Cortisol binds to both type 1 (mineralocorticoid) and type 2 (glucocorticoid) receptors. It is likely that glucocorticoid induced hypertension is mediated through effects of cortisol on both receptors. At the cellular level, cortisol availability is modulated by the two isoforms of the enzyme 11-betahydroxysteroid dehydrogenase (II-β HSD) (25
11-β HSD-1 is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme that is most abundantly expressed in liver and adipose tissue. It has bidirectional activity and catalyzes both dehydrogenation (conversion of cortisol to cortisone) and reduction (conversion of cortisone to cortisol) reactions. In vivo, it predominantly functions as a reductase, converting inactive cortisone to active cortisol. This reductase activity relies on high NADPH concentrations, which in turn are dependent on the activity of hexose-6-phosphate dehydrogenase within the endoplasmic reticulum.
11-β HSD-2 is an NAD-dependent enzyme and predominantly acts as a dehydrogenase to convert cortisol into inactive cortisone. It is abundantly expressed in the classical mineralocorticoid target tissues including the renal cortex, colon, and salivary glands (17
). Both 11-β HSD-1 and -2 are present in vascular endothelial cells, coronary artery cells and vascular smooth muscles thereby modulating local access of cortisol to the vasculature (26
In vitro, the mineralocorticoid receptor has similar binding affinity for both cortisol and aldosterone. However, the circulating levels of cortisol in healthy individuals are about 100- to 1000- times higher than aldosterone levels. The in vivo selectivity of the renal mineralocorticoid receptor for aldosterone requires conversion of cortisol to cortisone by 11-β HSD-2, rendering it unable to bind to the mineralocorticoid receptor (28
The global activity of 11-β HSD can be assessed by measurement of urinary steroid metabolites. Both cortisol and cortisone undergo A-ring reduction by 5 α- and 5 β-reductases and 3 α-hydroxysteroid dehydrogenase, yielding 5 β-tetrahydrocortisol (THF), 5 α-tetrahydrocortisol (allo-THF) and 5 β-tetrahydrocortisone (THE). The overall 11-β HSD-1 and 2 activity in the body is reflected in the ratio of urinary cortisol and cortisone metabolites (THF + allo-THF/THE). Alternatively, urine free cortisol-to-cortisone ratio or plasma cortisol-to-cortisone ratio can also help in the evaluation (25
One potential etiology for hypertension in Cushing’s syndrome is decreased renal conversion of cortisol to cortisone, which would increase mineralocorticoid action. In Cushing’s syndrome, the urinary THF + allo-THF/THE ratio is elevated, especially in patients with the highest UFC. These findings suggest that high cortisol levels can overwhelm the 11-β HSD-2 enzyme due to substrate saturation leading to spillover of cortisol to the mineralocorticoid receptor. This may cause a functional mineralocorticoid excess state with hypokalemia, increased renal tubular sodium reabsorption, intravascular volume expansion, and hypertension (14
). These findings are similar to those in patients with inactivating mutations of 11-β HSD-2 who have a “syndrome of apparent mineralocorticoid excess” (SAME) (25
). However, in SAME, THE, aldosterone and renin levels are suppressed in comparison to those seen in Cushing’s syndrome.
Other studies suggest that cortisol induced hypertension is not primarily mediated via sodium retention. Connell and colleagues gave ACTH (1 mg/day) to healthy volunteers on a sodium restricted diet (15mmol/day). They noted that systolic blood pressure rose significantly from a mean value of 116 mm Hg to 125 mmHg and plasma volume rose from a mean of 2.8 liters to 3.6 liters. The level of increase in blood pressure was less than that seen in previous studies in which ACTH was given to subjects on a normal sodium diet, suggesting that dietary sodium restriction lessens but does not prevent the rise in blood pressure with hypercortisolemia (32
). Williamson et al. demonstrated that mineralocorticoid blockade with spironolactone (400 mg/day) did not affect the increased blood pressure seen in patients given cortisol (80 and 200 mg/day), even though it completely blocked salt and water retention (33
). In another study, Whitworth and colleagues showed that administration of synthetic glucocorticoids with little or no mineralocorticoid activity increased blood pressure without salt and water retention (34
). Finally, the glucocorticoid antagonist mifepristone can normalize blood pressure in Cushing’s syndrome but does not bind to the mineralocorticoid receptor (35
). These findings indicate that a functional mineralocorticoid excess state is not the sole pathogenic mechanism, and the glucocorticoid receptor is involved in the development of hypertension in Cushing’s syndrome.