Hypermineralocorticoidism due to abnormal metabolism of cortisol

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Abstract

Mineralocorticoid receptors in distal nephron have no intrinsic specificity for mineralocorticoids over glucocorticoids, but they are protected from glucocorticoids (ie, cortisol in humans, corticosterone in rats) by the enzyme 11 β-hydroxysteroid dehydrogenase (11β-HSD), which inactivates these steroids to cortisone and 11-dehydrocorticosterone, respectively. Recent work has demonstrated that the enzyme is expressed as multiple tissue-specific isoforms, some of which catalyze the conversion of cortisone to cortisol. These may allow 11β-HSD to modulate access of ligands to glucocorticoid as well as mineralocorticoid receptors, and to amplify as well as attenuate tissue responses. Protection of mineralocorticoid receptors fails in congenital 11β-HSD deficiency and after inhibition of the enzyme by licorice or carbenoxolone. In these circumstances, cortisol-dependent mineralocorticoid excess and hypertension ensue. Recent studies illustrate that similar deficiencies of 11β-dehydrogenase activity may contribute to pathophysiology in ectopic corticotropin syndrome and essential hypertension. This novel mechanism of hypertension may therefore have an impact on everyday clinical practice.

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