Adrenomedullin: new inhibitory regulator for cortisol synthesis and secretion

in Journal of Endocrinology
Authors:
Simon Travers Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France

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https://orcid.org/0000-0003-0104-8260
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Laetitia Martinerie Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Service d’Endocrinologie Pédiatrique, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France
Université de Paris, Faculté de Santé, UFR de Médecine, Paris, France
PremUp Fondation, Paris, France

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Qiong-Yao Xue Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France

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Julie Perrot Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France

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Say Viengchareun Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France

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Kathleen M Caron Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

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Elizabeth S Blakeney Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

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Pascal Boileau Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Department of Neonatal Pediatrics, Centre Hospitalier Intercommunal de Poissy-Saint-Germain, Poissy, France
UFR des Sciences de la Santé, Simone Veil. Université Versailles St-Quentin en Yvelines, Montigny le Bretonneux, France

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Marc Lombès Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
PremUp Fondation, Paris, France

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Eric Pussard Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France

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Correspondence should be addressed to S Travers: simon.travers@aphp.fr
DOI:
https://doi.org/10.1530/JOE-20-0564
Volume/Issue:
Volume 251: Issue 1
Article Type:
Research Article
Page Range:
97–109
Online Publication Date:
08 Sep 2021
Copyright:
© Society for Endocrinology 2021
Restricted access
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Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age (P = 0.0004), cortisol production (P < 0.0001), and 11β-hydroxylase activity index (P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11β-hydroxylase activity index (P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2021
Page(s):
13
Article Type:
Research Article
Received Date:
26 Jul 2021
Accepted Date:
09 Aug 2021
Print Publication Date:
01 Oct 2021
Online Publication Date:
08 Sep 2021
Keywords:
adrenomedullin; adrenal; cortisol; hCYP11B1; prematurity

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