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Recent clinical trials revealed therapeutic potential of both all-<jats:italic>trans<\/jats:italic> and 9-<jats:italic>cis<\/jats:italic> 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-<jats:italic>cis<\/jats:italic> retinoic acid on adrenals from patients with ACTH-dependent Cushing\u2019s syndrome. Adrenal specimens from six patients with Cushing\u2019s disease were incubated with 10\u00a0nM\u20131\u00a0\u00b5M 9-<jats:italic>cis<\/jats:italic> retinoic acid with and without 10\u00a0nM 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\u2013100\u00a0nM 9-<jats:italic>cis<\/jats:italic> retinoic acid increased spontaneous cortisol secretion and expression of <jats:italic>STAR<\/jats:italic> and <jats:italic>CYP17A<\/jats:italic>. On the other hand, in wells treated with ACTH, 9-<jats:italic>cis<\/jats:italic> 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-<jats:italic>cis<\/jats:italic> retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing\u2019s disease.\n<\/jats:p>","DOI":"10.1038\/s41598-021-93672-0","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T10:03:29Z","timestamp":1626084209000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dual effects of 9-cis retinoic acid on ACTH-dependent hyperplastic adrenal tissues"],"prefix":"10.1038","volume":"11","author":[{"given":"Francesca","family":"Pecori Giraldi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Sesta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Tapella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Francesca","family":"Cassarino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Castelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"93672_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s12953-015-0063-8","volume":"13","author":"GH Dihazi","year":"2015","unstructured":"Dihazi, G. 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