Glucocorticoid hypersecretion and the age-impaired hippocampus: cause or effect?

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Abstract
Introduction Increased glucocorticoid secretion is a key feature of the stress response, serving to mobilise energy substrates, inhibit non-vital processes and restore stress effector systems. However, chronic glucocorticoid excess (in Cushing's disease or during pharmacotherapy) is associated with a broad spectrum of deleterious effects including diabetes mellitus, reproductive failure, hypertension, osteoporosis, immunosuppression, myopathy, growth impairment and, not least, affective and cognitive dysfunction. Clearly therefore, the autoregulatory (negative feedback) actions of glucocorticoids upon the hypothalamic-pituitary-adrenal (HPA) axis are of crucial importance. Glucocorticoids act, in large part, by binding to intracellular receptors. There are two types, mineralocorticoid (MR, type I) and glucocorticoid (GR, type II) (McEwen et al. 1986) receptors. Ligand-activated receptors function as nuclear transcription factors, attaching to specific DNA sequences and regulating target gene expression. Interactions with other nuclear factors, notably AP-1 (Pfahl 1993) and cyclic AMP response element binding protein (Stauber et al. 1992), may also occur and modulate

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