Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin:: In vivo and in vitro studies

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-HT(4) receptor antagonist GR 113808 and more potently by methiothepin, a nonspecific serotonergic antagonist having no affinity for the 5-HT(4) 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-HT(4) 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.