Effect of retinoic acid on human adrenal corticosteroid synthesis.

Abstract

AIMS:

Retinoic acid has recently yielded promising results in the treatment of Cushing's disease, i.e., excess cortisol secretion due to a pituitary corticotropin (ACTH)-secreting adenoma. In addition to its effect on the tumoral corticotrope cell, clinical results suggest an additional adrenal site of action. Aim of this study was to evaluate whether retinoic acid modulates cortisol synthesis and secretion by human adrenals in vitro.

MAIN METHODS:

Primary cultures from 10 human adrenals specimens were incubated with 10nM, 100nM and 1μM retinoic acid with and without 10nM ACTH for 24h. Cortisol levels were measured by radioimmunoassay and CYP11A1, STAR and MC2R gene expression analyzed by real-time PCR.

KEY FINDINGS:

Retinoic acid increased cortisol secretion (149.5±33.01%, 151.3±49.45% and 129.3±8.32% control secretion for 10nM, 100nM and 1μM respectively, p<0.05) and potentiated STAR expression (1.51±0.22, 1.56±0.15 and 1.59±0.14 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05). Concurrently, retinoic acid markedly blunted constitutional and ACTH-induced MC2R expression (0.66±0.11, 0.62±0.08 and 0.53±0.07 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05; 0.71±0.10, 0.51±0.07 and 0.51±0.08 fold change over ACTH alone, for 10nM, 100nM and 1μM respectively, p<0.05). No effect on CYP11A1 was observed.

SIGNIFICANCE:

Retinoic acid stimulates cortisol synthesis and secretion in human adrenals and at the same time markedly blunts ACTH receptor transcription. These results reveal a novel, adrenal effect of retinoic acid which may contribute to its efficacy in patients with Cushing's disease.

• Authors: Antonella Sesta, Maria Francesca Cassarino, Laura Tapella, Luigi Castelli, Francesco Cavagnini, Francesca Pecori Giraldi
• Journal: Life sciences (Life Sci) Vol. 151 Pg. 277-280 (Apr 15 2016) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26979774 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Phosphoproteins
• Receptor, Melanocortin, Type 1
• steroidogenic acute regulatory protein
• Tretinoin
• Adrenocorticotropic Hormone
• Cholesterol Side-Chain Cleavage Enzyme
• Hydrocortisone

Topics

• Adrenal Glands (drug effects, metabolism)
• Adrenocorticotropic Hormone (antagonists & inhibitors, pharmacology)
• Cholesterol Side-Chain Cleavage Enzyme (biosynthesis)
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Humans
• Hydrocortisone (biosynthesis, metabolism)
• Phosphoproteins (biosynthesis)
• Primary Cell Culture
• Receptor, Melanocortin, Type 1 (biosynthesis)
• Tretinoin (pharmacology)