Cortisol, Cushing’s Syndrome, and a Shrinking Brain—New Evidence for Reversibility

Bruce S. McEwen

Laboratory of Neuroendocrinology The Rockefeller University New York, New York 10021

Ever since the discovery of type 2 (glucocorticoid) and type 1 (mineralocorticoid) receptors in the brain (1), the adrenal steroids have acquired somewhat of a bad reputation as far as their effects on the nervous system. They have been implicated in damage processes associated with aging and the exacerbation of damage after ischemia and seizures (2). True as these may be, there is another side to the story that has been slowly emerging: adrenal steroids have beneficial effects on brain function, and the brain is not as brittle and damage prone as we had begun to believe. Moreover, changes in brain volumes that have been interpreted in the past as signs of irreversible damage have turned out to be reversible, at least in part. The latest addition to this story is the study in this issue by Bourdeau et al. (3) at the Centre Hospitalier de l’Universite de Montreal reporting reversal of brain volume changes in Cushing’s syndrome after correction of hypercortisolism. Before considering these new results, it is important to consider the more beneficial actions of adrenal steroids and the new appreciation of the resilience of the brain.

Adrenal steroids, along with catecholamines, enhance the learning of fear-related memories (4). Moreover, the DNA-binding domain of the glucocorticoid receptor is also implicated in glucocorticoid actions to improve learning in a spatial navigation task (5). These actions involve low to moderate levels of adrenal steroids and the participation of type 1 (mineralocorticoid) as well as type 2 (glucocorticoid) receptors. In fact, there is evidence for an inverted U-shaped dose-response curve, with low levels enhancing electrophysiological excitability and high levels having deleterious, albeit reversible, effects on memory (6, 7).

The brain is also a resilient structure that is capable of reversible structural changes, and new information on the effects of repeated stress and elevated glucocorticoids point to reversible changes in the structure of nerve cells, especially in the hippocampus, a brain region that is important for spatial and declarative memory (8). Both reversible branching and debranching of dendrites and the production of new nerve cells in the dentate gyrus are modulated by stress and stress hormones. The notion that the dentate gyrus continues to produce new nerve cells throughout adult life and that the retention of these cells is modulated by experience, exercise, and stress (9, 10) adds to the increasing appreciation of the fact that the adult brain is capable of structural adaptation.

Viewed in the light of these findings, the paper by Bourdeau et al. (3) studied 38 patients with Cushing’s syndrome and found that virtually all of them showed loss of brain volume that was very significantly reversed at 40 months after achieving eucortisolism. Brain volume measures were obtained from computed tomography and magnetic resonance imaging scans and involved measuring the distance between the heads of the caudate nuclei, as well as the diameter of the third ventricle and providing a subjective estimation of apparent cerebral atrophy by radiologists blinded to the treatment. None of these measures allow any inferences about the brain regions involved.

Nevertheless, these findings provide an important confirmation and extension of work by Starkman et al. (11, 12) showing that Cushing’s syndrome is associated with atrophy of the hippocampus and cognitive impairment and that correction of the hypercortisolism results in at least a partial reversal of the hippocampal atrophy. The studies by Starkman et al. (11, 12) measured hippocampal and caudate head volume in 22 patients with Cushing’s disease before and after correction of the hypercortisolemia. The magnitude of reduction of cortisol levels at an average of 16 months after surgery was correlated with an increase in volumes of the two brain structures, an increase that was twice as large in hippocampus as that in the head of the caudate. The longer postsurgery interval in the study by Bourdeau et al. (3) resulted in a larger percentage increase in volume measures than were found in the studies by Starkman et al. (11, 12). One caveat is that brain volume changes may be due, at least in part, to changes in water content of the brain, although the larger effects in the hippocampus compared with the caudate in the studies by Starkman et al. (11, 12) argue against such a possibility as the sole explanation.

Finally, the partial recovery of brain volume changes in both studies suggests that some aspects of the neurological effects of Cushing’s syndrome may not be totally reversible. Only a careful follow-up of these patients will be able to determine whether the reversal of atrophy continues after surgical correction and whether there is a residue of neuropsychological impairment that persists.

Acknowledgments

Footnotes

Address all correspondence and requests for reprints to: Bruce S. McEwen, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, New York 10021.

Received March 5, 2002.

Accepted March 9, 2002.

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