Endocrine Abstracts

Retinoic acid, a major modulator of adrenal development and differentiation, has also been shown to inhibit ACTH secretion by tumoral corticotropes. Recent clinical trials in patients with Cushing’s disease revealed that retinoic acid exerts beneficial effects in these patients (1, 2). Of note, the decrease in cortisol secretion during retinoic acid administration was more pronounced than the change in ACTH levels (1) suggesting a direct action at adrenal level. Aim of the present study was to evaluate the effect of retinoic acid on cortisol secretion and on genes involved in steroidogenesis and retinoic acid action in adrenals from patients with Cushing’s disease

Methods

Adrenal specimens from six patients with Cushing’s disease were incubated with retinoic acid with and without ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis (CYP17A, STAR, LIPE, MC2R, DAX-1, SF-1) as well as retinoic acid action (RARA, RARB, LXR, PPARD, COUP-TF1, SREBP1, mND1, mND6) were evaluated by real-time RT-PCR

Results

Incubation with 10–100 nM retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. As expected, retinoic acid increased RARA, RARB and SREBP1. In wells treated with 10 nM ACTH, retinoic acid markedly diminished MC2R, thus blunting ACTH receptor upregulation, and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced RARB expression, possibly enhancing sensitivity to retinoic acid

Conclusions

Our results indicate that retinoic acid stimulates spontaneous cortisol secretion but, in presence of ACTH, the decrease in adrenal ACTH receptor overrides this effect. These findings support the hypothesis of a direct adrenal action in patients with Cushing’s disease.

References

1. Pecori Giraldi et al. (2012) Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab 97, 3577–3583.

2. Vilar et al. (2016) The role of isotretinoin therapy for Cushing’s disease: results of a prospective study. Int J Endocrinol, article ID: 8173182.