Endocrine Abstracts

In the last decade, new evidence on Cushing’s syndrome (CS) complications and therapies have gradually emerged. CS is associated with well known systemic complications, mainly including metabolic syndrome, cardiovascular disease, immune and infectious disorders, skeletal diseases, neuropsychiatric disorders, as well as impairment of gonadal function with impact on reproduction and sexuality. However, more recently several studies specifically focused on muscle and brain structure and function, as well as on the role of cortisol rhythm loss as key determing factor in development, and of glucocrticoid receptor sensitivity in the clincial manifestations of cortisol excess-related complications, offering new perspectives in the clinical management of CS and its complications. Undoubtedly, the main advance in CS management, classically based on surgical tumor removal or irradiation, is represented by medical therapy, which was historically conceived as a marginal treatment, but recently acquired an emerging role in both preoperative and postoperative settings, and as an alternative to surgery. The first advance was the introduction of pituitary-directed drugs, specifically targeting the cause of pituitary CS, namely Cushing’s disease (CD), represented by cabergoline, a dopamine agonist, and pasireotide, a daily multi-ligand receptor somatostatin analogue, that showed a good efficacy on hormonal and tumour growth control, as well as an improvement in clinical picture. Although hyperglycemia was frequently reported during pasireotide treatment, european guidelines were provided for its safety management. More recently, a long-acting release pasireotide formulation showed similar efficacy and safety as compared to the daily formulation, with a potential better compliance. New advances appeared also on adrenal-directed drugs, with the introduction of osilodrostat and levoketoconazole, which showed a good efficacy on hormonal control and improvement in clinical picture, with a good safety profile. Compared to the classic steroidogenesis inhibitors metyrapone, also acting on 11β-hydroxylase, osilodrostat may allow higher efficacy at lower doses, due to its higher potency, and a twice-daily administration, due to its higher half-life. Similarly, compared to the classical ketoconazole, levoketoconazole, its 2S, 4R enantiomer, might allow higher efficacy at lower doses, due to its higher potency, and decreased hepatotoxicity, due to its diminished CYP7A activity. However, comparative studies are needed to confirm this hypothesis. Lastly, in recent years, new advances appeared on glucocorticoid receptor (GR)-antagonists, with the introduction of relacorilant, a selective GR-antagonist, able to improve glucose metabolism and blood pressure in patients with impairment of glucose metabolism and hypertension, respectively. Compared to the classic GR-antagonist mifepristone, relacorilant was not associated with endometrial thickening and vaginal bleeding, due to its lack of affinity for the progesteron receptor. Although these new medical therapies may offer promising therapeutic options for CS management, further researches and advances are required to allow a more personalized and tailored approach.