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Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

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Abstract

Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [3H2]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism.

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Acknowledgments

Material for the rat TSH RIA was provided by the National Hormone and Pituitary Program.

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Ethical standards

All procedures were approved by the NIH Committee for the use and welfare of laboratory animals, conformed to the International Ethical Standards (86/609-EEC) for the care and use of laboratory animals and conformed to the guidelines in the UFAW Handbook on the Care and Management of Laboratory Animals (published by the Universities Federation for Animal Welfare).

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  1. Department of Anatomy, School of Medicine, University of Athens, 75 Mikras Asias Str., Goudi, 11572, Athens, Greece

    Elena Nikolopoulou, Dimitrios Mytilinaios, Theodore Troupis & Elizabeth O. Johnson

  2. Section of Endocrinology, Andrology and Internal Medicine, Department of Medical and Pediatric Sciences, University of Catania, Catania, Italy

    Aldo E. Calogero

  3. Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA

    Themis C. Kamilaris

  4. 1st Department of Pediatrics, School of Medicine, University of Athens, Athens, Greece

    George P. Chrousos

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  1. Elena Nikolopoulou
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Nikolopoulou, E., Mytilinaios, D., Calogero, A.E. et al. Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism. Endocrine 49, 828–841 (2015). https://doi.org/10.1007/s12020-015-0528-7

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