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      Adrenocorticotropin Inhibition by Restoration of Normal Evening Cortisol Levels: A Measure of Putative Hippocampus-Mediated Glucocorticoid Feedback in Humans

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          Abstract

          Hippocampus-mediated glucocorticoid negative feedback is thought to be relevant to the pathophysiology of neuropsychiatric disorders, but no reliable method of measuring it in humans has been developed. Converging lines of evidence indicate that basal hypothalamic-pituitary-adrenal axis activity during the unstressed circadian trough is primarily regulated by this feedback process. To assess whether negative feedback can be demonstrated under these circumstances, we studied normal controls (n = 5) who were pretreated with metyrapone to lower their basal evening cortisol levels. On two separate occasions, in double-blind randomized order, subjects received an infusion of cortisol or of saline. Restoration of normal evening plasma cortisol by the cortisol infusion produced a drop in plasma adrenocorticotropin (ACTH) apparent in the last sample obtained at +200 min (p < 0.05). The ACTH response in schizophrenic patients (n = 4), whose mental illness may arise from hippocampal dysfunction, was relatively blunted compared to that seen in normals (p < 0.02). 11-Desoxycortisol levels paralleled the ACTH responses across conditions and subject groups. These preliminary data suggest that hippocampus-mediated glucocorticoid feedback can be measured in normal subjects and may provide an index of hippocampal dysfunction in neuropsychiatric patients.

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          Mineralocorticoid Receptor also Modulates Basal Activity of Hypothalamus-Pituitary-Adrenocortical System in Humans

          Hippocampal mineralocorticoid (MRs) and glucocorticoid receptors (GRs) have been demonstrated to regulate the activity of the hypothalamus-pituitary-adrenocortical (HPA) system. To elucidate the role of the hippocampal MR in the circadian activity of the human HPA system, we studied diurnal secretory profiles of corticotropin (ACTH) and cortisol in 10 healthy male humans before and after an 8-day treatment with the MR antagonist spironolactone. 24-hour blood sampling at 30-min intervals was performed for estimation of cortisol (q30) and ACTH (q120). Saliva cortisol was measured for estimation of unbound cortisol. At the end of the 24-hour sampling period a corticotropin-releasing hormone (CRH) challenge was performed. High plasma concentrations of the active metabolite canrenone were achieved (begin of sampling: 2,653 ± 693 nmol/l; end of sampling: 747 ± 177 nmol/l). There was a significant increase in the diurnal minima (37.1 ± 13.3 vs. 23.7 ± 8.9 nmol/l, p < 0.02) and mean cortisol (193.5 ± 25.8 vs. 173.0 ± 23.0 nmol/l, p < 0.03) plasma concentrations. However, the diurnal peak concentrations and pulsatile secretory features were unchanged after spironolactone treatment. For saliva cortisol, the only significant treatment difference was a decrease in the diurnal amplitude of cortisol relative to the diurnal mean concentration (2.56 ± 0.47 vs. 3.11 ± 0.87, p < 0.03). After spironolactone treatment there was a decrease in diurnal mean ACTH concentrations (46.2 ± 14.4 vs. 41.8 ± 10.3 pmol/l). There was no difference in the ACTH and cortisol response after infusion of CRH before and after spironolactone treatment. CBG plasma concentrations were significantly increased (22.4 ± 2.3 vs. 19.2 ± 2.7 mg/l, p < 0.01) after spironolactone treatment, which possibly contributed to the observed increase in plasma cortisol. In summary, as predicted from animal studies we found significant effects of MR antagonization to be restricted to time windows of low HPA system activity. These findings are similar to the effects of aging upon the HPA system. However, the effect of spironolactone treatment was small, suggesting that the HPA system activity in humans is modulated but not regulated by the hippocampal MR.
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            The R&D Portfolio: A Concept for Allocating Science and Technology Funds

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              The effects of treated and untreated nicotine withdrawal on smokers with schizophrenia

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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2000
                June 2000
                23 June 2000
                : 71
                : 6
                : 396-401
                Affiliations
                Psychiatric Institute, University of Illinois in Affiliation with University of Chicago, Department of Psychiatry, University of Chicago Pritzker School of Medicine, Chicago, Ill., USA
                Article
                54560 Neuroendocrinology 2000;71:396–401
                10.1159/000054560
                10878501
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 35, Pages: 6
                Categories
                Stress, Corticotropin and Central Effects ofAdrenal Steroids

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