Endocrine Abstracts

Glucocorticoids have profound effects on the brain, particularly during development and during the ageing process. The glucocorticoid metabolising enzymes, 11beta-hydroxysteroid dehydrogenases (11β-HSDs) type 1 and 2, interconvert active corticosterone (or cortisol) and inactive 11keto-derivatives to modify intracellular glucocorticoid levels. Hence, these enzymes add another layer of complexity to glucoocorticoid action in addition to circulating hormone and receptor (MR and GR) levels.

During development, there are several mechanisms in place to ensure a low glucocorticoid environment for both the fetus and the neonate, otherwise deleterious effects on cell proliferation, migration and differentiation can occur. One protective barrier is the expression of 11β HSD2, which is highly expressed in the placenta and the fetus and will inactivate the relatively high maternal levels of glucocorticoids. In mice lacking 11β HSD2, fetal and neonatal growth is reduced, abnormalities are seen in placental growth and function, and brain growth and maturation is delayed compared to wildtype littermates. Furthermore, expression of key, glucocorticoid-sensitive genes are altered in the brain during the neonatal period. As adults, the 11β HSD2-null mice showed increased anxiety behaviour, consistent with a ‘programmed’ phenotype.

High glucocorticoid levels are also deleterious in ageing, as chronic stress or glucocorticoid administration will cause cell loss and dentritic atrophy in hippocampal regions that are involved in learning and memory. Furthermore, the second isozyme of 11β-HSD, type 1, which is highly expressed in the brain including the hippocampus, acts as a reductase reactivating glucocorticoids within tissues. Mice lacking 11β a-HSD1 appear protected from cognitive defects associated with ageing due to lower intracellular corticosterone levels in the brain. Moreover, at 18 months of age, transgenic mice which overexpress 11β-HSD1 in the forebrain, show early signs of cognitive decline in the watermaze, in the absence of altered circulating corticosterone levels, again emphasizing the importance of intracellular metabolism on glucocorticoid action.

In conclusion, pre-receptor metabolism of glucocorticoids by 11β-HSDs have profound effects on behaviour, 11β HSD2 activity being neuroprotective during development and 11β-HSD1 deleterious in ageing.