Metabolic Alterations and Cardiovascular Outcomes of Cortisol Excess

Abstract

Cushing's syndrome (CS) is a severe chronic and systemic condition caused by endogenous or exogenous excess of glucocorticoids, associated with increased morbidity and mortality. Patients with active CS suffer from many metabolic alterations, including visceral obesity, systemic arterial hypertension, impairment of glucose metabolism and dyslipidemia. Additionally, in these patients several cardiovascular abnormalities, i.e. atherosclerosis, clotting disorders, left ventricular hypertrophy, concentric remodeling and diastolic dysfunction have been documented. These alterations, which persist even long after hypercortisolism remission, account for the increased cardiovascular risk and greatly contribute to the increased mortality observed in patients with CS. The current review aims to discuss the main adverse effects of CS on metabolism and cardiovascular risk, focusing on the active and remission phases of disease, and underlining the importance of long-term monitoring and treatment of these complications during active disease, as well as in the long-term follow-up after CS remission.

Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission

“…As expected, ACS presented various cardiometabolic comorbidities, while both ACS and RCS presented, as compared to matched CTR, increased inflammatory parameters such as hs‐CRP, fibrinogen and an increased WHR . Interestingly, platelet number was increased only in ACS, while in RCS, platelet number correlated with sVCAM‐1.…”

“…Several studies have demonstrated that remission of CS is associated with a significant improvement of metabolic parameters, although recovery is incomplete in the vast majority of cases, maintaining an increased cardiovascular risk . The mechanisms implicated are unclear and might involve vascular and circulatory factors due to the nonphysiological adrenal replacement therapy, another hormonal deficiency (growth or sexual hormones) and the persistence of increased visceral adipose tissue with deleterious cytokine secretion, maintaining an inflammatory and prothrombotic state and metabolic syndrome‐like features …”

“…Sustained evidence from clinical observational studies clustered in the two recent reviews by Colao et al and di Minno et al indicates that some clinical features of CS might remain resistant to change after correction of cortisol excess . Increased cardiovascular risk persists in patients with CS even 5 years after its successful remission, due to the maintenance of increased waist/hip ratio, diastolic blood pressure, total/HDL cholesterol ratio and plasma inflammatory markers, as compared with controls matched for body mass index (BMI) and age .…”

“…The mechanisms by which patients with CS in stable remission maintain subclinical atherosclerotic damage appear to be multifactorial, including the persistence of deleterious humoural and cellular sera factors, such as pro‐inflammatory adipokines, altered coagulation and thrombosis factors, platelet function and endothelial activation and dysfunction …”

“…Furthermore, the question remains open as to whether the defect is found in the endothelium of patients with CS or is a consequence of circulatory humoural factors derived from other GC target tissues/cells …”