et al 20 reported that 11␤-HSD activity in human kidney slices was not influenced by incubation with increasing doses of physiological ACTH (1-39) for 1 hour. Because ACTH-R is not expressed in the kidney 1 and because the authors examined a fast effect of ACTH on renal 11␤-HSD activity, their study may not be contradictory to our results.…”

Section: Discussionmentioning

confidence: 99%

Functional Adrenocorticotropic Hormone Receptor in Cultured Human Vascular Endothelial Cells

et al. 2000

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Abstract-Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11␤-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11␤-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11␤-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension. A drenocorticotropic hormone (ACTH) is the main hormone that regulates glucocorticoid synthesis and secretion in mammals by binding to specific receptors on the adrenal cortex. The ACTH receptor (ACTH-R) gene has been cloned, and the predicted amino acid sequence has demonstrated that this receptor is one of the smallest of the 7 transmembrane domain receptors identified to date. 1 This receptor is expressed in the adrenal cortex but has been recently identified in extra-adrenal tissues such as human skin 2 and mouse adipose tissue. 3 Previous studies showed that the administration of ACTH (1-24) caused an increase in blood pressure in normotensive and hypertensive subjects, whereas no change was observed in patients with adrenal insufficiency, 4 and the effect of ACTH (1-24) was mimicked by cortisol. 5 Thus, the rise in pressure has been believed to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. 6 It has been shown that the direct effect of cortisol on vascular tone plays a significant role in the rise in pressure, because the steroid may raise pressure in the absence of any classic glucocorticoid effects (increases in plasma volume or urinary sodium retention). 7 Cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones, including ␣-adrenergic agonists and angiotensin II. 8,9 In addition to the hormonal effect, ACTH has been suggested to have direct effects on vascular tone. In hypovolemic and hemorrhagic shock in humans, acute intravenous administration of ACTH (1-24) promptly restores blood pressure without any effect on heart rate. 10 However, little is known concerning the existence of ACTH-R in the vasculature.11␤-Hydroxyster...

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Section: Discussionmentioning

confidence: 99%

Functional Adrenocorticotropic Hormone Receptor in Cultured Human Vascular Endothelial Cells

et al. 2000

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“…The increased cortisol/cortisone ratio during ACTH infusion (14,15) suggests that this mechanism also operates in the mineralocorticoid manifestation of EAS. Based on a study of the urinary steroid metabolite profiles of two patients with EAS, Ulick et al (16) assumed saturation of 11/3-HSD by very high circulating cortisol concen¬ trations as a cause of the high urinary cortisol/cortisone ratio in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…We cannot exclude a long-term direct effect of ACTH on renal 11/3-HSD. The in vivo studies mentioned in the introduction (14,15) show a very fast effect of ACTH infusion on the cortisol/cortisone ratio; at least this fast effect does not seem to be mediated by direct inhibition of renal 11/3-HSD. Apart from our results, other facts speak against a direct effect of ACTH on renal 11/3-HSD: the recently cloned ACTH receptor is not expressed in the kidney (30) and ACTH treatment has no measurable effect on in vitro 11/3-HSD activity in adrenalectomized rats (31).…”

Section: Discussionmentioning

confidence: 99%

“…In EAS with higher ACTH levels than in pituitary Cushing's syndrome, the ratio of cortisol to cortisone in plasma (14) and urine (16) is increased, suggesting inhibition of renal 11/3-HSD by ACTH or by ACTH-dependent steroids. Walker et al (14) and Eisenschmid et al (15) observed a marked increase of the cortisol/cortisone ratio in urine or plasma during ACTH infusion, but not following hydrocortisone infusion in man. This led to the conclusion that ACTH directly or indirectly inhibits renal 11/3-HSD (14), while Ulick et al (16) favor saturation of the enzyme by cortisol excess per se as the cause of a high cortisol/ cortisone ratio in high ACTH states.…”

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confidence: 96%

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Human kidney 11β-hydroxysteroid dehydrogenase: regulation by adrenocorticotropin?

Diederich

Quinkler

Miller

et al. 1996

European Journal of Endocrinology

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In ectopic adrenocorticotropin (ACTH) syndrome (EAS) with higher ACTH levels than in pituitary Cushing's syndrome and during ACTH infusion, the ratio of cortisol to cortisone in plasma and urine is increased, suggesting inhibition of renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) by ACTH or by ACTH-dependent steroids. Measuring the conversion of cortisol to cortisone by human kidney slices under different conditions, we tested the possibility of 11 beta-HSD regulation by ACTH and corticosteroids. Slices prepared from unaffected parts of kidneys removed because of renal cell carcinoma were incubated with unlabeled or labeled cortisol, and cortisol and cortisone were quantitated after HPLC separation by UV or radioactive detection. The 11 beta HSD activity was not influenced by incubation with increasing concentrations (10(-12)-10(-9) mol/l) of ACTH (1-24 or 1-39) for 1 h. Among 12 ACTH-dependent steroids tested (10(-9)-10(-6) mol/l), only corticosterone (IC50 = 2 x 10(-7) mol/l), 18-OH-corticosterone and 11 beta-OH-androstenedione showed a significant dose-dependent inhibition of 11 beta-HSD activity. The percentage conversion rate of cortisol to cortisone was concentration dependent over the whole range of cortisol concentrations tested (10(-8) - 10(-5) mol/l. A direct inhibitory effect of ACTH on 11 beta-HSD is, therefore, unlikely. The only steroids inhibiting the conversion of cortisol to cortisone are natural substrates for 11 beta-HSD. Kinetic studies show a saturation of the enzyme at high cortisol concentrations. Thus, the reduced percentage renal cortisol inactivation in EAS seems to be due mainly to overload of the enzyme with endogenous substrates (cortisol, corticosterone and others) rather than to direct inhibition of 11 beta-HSD by ACTH or ACTH-dependent steroids, not being substrates of 11 beta-HSD.

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“…Recently, we and others have suggested that the increased ratio of cortisol to cortisone in plasma and urine during adrenocorticotrophin (ACTH) infusion in man (Eisenschmid et al 1987, Walker et al 1992 is not caused by a direct inhibitory effect of ACTH (Diederich et al 1996), but is due to an overload of 11 -HSD-2 substrates such as cortisol and corticosterone with subsequent 11 -HSD-2 inhibition (Ulick et al 1992).…”

Section: Introductionmentioning

confidence: 99%

Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig

Quinkler

Troeger²,

Eigendorff³

et al. 2003

Journal of Endocrinology

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The 11 -hydroxysteroid dehydrogenases (11 -HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11 -HSD type 1 (11 -HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11 -HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11 -HSDs in guinea pig liver and kidney.Tissue slices of untreated guinea pigs were incubated with 3 H-labelled cortisol or cortisone and ACTH 1-24 (10 10 and 10 9 mol/l). The 11 -HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH 1-24 .In addition, guinea pigs were treated with ACTH 1-24 or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with 3 H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11 -HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5 THF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment.The enhanced reductase activity of the hepatic and renal 11 -HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.

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20-Dihydroisomers of Cortisol and Cortisone in Human Urine: Excretion Rates under Different Physiological Conditions

Cited by 17 publications

References 19 publications

Functional Adrenocorticotropic Hormone Receptor in Cultured Human Vascular Endothelial Cells

Functional Adrenocorticotropic Hormone Receptor in Cultured Human Vascular Endothelial Cells

Human kidney 11β-hydroxysteroid dehydrogenase: regulation by adrenocorticotropin?

Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig

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