Potential Role for Retinoic Acid in Patients with Cushing's Disease

Abstract

Context: Cushing's disease, i.e. cortisol excess due to an ACTH-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but no satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains ACTH secretion by tumoral corticotropes.Objective: Our objective was to evaluate the efficacy and safety profile of retinoic acid treatment in patients with Cushing's disease.Design: This is a prospective, multicenter study. Seven patients with Cushing's disease (three men, four postmenopausal women) were started on 10 mg retinoic acid daily and dosage increased up to 80 mg daily for 6 -12 months. ACTH, urinary free cortisol (UFC), and serum cortisol as well as clinical features of hypercortisolism and possible side effects of retinoic acid were evaluated at baseline, during retinoic acid administration, and after drug withdrawal.Results: A marked decrease in UFC levels was observed in five patients; mean UFC levels on retinoic acid were 22-73% of baseline values and normalization in UFC was achieved in three patients. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients whereas no clear-cut pattern could be detected for serum cortisol. Blood pressure, glycemia, and signs of hypercortisolism, e.g. body weight and facial plethora, were ameliorated to a variable extent on treatment. Patients reported only mild adverse effects, e.g. xerophthalmia and arthralgias. Abbreviations: COUP-TF1, Chicken ovoalbumin upstream promoter transcription factor 1; PPAR␥, peroxisome proliferator-activated receptor ␥; UFC, urinary free cortisol; WBC, white blood cells.

Treatment of Cushing's disease: a mechanistic update

“…Such preliminary results promoted a randomized treatment with retinoic acid vs ketoconazole in dogs with CD (Labeur et al 2009). Recently, seven patients with CD were treated with 10-80 mg of retinoic acid in a longitudinal, non-controlled, non-randomized, multicenter study (Pecori Giraldi et al 2012). After 6-12 months, three patients displayed normalized UFC with mild adverse effects (Table 3).…”

Metabolic comorbidities in Cushing's syndrome

“…Pasireotide, alone or in combination with cabergoline and ketoconazole, has been demonstrated to improve hypertension (202,203). Retinoic acid has been demonstrated to be effective in reducing blood pressure as well (204 …”

Medical Treatment of Cushing Disease

“…Further details on studies with pasireotide are presented in Table 2. 8,[12][13][14][15]17,20,21,[27][28][29] Pasireotide long-acting release (LAR) is currently being studied in a large randomized, double-blind, multicenter, phase III study to evaluate efficacy and safety in CD patients (http://clinicaltrials.gov/show/NCT01374906).…”

“…1,[6][7][8] This article focuses on the most recent medical therapeutic advances, in particular newly approved ACTH modulators, a glucocorticoid receptor blocker, and a novel adrenal steroidogenesis inhibitor; other drugs are also discussed ( Table 1). 1,6,7,[9][10][11][12][13][14][15] PITUITARY TARGETED MEDICAL THERAPY Medications that exert effects at the level of the pituitary represent an appealing option for CD treatment. [16][17][18][19] Somatostatin receptor ligands (SRLs) and dopamine agonists (DAs) that target corticotroph adenomas, which predominantly express somatostatin receptor (Sstr) subtype 5 and DA2 receptors, currently represent the 2 main classes of centrally acting drugs used to treat CD.…”