Review11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress

Glucocorticoids have profound effects on brain development and adult CNS function. Excess or insufficient glucocorticoids cause myriad abnormalities from development to ageing. The actions of glucocorticoids within cells are determined not only by blood steroid levels and target cell receptor density, but also by intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives and is widely expressed throughout the adult CNS. Elevated hippocampal and neocortical 11β-HSD1 is observed with ageing and causes cognitive decline; its deficiency prevents the emergence of cognitive defects with age. Conversely, 11β-HSD2 is a dehydrogenase, inactivating glucocorticoids. The major central effects of 11β-HSD2 occur in development, as expression of 11β-HSD2 is high in fetal brain and placenta. Deficient feto-placental 11β-HSD2 results in a life-long phenotype of anxiety and cardiometabolic disorders, consistent with early life glucocorticoid programming.

Expression and function of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. 11β-HSD1 is widely expressed throughout the adult CNS and is key to HPA axis function and cognitive decline during ageing. Conversely, the major central effects of 11β-HSD2 are seen in development, as expression of 11β-HSD2 is high in fetal tissues including the neonate brain and placenta. Loss of 11β-HSD2 from the fetus and fetally-derived tissues results in a life-long phenotype of anxiety, consistent with developmental programming.