Cardiovascular and other effects of 11β-hydroxysteroid dehydrogenase type 2 and the syndrome of apparent mineralocorticoid excess

Abstract

Cortisol has a number of surprising abilities. Perhaps the most interesting of these is its ability to bind to the mineralocorticoid receptor with an affinity equivalent to that of aldosterone. In sodium-transporting epithelia, 11β-hydroxysteroid dehydrogenase type 2(11βHSD2) converts cortisol to the receptor-inactive cortisone, allowing aldosterone to bind to its receptor in the setting of much higher circulating levels of glucocorticoid. Mutations in 11βHSD2 account for the congenital syndrome of apparent mineralocorticoid excess (AME), a low-renin, life-threatening form of hypertension resulting from overstimulation of the mineralocorticoid receptor by cortisol in the distal tubule of the kidney. The receptor and enzyme also colocalize in the gut, the sweat glands, and the lung. There is increasing evidence that the actions of 11βHSD2 also play an important role in other physiologic processes, notably reproduction. In the placenta, 11βHSD2 protects the fetus from high levels of maternal glucocorticoids; in other tissues, high localized levels of the enzyme lower the intracellular levels of glucocorticoids in specialized cells such as the nonluteinized granulosa cells of the human ovary and the epithelial cells of the endometrium, suggesting that fertility may also be affected in patients with AME. The extent to which these tissues are affected will be determined, inter alia, by the presence of other yet undiscovered oxidative isoforms of 11β-hydroxysteroid dehydrogenase.