Effect of retinoic acid on human adrenal corticosteroid synthesis

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 10 nM, 100 nM and 1 μM retinoic acid with and without 10 nM ACTH for 24 h. 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 10 nM, 100 nM and 1 μM 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 10 nM, 100 nM and 1 μM 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 10 nM, 100 nM and 1 μM respectively, p < 0.05; 0.71 ± 0.10, 0.51 ± 0.07 and 0.51 ± 0.08 fold change over ACTH alone, for 10 nM, 100 nM and 1 μM 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.