In vitro effect of serotonin (5-HT) on cortisol secretion in primary pigmented nodular adrenal disease
Estelle Louiset1, Céline Duparc1, Véronique Perraudin1, Sylvie Renouf1, Rossella Libé2, Constantine A Stratakis3, Jérôme Bertherat2 & Hervé Lefebvre1,4
Illegitimate membrane receptors are known to play a role in cortisol secretion in adrenal adenomas and ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushings syndrome. Conversely, illegitimate receptors have never been described in primary pigmented nodular adrenal disease (PPNAD). In the normal adrenal gland, serotonin (5-HT) has been shown to stimulate cortisol secretion through activation of 5-HT receptor type 4 (5-HT4) whereas, in some AIMAH tissues, the corticotropic effect of 5-HT is mediated by ectopic 5-HT7 receptors. The aim of the present study was to evaluate in vitro the effect of 5-HT on cortisol release by cultured adrenocortical cells removed from four patients with PPNAD. Graded concentrations of 5-HT induced a doseresponse increase in cortisol production. The potency and efficacy of 5-HT to stimulate cortisol were higher in PPNAD than in normal adrenocortical cells. Conversely, the 5-HT4 receptor agonists cisapride and metoclopramide did not influence corticosteroidogenesis. The action of 5-HT on PPNAD cells was also investigated in the presence of the specific 5-HT4 receptor antagonist GR113808 and the specific 5-HT7 receptor antagonist SB269970. GR113808 (10−7 M) significantly inhibited the stimulatory effect of 5-HT on cortisol by both reducing the potency and efficacy of the indolamine. Similarly, the cortisol response to 5-HT was inhibited by SB269970 (10−7 M). These data indicate that, in PPNAD cells, the stimulatory action of 5-HT on cortisol release is mediated, at least partly, by an ectopic 5-HT7 receptor. In addition, they suggest that 5-HT-induced cortisol production also involves an isoform of the 5-HT4 receptor with an atypical pharmacological profile. The present study constitutes therefore the first demonstration of the occurrence of functional ectopic receptors in PPNAD cells. Finally, as 5-HT has been shown to be produced in the adrenal gland by perivascular mast cells, our results show that, in PPNAD tissues, 5-HT may modulate cortisol secretion through a paracrine mechanism. This work was supported by INSERM U982, the Carney Complex and COMETE (PHRC AOM06179) networks and ANR Genopat 2008.