Management and Medical Therapy of Mild Hypercortisolism

Abstract

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-βhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

Keywords: 11 betahydroxysteroid dehydrogenase; adrenal steroidogenesis; dopamine; glucocorticoid receptor; hypercortisolism; somatostatin.

Figure 1

Mechanisms underlying the effects of medical therapy of hypercortisolism. Footnotes: Cabergoline inhibit pituitary corticotrophs via dopamine receptor type 2 (DR2). Cabergoline is also thought to exert a stimulatory role on cortisol secretion on adrenal cortex cells via DR1 dopamine receptor type 2. Pasireotide inhibits pituitary corticotrophs via somatostatine receptors type 5 (SSTR5). Metyrapone inhibits adrenal 11-βhydroxylase and, to a lesser degree, 18-hydroxylase (CYP11B1). Metyrapone is also hypothesized to reduce at the peripheral target tissues (i.e., muscle, adipocytes and liver) the conversion of cortisone into the more active cortisol via modulation of 11beta-hydroxysteroido-dehydrogenase (11BHSD) and to inhibit pituitary corticotrophs via reduction of GC-driven positive-feedback and via SSTR5 and DR2 receptors expression via the modulation of β-arrestin 1 and β-arrestin 2 expression. Ketoconazole and levoketoconazole act on the adrenal steroidogenesis via 11-βhydroxylase (CYP11B1) inhibition, 18-hydroxylase (CYP11B2) inhibition, 20,22-desmolase (CYP11A1) inhibition and on 17a-hydroxylase and 17,20-desmolase (CYP17) inhibition. Ketoconazole and levoketokonazole are also hypothesized to inhibit pituitary corticotroph inhibition by impairing adenylate cyclase activation. Osilodrostat is a steroidogenesis inhibitor acting on CYP11B1) via 11-βhydroxylase inhibition. Mifepristone inhibits the peripheral effects of glucocorticoids (GC) by non-selectively antagonizing the GC receptor. Relacorilant is a selective inhibitor of GC receptor. Finally, some 11 beta-hydroxysteroid dehydrogenase (11BHSD) type 1 (11BHSD1) inhibitors (for example INCB13739, S-707106 and chenodeoxycholic acid) have been suggested to decrease cortisone-to-cortisol conversion, therefore reducing the amount of cortisol (more active) at peripheral target tissues level. Dotted lines are used for not clearly demonstrated pathways.