New Insights in Cushing Disease Treatment With Focus on a Derivative of Vitamin A

Abstract

Cushing’s disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient’s mortality. First-line of treatment for CD is pituitary’s surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy. The latter plays a key role in cortisol excess control. Its targets are inhibition of adrenocorticotropic hormone (ACTH) production, inhibition of adrenal steroidogenesis, or antagonism of cortisol action at its peripheral receptor. Retinoic acid (RA) is a metabolic product of vitamin A (retinol) and has been studied for its antiproliferative effects on corticotroph tumor cells. It has been shown that this drug regulates the expression of pro-opiomelanocortin (POMC), ACTH secretion, and tumor growth in corticotroph tumor mouse cell lines and in the nude mice experimental model, via inhibition of POMC transcription. It has been shown to result in tumor reduction, normalization of cortisol levels and clinical improvement in dogs treated with RA for 6 months. The orphan nuclear receptor COUP-TFI is expressed in normal corticotroph cells, but not in corticotroph tumoral cells, and inhibits RA pathways. A first clinical human study demonstrated clinical and biochemical effectiveness in 5/7 patients treated with RA for a period of up to 12 months. In a recent second clinical trial, 25% of 16 patients achieved eucortisolemia, and all achieved a cortisol reduction after 6- to 12-month treatment. The goal of this review is to discuss in the context of the available and future pharmacological treatments of CD, RA mechanisms of action on corticotroph tumor cells, and future perspectives, focusing on potential clinical implementation.

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

“…This evidence led to clinical trials with tretinoin and isotretinoin in patients bearing an ACTH-secreting pituitary adenoma, i.e., Cushing’s disease 11 , 12 , with promising results. So far, over 20 patients with this severe endocrine disorder have been tested and contaiment of cortisol excess could be observed in up to one third of patients, much like it occurs with other pituitary-acting drugs 13 , 14 . Interestingly, although the rationale for efficacy of retinoids in these patients rests on evidence collected on the tumoral corticotrope—thus inhibition of ACTH is expected to drive the reduction in adrenal secretion-, the decrease in cortisol levels appeared more pronounced and not strictly parallel to ACTH concentrations.…”

“…Interestingly, the decrease in cortisol secretion during either retinoid was more pronounced that the change in ACTH levels. While this phenomenon is not uncommon in patients with Cushing’s disease treated with pituitary-acting drugs 13 , 14 , it could be due to a direct action on adrenal glands. In our first study on normal adrenal cortex tissue, we observed a dual effect of 9- cis retinoic acid: stimulation of cortisol secretion and STAR expression by roughly 1.5-fold on one side and halving of ACTH receptor synthesis on the other 15 .…”

Treatment challenges in pediatric Cushing’s disease: Review of the literature with particular emphasis on predictive factors for the disease recurrence

“…Ketoconazole has not been approved by the FDA for CD treatment neither in children nor in adults [80], because of the risk of severe liver injury and harmful interactions with other medications [80]. The European Agency EMA had recommended a permission of a marketing authorization for KCN (HRA Pharma) in the treatment of CS [83]. Metyrapone increases cortisol metabolites in the serum and urine due to the predominant inhibition of 11-hydroxylase (also the other steroidogenesis enzymes but to a lesser extent) [84].…”

Vitamin A failed to ameliorate clinical signs in dogs with pituitary‐dependent hypercortisolaemia

“…1 In human medicine, there has been recent focus on the use of a vitamin A derivative, retinoic acid, to decrease endogenous adrenocorticotropic hormone (ACTH) secretion from the pituitary tumour. 2 Retinoic acid has been shown to have antiproliferative effects on mouse corticotroph tumour cells in vitro, resulting in decreased corticosterone production from adrenal cortex cells. 3 When administered to dogs with hypercortisolaemia, retinoic acid resulted in a significant reduction in both plasma ACTH and urine cortisol:creatinine ratio at four months post-treatment, with improvement of clinical signs.…”