Mechanisms of Blood Pressure Elevation in Cushing Syndrome
Excess cortisol in Cushing syndrome increases blood pressure primarily by overwhelming the kidney's protective enzyme (11β-hydroxysteroid dehydrogenase type 2), allowing cortisol to directly overstimulate mineralocorticoid receptors, which causes excessive renal sodium retention, volume expansion, and hypertension in 70-90% of patients. 1, 2
Primary Mechanism: Mineralocorticoid Receptor Overstimulation
Cortisol directly activates mineralocorticoid receptors in the kidney when it overwhelms the 11βHSD2 enzyme, which normally protects these receptors by converting cortisol to inactive cortisone 1
This mineralocorticoid receptor activation increases renal sodium absorption and retention, leading to volume expansion 2, 1
The resulting sodium and fluid retention causes intravascular volume expansion, which is the cornerstone mechanism driving hypertension 1
Secondary Mechanisms Contributing to Hypertension
Renin-Angiotensin System Activation
Hypercortisolism activates the renin-angiotensin system, further promoting vasoconstriction and sodium retention 2, 3
Plasma renin substrate levels are increased in Cushing syndrome, contributing to enhanced angiotensin II generation 4
Enhanced Vascular Reactivity
Glucocorticoids sensitize blood vessels to catecholamines, causing exaggerated pressor responses to norepinephrine 2, 4
Pressor responses to both norepinephrine and angiotensin II are significantly increased in Cushing syndrome patients 4
Suppression of Vasodilatory Systems
Cortisol excess impairs endogenous nitric oxide bioavailability, reducing vasodilation 2
Urinary kallikrein and prostaglandin E2 (both vasodilatory substances) are decreased in Cushing syndrome 4
Hemodynamic Changes
Plasma volume, peripheral vascular resistance, and cardiac output are all increased in Cushing syndrome, creating a perfect storm for sustained hypertension 3, 5
Vascular remodeling occurs with chronic glucocorticoid excess, contributing to persistent hypertension even after treatment 6
Contributing Comorbidities
Insulin resistance syndrome and metabolic abnormalities are major contributors to hypertension severity 2, 7
Obstructive sleep apnea is common and independently worsens blood pressure control 2
The severity of hypertension correlates directly with the duration and intensity of hypercortisolism 3, 6
Clinical Significance
Hypertension in Cushing syndrome is present in approximately 80% of adults and 47% of children, making it one of the most distinguishing features 3, 5
Target organ damage is more severe than in primary hypertension due to the multiple pathophysiologic mechanisms 2
Approximately 30% of patients have persistent hypertension even after successful treatment of the underlying Cushing syndrome, indicating irreversible vascular changes 6