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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

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 413, EA4310, L’Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, Laboratory of Differentiation and Neuronal and Neuroendocrine Communication (E.L., V.P., H.L.), University of Rouen, Mont Saint Aignan, 76821, France; Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics (C.A.S., K.J.G.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892; Department of Endocrinology (R.L., L.G., J.B.), Centre Hospitalier Universitaire Cochin and Institut Cochin, INSERM U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Fédératif de Recherche 116, Université Paris V-René Descartes, 75014 Paris, France; Department of Pediatric Endocrinology (S.C.), University Paris VI-Pierre-et-Marie-Curie, Hospital Trousseau, 75571 Paris, France; Department of Endocrinology (B.F., J.Y.), University Paris-Sud 11, Hospital Bicêtre, 94275 Le Kremlin Bicêtre, France; and Department of Endocrinology (H.L.), University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, 76031Rouen, France

Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, Institut National de la Santé et de la Recherche Médicale Unité 413, EA4310, L’Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, Department of Endocrinology, Hospital of Boisguillaume, Centre Hospitalier Universitaire of Rouen, 76031 Rouen Cedex, France. E-mail: herve.lefebvre{at}chu-rouen.fr.

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.