INTRODUCTION — Glucocorticoids play an important role in the function and homeostasis of the central nervous system. Chronic exposure to supraphysiologic levels of glucocorticoids in Cushing's syndrome is associated with anatomical brain changes and an increased prevalence of psychiatric diseases, cognitive impairment, mood alterations, and sleep disturbances [1-5]. The effects of glucocorticoids on the nervous system and behavior will be discussed here; effects on other systems are reviewed separately. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
EFFECTS ON CENTRAL NERVOUS SYSTEM — At the cellular level, glucocorticoids exert several actions on the central nervous system.
Intracellular receptors — Glucocorticoids penetrate the brain and bind to two types of intracellular receptors: glucocorticoid receptors, which are expressed in cerebral neurons and glial cells, and mineralocorticoid receptors, which are mainly expressed in limbic brain areas such as the hippocampus. Mineralocorticoid receptors bind cortisol with an affinity 10-fold higher than glucocorticoid receptors [4].
Low basal cortisol levels predominantly occupy high-affinity mineralocorticoid receptors, whereas glucocorticoid receptors can also be activated when glucocorticoid concentrations are elevated, such as during the active period of the circadian cycle or stress, and in Cushing's syndrome [4,6-8].
Metabolism of glucocorticoids — Metabolism of glucocorticoids occurs intracellularly and is mediated by 11-beta-hydroxysteroid dehydrogenases (11b-HSDs) [8,9]. There are two isoforms of 11b-HSDs: type 1, which elevates intracellular cortisol levels, and type 2, which inactivates glucocorticoids by converting cortisol into the inactive cortisone molecule.
In hippocampal cells, only 11b-HSD type 1 is expressed, leading to conversion to cortisol. Because 11b-HSD type 2 is not expressed in the hippocampus or other limbic structures, mineralocorticoid receptor activation by glucocorticoids occurs in these brain areas [10].
Acute versus chronic effects — Certain effects of glucocorticoids occur so rapidly (ie, within two minutes after exposure to the hormone) that a direct membrane effect is likely [11].
The effects of more chronic exposure to glucocorticoids include inhibition of the regenerative sprouting of axons that follows differentiation of hippocampal neurons [12,13] and reduction in the number of these neurons [14]. High levels of glucocorticoids induce increases in oxidative stress damage in mitochondria and decrease transport of mitochondria to synaptic regions where neurotransmitter release occurs. In brain cells, the glucocorticoid receptor is translocated from the cytosol to the mitochondria; stress and corticosteroids have a direct influence on mitochondrial DNA transcription and mitochondrial physiology [15].
Brain-derived neurotrophic factor (BDNF) is involved in many functions, such as neuronal growth, survival, synaptic plasticity, and memorization; glucocorticoid receptors downregulate BDNF expression [16].
Glial cells also appear to be targets for glucocorticoids. As an example, glucocorticoids induce glutamine synthetase activity in cultured astrocytes [17-19] and glycerol-3-phosphate dehydrogenase activity in cultured oligodendrocytes [20,21]. These effects appear to be exerted at the transcriptional level [22].
Apoptosis — Glucocorticoids stimulate apoptosis of cells in several tissues:
●T-lymphocytes of the immune system.
●In hippocampal neurons, chronic hypercortisolemia leads to atrophy and cell death [23].
●In rats, increased corticosterone levels induced by sleep deprivation results in decreased neurogenesis in the hippocampus [24].
In contrast, in glial cells, glucocorticoids stimulate expression of the cellular inhibitor of apoptosis-2, protecting them from cell death [25].
AUTONOMIC NERVOUS SYSTEM AND ADRENAL MEDULLA — It is not known if there are major clinical effects of hypercortisolism on the autonomic nervous system. Glucocorticoids are important for the normal development and function of the adrenal medulla, and their deficiency leads to abnormal medullary structure and decreased epinephrine secretion [26,27]. However, the hypertension in patients with Cushing's syndrome is not caused by excess catecholamine secretion. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Cardiovascular'.)
Glucocorticoids stimulate the differentiation of neural crest epithelial cells into chromaffin cells. Neural crest cells are precursors for a variety of more differentiated cell types, including autonomic ganglion cells and adrenal medullary cells [28].
