NDLI: The paradoxical increase in cortisol secretion induced by dexamethasone in primary pigmented nodular adrenocortical disease involves a glucocorticoid receptor-mediated effect of dexamethasone on protein kinase A catalytic subunits.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Libé, Rossella Cabrol, Sylvie Young, Jacques Groussin, Lionel Stratakis, Constantine A. Louiset, Estelle Perraudin, Véronique Bertherat, Jérôme Griffin, Kurt J. Lefebvre, Hervé Fève, Bruno
Description	Country affiliation: France Author Affiliation: Louiset E ( Institut National de la Santé et de la Recherche Médicale, Unité 413, EA4310, Laboratory of Differentiation and Neuronal and Neuroendocrine Communication, University of Rouen, Mont Saint Aignan, France.)
Abstract	CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) results in most cases from mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene. Patients with PPNAD exhibit a paradoxical increase in cortisol secretion in response to dexamethasone. OBJECTIVE: The aim was to investigate the mechanism of the action of dexamethasone on adrenocortical cells removed from patients with PPNAD and a transgenic model of PPNAD [Tg(tTA/X2AS) mice]. DESIGN AND SETTING: We performed an in vitro study in an academic research laboratory. PATIENTS: Eleven patients with histologically proven PPNAD were included in the study. INTERVENTION: Cultured PPNAD cells were incubated with dexamethasone in the presence of various modulators of the cAMP/PKA pathway and the glucocorticoid receptor antagonist RU486. MAIN OUTCOME MEASURE: Cortisol and corticosterone were measured by radioimmunological assays in cell culture supernatants. RESULTS: Dexamethasone stimulated in vitro cortisol secretion from PPNAD tissues in six patients. The stimulatory effect of dexamethasone on cortisol release was not reduced by the adenylyl cyclase inhibitor SQ22536 or potentiated by the phosphodiesterase inhibitor IMBX and the cAMP analog 8Br-cAMP. Conversely, the PKA inhibitor H89 and RU486 inhibited the cortisol response to dexamethasone. Dexamethasone had no effect on cortisol production from normal human adrenocortical cells but stimulated corticosteroidogenesis in the presence of RU486. Similarly, dexamethasone failed to influence corticosterone release by adrenocortical cells removed from Tg(tTA/X2AS) mice but stimulated corticosteroidogenesis in the presence of RU 486. CONCLUSIONS: These results indicate that, in human PPNAD tissues, dexamethasone paradoxically stimulates cortisol release through a glucocorticoid receptor-mediated effect on PKA catalytic subunits.
ISSN	0021972X
e-ISSN	19457197
DOI	10.1210/jc.2009-0031
Journal	The Journal of Clinical Endocrinology & Metabolism
Issue Number	7
Volume Number	94
Language	English
Publisher	Oxford University Press
Publisher Date	2009-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adrenal Cortex Diseases Metabolism Cyclic Amp-dependent Protein Kinase Catalytic Subunits Genetics Dexamethasone Pharmacology Hydrocortisone Secretion Pigmentation Disorders Receptors, Glucocorticoid Physiology Adolescent Complications Animals Cells, Cultured Child, Preschool Gene Expression Regulation, Enzymologic Drug Effects Mice Mice, Transgenic Up-regulation Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Endocrinology Discipline Metabolism
Content Type	Text
Resource Type	Article
Subject	Biochemistry (medical) Endocrinology, Diabetes and Metabolism Clinical Biochemistry Biochemistry Endocrinology

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