Abstract
Cushing's disease is characterized by excessive adrenocorticotropin hormone (ACTH) secretion caused by a corticotroph tumor of the pituitary gland, leading to hypercortisolism and increased morbidity and mortality. The molecular causes of the disease are not completely understood, therefore more research is needed to discover novel molecular targets and more effective treatments. To date, the SSTR-analog pasireotide is the only approved drug for Cushing's Disease treatment that is directly targeting the source of the disease. Targeting directly the activity of glucocorticoid receptor or the factors modulating it might be a new valid option for the medical management of Cushing's disease. Here, we briefly review the molecular mechanisms involved in the glucocorticoid negative feedback and glucocorticoid resistance and examine novel targets and therapies that might effectively restore glucocorticoid sensitivity.
Highlights
Cushing’s disease is a rare endocrine disease resulting from chronic exposure to high cortisol levels as consequence of a pituitary corticotroph tumor that hypersecretes adrenocorticotroph hormone (ACTH)
The current knowledge suggest that Ubiquitin-specific-protease 8 gene (USP8)-mutations result in hyperactivation of the Epidermal growth factor receptor (EGFR) signaling due to increased EGFR deubiquitination with subsequent higher Proopiomelanocortin (POMC) promoter activity and increased ACTH secretion
The partial lack of response to the glucocorticoid negative feedback is used in clinical practice, through the administration of dexamethasone, for the initial diagnosis of Cushing’s disease and to differentiate between Cushing’s disease and ectopic source of ACTH secretion
Summary
Cushing’s disease is a rare endocrine disease resulting from chronic exposure to high cortisol levels as consequence of a pituitary corticotroph tumor that hypersecretes adrenocorticotroph hormone (ACTH) It represents around 80% of all cases of endogenous hypercortisolism [1,2,3]. The current knowledge suggest that USP8-mutations result in hyperactivation of the Epidermal growth factor receptor (EGFR) signaling due to increased EGFR deubiquitination with subsequent higher Proopiomelanocortin (POMC) promoter activity and increased ACTH secretion. To date, this molecular mechanism does not seem to have an impact on the glucocorticoid resistance itself. After a short overview of the glucocorticoid negative feedback mechanism, we describe the most recent molecular discoveries in this field
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