Endocrine Abstracts

Glucocorticoids have potent effects on almost every tissue in the body and this is exemplified in patients with Cushing’s disease. Whilst Cushing’s disease is rare, glucocorticoids are commonly prescribed for their anti-inflammatory actions, but their use is associated with a series of undesirable adverse effects, including obesity, insulin resistance, hypertension, myopathy and osteoporosis. 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. Using combinations of cellular and rodent models, complemented by bespoke, proof-of-concept, clinical experimental medicine studies, we have been able to show that the isoforms of 5α-reductase (that inactivate cortisol and prednisolone), potently regulate exogenous glucocorticoid action. Inhibition of 5α-reductase increases cortisol and prednisolone availability and worsens adverse effects. Contrasting with this, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), regenerates active glucocorticoid (cortisol from cortisone and prednisolone from prednisone). Fuelled by observations in a patient with Cushing’s disease who was protected from the development of adverse metabolic features due a defect in 11β-HSD1 activity, we tested the hypothesis that 11β-HSD1 inhibition may represent a novel approach to selectively limit the adverse effects of prescribed glucocorticoids. Rodent data, alongside evidence from a randomized, double-blind placebo-controlled trial have endorsed the hypothesis and identified a crucial role for active glucocorticoid regeneration specifically within adipose tissue. Taken together, these data not only demonstrate the critical importance of pre-receptor metabolism (perhaps over and above what we measure in the circulation) in regulating glucocorticoid action, but also highlight the potential of 11β-HSD1 inhibition as a strategy to limit the adverse effects of prescribed glucocorticoids.