Illicit Upregulation of the Serotonin Signaling Pathway in Adrenals of Patients with 21-Hydroxylase Deficiency or Cushing’s Disease

Presentation Number: MON 386
Date of Presentation: April 3rd, 2017

Julie Le Mestre1, Céline Duparc1, Yves Reznik2, Jerome Yves Bertherat3, Philippe Touraine4, Olivier Chabre5, Jacques Young6, Celso E. Gomez-Sanchez7, Herve Lefebvre*8 and Estelle Louiset1
1Normandie University, UNIROUEN, INSERM U982, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, ROUEN, France, 2Caen University Hospital, Caen, France, 3INSERM U 1016, Cochin Institute, Paris Descartes University, Paris, France, 4AP-HP, Hôpital Pitié-Salpêtrière, Paris, France, 5Grenoble University Hospital, Grenoble, France, 6AP-HP, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France, 7University of Mississippi Medical Center, Jackson, MS, 8Normandie University, UNIROUEN, INSERM U982, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, Rouen, France


In the human adrenal glands, serotonin (5-HT) is released by subcapsular mast cells and increases aldosterone secretion by the zona glomerulosa (ZG) cells. Those effects are mediated by the type 4 serotonin receptor (5-HT4R) which is positively coupled to cAMP/proteine kinase A (PKA) signaling pathway and calcium influx. Conversely, the 5-HT4R is weakly expressed in the zona fasciculata (ZF). Interestingly, illicit synthesis of 5-HT in adrenocortical cells as well as overexpression of the 5-HT4R and ectopic expression of the types 6 and 7 serotonin receptors (5-HT6R, 5-HT7R) have been observed in primary adrenal diseases responsible for hypercortisolism such as primary pigmented nodular adrenocortical disease (PPNAD; Bram et al., 2016). In PPNAD cells, upregulation of the 5-HT signaling pathway appears to be the consequence of the activation of PKA by PRKAR1Agene mutations which cause the disease (ref. 1).

The study aimed at investigating the expression of the key enzyme of 5-HT synthesis tryptophan hydroxylase 1 (Tph1) and the 5-HT4R, 5-HT6R, 5-HT7R in the ZF in 18 patients suffering from adrenal diseases associated with high ACTH blood levels, namely Cushing’s disease (CD), ectopic secretion of ACTH, and 21-hydroxylase deficiency, in comparison with normal adrenals. We also verified whether 5-HT was able to induce an increase in cortisol secretion by cultured adrenocortical cells derived from adrenal hyperplasia due to ectopic secretion of ACTH.

Quantitative PCR analyses showed an increase in Tph1 mRNA levels in CD, suggesting local production of 5-HT. 5-HT4R mRNA expression rate was elevated in 21-hydroxylase deficiency but not in CD. 5-HT6R and 5-HT7R mRNA expression levels were significantly increased in CD. Immunochemistry studies revealed high expression of 5-HT4R, 5-HT6R and 5-HT7R mRNA in clusters of ZF cells. Moreover, 5-HT induced a strong increase in cortisol secretion from cultured adrenocortical cells.

Our results indicate that a sustained increase in plasma ACTH levels induces an aberrant serotonergic stimulatory loop in zona fasciculata. Because the ACTH receptor is positively coupled to adenylyl cyclase, this process likely results from activation of the cAMP/PKA pathway, as formerly shown in PPNAD. Our data also suggest that the intraadrenal 5-HT signaling pathway may participate in the pathophysiology of ACTH-dependent hypercortisolism and could represent an adaptive mechanism to increase glucocorticoid synthesis in 21-hydroxylase deficiency.

1. Bram Z. et al., PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. J Clin Invest Insight, 1(15):e87958, 2016.


Nothing to Disclose: JL, CD, YR, JYB, PT, OC, JY, CEG, HL, EL