Paradoxical Inhibitory Effect of Serotonin on Cortisol Production from Adrenocortical Lesions Causing Cushing's Syndrome

Abstract

In the human adrenal gland, serotonin (5‐HT) stimulates cortisol production through a paracrine mechanism involving 5‐HT4 receptors positively‐coupled to adenylyl cyclase. A hyperresponsiveness of adrenocortical tissue to 5‐HT has also been described in several cases of ACTH‐independent bilateral macronodular adrenal hyperplasias (AIMAHs) and adenomas causing Cushing's syndrome. In the present study, we report two cases of cortisol‐producing adrenocortical lesions, i.e. one AIMAH (case 1) and one adenoma (case 2), whose secretory activity was inhibited in vitro by 5‐HT. The potencies (pIC50) and efficacies (Emax) of 5‐HT to inhibit cortisol secretion were 8.2 ± 0.4 and − 64.1% ± 7.5% in case 1, and 9.2 ± 0.5 and − 32.3% ± 3.8% in case 2. The specific 5‐HT4 antagonist GR 113808 failed to influence the 5‐HT‐induced decrease in cortisol production by the two tissues, indicating that the paradoxical inhibitory effect of 5‐HT could not be accounted for by activation of eutopic 5‐HT4 receptors. These results suggest that the tissues expressed aberrant 5‐HT receptors. In conclusion, the present study provides the first evidence for an inhibitory effect of 5‐HT on cortisol secretion in adrenocortical lesions causing Cushing's syndrome. Our data also suggest that expression of illegitimate membrane receptors by cortisol‐producing adrenal hyperplasias and/or adenomas may convert a paracrine stimulatory factor into an inhibitory signal.