Does altered glucocorticoid homeostasis increase cardiovascular risk?

The hypothalamic-pituitary-adrenal (HPA) axis, like the sympathetic nervous system and the renin-angiotensin-aldosterone (RAA) system, sustains life in stressful situations by increasing vascular tone and ensuring fuel availability. It also modulates inflammation and tissue repair processes. Untoward cardiovascular effects of chronic sympathetic and RAA activation are well recognized, illustrating that the short-term benefit of the physiologic stress response can be detrimental in the long term. Similarly, chronic tissue exposure to glucocorticoids may lead to metabolic and vascular changes that accelerate vascular senescence. Specific situations associated with chronic activation of the HPA axis-such as major depression, inflammatory disease and perhaps the metabolic syndrome-may derive some of their associated cardiovascular risk from untoward glucocorticoid effects. Since there are no definitive clinical studies directly addressing the relationship between the HPA axis and cardiovascular disease, we present indirect evidence from two types of studies: (1) studies that examine the cardiovascular effects of exogenous glucocorticoids, and (2) studies demonstrating that endogenous glucocorticoid activity varies between individuals. The effects of physiologic increases in endogenous glucocorticoid activity may not always mirror the effects of supraphysiologic glucocorticoids. Nevertheless, the known effects of exogenous glucocorticoids provide important insights into the putative effects of endogenous glucocorticoids.