Endocrine Abstracts

Within tissues, glucocorticoids (both endogenous and exogenous) are metabolised by a series of enzymes that have the ability to tightly control local hormone availability and thus regulate binding to, and activation of, the glucocorticoid receptor. The 11β-hydroxysteroid dehydrogenases (type 1 [11β-HSD1] and type 2 11β-HSD2]) interconvert active (cortisol, prednisolone and corticosterone) and inactive glucocorticoids (cortisone, prednisone and 11-dehydrocorticosterone). 11β-HSD1 is highly expressed in metabolically active tissues (including liver, adipose and muscle) where it regenerates active glucocorticoids, amplifying their action. Increased 11β-HSD1 activity and expression have been postulated to drive adverse metabolic features in rodents and humans. As a result, selective 11β-HSD1 inhibitors have been developed as a treatment for the metabolic syndrome acting to limit tissue-specific glucocorticoid regeneration and action. Whilst cellular and preclinical data showed marked promise, data from clinical studies were less impressive and as a result, interest in their use as metabolic modifying drugs has waned. However, more recently data are emerging to suggest that these drugs may have a re-purposed role to limit the adverse effects of prescribed glucocorticoids. However, rodent studies have added a note of caution suggesting that in addition to limiting adverse effects, there may be some amelioration of the desirable, anti-inflammatory actions.