Dual effects of 9-cis retinoic acid on ACTH-dependent hyperplastic adrenal tissues

Abstract

Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing’s syndrome. Adrenal specimens from six patients with Cushing’s disease were incubated with 10 nM–1 µM 9-cis retinoic acid with and without 10 nM ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis as well as retinoic acid action were evaluated by real-time RT-PCR. Incubation with 10–100 nM 9-cis retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. On the other hand, in wells treated with ACTH, 9-cis retinoic acid markedly diminished ACTH receptor upregulation and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced retinoic acid receptor expression, possibly enhancing sensitivity to retinoic acid. Our findings indicate that the effect of 9-cis retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing’s disease.

Novas abordagens terapêuticas na síndrome de Cushing

“…Atualmente, esses ácidos retinóicos são amplamente reconhecidos e utilizados no tratamento da leucemia promielocítica aguda. Além disso, estão sendo estudados quanto aos seus potenciais benefícios em outros tipos de câncer, como o neuroblastoma e o câncer de mama (GIRALDI FP, et al, 2021).…”

“…Essa característica é crucial para o entendimento de como os retinóides podem ser eficazes no tratamento de pacientes com doença de Cushing. Ao regular a produção de cortisol e afetar o feedback negativo, eles podem contribuir para a normalização dos níveis de cortisol e, consequentemente, para o controle da doença (GIRALDI FP, et al, 2021).…”

Clinical Parameters and Metabolomic Biomarkers That Predict Inhospital Outcomes in Patients With ST-Segment Elevated Myocardial Infarctions

“…The fact that LMCAD is the highest-risk lesion subset in coronary heart disease and leads to worse outcomes, following STEMI onset can partially explain the findings of this study. Furthermore, 9cRA stimulates spontaneous cortisol secretion and reduces pituitary corticotropin (ACTH) receptor synthesis ( Pecori Giraldi et al, 2021 ). Increased cortisol secretion can lead to sugar, fat, and protein metabolism disorders.…”

Current and Emerging Medical Therapies in Pituitary Tumors

“…Retinoid acid has been identified in previous experimental studies as an inhibitor of both ACTH and cortisol secretion, and corticotroph growth [195] but also as a negative modulator of cortisol secretion at the adrenal level [196,197]. At the molecular level, it was shown that retinoic acid exerted its effect, at least partially, by increasing DRD2 expression in the AtT20 cells, and was associated with sthe ynergistic effect of bromocriptine in nearly 45% of CD primary cultures [198].…”