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Abnormal Sensitivity of Cortisol-Producing Adrenocortical Adenomas to Serotonin: In Vivo and in Vitro Studies

Institut National de la Santé et de la Recherche Médicale (INSERM) U413 (V.C., E.L., C.D., D.C., F.S., J.-M.K., H.V., H.L.), Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), University of Rouen, 76821 Mont-Saint-Aignan, France; Department of Endocrinology (Y.R.), Centre Hospitalier Universitaire of Caen, 14033 Caen, France; Center for Clinical Investigation (C.D., J.-M.K., H.L.), INSERM Centre d’Investigation Clinique 204 and Department of Pathology (A.L.), University Hospital of Rouen, 76031 Rouen, France; and Laboratory of Oncologic Genetics (F.P.), Centre Henri Becquerel, 76038 Rouen, France

Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, Institut National de la Santé et de la Recherche Médicale Unité 413, Institut Fédératif de Recherche 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.

Two patients with incidentally discovered adrenocortical adenomas underwent a series of pharmacological and physiological tests after pretreatment with dexamethasone. Illicit plasma cortisol responses to the serotonin (5-HT)₄ receptor agonist cisapride were observed in the two patients. Significant increases in plasma cortisol levels were also noticed after glucagon and combined TRH/GnRH/GHRH stimulation tests in patient 1 and after administration of the lysine vasopressin precursor terlipressin in patient 2. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured tumor cells to serotonergic ligands and peptide hormones. In the two cases, 5-HT stimulated cortisol secretion from tumor cells with increased efficacy and/or potency to activate steroidogenesis by comparison with normal adrenocortical cells. The corticotropic effect of 5-HT was inhibited by the specific 5-HT₄ receptor antagonist GR 113808 and more potently by methiothepin, a nonspecific serotonergic antagonist having no affinity for the 5-HT₄ receptor. These results show that the hypersensitivity of the tumors to 5-HT was related to tissue expression of an ectopic serotonergic receptor in addition to the eutopic 5-HT₄ receptor. In the two adenoma tissues, immunohistochemical studies revealed the presence of 5-HT-like immunoreactivity within clusters of steroidogenic cells, suggesting that 5-HT acted through an autocrine/paracrine mechanism to stimulate steroidogenesis. Glucagon and GnRH but not TRH, GHRH, and human chorionic gonadotropin stimulated cortisol secretion from tumor 1 cells. In conclusion, this study provides the first observation of adrenocortical cortisol-producing adenomas hypersensitive in vivo and in vitro to serotonergic agonists. Our results also show that cortisol-producing adenomas can express simultaneously several illegitimate receptors.

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