ECE2019 Poster Presentations Adrenal and Neuroendocrine Tumours 3 (70 abstracts)
Abnormal serotonin regulatory loop in adrenals of patients with Cushing’s syndrome and 21-hydroxylase deficiency
Julie Le Mestre 1 , Celine Duparc 1 , Yves Reznik 2 , Fideline Bonnet-Serrano 3, , Philippe Touraine 5 , Olivier Chabre 6 , Jacques Young 7 , Mathilde Sibony 3, , Françoise Gobet 8 , Gerald Raverot 9 , Jerome Bertherat 3, , Estelle Louiset 1 & Herve Lefebvre 1,
1University, UNIROUEN, DC2N, Inserm U1239, Rouen, France; 2Caen University Hospital, Department of Endocrinology-Diabetology, Caen, France; 3Assistance Publique des Hôpitaux de Paris, Cochin Hospital, Paris, France; 4Institut Cochin, INSERMU1016, CNRSUMR8104, Université Paris Descartes, Paris, France; 5Assistance Publique des Hôpitaux de Paris, Pitie-Salpetriere Hospital, Paris, France; 6Department of Endocrinology, Diabetes and Nutrition, INSERM, U1036, Grenoble-Alpes University Hospital, Grenoble, France; 7Department of Endocrinology and Reproductive Medicine, AP-HP, Bicetre Hospital, Le Kremlin Bicetre, France; 8Rouen University Hospital, Department of Pathology, Rouen, France; 9Department of Endocrinology, Hospices Civils de Lyon, Groupement Hospitalier Est, Lyon, France; 10Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen, France.
In the human adrenal gland, serotonin (5-HT), released by subcapsular mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R) positively coupled to cAMP/proteine kinase A (PKA) signaling pathway and calcium influx. The 5-HT4R is principally expressed in zona glomerulosa cells explaining why 5-HT strongly stimulates aldosterone production but only exerts a modest stimulatory action on cortisol. Interestingly, in primary pigmented nodular adrenocortical disease (PPNAD) cells, activation of the cAMP/PKA pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) together with the 5-HT4, 5-HT6 and 5-HT7 receptors. 5-HT strongly stimulated cortisol production and inhibition of TPH reduced corticosteroidogenesis in cultured PPNAD cells. ACTH stimulates cortisol secretion through binding to the melanocortin receptor type 2 (MC2R) and activation of PKA. We have thus investigated the 5-HT signaling pathway in adrenal tissues removed from patients suffering from diseases associated with chronically high plasma ACTH levels, such as Cushing’s disease (CD), ectopic secretion of ACTH, and 21-hydroxylase deficiency (21-OHD), in comparison with normal adrenals. Like in PPNAD tissues, TPH and 5-HT4/6/7 receptors were overexpressed in the different types of tissues studied. In one adrenal tissue removed from a patient with paraneoplastic Cushing’s syndrome, the cortisol response to 5-HT in vitro was exaggerated vs normal adrenals and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Finally, 5-HT was found to dose-dependently stimulate dehydroepiandrosterone secretion from cultured normal adrenocortical cells, suggesting that enhancement of the adrenal 5-HT tone in 21-OHD tissues may favor androgen hypersecretion together with ACTH. Collectively, our results indicate that activation of the cAMP/PKA pathway in adrenocortical cells resulting either from PRKAR1A mutations or activation of the MC2R by sustained increase in plasma ACTH levels induces an aberrant serotonergic stimulatory loop in zona fasciculata. Potentiation of the intraadrenal 5-HT signaling pathway may participate in the pathophysiology of hypercortisolism and could represent an adaptive mechanism to increase glucocorticoid synthesis in 21-hydroxylase deficiency.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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