title: Effect of retinoic acid on human adrenal corticosteroid synthesis.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Sesta
authors.affiliation: Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cassarino
authors.affiliation: Department of Clinical Sciences & Community Health, University of Milan, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tapella
authors.affiliation: Dept. Surgery, Clinica San Carlo, Paderno Dugnano, MI, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Castelli
authors.affiliation: Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavagnini
authors.affiliation: Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, MI, Italy; Department of Clinical Sciences & Community Health, University of Milan, Milan, Italy. Electronic address: fpg@auxologico.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pecori Giraldi
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis* / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis; D061251:Primary Cell Culture; D044102:Receptor, Melanocortin, Type 1 / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D044102:Receptor, Melanocortin, Type 1; D000098682:Steroidogenic Acute Regulatory Protein; D014212:Tretinoin; D000324:Adrenocorticotropic Hormone; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006854:Hydrocortisone
keywords: Adrenal; Cortisol; Cushing's syndrome; MC2R; Retinoic acid; STAR