Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Abstract

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Increased Risk of Vertebral Fractures in Patients With Mild Autonomous Cortisol Secretion

“…The term mild hypercortisolism (also known as hidden hypercortisolism or subclinical hypercortisolism or subclinical Cushing syndrome ) defines a condition of biochemical hypercortisolism in the absence of the classical clinical features of cortisol excess ( 1 , 2 ). The importance of this disorder is related to the fact that: (i) it is associated with the same cardiometabolic consequences of the clinically overt cortisol excess (ie, Cushing syndrome) ( 3 , 4 ); and (ii) unlike Cushing's syndrome, it is not a rare disease, being present in up to 50% of patients with adrenal incidentalomas (AI), which, in turn, are found in up to 7% of individuals older than 60 years ( 5 ).…”

Cardiometabolic characteristics of type 2 diabetes patients depending on obesity phenotypes

“…Посилену периферичну продукцію кортизолу у вісцеральній жировій тканині пов'язують зі збільшенням експресії та активності ферменту 11β-гідроксистероїддегідрогенази типу 1, який здійснює локальну внутрішньоклітинну конверсію неактивного кортизону в активний кортизол [13]. Виявлено, що МС і ЦД 2-го типу супроводжуються змінами активності 11β-ГСД1 [14,15].…”

Management of Adrenal Cortical Adenomas: Assessment of Bone Status in Patients with (Non-Functioning) Adrenal Incidentalomas

“…RANKL is a regulator and activator of osteoclasts, while osteoprogerin acts as a decoy receptor for RANKL, preventing its interaction with RANK and causing the inhibition of osteoblastogenesis [ 29 , 30 , 31 ]. The severity of hypercortisolism-associated skeletal effects also depends on one’s sensitivity to hormones, as, for instance, has been shown by polymorphism studies of glucocorticoid receptor [ 32 ]. In the general population, BclI and N363S polymorphisms are associated with an increased sensitivity to glucocorticoids and a low bone mineral density (BMD) [ 33 , 34 ], while ER22/23EK is correlated with reduced sensitivity to glucocorticoids [ 35 ].…”