The hypertension of Cushing's syndrome

Abstract

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population

“…Although serum cortisol levels are responsible for the GC receptor-mediated effects that lead to diabetes [4, 30], serum cortisol levels can also represent hypothalamus-pituitary-adrenal axis (HPA axis) activity, and HPA activation is known to result in diabetes. The effects of the HPA axis have been well documented in humans with pathologically high HPA activation levels, as seen in Cushing syndrome [1, 2]. The HPA axis is a major stress response mediator and acts in conjunction with another major mediator, the autonomic nervous system (ANS).…”

“…Glucocorticoids (GCs) are known to be among the various conditions and factors involved in the pathophysiology of diabetes, with an excess of GC, from GC administration or in pathological conditions such as Cushing syndrome, leading to diabetes [1–7]. GCs promote gluconeogenesis by inducing expression of gluconeogenic genes in the liver; and by suppressing glucose uptake in skeletal muscle and adipocytes (inhibiting translocation of glucose transporter GLUT 4 to the cell surface) [5–9], which induces insulin resistance.…”

“…If this compensatory increase in insulin secretion fails, plasma glucose levels rise leading to diabetes. Indeed, increased serum insulin levels were observed in most studies with Cushing syndrome or GC administration [1, 10–15]. However, these facts cannot be simply explained that GC increases ß-cell function.…”

Metabolic comorbidities in Cushing's syndrome

“…Angiotensinconverting-enzyme inhibitors and angiotensin receptor blockers, with their cardioprotective effects, have been recently proposed as a first-line treatment to which calcium-antagonists, known to delay atherosclerosis and prevent stroke, and/or mineralocorticoid receptor antagonists can be added according to the severity of the condition and the presence of hypokalaemia (197). In the proposed treatment algorithm, a-blockers could be considered as the further next step.…”

“…In the proposed treatment algorithm, a-blockers could be considered as the further next step. The use of thiazides and b-blockers should be limited to selected cases after the appropriate dose titration of the previously mentioned agents due to their potential metabolic side-effects (197).…”