title: Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome.
abstract: Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a beta-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.
authors.affiliation: Unité INSERM 878, Institut de Recherches en Technologies et Sciences pour le Vivant, CEA-Grenoble, France. tmazzuco@uel.br
authors.forename: Tânia L
authors.initials: TL
authors.lastname: Mazzuco
authors.forename: Michaël
authors.initials: M
authors.lastname: Thomas
authors.forename: Monique
authors.initials: M
authors.lastname: Martinie
authors.forename: Nadia
authors.initials: N
authors.lastname: Cherradi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Olivier
authors.initials: O
authors.lastname: Chabre
mesh_terms: D000302:Adrenal Cortex / Q000473:pathology*; D000307:Adrenal Gland Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis; D003480:Cushing Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006965:Hyperplasia / Q000150:complications / Q000473:pathology; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000319:Adrenergic beta-Antagonists; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone