Subject(s)
Adrenal Gland Neoplasms/diagnostic imaging , Lymphoma, B-Cell, Marginal Zone/diagnostic imaging , Myelolipoma/diagnostic imaging , Tomography, X-Ray Computed , Adrenal Gland Neoplasms/pathology , Aged , Diagnosis, Differential , Female , Humans , Lymphoma, B-Cell, Marginal Zone/pathology , Myelolipoma/pathologyABSTRACT
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.
Subject(s)
Adrenal Cortex Diseases/metabolism , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics , Dexamethasone/pharmacology , Hydrocortisone/metabolism , Pigmentation Disorders/metabolism , Receptors, Glucocorticoid/physiology , Adolescent , Adrenal Cortex Diseases/complications , Adrenal Cortex Diseases/genetics , Adult , Animals , Cells, Cultured , Child , Child, Preschool , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism , Female , Gene Expression Regulation, Enzymologic/drug effects , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Pigmentation Disorders/complications , Pigmentation Disorders/genetics , Receptors, Glucocorticoid/metabolism , Up-Regulation/drug effects , Young AdultABSTRACT
CONTEXT: Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor. OBJECTIVE: The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism. DESIGN: The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion. SETTING: The study was conducted at a university hospital and research laboratory. PATIENTS: The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism. MAIN OUTCOME MEASURES: Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured. INTERVENTION: SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout. RESULTS: We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH. CONCLUSIONS: The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.