Endocrine Abstracts

Retinoic acid, a derivative of vitamin A, has recently yielded promising results in the treatment of Cushing’s disease (Pecori Giraldi et al. JCEM 2012). Its main site of action appears to be the tumoural corticotrope as retinoic acid inhibits POMC transcription and corticotrope proliferation (Paez-Pereda et al. JCI 2001). Studies on tumoural adrenal cell lines have revealed an additional inhibitory effect on cell proliferation and stimulated corticosteroid secretion (Paez-Pereda et al. JCI 2001). Aim of the current study was to evaluate whether retinoic acid modulates corticosteroid secretion by normal human adrenals in vitro.

Methods: Primary cultures from nine normal human adrenals were incubated with 10 nM, 100 nM and 1 μM retinoic acid with and without 10 nM ACTH for 24 h. Cortisol levels in medium were measured by Coat-A-Count RIA (Siemens Healthcare Diagnostics, Erlangen, Germany); CYP11A, STAR and MC2R gene expression were analyzed by real-time PCR (7900 HT Sequence Detection System, Applied Biosystems, Foster City, USA) normalized to RPLP0.

Results: A clear-cut increase in cortisol secretion during retinoic acid incubation was observed in five adrenal specimens (10 nM: 183.9±55.9%, 100 nM: 210.1±82.6% and 1 μM: 141.3±11.7% baseline). Gene expression analysis revealed a marked decrease in MC2R expression (10 nM: 0.65±0.13, 100 nM: 0.63±0.09 and 1 μM: 0.55±0.08 over baseline) and an increase in STAR in wells treated with retinoic acid (10 nM: 1.53±0.26, 100 nM: 1.62±0.17 and1 μM: 1.63±0.16 over baseline). CYP11A was on average unchanged by retinoic acid. Incubation with ACTH led to a marked increase in cortisol secretion and in CYP11A1, STAR and MC2R expression. Retinoic acid and ACTH co-incubation resulted in a sligthly greater cortisol release (10 nM: 125.4±16.6%, 100 nM: 141.1±29.5% and 1 μM: 139.6±31.3% ACTH) and MC2R inhibition (10 nM: 0.76±0.13, 100 nM: 0.56±0.07 and 1 μM: 0.64±0.09 over ACTH) than ACTH alone.

Conclusions: Retinoic acid exerts a stimulatory effect on adrenal corticosteroid secretion in vitro, activates STAR expression and blunts MC2R transcription. This paves the way for novel avenues of research in patients with Cushing’s syndrome.