Under the influence of nerve growth factor (NGF), for example, sympathetic ganglion cells enlarge, develop neuronal processes and synaptic vesicles, and produce a variety of neuron-specific proteins, such as SCG-10, GAP-43 (believed to be involved in neuronal growth and plasticity), and NF-68 (a neurofilament component) [29-32].
Under the influence of glucocorticoids, neural crest precursor cells that invade the embryonic adrenal gland cease to express "neuron-specific" gene products, such as neurofilaments, and acquire the characteristic morphology of adrenomedullary chromaffin cells [31]. They also lose their neural processes and begin to produce catecholamine-synthesizing enzymes, such as phenylethanolamine-N-methyltransferase, which converts norepinephrine to epinephrine. The exact mechanism by which glucocorticoids induce this differentiation is not known.
EFFECTS OF GLUCOCORTICOID EXCESS
Behavior — Glucocorticoids have effects on behavior in humans, including cognition, mood, and modulation of sleep patterns [3,33,34].
Cognition and memory — Glucocorticoids affect cognitive function through their effects on the hippocampus, an area that is critical to the processing and storage of memory. Normal to moderately elevated levels of glucocorticoids facilitate learning and memory processes, but chronic exposure to high cortisol concentrations may cause long-lasting deficits in attention, visuospatial processing, memory, conditional response, reasoning, and verbal fluency [5,35-37]. The deficit appears to be mainly in information recall, rather than in its acquisition [38]. Acute administration of 0.4 mg of the mineralocorticoid receptor agonist fludrocortisone improved visuospatial, short-term, and working memory in young and older individuals [39].
In addition to confirming verbal learning and delayed recall impairments, a study of 15 female patients with endogenous Cushing's syndrome found additional deficits in slow learning rate, short-term memory volume, memory contamination, and false appraisal of task performance, which suggest extrahippocampal effects of glucocorticoids on memory impairment [34]. Subtle cognitive and memory defects may persist after treatment and resolution of hypercortisolism. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Acute exposure to intravenous methylprednisolone (500 mg daily during five days) in 30 patients with optic neuritis or multiple sclerosis also produced a rapidly reversible effect on long-term memory, but not on short-term memory, or attentional or alertness tasks [40].
Brain-derived neurotrophic factor (BDNF) is necessary for memory formation and protects against stress-dependent impairment of spatial memory [41]. Its expression is decreased by excess glucocorticoids [16].
Glucocorticoids may also affect cognitive function through effects on the frontal lobes and amygdala [42].
The hippocampus also projects axons to the paraventricular nucleus. Activation of these neurons inhibits the secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin into the hypophysial portal blood and, thus, corticotropin (ACTH) secretion by the anterior pituitary. This action is mediated both by glucocorticoids and by gamma-amino butyric acid, for which there are receptors in both the hippocampus and paraventricular nucleus [43].
Stimulation of the mineralocorticoid receptor improves memory in young and older healthy individuals; occupancy of mineralocorticoid receptor with low doses of hydrocortisone improves memory deficit produced by chronic administration of dexamethasone for various medical conditions [39,44].
Mood — The evidence for glucocorticoid-induced alterations in mood and cognitive function comes largely from clinical observations. When evaluated by formal psychiatric interview, approximately one-half of patients with either spontaneous or iatrogenic Cushing's syndrome have a psychiatric diagnosis based upon Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, depression being the most common [3,18]. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Patients with exogenous Cushing's syndrome have been thought to have euphoria more often than those with endogenous Cushing's, but if so, it is probably because of relief of symptoms of the disorder for which glucocorticoid therapy was given.
Varying degrees of manic behavior and even overt psychosis can occur. Many patients have a more subtle disturbance in mood, especially lability and irritability [45]. Mood symptoms may persist in spite of treatment and resolution of hypercortisolism [3]. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Patients with adrenal insufficiency also may have psychiatric disturbances, mainly depression, apathy, and lethargy. The mechanisms that mediate these behavioral effects of glucocorticoids are unknown.
