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      Increased Response of Plasma Allopregnanolone to Corticotropin-Releasing Hormone in Obese Patients

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          Abstract

          Allopregnanolone is a neuroactive steroid present in the brain, but also measurable in systemic circulation. It exhibits anxiolytic and anticonvulsant effects and is able to produce hyperphagia. Since eating behavior disturbances and increased peripheral basal sympathetic activity have been reported in obese subjects, the present study investigated allopregnanolone and catecholamine (epinephrine and norepinephrine) responses to corticotropin-releasing hormone (CRH) in obese subjects. Blood was sampled from 39 obese (14 men and 25 women) and 57 normal-weight subjects (20 men and 37 women) and assayed for cortisol, allopregnanolone and catecholamines concentrations. In addition, 13 obese patients (5 men and 8 women) and 18 control subjects (9 men and 9 women) were submitted to a CRH test. Plasma allopregnanolone and norepinephrine levels were significantly higher in obese than in control subjects (p < 0.01), but plasma cortisol and epinephrine concentrations were comparable in both groups. No correlation was found in any group between plasma allopregnanolone and norepinephrine or epinephrine levels. Acute CRH administration significantly stimulated allopregnanolone secretion, with peak levels at 15 min in obese subjects, whereas maximal concentrations were reached after 60 min only in controls. In obese patients the allopregnanolone secretory incremental area was significantly higher than in controls (p < 0.02). CRH injection increased cortisol levels to a comparable extent in both groups. Plasma norepinephrine or epinephrine levels did were not significantly affected by CRH test in either group. In conclusion, obese subjects present higher allopregnanolone levels and a greater response to CRH than normal subjects. Since allopregnanolone has hyperphagic effects in rats, hypersecretion of the hormone in obese patients may represent one of the mechanisms underlying obesity.

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          Most cited references 9

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          The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus.

          The ring-A-reduced progesterone derivative 5 alpha-pregnan-3 alpha-ol-20-one (tetrahydroprogesterone) is synthesized under normal physiological conditions in the brain and is a potent modulator of the GABA receptor. This neurosteroid has significant sedative and anxiolytic properties. Corticotropin-releasing hormone plays a major role in stress-induced activation of the hypothalamo-pituitary-adrenal axis, and sustained hyperactivity of hypothalamic corticotropin-releasing hormone-producing neurons may be causally related to both, increased pituitary-adrenal secretion and behavioural symptoms observed in anxiety and affective disorders. We investigated the effect of tetrahydroprogesterone on corticotropin-releasing hormone-induced anxiety, the basal and methoxamine-stimulated release of corticotropin-releasing hormone from hypothalamic organ explants in vitro, and adrenalectomy-induced up-regulation of the gene expression of corticotropin-releasing hormone in the hypothalamic paraventricular nucleus in rats. At doses of 5 and 10 micrograms i.c.v., tetrahydroprogesterone counteracted the anxiogenic action of 0.5 microgram of corticotropin-releasing hormone. Tetrahydroprogesterone did not alter the basal release of corticotropin-releasing hormone in vitro, but suppressed the stimulatory effect of the alpha 1-adrenergic agonist methoxamine on this parameter. Measurements of the steady-state levels of mRNA coding for corticotropin-releasing hormone by quantitative in situ-hybridization histochemistry revealed that tetrahydroprogesterone was equipotent with corticosterone in preventing adrenalectomy-induced up-regulation of peptide gene expression. Systemic administration of tetrahydroprogesterone also restrained adrenalectomy-induced thymus enlargement. These results demonstrate that tetrahydroprogesterone has anxiolytic effects that are mediated through interactions with hypothalamic corticotropin-releasing hormone in both, genomic and non-genomic fashions.
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            Stress-induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary-adrenocortical and sympathoadrenal activity: in vivo microdialysis studies.

            The hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system are major effector systems that serve to maintain homeostasis during exposure to stressors. In the past decade, interest in neurochemical regulation and in pathways controlling activation of the HPA axis has focused on catecholamines, which are present in high concentrations in specific brain areas--especially in the hypothalamus. The work described in this review has concentrated on the application of in vivo microdialysis in rat brain regions such as the paraventricular nucleus (PVN) of the hypothalamus, the central nucleus of the amygdala (ACE), the bed nucleus of the stria terminalis (BNST), and the posterolateral hypothalamus in order to examine aspects of catecholaminergic function and relationships between altered catecholaminergic function and the HPA axis and sympathoadrenal system activation in stress. Exposure of animals to immobilization (IMMO) markedly and rapidly increases rates of synthesis, release, and metabolism of norepinephrine (NE) in all the brain areas mentioned above and supports previous suggestions that in the PVN NE stimulates release of corticotropin-releasing hormone (CRH). The role of NE in the ACE and the BNST and most other areas possessing noradrenergic innervation remains unclear. Studies involving lower brainstem hemisections show that noradrenergic terminals in the PVN are derived mainly from medullary catecholaminergic groups rather than from the locus ceruleus, which is the main source of NE in the brain. Moreover, the medullary catecholaminergic groups contribute substantially to IMMO-induced noradrenergic activation in the PVN. Data obtained from adrenalectomized rats, with or without glucocorticoid replacement, and from hypercortisolemic rats suggest that glucocorticoids feedback to inhibit CRH release in the PVN, via attenuation of noradrenergic activation. Results from rats exposed to different stressors have indicated substantial differences among stressors in eliciting PVN noradrenergic responses as well as of responses of the HPA, sympathoneural, and adrenomedullary systems. Finally, involvement of other areas that participate in the regulation of the HPA axis such as the ACE, the BNST, and the hippocampus and the importance of stress-induced changes in expression of immediate early genes such as c-fos are discussed.
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              Anxiolytic activity of an endogenous adrenal steroid.

              The A-ring reduced metabolite of deoxycorticosterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) was recently shown to act at the gamma-aminobutyric acid receptor-chloride ion channel complex in rat brain. The behavioral profile of THDOC was investigated using two animal models of anxiety, the two-chambered mouse exploration test and the lick suppression conflict test. THDOC showed anxiolytic activity in both animal models, with an anxiolytic dose range, 5-15 mg/kg i.p., separable from the sedative dose range, above 20-30 mg/kg i.p.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2002
                February 2002
                22 February 2002
                : 75
                : 2
                : 124-129
                Affiliations
                aCentro di Nutrizione Clinica e Malattie del Metabolismo, Department of Internal Medicine, University of Modena; bChair of Obstetrics and Gynecology, University of Siena, and cDepartment of Reproductive Medicine and Child Development, Section of Obstetrics and Gynecology, University of Pisa, Italy
                Article
                48228 Neuroendocrinology 2002;75:124–129
                10.1159/000048228
                11867940
                © 2002 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: 2, Tables: 1, References: 41, Pages: 6
                Categories
                Clinical Neuroendocrinology

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