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.
BACKGROUND
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].


METHODS
We performed an in vitro study in an academic research laboratory.


METHODS
Eleven patients with histologically proven PPNAD were included in the study.


METHODS
Cultured PPNAD cells were incubated with dexamethasone in the presence of various modulators of the cAMP/PKA pathway and the glucocorticoid receptor antagonist RU486.


METHODS
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.
Louiset
Estelle
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.
Stratakis
Constantine A
CA
Perraudin
Véronique
V
Griffin
Kurt J
KJ
Libé
Rossella
R
Cabrol
Sylvie
S
Fève
Bruno
B
Young
Jacques
J
Groussin
Lionel
L
Bertherat
Jérôme
J
Lefebvre
Hervé
H
D000293:Adolescent; D000303:Adrenal Cortex Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010859:Pigmentation Disorders / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D006854:Hydrocortisone