There is evidence of hypothalamic-pituitary-adrenal hyperactivity (pseudo-Cushing's syndrome) in patients with mood disorders, particularly in patients with acute major depressive disorder [46]. Some investigators have reported success in treating depression with adrenal steroidogenic enzyme inhibitors or glucocorticoid antagonists [47]. Major depressive disorder may be considered, at least in part, as a dysregulation of the response to stress [48]. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Sleep — The duration of rapid eye movement (REM) sleep is decreased in patients with Cushing's syndrome and in normal subjects given high doses of glucocorticoids or in whom endogenous cortisol secretion is stimulated by corticotropin. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Loss of brain volume — Several studies have examined the effects of glucocorticoid excess on brain structures in humans [2,49]. In patients with Cushing's syndrome, autopsy studies demonstrate lower brain weight, loss of brain volume, and ventricular enlargement [50-54]. As an example, in a pneumoencephalographic study of 31 patients with Cushing's disease, cortical atrophy was present in the cerebral or cerebellar hemispheres in 90 and 74 percent of patients, respectively [51]. Using modern brain imaging, hippocampal volume was reduced in a high proportion of patients in several studies [49,55,56]. An association was found between elevated cortisol levels, reduced hippocampal formation, and memory dysfunction, suggesting a possible link between anatomic structure and neuropsychological function [55].
More diffuse loss of brain volume was found in 63 patients with Cushing's disease, compared with an age- and sex-matched control group studied using computed tomography (CT) and magnetic resonance imaging (MRI) scans [57]. The cerebellar cortex volume was also smaller in patients with active Cushing's syndrome than in controls, and this was associated with poor visual memory and quality of life and was more pronounced in patients with older age at diagnosis [58]. Smaller left amygdala volumes were negatively correlated with depression and anxiety scores in patients with Cushing's syndrome [59]. Reductions of white matter integrity have also been reported in patients with both active and remitted Cushing's syndrome and appear to be caused by demyelination of the white matter tracts [60-62].
Exogenous glucocorticoids have similar effects to those of endogenous glucocorticoids on brain volume. In a study of patients under age 40 years with a diagnosis of cerebral atrophy, approximately 10 percent were on chronic glucocorticoid therapy [63]. In a second study, pharmacologic doses of glucocorticoids were associated with cerebral atrophy in two groups of either systemic lupus erythematosus or non-lupus patients compared with age- and gender-matched normal subjects [64].
Other studies also report a possible link between cerebral atrophy and conditions associated with the increased endogenous secretion of cortisol including alcoholism [65], endogenous depression [66-68], and posttraumatic stress syndrome [69].
The hippocampi of 10 neonates who had been treated with antenatal glucocorticoids (typically mothers received two intramuscular doses of 12 mg betamethasone with a 24-hour interval) showed a lower density of neurons and particularly large neurons as compared with those of 11 neonates who were not exposed to antenatal glucocorticoids [70].
Brain metabolic and functional changes — A significant decrease in the choline-to-creatine ratio (Cho/Cr), a membrane marker of phosphatidylcholine metabolism, was measured by proton magnetic resonance spectroscopy (MRS) in the frontal (-24 percent) and thalamic (-17 percent) areas, but not in temporal areas, of 13 patients with Cushing's syndrome (7 pituitary, 6 adrenal) as compared with 40 normal control subjects [71]. The other metabolite ratios, ie, N-acetyl-aspartate (NAA/Cr), a neuron marker, and myoinositol (mI/Cr), a glial marker, were unaffected by Cushing's syndrome [71]. The concentration of metabolites was studied in the ventromedial prefrontal cortex (vmPFC) of 22 Cushing's syndrome patients, of which 15 were in remission; lower concentrations of glutamate and total
NAA were identified and were correlated with the duration of hypercortisolism and state anxiety [72]. In Cushing's disease patients, glucose uptake was decreased in several brain regions, mainly hippocampus, amygdala, and cerebellum but also in the frontal and occipital cortex, as assessed by 18F-fluorodeoxyglucose positron emission tomography [73].
The effects of exogenous glucocorticoids on brain proton MRS were also investigated in 13 patients treated with 5 to 50 mg of prednisone per day for periods varying between 2 to 22 years for various pathological conditions; compared with normal subjects, none of the MRS metabolites reached a significant change, but a decrease of 1.3 percent per year of the Cho/H2O ratio was found as a function of the treatment period [74].
