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Fig. 1.0 The role of retinoic acid in anterior corticotroph pathophysiology.<\/strong> AP-1 and Nur77 are critical transcription factors required for POMC promotor gene activation in a corticotroph cell. The COUP-TF1 transcription factor prevents RA’s inhibitory action on both AP-1 and Nur77, allowing POMC transcription and ACTH secretion to proceed in normal physiology(image A1)<\/em>(1). In contrast, corticotroph tumors have a reduced expression of COUP-TF1, which allows RA to inhibit AP-1 and Nur77 (critical mediators of POMC promotor gene activation) (image A2)<\/em>(3). The thickness of the dashed circle = Degree of expression of COUP-TF1<\/em>. Adapted and modified from Pecori GF et al. (2012) Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab 97:3577\u20133583<\/em><\/p>\n RA reduces cortisol synthesis in subjects with Cushing’s disease through various observed mechanistic pathways.<\/p>\n The first proof-of-concept study of RA in humans with Cushing’s disease was carried out in 7 subjects, with a variable decrease in UFC levels, ranging from 22 to 73%(3). A recent open-label prospective trial evaluated the safety and efficacy of isotretinoin (13-cis-isomer of RA) in patients with persistent or recurrent Cushing’s disease(7).<\/p>\n Key Message<\/strong>Retinoic acid (a novel treatment approach) was associated with a greater than 50% reduction in urinary-free cortisol levels compared to baseline in this small study. Retinoic acid is a potential therapeutic option in patients with persistent or recurrent Cushing’s disease.<\/p>\n<\/blockquote>\n In this open-label, single-arm, prospective study over a 12-month period, 16 patients with persistent or recurrent Cushing’s disease after transsphenoidal surgery were managed with isotretinoin monotherapy. All subjects received oral isotretinoin 20mg once daily. This was increased by 20mg every 4 weeks to a maximum dose of 80mg once daily.<\/p>\n The primary outcome was defined as either normalization of urinary free cortisol or >50% reduction in urinary free cortisol. At the end of the study, 4 patients (25%) presented with sustained normalization of UFC(7). COUP-TF1 expression (determinant of response to RA) by pituitary corticotrophs was not assessed in this study. This may explain the low response rate observed in the study<\/p>\nMechanism of action<\/h2>\n
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