In a group of 12 adolescents with endogenous Cushing's syndrome, functional MRI during an emotional faces encoding task showed greater left amygdala and right anterior hippocampus activation in patients compared with 22 healthy, adolescent controls [75]. As adolescents with Cushing's syndrome appear to be less likely to develop mood disorders than their adult counterparts, this functional activation may represent protective neutral mechanisms at that stage of cerebral development.
CORRECTION OF HYPERCORTISOLISM — Correction of hypercortisolism results in improvement, but not normalization, of brain volume or cognitive function [2], as illustrated by the following findings (see "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'):
●In 22 adult patients with endogenous Cushing's syndrome studied 39.7±34.1 months after achieving eucortisolism, the measures of apparent brain volume loss improved significantly but did not reach the normal control group values [54].
●The volume of hippocampal formation increased significantly by 3 percent following treatment in 22 patients with Cushing's syndrome with a mean follow-up of 16±9.3 months, and this increase was found to correlate significantly with the reduction in urinary free cortisol levels [76]. In 10 patients studied 12 months after pituitary surgery for Cushing's disease, hippocampus subregions were examined; reversibility of the effects of hypercortisolism were predominantly located in the hippocampal head region [77].
●In 12 children with Cushing's syndrome, correction of hypercortisolism completely reversed the apparent cerebral atrophy within one year, but cognitive decline was not corrected simultaneously [50]. In a group of children with corticotropin (ACTH)-dependent Cushing's syndrome, psychiatric morbidities deteriorated despite remission of hypercortisolism [78].
●Alterations in decision making were related to persistent reduction in cortical thickness in frontal areas in 35 patients with endocrine remission of their Cushing's syndrome [79].
●Limited improvement in cognitive performance occurred even after 36 months of achieving eucortisolism in 18 patients with endogenous Cushing's syndrome [80].
●Twenty-two patients in remission of Cushing's disease showed widespread changes of white matter integrity in the brain, which was related to the severity of depressive symptoms, suggesting persistent structural effects of hypercortisolism [60].
●The brain metabolic changes described above also appear to improve with correction of hypercortisolism [81]. However, abnormal metabolites persisted in the hippocampi of Cushing's syndrome patients, despite correction of their hypercortisolism (15 pituitary, three adrenal) [82]. The alterations in metabolites correlated with measures of anxiety [72].
●Decreased functional coupling was identified between the ventromedial prefrontal cortex and posterior cingulate cortex in Cushing's disease patients in remission during functional magnetic resonance imaging (MRI) studies, confirming a link between structural and neuropsychopathology functions [83,84].
●White matter alterations assessed by diffusion tensor MRI in patients with Cushing's syndrome suggest diffuse loss of white matter integrity and demyelination, which persists after remission or cure [61].
●Low blood brain-derived neurotrophic factor (BDNF) levels are associated with affective alterations in Cushing's syndrome patients in remission, including depression, anxiety, and impaired stress perception [85].
The loss of brain volume observed in patients with Cushing's syndrome is likely multifactorial and includes loss in water content in the brain, catabolic effects on proteins, neuronal and dendritic atrophy, and possibly neuronal and/or glial cell death. The rapid reversibility observed may reflect the reversibility of brain water content redistribution and of neuronal cell volume. The incompleteness of the reversibility suggests a permanent neuronal loss, possibly as a later stage of chronic exposure to elevated glucocorticoid levels [3].
In a group of 51 patients with long-term cured Cushing's disease, an increased prevalence of psychopathology and maladaptive personality traits remained despite mean duration of remission of 11 years. Compared with nonfunctioning pituitary macroadenoma patients, patients treated for Cushing's disease scored worse on apathy, irritability, anxiety, negative affect, and lack of positive affect and somatic arousal. These observations indicate that some effects of previous glucocorticoid excess on the central nervous system are not completely reversible [86].
SUMMARY — Glucocorticoids play an important role in the function and homeostasis of the central nervous system. Chronic exposure to supraphysiologic levels of glucocorticoids in Cushing's syndrome is associated with anatomical brain changes and an increased prevalence of psychiatric diseases, cognitive impairment, mood alterations, and sleep disturbances. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Neuropsychologic changes and cognition'.)
Correction of hypercortisolism results in improvement, but not normalization, of brain volume, cognitive function, and mood disorders. (See 'Correction of hypercortisolism' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
